LECTURE NOTES

VETERINARY PHARMACOLOGY

(Pharmacotherapeutics II)

ANECITO G. JUAN, DVM, DipVSt, MS

DEPARTMENT OF ANATOMY, PHYSIOLOGY & PHARMACOLOGY

College of Veterinary Medicine

Central Mindanao University

University Town, Musuan, Bukidnon

June 2014
 ANTI-INFLAMMATORY DRUGS

INFLAMMATION

- The complex pathophysiologic response of vascularized tissue to injury.

- Injury may result from various stimuli:
o Thermal
o Chemical
o Physiologic damage
o Ischemia
o Infectious agents
o Antigen-antibody interactions
o Other biologic processes

- 3 distinct phases of tissue healing:

o Inflammatory phase
o Repair phase
o Remodeling phase

- Initial inflammation phase consists of 3 sub phases:

o Acute
 1-3 days
 5 classic clinical signs (heat, redness, swelling, pain, loss of function)
 Response occur at microcirculation at the site of injury
o Subacute
 3-4 days – 1 month
 Corresponds to cleaning phase required before the repair phase
 Movement of phagocytic cells to site of injury
o Chronic
 If subacute phase is not resolved w/in 1 month
 Tissue degeneration, tearing and rupture
 Fibrosis occurs
- Desired outcome of the inflammatory response is the isolation and elimination of the
injurious agent in order to prepare for the repair of tissue damage at the site of injury and
restoration of function.

CHEMICAL MEDIATORS OF INFLAMMATION

1. Mediators derived from plasma

a. Complement-derived Peptides
i. Increase vascular permeability
ii. Smooth muscle contraction
iii. Activate leukocytes
iv. Induce mast-cell degranulation
b. Kinins
i. Bradykinin – the most important
ii. Increase vascular permeability and vasodilation
iii. Activates phospholipase A2 to liberate arachidonic acid
iv. Pain response
2. Mediators derived from injured tissue or WBC at site of Injury
a. Histamine
i. Released by mast cells, platelets, and basophils
ii. Arteriolar dilation
iii. Increase capillary permeability
iv. Contraction of nonvascular smooth muscle
v. Eosinophil chemotaxis
vi. Pain response
vii. Allergies and anaphylaxis
viii. Cause fever producing heat (pyrogens)
ix. Once histamine is release, there are 3 receptor that will be activated:
 H1 Receptors
a. Present in endothelial cells and Smooth muscle cells
 H2 Receptors
a. Present in gastric mucosa, cardiac muscles and immune
cells
 H3 Receptors
a. Present in the CNS
b. Serotonin
i. Similar to histamine and found in mast cells and platelets of the GIT and
CNS
ii. Increases vascular permeability
iii. Dilates capillaries
iv. Contraction of nonvascular smooth muscles
3. Cytokines
a. Includes IL-1-10, TNF-α, INF-ϒ
b. Produced predominantly by macrophages and lymphocytes, but can be
synthesized by other cell types as well
c. Role in inflammation is complex
d. Modulate activity and function of other cells to coordinate and control the
inflammatory response
4. Lipid-Derived Autacoids
a. Eicosanoids
i. Synthesized by activated leukocytes, mast cells, platelets
ii. Widely distributed
iii. Includes prostaglandins, prostacyclin, leukotrienes, thromboxanes, and
platelet activating factor (PAF)
iv. Major source or precursor is arachidonic acid, released from tissue
phospholipids by the action of phospholipase enzyme
v. Once it is released, it will go to the 2 pathways:
 Cyclooxygenase Pathway/System
a. All eicosanoids with ring structure that is prostaglandin,
thromboxanes, and prostacyclin are synthesized via this
system
 Lipoxygenase System
a. Act on arachidonic acid to form 5-HPETE, 12-HPETE and
15-HPETE
vi. Thromboxanes
 Known to cause contraction of muscle and aggregation of
platelets
 Very useful physiologically because it inhibits blood loss
 vii. Prostacyclin
 Relaxes smooth muscle and inhibits aggregation of platelets
viii. Leukotrienes
 Known to be potent vasodilators
 Slow reacting substances inducing anaphylaxis
 Potency is better than with histamine
 Have chemotactic properties
 Causes WBC to adhere to the walls of blood vessel
 Some can cause relaxation and constriction of the airway
ix. Platelet Activating Factor
 Produce by mast cells, platelets, WBC and endothelial cells
 Said to be limited in producing PAF but have widespread effect
and is well distributed
 Cause vasodilation, bronchoconstriction, aggregates platelets,
degranulates platelets as well as neutrophils, formation of sulfur
oxide especially in the granulocytes

ANTIHISTAMINES

H1 Antagonists
- Block the actions of histamine responsible for increased capillary permeability and wheal
and edema formation
- May be useful in the treatment of the immediate hypersensitivity reactions such as
anaphylaxis by blocking bronchoconstriction and vasodilation
- Major effect:
a. Atropine-like action
 Anticholinergic action
 Drying of the mucous membrane
 Dilation of the pupils
 Increase in HR
b. Alpha-blocking action
 Present in BV (alpha 1)
 Hypotension problem
c. Anti-motion sickness
 Prevent vomiting or nausea
d. Cause sedation specially for the classical H1 blocker
e. Mild local anesthetic effect
f. Has anti-serotonin action
g. Useful for those that have sleeping problem
- H1 reduces the mental activity so this could not be an advantage to use when having
motor activity
- Uses:
a. For motion sickness (man and animals)
b. For allergic reactions
c. For nausea/vomiting, especially in pregnant women
d. Useful for laminitis in large animals (horse and cattle)

H1 ANTAGONISTS
ETHANOLAMINES
Diphenhydramine  Antihistamine used primarily for its antihistaminic effects, but
HCL used for a variety of things (prevention of motion sickness,
sedative, antiemetic, etc)
 Contraindicated: hypersensitive to it or others in class. Caution:
angle closure glaucoma, GI or urinary obstruction,
hyperthyroidism, seizure disorders, cardiovascular disease or
hypertension. May mask symptoms of ototoxicity.
 Adverse effects: CNS depression and anticholinergic effects. GI
effects (diarrhea, vomiting, anorexia) are less common.
Dimenhydrinate  Antihistamine used primarily for prevention of motion sickness in
dogs and cats
 Contraindicated: hypersensitive to it or others in class. Caution:
angle closure glaucoma, GI or urinary obstruction,
hyperthyroidism, seizure disorders, cardiovascular disease or
hypertension. May mask symptoms of ototoxicity.
 Adverse effects: CNS depression and anticholinergic effects. GI
effects (diarrhea,vomiting, anorexia) are less common.
Tripelennamine  Oral and injectable antihistamine
HCL  Contraindicated: Do not give IV to horses
 Adverse effects: CNS stimulation (if given IV to horses),
sedation, depression, ataxia, GI effects (oral use)
PIPEROZINE DERIVATIVES

Hydroxyzine  Used principally for antihistaminic, antipruritic and

sedative/tranquilization qualities, often in atopic patients
 Contraindications: hypersensitive. Caution in pts w/ prostatic
hypertrophy, bladder neck obstruction, severe cardiac failure,
angle-closure glaucoma, or pyeloduodenal obstruction
 Adverse Effects: sedation most likely. Dogs rarely: tremors,
seizures. Cats: polydipsia, depression or behavioral changes.
Cyclizine &  Antihistamine with sedative and antiemetic effects, used primarily
Meclizine for motion sickness
 Contraindications: known hypersensitivity. Caution: prostatic
hypertrophy, bladder neck obstruction, severe cardiac failure,
angle-closure glaucoma or pyeloduodenal obstruction.
 Adverse Effects: sedation; less frequently anticholinergic effects
may be noted (dry mucous membranes, eyes, tachycardia, etc.).
Contradictory CNS stimulation possible
 May be a teratogen
ALKYLAMINES

Chlorpheniramine  An alkylamine antihistamine used primarily for its

Maleate antihistamine/antipruritic effects; occasionally used for CNS
depressant (sedative) effects
 Common in cats for the treatment of pruritis
 Contraindicated: hypersensitivity. Caution: narrow angle
glaucoma, hypertension, GI or urinary obstruction,
hyperthyroidism, cardiovascular disease
 Adverse effects: sedation, anticholinergic effects, GI effects
PIFERIDINE GROUP
 Asthmizole  Second Generation Antihistamine
 Non-sedating
Terfenidine  Highly selective for H1 receptors
 Significant anticholinergic actions and penetrate poorly into the
CNS

H2 Antagonist
- Routinely used to block the gastric secretory effects of histamine and have limited anti-
inflammatory effects
- Much better than anti-emetics

H2 ANTAGONISTS
Cimetidine  Prototype histamine-2 blocker used to reduce GI acid production
 Newer H2 blockers (e.g., ranitidine, famotidine) and other agents
(e.g., omeprazole) may be more effective, have longer duration of
activity and fewer drug interactions
 Contraindicated: hypersensitivity. Caution: geriatric pts., hepatic or
renal insufficiency
Ranitidine  H2 receptor antagonist similar to cimetidine, but fewer drug
interactions. Used to reduce acid output in stomach; also has
prokinetic activity.
 Contraindicated: hypersensitivity. Caution: geriatric pts., hepatic or
renal insufficiency
 Adverse effects: rare. Potentially: mental confusion,
agranulocytosis, transient cardiac arrhythmias (too rapid IV
injection). Pain at the injection site after IM administration.
Famotidine  H2-receptor antagonist used to reduce GI acid production
 Has longer duration of activity and fewer drug interactions than
cimetidine
 Contraindicated: hypersensitivity. Caution: pts w/ cardiac disease,
significantly impaired hepatic or renal function. (consider dosage
reduction).
 Adverse Effects: Too rapid IV infusion may cause bradycardia.
Potentially: GI effects, headache, or dry mouth or skin,
intravascular hemolysis when given IV to cats.
Nizatidine  H2 receptor antagonist similar to ranitidine. Used primarily for its
prokinetic activity.
 Contraindicated: hypersensitivity. Caution: geriatric pts., hepatic or
renal insufficiency
 Adverse effects: rare

Serotonin Antagonist

SEROTONIN ANTAGONISTS
Cyproheptadine  Serotonin antagonist antihistamine used as an appetite stimulant
in cats and as an antipruritic/antihistamine in dogs and cats. Used
 in horses for photic head shaking.
 Contraindicated: hypersensitive. Caution: urinary or GI
obstruction, narrow angle glaucoma
 Adverse effects: sedation (cats may demonstrate paradoxical
hyperexcitability) and anticholinergic effects

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

NSAID
- Act primarily to reduce the biosynthesis of prostaglandins by inhibiting cyclooxygenase
(COX).
- NSAID’s work by inhibiting the prostaglandin E so pyrogen formation will be inhibited,
therefore it has no activity on increase body temperature during exercise or heat stroke;
it will not have the activity of inducing body temperature and is specific to pyrogen
- They do not inhibit lipoxygenase formation, or the formation of other inflammatory
mediators
- All NSAID (except for Acetaminophen/Paracetamol) are antipyretic, analgesic, and anti-
inflammatory
- Vomiting is the most common adverse effect of NSAID, while GI ulceration is the most
common life-threatening adverse effect
- COX isoforms:
a. COX-1
- Expressed in virtually all tissues of the body
- Regulate homeostasis
- Very important for physiologic function
- Concurrent inhibition of COX-1 may result in unwanted effects of NSAID
including gastric ulceration and renal toxicity
b. COX-2
- Activated in damaged and inflamed tissues and catalyzes the formation of
inducible prostaglandin associated with intensifying the inflammatory
response
- Thermoregulation and pain response to injury
- Inhibition by NSAID is thought to be responsible for antipyretic, analgesic,
and anti-inflammatory actions of NSAID
- Because NSAID vary in their ability to inhibit each COX isoform, a drug that inhibits
COX-2 at a lower concentration than that necessary to inhibit COX-1 would be
considered safer; drugs with ratios suggesting preferential activity against COX-2 may
have fewer adverse effects due to COX-1 inhibition
- COX selectivity of NSAID varies by species

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID)

SALICYLATES
Aspirin  NSAID used for analgesic, antiinflammatory and antiplatelet
effects in a variety of species
 Non-selective; Activity is more on COX-1 as compared to COX-2
 The most common adverse effect of aspirin at therapeutic doses
is gastric or intestinal irritation with varying degrees of occult GI
blood loss occurring. The resultant irritation may result in vomiting
 and/or anorexia. Severe blood loss may result in a secondary
anemia or hypoproteinemia.
 Contraindicated in patients hypersensitive to it and w/active GI
bleeding; relatively contraindicated in pts. w/ bleeding disorders,
asthma, renal insufficiency (but has been used to treat glomerular
disease)
 Cats relatively sensitive to salicylates (dose carefully); dogs
relatively sensitive to GI effects (bleeding)
 Low grade teratogen and may delay labor; avoid use in
pregnancy
Acetaminophen  Produces analgesia and antipyresis. Unlike aspirin, it does not
(Paracetamol) possess significant antiinflammatory activity.
 Occasionally used as an oral analgesic in dogs. In conditions of
more severe pain, it may be used in combination with oral
codeine phosphate.
 Contraindicated in cats at any dosage. Severe
methemoglobinemia, hematuria, and icterus can be seen. Cats
apparently are unable to significantly glucuronidate
acetaminophen leading to toxic metabolites being formed and
resultant toxicity.
PYRAZOLONE DERIVATIVES
Phenylbutazone  NSAID used primarily in horses; little reason to use in dogs today
 Acts on both COX-1 and -2, having greater inhibition in COX-1
 Contraindicated: known hypersensitivity, history or preexisting
hematologic or bone marrow abnormalities, preexisting GI ulcers,
food producing animals Caution: foals or ponies, preexisting renal
disease, CHF, other drug allergies.
 Adverse effects: Horses: oral and GI erosions and ulcers,
hypoalbuminemia, diarrhea, anorexia, and renal effects. Dogs: GI
ulceration, sodium and water retention, diminished renal blood
flow, blood dyscrasias.
 Do not give IM or SC. IA injections may cause seizures.
Meclofenamic  NSAID used in horses and sometimes dogs (safer alternatives
(Mefenamic acid) exist for dogs)
 it is non-selective to COX-1 and COX-2 but the activity to COX-1
is much greater
 Contraindications: Known hypersensitivity (including to
salicylates), “active
 gastrointestinal, hepatic or renal diseases”. Relatively
contraindicated: active or historical hemorrhagic disorders, or
bronchospastic disease. Avoid use in pregnancy (esp. near term).
 Adverse Effects: Horses: hematologic changes (decreased
hematocrit/PCV) and GI effects (buccal erosions, diarrhea, colic,
anorexia, changes in stool consistency). Heavy Bot infestation
may increase GI effects. Dogs vomiting, decreased hemoglobin,
leukocytosis, tarry stools, and small intestinal ulcers.
 Pts with hypoproteinemia may require dosage adjustment
Flunixin  Veterinary-only non-steroidal antiinflammatory agent used in a
Meglumine variety of species
  Contraindications: History of hypersensitivity.
 Caution in pts. w/ preexisting GI ulcers, renal, hepatic or
hematologic diseases. In horses w/ colic may mask the
behavioral and cardiopulmonary signs associated with
endotoxemia or intestinal devitalization
 Because of adverse effects in dogs and cats, most recommend
using one dose only.
 If first dose is ineffective for pain control, subsequent doses
unlikely to be of benefit
 Adverse Effects: Horses and cattle: Rare anaphylaxis (esp. after
rapid IV
 Administration: IM injections may cause pain/swelling. GI
distress/ulceration likely in dogs if used chronically.
OXICAM GROUPS
Peroxicam  NSAID w/ anti-inflammatory and antitumor (indirect) activity
 More on COX-1
 Contraindicated: Hypersensitivity or severely allergic to aspirin or
other NSAIDs. Extreme caution: active, or a history of GI ulcer
disease or bleeding disorders, cats.
 Caution: severely compromised cardiac function.
 Adverse effects: GI ulceration and bleedin, renal papillary
necrosis, and peritonitis.
 Probably safer NSAIDs available for pain/inflammation for dogs
and cats
Meloxicam  NSAID used in dogs and cats; COX-2 preferential
 GI adverse effects are less likely, but can occur
 Thus far has not shown hepatotoxicity or renal toxicity
OTHERS
Etodolac  NSAID (oral) used in dogs, relatively few adverse effects and
labeled for once daily
 It is non-selective but more active to COX-2 than COX-1
 Contraindications: Hypersensitive. Caution: pts w/ preexisting or
occult GI, hepatic, renal, cardiovascular or hematologic
abnormalities.
 Safe use not established for dogs less than 12 months of age or
in breeding, pregnant, or lactating dogs
 Adverse Effects: vomiting, diarrhea, lethargy, and
hypoproteinemia.
Naproxen  Contraindicated: active GI ulcers or history of hypersensitivity to
the drug. Relatively contraindicated: hematologic, renal or hepatic
disease. Caution: history of gastric ulcers, heart failure
 Because of difficulty in accurately dosing, adverse effects, and
safer alternatives, usually not used in dogs
 Adverse effects: Relatively uncommon in horses: Possible GI
(distress, diarrhea, ulcers), hematologic (hypoproteinemia,
decreased hematocrit), renal (fluid retention) and CNS
(neuropathies) Dogs: GI ulcers and perforation, renal effects
(nephritis/nephrotic syndrome) and hepatic (increased liver
enzymes) effects
Carprofen  NSAID used in dogs and other small animals
 Contraindicated in dogs w/ bleeding disorders (e.g., Von
Willebrand’s), history of serious reactions to it or other propionic-
class NSAIDs
 Caution: in geriatric patients or those with preexisting chronic
diseases (e.g., inflammatory bowel disease, renal or hepatic
insufficiency)
 GI adverse effects are less likely, but can occur
 Rarely may cause hepatic failure; monitor liver enzymes
Ketoprofen  Nonsteroidal antiinflammatory agent used in horses, cats and
dogs
 inhibits both COX and lipoxygenase
 Contraindications: hypersensitivity to ketoprofen. Cautions: GI
ulceration or bleeding, hypoproteinemia, breeding animals
(especially late in pregnancy), significant renal or hepatic
impairment. May mask the signs and symptoms (inflammation,
hyperpyrexia) of infection.
 Adverse Effects: Horses: Potentially, gastric mucosal damage
and GI ulceration, renal crest necrosis, and mild hepatitis may
occur. Dogs: vomiting, anorexia, and GI ulcers
 Do not administer intra-arterially and avoid SC injections

CORTICOSTEROIDS

- The most commonly used anti-inflammatory drugs (Hence called the “wonder drug”).
However, their pharmacologic and physiologic effects are broad and the potential for
misuse is considerable.

- Two classes of steroid hormones are naturally synthesized in the adrenal cortex from
cholesterol:
a. Mineralocorticoids (aldosterone)
- Important in maintaining electrolyte homeostasis
- Also trigger a broader range of functions in non-classic target cellular
sites, including some effects on wound healing following injury
b. Glucocorticoids
- Play significant role in carbohydrate, protein, and lipid metabolism; the
immune response; and the response to stress
- Natural glucocorticoids have some mineralocorticoid activity (thus affect
electrolyte and fluid balance).

- MOA: Glucocorticoids are capable of suppressing the inflammatory process through

numerous pathways. They interact with specific intracellular receptor proteins in target
tissues to alter the expression of corticosteroid-responsive genes. Glucocorticoid-
specific receptors in the cell cytoplasm bind with steroid ligands to form hormone-
receptor complexes that eventually translocate to the cell nucleus. There these
complexes bind to specific DNA sequences and alter their expression. The complexes
may induce the transcription of mRNA leading to synthesis of new proteins. Such
proteins include lipocortin, a protein known to inhibit PLA2a and thereby block the
 synthesis of prostaglandins, leukotrienes, and PAF. Glucocorticoids also inhibit the
production of other mediators including AA metabolites such as those produced via
COX activation (both COX-1 and COX-2), cytokines, the interleukins, adhesion
molecules, and enzymes such as collagenase.
- Endogenously, the body is capable of producing glucorticoids (cortisol)
a. In man, pigs, dogs: more cortisol
b. Lab animals: more on corticosterone
c. Ruminants: produce both of cortisol and corticosterone
- Clinical use of Glucocorticoids:
a. Inflammatory condition (ex. musculoskeletal inflammation)
b. Lameness (in horses)
c. Autoimmune disorder
d. Anaphylaxis/allergic reaction (ex. contact dermatitis that are nonresponsive to
other agents)
e. Pruritis/itching
f. Systemic diseases
g. Helpful in some form of cancers
h. In some practices, it terminates unwanted pregnancy
- Glucocorticoid is considered as a last option drug
- Weight loss, increase fatiguability, diarrhea, behavioral changes, and incoordination can
be observed in prolong use of these drugs (in animals)
- In order to avoid systemic problem, start using topical rather than giving it orally or by
injection because the concentration produced is much lower
- By injection, use the alternate day therapy (beware of drugs given daily)
- Use the lowest possible effective dose
- Withdraw the drug slowly and gradually reducing the amount of drug (to give time for the
pituitary gland to regain its function)
- Effect is said to be palliative, not curative. To become effective, you have to eliminate
the etiologic agent
- MOA of glucorticosteroids
a. Increase in gluconeogenesis (increase production of glucose from other source
like amino acids)
b. Cause of its diabetogenic effect, wasting disease is commonly observed
c. Increase lipolysis; there would be an abnormal distribution of fats
- Effects on the immune system:
a. Common is suppressing the immune system (ex. organ transplant)
b. It is not wise to use it as an antagonist
c. By suppressing the immune system, it can cause
- Eosinophenia
- Decrease Ab production
- Suppress WBC accumulation at the inflammatory site
- Inhibit synthesis of viral interferon
- Effect on the Cardiovascular system:
a. Increase in the force and frequency of heart activities
b. Maintains the microcirculation by reducing the vascular permeability and reduce
edema
c. Useful only during the early stages of inflammation
- Effects on the CNS:
a. Man: can improve the euphoric feeling that why it is abused more often; can
cause mental and physical dependence
 b. Animals: if given to dying patient, it will have an immediate perfect condition
before the body will give up
- Effects on the Endocrine system:
a. Carbohydrate metabolism
b. Fat metabolism
c. Protein metabolism
d. Drug is said to be diabetogenic (induce diabetes)
e. Have anti-insulin property
f. Suppresses the synthesis of ACTH, TTH, STH (growth hormones)
- Adverse Effects:
a. Iatrogenic Cushing’s syndrome – long-term administration and if given
indiscriminately in high doses
b. The gluconeogenic and insulin antagonistic effects may precipitate the onset of
diabetes mellitus or exacerbate diabetes in animals with existing disease
c. Abrupt discontinuation of glucocorticoid therapy may lead to Addison’s disease
d. Glucocorticoids potentiate the ulcerogenic effects of NSAID
e. Reduce collagen synthesis and may lead to thinning and increased fragility of the
skin
f. In horses, high doses may induce or exacerbate laminitis
g. Mood and behavioral changes
h. Urinary tract infections in long term glucocorticoid therapy
- The adverse effects of long term glucocorticoid therapy can be diminished using an
alternate-day treatment regimen
- Therapeutic corticosteroids are typically classified based on their relative glucocorticoid
and mineralocorticoid potency as well as duration of effect
- Compounds with the most potent glucocorticoid activity are also the most potent
suppressors of the hypothalamic-pituitary-adrenal axis (HPAA).

RELATIVE POTENCIES OF COMMONLY USED CORTICOSTEROIDS

Drug Relative Relative Duration of Action
Glucocorticoid Mineralocorticoid
Activity Activity
SHORT ACTING
Hydrocortison 1 1 <12 hrs
Cortosone .8 0.8 <12 hrs
INTERMEDIATE ACTING
Prednisone 5 0.8 12-36 hrs
Prednisolone 5 0.8 12-36 hrs
Methylprednisolone 5 0.5 12-36 hrs
Fludrocortisone 10 125 12-36 hrs
Triamcinolone 5 0 12-36 hrs
Triamcinolone 30 0 12-36 hrs
acetonide
LONG ACTING
Betamethasone 35 0 > 2 days
Dexamethasone 25 0 >2 days
Flumethasone 120 0 >2 days
Isoflupredone 25 25 >2 days
MISCELLANEOUS DRUGS WITH ANTI-INFLAMMATORY PROPERTY
(Actions not related to NSAID and Glucocorticoids)

MISCELLANEOUS ANTI-INFLAMMATORY DRUGS

Dimethyl  Free radical scavenger that has antiinflammatory,
Sulfoxide cryopreservative, antiischemic and radioprotective effects
(DMSO)  Caution: mastocytomas, dehydration/shock. May mask existing
pathology.
 Handle cautiously; will be absorbed through skin. Can carry toxic
compounds across skin.
 May cause localized “burning” when administered topically.
 When giving IV to horses give slowly and at concentrations of 20%
or less. May occasionally cause diarrhea, tremors, colic.
 Garlic-like odor may be an issue
Selenium  Known to inhibit the formation of peroxide
 Use for chronic inflammatory condition and those involving
nutritional muscular dystrophy

CHONDROPROTECTIVE AGENTS

CHONDROPROTECTIVE AGENTS
Polysulfated  Prepared from bovine tracheal cartilage
Glycosaminoglycan  Proteolytic enzyme inhibitor used IM or intra-articularly for non-
(PSGAG) infectious and/or traumatic joint dysfunction and associated
lameness of the carpal joints in horses and non-infectious
degenerative and/or traumatic arthritis in dogs.
 Contraindicated: Intra-articular injection if patient hypersensitive
to it. Should not be used in place of other tx when infection
suspected or present or when surgery or joint immobilization
required.
 Adverse effects: IM use: unlikely. Intraarticular: post-injection
inflammation possible. Dogs: dose-related inhibition of
coagulation/hemostasis possible.
Pentosan  It is a polysulfate ester of xylan, a polymer prepared
Polysulfate Sodium semisynthetically from beechwood plant material
(PPS)  Oral capsules for the treatment of interstitial cystitis in man;
injectible product available for humans, dogs, and horses
 Stimulates hyaluronic acid and GAG systhesis in damaged
joints, inhibits preteolytic enzymes, and scavenges free radicals
 In canine models of osteoarthritis, IM administration of PPS
significantly decreased overall cartilage damage
Hyaluronan  Formerly hyaluronic acid
 A component of synovial fluid and articular cartilage
 Responsible for the viscosity of the synovial fluid and contributes
to its lubricating function in joint movement
 For osteoarthritis; intra-articular administration may improve joint
lubrication
  May inhibit inflammatory enzymes and reduce pain
 Mostly used in horses
Orgotein  Has superoxide dismutase activity scavenging free oxygen
radicals
 Available as an injectable formulation
 Used for the treatment of soft-tissue inflammation in horses and
arthritis in dogs
 Typically administered as an intra-articular injection, as its large
molecular size may limit absorption via other routes
 Intra-articular administration effective in cases of acute
lameness in horses
 Has wide margin of safety

Cardiovascular Drugs

A. Positive inotropic drugs

B. Anti-arrhythmic

C. Vasodilators Drugs

D. Diuretics

(+) inotropic drugs

• Drugs that increase the force of contraction; termed as (+) inotropic drugs

• All of these drugs have the ability to increase myocardial oxygen consumption.

• These drugs can cause sympatomatic improvement and enhance the quality of life of
the patient.

• All these drugs have the potential to increase intracellular calcium levels or increase
sensitivity of contractile myofibrils to intracellular calcium.

(+) inotropic drugs

1.Cardiac glycosides or digitalis

2.Catecholamines

3.Phospodiesterase inhibitor

4.Anticholinergics

1. Cardiac Glycosides

Source of this is digitalis plants known long time ago

• MOA: positive inotropic effect. Binds to and inhibits sodium pump (Na+ - K+ -
ATPase) at the myocardial cell membrane.
 • -inhibition causes reduction of the Na+ transport out of the cell.
This causes increase in intracellular Na+ conc. This results to
accumulation of Ca+ in the cell.

- Negative chronotropic effect (anti-arrhythmia).

Drugs under Cardiac glycosides

• Digoxin

• Digitoxin

• Ouabain

Pharmacokinetics:

• Digitoxin is more lipid-soluble than digoxin.

• Plasma protein binding: digitoxin (25%), digoxin (25%)

• T1/2: Digitoxin, 12 hrs; Digoxin 1-7 days in dogs.

Excretion and metabolism

• Digoxin is eliminated unchanged in the kidney. Digitoxin is metabolized in the

liver.

Adverse effect:

• Stimulation of the CTZ

Vomiting, Nausea, Anorexia, Diarrhea

• CNS: drowsiness

• Hypokalemia

Treatment

• Discontinuation of digitalis therapy

• Use of anti-arryhthmics

• Potassium administration

Clinical uses/Indication:

• To restore adequate circulation in animals with CHF

• Slow down supraventricular arrhythmias.

Contraindications:

• Cats with hypertropic cardiomyopathy.

• Patients with ventricular fibrillation

 • Extreme caution with patient with glomerulonephritis

• Used in caution with patient with severe pulmonary disease, hypoxia, acute myocarditis.

2. Catecholamines

• Beta-adrenergic blocker

• Beta-1 receptor are mostly located in the heart and stimulation of these receptors results
in positive inotropic and chronotropic response.

• Beta 2 receptor are mostly found in the vascular and bronchial smooth muscles and their
stimulation can cause relaxation(vasodilation and bronchodilation)

• Alpha 1 receptor are found primarily in vascular smooth muscle and myocardium and
their stimulation results in vasoconstriction and positive inotropic response.

Commonly used Catecholamines

• Epinephrine

• Isoproterenol

• Dopamine

• Dobutamine

Therapeutic uses:

1. Drug of choice for positive inotropic action e.g. cardiac arrest

• potent a1, b1 and b2 agonist

• Increases contractility, heart rate, blood pressure and cardiac output.

 Isoprenaline - prototype of beta agonist, acting on b1 and b2 receptors. Not used in the
management of cardiac arrest or myocardial failure because of its arrhythmo-genicity
and hypotensive effects

2. Treatment of complete AV nodal block that is unresponsive to anticholinergics.

3. Drug of choice in patient experiencing bradycardia.

Dopamine

• Biosynthetic precursor to norepinephrine.

• Acts on beta1 and dopaminergic receptor.

• Vasodilatory effect improve renal blood flow.

• Desirable for management of acute heart failure.

Dobutamine

• A synthetic analog of dopamine but does not cause vasodilation of renal , coronary
and cerebral.

MOA: Positive inotropic effect similar to dopamine but does not cause vasodilation

Contraindication: patients with heart disease characterized by ventricular hypertrophy.

Adverse effect - similar to dopamine: tachyarrhythmias, vomiting, nervousness,

seizure.

3. Phosphodiesterase inhibitor

• Phospodiesterase enzyme are responsible for the inactivation of cyclic AMP. Inhibition of
these enzyme leads to increase intracellular calcium concentration.

• Xanthine derivatives – caffeine, theophylline, theobromine

• Bipyridine derivatives- Amrinone, Milrinone, Pimobendan

Amrinone

• Increases cardiac contractility and cause vasodilation, decreasing preload and afterload.

• May cause hypotension, arrhythmia, or GI distress.

Milrinone

• Possess 20-50x the potency of amrinone

• Approved for used in dogs

Pimobendan (Vetmedin)

• Increases sensitivity of myocardial calcium-regulatory proteins to calcium.

• It has both inotropic and vasodilator effects.

• Indication: used to treat dogs with CHF secondary to dilated cardiomyopathy or chronic
mitral valve insufficiency.

• Contraindication: animals hypersensitive to it, used with caution in patients with

uncontrolled cardiac arrhythmias.

• Adverse effect: may increase the development of cardiac arrhythmias, atrial fibrillation
or increase ectopic beats have been reported in dogs.

4. Anticholinergic drugs

• MOA: deny access of acetylcholine to muscarinic receptors. Acetylcholine causes

negative inotropic effect, negative chronotropic effect and vasodilation.

• Drugs: Atropine, Propantheline, Methyliscopalamine, Atropine sulfate

 • Indication: preanesthetic, treat sinus bradycardia, sino atrial arrest and incomplete AV
block. Antidote for organophosphate.

• Contraindication: with narrow angle glaucoma.

• Adverse effect: xerostomia (dry mouth), vomiting, constipation, thirst.

What is arrhythmia?

• Arrhythmia refers to any deviation from the normal cardiac rate and rhythm.

• Abnormal impulse initiation.

• Abnormal impulse condition.

General classification

1. Class I Local Anesthetics (membrane stabilizers)

2. Class II (beta blockers)

3. Class III (repolarization prolonging drugs)

4. Class IV (Calcium blockers)

I. Class I - membrane stabilizers

• MOA: selectively blocks the sodium channels, decreasing sodium influx during
phase 0.

1. Class IA: Quinidine, Procainamide, Disopyramide

• Quinidine

• Derived from the bark of the concha tree

• Decreases conduction velocity, increases refractory period, decreases rate of

spontaneous depolarization in pacemaker cells.

• Prolong P-R interval, widen QRS. Has anticholinergic effects (hypotension)

• Clinical uses:

• Treatment for ventricular arrhythmia in small and equine animals.

• Refractory ventricular tachycardias.

• Supraventricular arrhythmias e.g. acute atrial fibrillation.

• Adverse Effect: anorexia, vomiting, diarrhea, cardiovascular: weakness,

hypotension.

• Contraindications: 3rd degree heart block, digitalis intoxication, ventricular tachycardia

with long Q-T intervals, severe hepatic failure
Procainamide

• less ability to induce hypotension and increase AV conduction than quinidine

• Clinical Indications:

• Use with other agents and beta blocker in treating refractory arrhythmias.

• Ventricular tachycardia

• Supraventricular tachycardia

• Contraindication: Myasthenia gravis

• Adverse effect: anorexia, vomiting, diarrhea, weakness, hypotension, negative

inotropism

• Dosage should be reduced in patient with renal failure.

Disopyramide

• Second-line drugs for refractory Arrhythmias

• Possess strong negative inotropic tendencies

• Contraindications: CHF, pulmonary edema, glaucoma, urinary retention, advanced AV

block, SA node dysfunction

2. Class IB – Lidocaine, Tocainide, Mexidectine, Phenytoin

• Lidocaine

• Used for acute life threatening ventricular arrhythmias

• Causes significant suppression of automaticity, conduction velocity.

• Intoxication causes seizures

• Tocainide

• Used to follow-up Lidocaine

• Causes corneal edema in Doberman pinchers

• Mexiletine

• Synergistic with other class 1A drugs

• Phenytoin

• Similar to Lidocaine but more effective in controlling supraventicular tachycardia.

• Indicated in controlling digitalis induced arrhythmias.

3. Class IC – Flecainide, Encainide

• Contraindications: AV block, bundle branch block, myocardial depression.

II. Class II - beta blockers

• MOA: blockade of b1 receptors leading to slow opening of calcium channels and

rate of pacemaker discharge.

• Agents: Propanolol, Atenolol, Esmolol

• Propanolol – b1 and b2 blocker, non selective

• Reduce the heart rate and therefore it reduces the oxygen demand

• Uses: for myocardial hypertrophy, ventricular tachycardia

• Side effects: bradycardia, lethargy, depression, bronchospasm

• monitor the heart rate: do not give to patients with slow HR.

• Atenolol - beta-1 selective blocker

• Esmolol - beta-1 selective blocker

III. Class III – drugs that prolong repolarization

• MOA: inhibition of K+ channel (inhibition of repolarization) prolong APD and

refractory period

• Agents; Amiodarone, ,Bretylium (not use in Vet. practice)

• Amiodarone:

• Indication: Doberman pinchers exhibiting recurrent VPC’s when other drugs

are ineffective.

• Contraindication: severe sinus-node dysfunction with severe sinus bradycardia.

• Adverse effect: anorexia, vomiting

IV. Class IV - calcium entry blocker

• MOA: blocks calcium channel, inhibiting calcium entry across the membrane
during phase1 and 2 of AP.

• Agents: Verapamil, Nifedifine, Diltiazem

• Indication: supraventricular tachycardias in dogs and cats e.g. atrial fibrillation

• Contraindication: cardiogenic shock or severe CHF, digitalis-intoxication. Caution:

patients with heart failure.

• Adverse effect: hypotension, bradycardia, pulmonary edema.

 • Diltiazem HCl:

• Indication: drug of choice feline hypertrophic cardiomyopathy. Treatment for

hypertension, atrial fibrillation and supraventricular tachycardias.

• Contraindication: severe hypotension, used in caution in patient with hepatic or

renal impairment.

• Adverse effect: bradycardia in dogs, vomiting in cats, GIT distress, hypotension,

heart block.

Vasodilator drugs

• Vasodilators are classified based on their primary site of action. Drugs that dilate veins
are venodilators. Drugs that dilate systemic arterioles are arteriolar dilators. Drugs that
dilate both systemic arterioles and veins are called mixed or balance dilators.

• ACE inhibitor: mixed dilator - captopril, lisinopril

• Hydralazine - arteriolar dilator

• Specific Venodilator: prazosin, nitrate and nitroprusside (nitroglycerin, nitroprusside,

isosorbide dinitrate)

Angiotensin antagonist

• Losartan

• Telmisartan

ACE inhibitor

• MOA: inhibition of angiotensin-converting enzyme caused systemic vasodilation

(decrease both preload and afterload) and reduces aldosterone and ADH release,
promotes Na+ and water loss thereby reducing edema.

• Angiotensin action: potent vasoconstrictor (arteries & veins), stimulates release of

aldosterone from the adrenal gland and stimulates vasopressin ADH release from
posterior pituitary gland.

• Captopril

• Indication: treatment for CHF and hypertension.

• Contraindication: hyponatremia, collagen vascular disease.
• Adverse effect: hypotension, renal failure, hypokalemia, vomiting and diarrhea.

• Lisinopril

• Indication: heart failure or hypertension, valvular heart disease.

• Contraindication: hyponatremia,

• Adverse effect: anorexia, vomiting, diarrhea, cough, weakness, hypotension,

renal dysfunction.
• Hydralazine

• Indication: afterload reducer for CHF in small animals.

• Directly relaxes arteriolar smooth muscle but has little effect on the venous system

• Contraindication: coronary heart disease.

• Adverse effect: hypotension, sodium/water retention.

• Venodilators

• Prazosin

• MOA: blocks post synaptic alpha1 adrenergic receptors(dilate both arterioles and
veins)

• Indication: used in systemic hypertension or pulmonary hypertension in dogs.

• Contraindication: chronic renal failure.

• Adverse effect: nausea, vomiting, diarrhea, constipation.

Nitrates and Nitroglycerin

• MOA: stimulates quanylate cyclase to produce cGMP (cyclic guanosine

monophospate).

• Nitroglycerine (dilates veins)

• Indication: adjunctive vasodilator in heart failure. Used as anti-anginal agent.

• Contraindication: severe anemia, with cerebral edema.

• Adverse effect: hypotension

Isosorbide dinitrate

• Decreases preload

• Dilates coronary artery

• Relieves anginal attacks

Nitroprusside (dilates both arterioles and veins)

• Rapidly lower blood pressure. Produces peripheral vasodilation.

• Contraindication: hyperthyroidism

• Adverse effect: nausea, restlessness

Mixed vasodilator

• ACE inhibitor

• Captopril

• Lisinopril

• Enalapril

• Losartan (NEW) – angiotensin antagonist

• Telmisartan (NEW) - angiotensin antagonist

Diuretics

• Increases volume of urine, increase release of water and electrolyte

• Imbalance of electrolytes and dehydration

• Could cause some bad results when used in excess

• Loss of water and loss of ECF volume

• Chemical uses:

• Lowering ECF volume

• Decreasing blood volume and pressure

• Diuretics + Vasodilators are used to treat hypertension

• Diuretics

• Osmotic Diuretics

• Carbonic Anhydrase Inhibitor

• ACETAZOLAMIDE

• DICHLORPENAMIDE

• Thiazides Diuretics

• HYDROCHLOROTHIAZIDE

• CHLOROTHIAZIDE

• HYDROFLUMETHIAZIDE

• High Ceiling (Loop) Diuretics

• Potassium-Sparing Diuretics

• SPIRONOLACTONE

• TRIAMTERENE and AMILORIDE

DRUGS USED FOR HEARTWORM

• Diethlycarbamazine

• Ivermectin

• Milbemycin

• Caparsolate Sodium

• Melarsomine Sodium

• Moxidectin, Selamectin

Drugs Acting on the Blood

HEMATINICS

A hematinic is a medicine that increases the hemoglobin content of the blood.

 Vitamin B 12
-part of coenzyme for myelin and DNA synthesis essential in RBC production.
-deficiency causes inhibited nuclear maturation and division. Arrest in RBC maturation in
the bone marrow leads to megaloblastic or pernicious anemia
-available in oral and parenteral preparations of cyanocobalamin (dogs: 100–200 μg,
PO, SC, sid; cats: 50–100 μg, PO, SC, sid)

 Folic acid (folacin)

-coenzyme needed for DNA and RNA synthesis essential for hemoglobin production.
- deficiency is characterized as megaloblastic anemia
- available in both oral and parenteral formulations (dogs: 5 mg, PO, sid; cats: 2.5 mg,
PO, sid)

 Iron
-is necessary for hemoglobin synthesis
-iron is available in both oral and parenteral preparations
-oral preparations: sulfate, gluconate, and fumarate (dogs: 100–300 mg, sid; cats: 50–
100 mg, sid)
- Iron dextrans can be given as a single IM injection (100 mg) at 2–4 days of age in
newborn piglets
- Toxicity may be seen and is manifest as pale skin, bloody diarrhea, and shock

 Epoetin alfa
-is the synthetic form of the human glycoprotein erythropoietin (ERP)
-Epoetinalfa is indicated in the treatment of anemia associated with chronic renal failure
in dogs and cats
-the initial dosage is 100 U/kg, SC, 3 times/wk for 4 mo, while monitoring PCV, followed
by a maintenance dosage of 75–100 U/kg, SC, 2–3 times/wk
-the most significant adverse effects in dogs and cats are the development of antibodies
to ERP, resistance to treatment, and worsening of anemia.
  Anabolic steroids
-are compounds structurally related to testosterone
- increased ERP production via ERP-stimulating factor, differentiation of stem cells into
ERP-stimulating factor-sensitive cells and direct stimulation of erythroid-progenitor cells
- Clinical indications for use of anabolic steroids include chronic, non-regenerative
anemias
- They are available as oral and parenteral preparations, including oil-based products
- Most are eliminated after hepatic metabolism
- The alkylated products are more effectively absorbed when given PO and are more
effective stimulants of bone marrow. Alkylated anabolic steroids include oxymetholone
(dogs and cats: 1–5 mg/kg, PO, every 18–24 hr)
- Non-alkylated anabolic steroids include nandrolone decanoate (dogs: 1–1.5 mg/kg,
IM/wk; cats: 1 mg/kg, IM/wk; horse: 1 mg/kg, IM, once every 4 wk). Boldenone
undecylenate is approved for horses at 1.1 mg/kg, IM, every 3 wk.
- Side effects of anabolic steroids include sodium and water retention, virilization, and
hepatoxicity.
- The alkylated products are more hepatotoxic than the non-alkylated products,
particularly in cats. Cholestatic liver damage develops early and can be significant but
frequently is reversible.

HEMOSTATICS

A substance that arrests the flow of blood.

 Lyophilized concentrates
- provide an artificial factor or structural matrix that facilitates control of capillary bleeding
- available as topical or local hemostatics. Concentrated factors include thromboplastin,
thrombin (powder, solution, or sponge), collagen, and fibrinogen. Artificial matrices
include fibrin foam, absorbable gelatin sponge, and oxidized cellulose

 Astringents
-act locally by precipitating proteins
-do not penetrate tissues and, thus, are restricted to surface cells.
-examples include ferric sulfate, silver nitrate, and tannic acid

 Epinephrine and norepinephrine

-are hemostatics by virtue of their vasoconstrictive effects
-may be included in topical medications to decrease blood flow to the tissues, or applied
intranasally in tampons to decrease epistaxis.

 Systemic hemostatics
- include fresh blood or blood components administered to animals that have a
coagulation factor deficiency
 -examples include fresh plasma, fresh frozen plasma, cryoprecipitate, and platelet-
rich plasma

 Vitamin K
-is essential for carboxylation, synthesis and activation of hepatic coagulation factors II,
VII, IX, and X
-for treatment of rodenticide (warfarin) toxicity, moldy sweet clover poisoning
(dicoumarol), and sulfaquinoxaline toxicity
- routes for administering are SC and PO, although it can be given by slow IV or IM
injections

 Desmopressin
-is a synthetic analog of vasopressin
-used to treat diabetes insipidus
-may be useful in dogs with von Willebrand's disease (0.4 μg/kg, SC; 1 μg/kg, IV,
diluted in 20 mL of saline and given over 10 min), permitting surgical procedures or
controlling capillary bleeding

ANTICOAGULANTS

An agent that is used to prevent the formation of blood clots.

 Heparin
-a heterogeneous mixture of sulfated (anionic) mucopolysaccharides.
- acts indirectly to facilitate endogenous anticoagulants, antithrombin III and heparin
cofactor II.
-for prevention or treatment of venous or pulmonary embolism and embolization
associated with atrial fibrillation.
- available as sodium or calcium salt
-oral absorption is poor; hence, it is a parenteral anticoagulant
-high-dose heparin therapy (dogs: 150–250 U/kg, SC, tid; cats: 250–375 U/kg, SC, bid)
has been recommended for established acute thromboembolism.
-lower dosages (dogs and cats: 75 U/kg, SC, tid; horses: 25–100 U/kg, SC, tid) are
indicated in the management of DIC.
-Adverse effect and toxicities: hemorrhage and possible allergic reactions
-Contraindication: bleeding animals and in DIC unless replacement blood or plasma
therapy is also given.

 Vitamin K antagonists (oral anticoagulants)

-for oral long term treatment and prevention of recurrence of thrombotic conditions (eg,
aortic or pulmonary thromboembolism and venous thrombosis) in cats, dogs, and horses
-interferes with the hepatic synthesis of vitamin-K-dependent clotting factors by blocking
the reduction of vitamin K epoxide after clotting factor synthesis
- are rapidly and completely absorbed after administration PO. Levels peak in 1 hr
- Warfarin sodium is the most commonly used therapeutic preparation. The dosage is
0.1–0.2 mg/kg, PO, sid, for dogs and cats, and 0.067–0.167 mg/kg, PO, sid, for horses.
Toxicity, manifest as hemorrhage.
-used orally in cats that survive an acute thromboembolic event.
 Low-molecular-weight heparins (LMWH), e.g. dalteparin and enoxaparin.
- Alternatives to “unfractionated heparin” and are used extensively in humans as
anticoagulants for various acute thromboembolic conditions.
-LMWH differ from heparin, the molecular weights are approximately one-tenth that of
heparin, dosing can be sid-bid in humans. There is no need to monitor activated partial
thromboplastin time, the risk of bleeding and thrombocytopenia is smaller, and the
effect on thrombin is less than that of heparin
-LMWH target antifactor Xa activity
-a suggested dosage regimen for dalteparin in dogs and cats is 100–200 IU/kg, SC, sid-
bid, and a suggested dosage regimen for enoxaparin in dogs and cats is 1–2 mg/kg, SC,
bid, while monitoring prothrombin time.

 Streptokinase is a thombolytic agent, useful for acute thromboembolism

a. Mechanism of action. These drugs enhance the production of plasmin and cause
generalized clot lysis. A potential for excess bleeding exists.
b. Administration. Intra-arterial administration close to the clot would probably have greater
positive effects than intravenous administration, but is usually impractical.

 Fibrinolytic agents
-increase the activity of plasmin (fibrinolysin), the endogenous compound that is
responsible for dissolving clots.
- used locally as a powder, infusion, or irrigation in the treatment of selected chronic
wounds e.g. burns, ulcers, chronic eczemas, ear hematomas, otitis externa,
osteomyelitis, chronic sinusitis, or other chronic lesions.
-Tissue-type plasminogen activator (tPA) preferentially activates the fibrin-bound form
of plasminogen.
-tPA has been used to treat acute thromboembolism in cats (0.25–1.0 mg/kg/hr, IV, for
a total dosage of 1–10 mg/kg)

 Antithrombotic drugs
-affect platelet activity, which is normally controlled by substances (such as
prostaglandins) generated both outside and within the platelet.
-NSAID inhibit the formation of cyclooxygenase, the enzyme responsible for the
synthesis of prostaglandin products from arachidonic acid that has been released into
cells and platelets.
-Aspirin is a potent inhibitor of platelet activity. The antiplatelet dosage for dogs is 5–10
mg/kg, PO, every 24–48 hr, and for cats 80 mg, PO, every 48–72 hr.
- used to reduce further platelet aggregation after a thombo-embolic event.

ENDOCRINE PHARMACOLOGY

A. Animals constantly adapt to changes in the environment.

B. The endocrine system and nervous system constitute the 2 major control mechanisms of
the body:
a. Nervous system
- Respond to short term changes
- Send electrical impulses along nerves
 b. Endocrine System
- Brings longer-term adaptations
- Send chemical messengers (hormones) into the blood stream.
C. Endocrine Glands
- Collection of specialized cells that synthesize, store and release their secretion
into the bloodstream.
- Respond to changes in the internal and external environment
D. Endocrine secretions
- Proteins
- Polypeptides
- Steroids
- Catecholamines
- Iodothyronine hormones
E. Degradation
- by peptidases on the cell surface
- Lysosomal enzymes after uptake by cells
- Excretion in the bile or urine after conjugation with glucuronide or sulfate
F. Endocrine Glands
- Pituitary
- Adrenals
- Thyroid
- Ovaries
- Testicles
- Pancreas
- Kidneys
 Fig.1 Endocrine System of Do

Fig.2 Endocrine System of Cats

G. Reasons of hormone administration to animals:

 Correct a deficiency of that hormone
 To obtain a desired effect
H. Endogenous and Exogenous Hormone
 Endogenous hormone
 o produced naturally
 Exogenous hormone
o administered
____________________________________________________________________________
Anatomy of the Pituitary Gland:
A. Pituitary Gland
- Master gland
- Ventral to the hypothalamus
o 2 main lobes : Anterior lobe (adenohypophysis) and Posterior lobe
(neurohypophysis)
B. Hypothalamus
- Exerts control over the anterior pituitary through the transport of releasing
hormones, or factors, down the hypophyseal portal system.
- Trophic hormones are then released in the anterior pituitary

 Trophic Hormones of the Anterior Pituitary Gland

- Indirect-acting
1. TSH (Thyroid- Stimulating Hormone)
- Important for growth and secretion of thyroid)
2. ACTH (Adrenocortropic Hormone)
- For growth and secretion of adrenal cortex (corticosteroids and
mineralocorticoids)
3. FSH ( Follicle stimulating homone)
- For secretion of estrogen and growth of ovaries and production of
sperm
4. LH (Luteinizing Hormone)
- Female, for ovulation; maintenance of pregnancy. Male, increases
testosterone synthesis from Leydig cells.
5. LH/ICSH ( Interstitial Cell Stimulating Hormone)
- For secretion of testosterone
6. LTH (Prolactin) – for secretion of milk and the behaviour of a mother
7. GH or Somatotropin (Growth Hormone)
- For body growth
 8. MSH (Melanocyte Stimulating Hormone)
- For skin pigmentation

 Hormones of the Posterior Pituitary

- Produced in the hypothalamus and travel down nerve fibers to the posterior
pituitary
- Direct-acting
1. Vasopressin (antidiuretic hormone)
2. Oxytocin

A. CONTROL OF THE ENDOCRINE SYSTEM

 Feedback Mechanism
- The plasma level of a particular hormone controls the activity of the gland that
produces it.
- Sensed by the hypothalamus
 Negative Feedback
- Decreases the amount of the releasing factor of the hormone that has a high
plasma level.
- Lower the amount of the hormone in the plasma.
 Positive feedback
- Release of the appropriate releasing factor increases.

 Neurohormonal Reflex
- Applies to oxytocin release
1. Stimulation of the udder by a nursing calf or by preparation of the udder for milking
2. Stimulation of the uterus and vagina in parturition
3. Stimulation of the cerebral cortex by sensory stimuli associated with nursing or milking

B. CONTROL OF THE REPRODUCTIVE SYSTEM

 Coordinated in the hypothalamus

 GnRH is produced in response to stimuli like photoperiod, pheromones, and positive and
negative internal feedback mechanisms.
 GnRH causes release of FSH and LH from anterior pituitary.
 FSH causes the growth and maturation of a follicle (follicular phase).
- Produce increased amounts of estrogen as it matures
- Produce inhibin, along with estrogen, will inhibit release of GnRH
  Estrogen causes the changes that occur in pro-estrus and estrus including the
behavioral characteristics associated with estrus e.g. standing to be mounted.
 LH release causes ovulation of the mature follicle and the formation of a corpus
luteum (CL) in its place.
- Signals the beginning of di-estrus and beginning of the luteal phase.
- CL produces progesterone.
- Progesterone levels serve as negative feedback to prevent release of GnRH
and development of new follicles.
 Near the end of gestation, the fetus begins to produce increasing amounts of ACTH.
- Increase amounts of cortisol
- Increase production of estrogen and prostaglandin
- Sensitize uterus to the contraction-producing effects of oxytocin.
- Prostaglandin also causes the lysis of the corpus luteum at the end of
pregnancy and at the end of di-estrus if pregnancy does not occur.

HORMONAL DRUGS ASSOCIATED WITH REPRODUCTION

I. Gonadotropins and Gonadal Hormones

- synchronization of estrus
- Suppression of estrus
- Induction of estrus
- Treatment of cystic ovaries
- Termination of pregnancies

A. Gonadotropins
- Acts like GnRH, LH, or FSH.
- Cause release or produce an activity like that of LH and FSH

a. Gonadorelin (GnRH)
- causes release of FSH and LH by the anterior pituitary gland
 Clinical Use
- Dairy cattle - cystic (follicular) ovaries
- Dogs and Cats - induce estrus
 Dosage Forms
1. Cystorelin
2. Factrel
3. Fertagyl

 Adverse Effects: Minimal

b. Chorionic Gonadotropin (HCG)

 - Secreted by the uterus and obtained from the urine of pregnant
women, mimics effects of LH.
- In males, stimulates production of male hormones by the testicles

 Clinical Use:
- Dairy cattle - treat cystic ovaries
- Male - treat cryptorchidism and infertility caused by low
testosterone levels.
 Dosage Forms:
1. Follutein
2. Chlorulon
3. Chorionic gonadotropin injection
 Adverse Effects:
- hypersensitivity reactions
- abortion in mares

c. Follicle-Stimulating Hormone (FSH) – Pituitary

- causes growth and maturity of the ovarian follicle

 Clinical use:
• Induces superovulation
• For out-of-season breeding
 Dosage form:
• FSH-P
 Adverse Effects:
• Endometrial hyperplasia
• Superovulation
• Follicular cyst

d. PMSG has FSH-like activity. It is secreted from the placenta and extracted
from the serum of pregnant mares.

B. Estrogen
- necessary for normal growth and development of the female gonads
- cause secondary female characteristics
- cause female sex drive (libido)
- inhibit ovulation
- increase uterine tone
- cause proliferation of the endometrium

 Clinical use:
 1. Cattle
- persistent CL
- expel purulent material from the uterus,
- expel retained placentas and mummified fetuses,
- promote weight gain
2. Dogs
- Induce abortion
- Control urinary incontinence
3. Horses
- Induction of estrus
 Dosage Forms:
1. Estradiol cypionate
2. Diethylstilbestrol (DES)
3. Implants
 Adverse effects:
• Severe anemia
• prolonged estrus
• genital irritation
• follicular cysts

C. Androgens
- Male sex hormones produced in the testicles, ovaries and the adrenal cortex.
- For growth and development of the male sex organ.
- Secondary male sex characteristics
- Produce male libido
 Clinical use:
• Male dogs. Urinary incontinence
• Domestic animals. Increase libido and fertility
 Dosage forms
1. Testosterone cypionate
2. Testoterone enanthate
3. Testosterone propionate
4. Depo-testosterone
5. Combination with estradiol as growth implants
 Adverse effects: uncommon

 Mibolerone
- Blocks release of LH, ovulation does not occur
- Prevents complete development of follicle
 Clinical Uses:
• Prevention of estrus in dogs
• Treatment of pseudocyesis
 Dosage Forms:
 1. Oral drops
2. Implants to promote weight gain
 Adverse effects:
- Premature epiphyseal closure
- Vaginitis in immature females
- Vulvo-vaginitis
- Clitoral hypertrophy
- Riding behavior
- Increased body odor
 Contraindicated for cats

D. Progestins
- Cause increased secretions by endometrium
- Decreased motility in uterus
- Increased secretory development in mammary glands.
- Inhibit release of gonadotropin to produce inactive ovary

 Megestrol Acetate
- Labeled for use in dogs
- Used in cats for some behavioral and dermatologic conditions.
 Uses:
• Control estrus (estrus synchronization)
• Treat false pregnancy
• Prevent vaginal hyperplasia
• Treat severe galactorrhrea
• Control male behaviour
 Dosage Forms:
1. Ovaban
2. Megace
 Adverse Effects:
• Hyperglycemia
• Adrenal suppressionb
• Endometrial hyperplasia
• Increased appetite

II. PROSTAGLANDINS
- Regulation of activity in and treatment of conditions of the female reproductive
tract

 Prostaglandin F2α
- Causes lysis on CL
- Signal the initiation of new cycle
- Causes contraction of uterine muscles
 - easily absorbed on skin, very lipid soluble
 Clinical uses/Treatment:
• silent heater
• pyometra
• Expulsion of mummified fetus
• Used for estrus synchronization
• Used for treatment of luteal cysts and mummified fetuses,
• Termination of pregnancy (Induces abortion)
 Caution:
• Pregnant animal
• Asthma
• Dosage Forms:
1. Dinoprost Tromethamine (Lutalyse®)
• Labeled for use in cattle, horses and swine
• Accepted in dogs, cats, sheep, goats
• Effective only to animals with CL
2. Fenprostalene (Bovilene®)
3. Fluprostenol (Equimate®)
• Adverse effects: sweating, increased respiration, abdominal discomfort, and
defecation.
4. Cloprostenol Sodium (Estrumate®)

III. DRUGS THAT AFFECT UTERINE CONTRACTILITY

- To cause abortion
- Induce parturition
- Aid in delivery of the fetus or placenta
- To cause involution of the uterus after delivery.
- Cervix should be dilated before administration

 Oxytocin
- Causes stronger uterine contractions by increasing the contractility of uterine myofibrils.
- Also responsible for milk let-down from mammary glands
• Uses:
- To aid in delivery of the placenta
- Treatment of agalactia in sows
 Ergot
- Ergonovine maleate
- Not commonly used
 Prostaglandins
 Corticosteroids
- Mimics the natural rise in production of corticosteroids by the fetus near delivery.
____________________________________________________________________________
DRUGS THAT AFFECT THE THYROID GLAND

Anatomy:

A. Hypothyroidism
a. Deficiency of thyroid hormone:
- T4 (Thyroxine)
- T3 (Tri-iodothyronine)
b. Function of Thyroid hormones:
- Metabolic growth
- Immune functions
- Regulate lipid and CHO metabolism
- Heat production
 Synthesis of thyroid Hormones:
 Ingested food and water

iodide is trapped

converted to iodine

combine to thyroxine

form iodothyroxine

molecules combine

T4 and T3 stored on thyroid.

 Deficiency:
- Loss of hair
- Gain in weight
- increased appetite
- Intolerance to cold
- Susceptible to mites
- Reproductive failure

• Diagnosis:
- Analysis of T4 and T3 on blood sample

• Drugs:
- Replace normal thyroid state

1. Levothyroxine (L-thyroxine or T4) - e.g. Soloxine ®

- synthetic L-isomer of T4, long half-life
2. Liothyronine (synthetic salt of T3), short half-life
- used if not reactive to T4
3. Thyroid-stimulating hormone - TSH

B. Hyperthyroidism
- Excessive activity of thyroid
- High level of metabolism
- Increase excessive heat
- Increase nervous activity
- Increased appetite with loss of weight; thirsty
- Increased stool formation
 - Increased HR
- Restlessness
• Treatment:
• Surgery
• Anti-thyroid drugs

• Anti-thyroid drugs:

• Methimazole
- Interfere with incorporation of iodine in molecules of T3 and T4
• Carbimazole
- Used for treatment of feline hyperthyroidism
- Inhibits synthesis of thyroid hormones
• Propanolol – control tachycardia
• Propylthiouracil – destroy thyroid
• Radioactive Iodine – destroy thyroid

____________________________________________________________________________
DRUGS AFFECTING THE ADRENAL GLAND

• The adrenal glands are situated on the cranial surface of the kidneys.
• There are two parts to this endocrine gland, an outer cortex and an inner medulla

Gross Anatomy of the Adrenal Gland

Adrenal Deficiency and Treatment:

A. Addison’s Disease (hypoadrenocorticism)

- caused by atrophy of adrenal gland due to an excessive supplementation
and improper termination of glucocorticoids.
• Signs:
• Weakness
 • Lethargy
• Anorexia
• Vomiting
• Diarrhea
• PU/PD
• Treatment:
•
Deoxycortisone + Prednisone

Mineralocorticoids Corticosteroids

• Fludrocortisone

• Side Effects:
• Hypertension, edema, electrolyte imbalance

B. Hyperadrenocorticism

• Etiology
• Adrenal Tumor
• Excessive administration of corticosteroids
• Signs:
- PU/PD
- Loss of Hairs
- Pendulous abdomen
• Therapy:
 Mitotane – destroy the tumor
 Ketoconazole – block enzyme for steroid synthesis
- Anti-fungal and anti-hyperadrenocorticism.
 Seleginine – inhibit MAO

____________________________________________________________________________
AGENTS FOR THE TREATMENT OF DIABETES MELLITUS

A. Diabetes Mellitus
• Usually exhibited by aged dogs and cats
• Increase in blood glucose level
• Increase in glucose on urine
 • Thirsty, polyuria
• Causes toxicity which will lead to coma
• Common on female obese dog

• Treatment:
• Give insulin injection
- Expression of Insulin: units/ml

 INSULIN
- Maintain glucose level at narrow range
- Primary treatment for type 1 diabetes
- Secreted by β cells of the islets of langerhans
- Respond promptly
- Promote glucose uptake for energy in the body and storage in the liver as glycogen
- Stable at room temperature
- Destroyed by high or low temperature shown by change in color or presence of
precipitate
 Never shake it
 Insulin is protein coated, it is easily digested on GIT.

 Classification of Insulin:

1. Short acting insulin

- IM, IV, SC
- regular insulin crystalline
- semi-lente insulin
- Useful for diabetic ketoacidosis
- Effect: ½ - 2 hrs

2. Intermediate acting insulin

- NDH insulin
- Lente Insulin
- Useful for uncomplicated diabetes
mellitus
- Duration: 6-24 hrs, dogs
- 4- 10 hrs, cats

3. Long acting insulin

- Protamine Zinc
- Ultra-lente insulin
- maintain long lasting blood level
- Duration: 6 -28 hrs, dogs & cats
 A. Hypoglycemia – signs: weakness, ataxia
 Hyperglycemic Agents:
• Diazoxide
- For hypoglycaemia
- MOA: Inhibit B-cells secretion of insulin
• Corticosteroid
• Epinephrine
- For animals with hypoglycemia
- Increase blood glucose level in ewe
- Inhibiting the release of insulin from beta cells of the pancreas.

B. Hyperglycemia – signs: thirsty, polyuria

 Treatment:
• Oral Hypoglycemic Agents
- MOA: Stimulate β cells to secrete insulin
1. Sulfonylureas – tolbutamide, glipizide
- Glipizide (Glucotrol®) – for hyperglycemia
- for type 2 diabetes, not effective on dogs which are dependent on
insulin
 Adverse SE:
• Hypoglycemia, Liver toxicity, GIT upsets

____________________________________________________________________________
AGENTS FOR THE TREATMENT OF HYPOCALCEMIA

1. Regulation of serum calcium

a. Secretions and actions of Parathyroid Hormone (PTH) from parathyroid
gland.
- increase in response to hypocalcemia and decreased in response to
hypercalcemia.

b. Secretion and actions of calcitonin from the thyroid gland.

- increase in response to hypercalcemia and decrease in response to
hypocalcemia.

2. Preparations used to treat hypocalcemia

a. Calcium Gluconate
 Therapeutic Uses:
- For hypocalcemia, for cardiac arrhythmias induced by hyperkalemia
 Adverse effects:
- Hypercalcemia may occur
- Rapid IV injection can cause hypotension, arrhythmias, and cardiac arrest
  Contraindications
- Ventricular fibrillation
- Hypercalcemia
- Renal or cardiac disease
- Concurrent treatment with digitalis

b. Dihydrotachysterol
- MOA: Vitamin D and its analogs increase the synthesis of calcium-
binding proteins through promotion of RNA synthesis and rapidly increase
calcium influx by activating the receptors in the plasma membrane.
 Therapeutic uses:
- Hypocalcemia associated with hypoparathyroidism
 Adverse Effect:
- hypercalcemia, hyperphosphatemia, nephrocalcinosis

SYSTEMIC PHARMACOTHERAPEUTICS OF THE RESPIRATORY SYSTEM

OVERVIEW OF THE RESPIRATORY SYSTEM

1. Anatomy
a. nares (nostrils)
b. nasal cavity and sinuses within the skull
c. pharynx (back of the mouth)
d. larynx (voice box)
e. trachea (windpipe)
f. bronchi (the branches of the trachea going into the lungs)
g. lungs
- divided into left and right lung
- further divided into lobes (sections)
- within the lungs, bronchi divide into smaller bronchioles
- alveolar sac and alveoli, which is supplied by a vast network of microscopic blood
vessels known as capillaries (point of gas exchange)

2. Functions
a. delivers oxygen to the cardiovascular system for distribution to the body and
removes carbon dioxide
- gas transfer occurs in the alveoli of the lungs, where the air-blood barrier is a
thin, permeable membrane
- failure or major dysfunction of gas transfer have serious effects (due to diseases)
b. maintaining acid-base balance
c. acting as a blood reservoir
d. filtering and probably destroying emboli
e. metabolizing some bioactive substances (eg, serotonin, prostaglandins,
corticosteroids, and leukotrienes)
f. activating some substances (eg, angiotensin)
 g. protects its own delicate airways by warming and humidifying inhaled air and by
filtering out particulate material
h. provide for the sense of smell (olfaction)
i. play a role in temperature regulation in panting animals

3. Defense Mechanisms (Factors that determine species and individual susceptibility to

disease)
a. mucociliary “blanket”
- mucous lining of the nasal passages, larynx, trachea, and bronchi
- carry large airborne particles to the pharynx to be swallowed or expectorated
b. alveolar macrophages
- phagocytize small particles that reach the alveoli
c. anatomic structures
d. nonspecific and immunologic mechanisms (both cellular and humoral)
- the macrophage, which phagocytizes invaders and presents them (or at least
their important antigens) to lymphocytes for stimulation of an immune response
(IGA: antibody produce on MM surfaces).
- neutrophil, which often dies in its fight against invaders and must be removed
along with its potentially damaging enzymes
e. other mechanical factors
1. tortuosity of nasal passages
2. presence of hairs, cilia, and mucus
3. the cough and sneeze reflex
4. bronchoconstriction
5. secretory defences
- interferon for antiviral defences
- complement for lysis of invaders
- surfactant lining the alveoli to prevent their collapse and to facilitate macrophage
function
- fibronectin to modulate bacterial attachment, antibodies, and mucus.
*may be manipulated by using various management techniques, vaccines,
antimicrobials, and other agents such as interferons and lymphokines

4. Functions are impaired by:

a. fibrosis or hydro-, chylo-, pneumo-, or hemothorax - processes that oppose
expansion of the lung
b. nasal tumors, bronchiolitis, bronchoconstriction, laryngeal paralysis, or pulmonary
edema - impede the flow of air
c. interstitial pneumonia due to viruses or toxins, pulmonary edema - thicken the air-
blood interface

DRUGS USED TO TREAT RESPIRATORY CONDITIONS

These drugs can be classified in several categories: ANTITUSSIVES,

BRONCHODILATORS, EXPECTORANTS and MUCOLYTICS, DECONGESTANTS,
and RESPIRATORY STIMULANTS. ANTIMICROBIALS and ANTI-IFLAMMATORY
drugs are also used in therapy of many respiratory diseases.

1. Antitussives - drug that inhibits or suppresses the cough reflex

 Mechanism: opiates or opioids that directly suppress the cough center in the medulla
oblongata; antitussive effect does not appear to be related to the binding of traditional
opiate receptors
- indicated to relieve the discomfort associated with non-productive coughing
but are contraindicated when secretion of airway mucus is excessive
- contraindicated with atropine because atropine increases the viscosity of airway
secretions

a. Morphine
- effective antitussive at doses lower than the doses that produce analgesia and
sedation
- not commonly used due to adverse effects and the potential for abuse and
addiction
- poor oral bioavailability due to a significant first-pass effect by the liver

b. Codeine (methylmorphine)
- codeine phosphate and codeine sulfate(tablets, liquids, and syrups)
- analgesic effects that are about one-tenth that of morphine, but its antitussive
potency is about equal to that of morphine
- adverse effects significantly less than those seen with morphine at antitussive
doses
- toxicity (especially in cats) is exhibited as excitement, muscular spasms,
convulsions, respiratory depression, sedation, and constipation; should not be
used after GI tract surgery; potential for addiction and abuse is lower

c. Hydrocodone
- chemically and pharmacologically similar to codeine but more potent
- combined with an anticholinergic drug (homatropine) to discourage abuse by
people
- prescribed for small animals but should be used with caution in cats

d. Dextromethorphan
- not considered an opiate; D-isomer of levorphanol
- L-isomer of levorphanol has addictive and analgesic properties
- recommended anecdotally for the treatment of cough; has short elimination half-
life, rapid clearance, and poor oral bioavailability, making its use as an orally
administered cough suppressant in dogs questionable

e. Butorphanol
- opioid agonist-antagonist
- analgesic and antitussive in dogs; more potent than morphine as an analgesic
and more potent than codeine as an antitussive; may produce considerable
sedation
- due to poor bioavailability, the oral dose in dogs is 10 times the SC dose
- use in cats is controversial

2. Bronchodilators (Systemic Therapy) - widening of the lumen of bronchi and

bronchioles. Airway resistance is decreased, and airflow is increased.
2.1 β-Adrenergic Agonists
 Mechanism: stimulates β2-adrenergic receptors in leads to increased activity of the
enzyme adenylate cyclase, increased cAMP, and relaxation of bronchial smooth
muscle; stimulate β receptors on mast cells decreases the release of inflammatory
mediators from mast cells; β-adrenergic receptor agonists increase mucociliary
clearance in the respiratory tract
- have beneficial effects in the treatment of broncho-constrictive respiratory tract
disease

a. Epinephrine (adrenaline)
- stimulates α and β receptors, resulting in pronounced vasopressive and cardiac
effects in addition to bronchodilation
- emergency treatment of life-threatening bronchoconstriction e.g. anaphylaxis
- unsuitable for long-term use; onset of action is immediate, and the duration of
effect is 1–3 hr

b. Isoproterenol
- potent β-receptor agonist; non-selective for β receptors, cardiac (β1) effects make
it unsuitable for long term use
- inhalation or injection; short duration of action (<1 hr)
- emergency relief of bronchoconstriction in horses; administration is discontinued
when the heart rate doubles

c. Terbutaline
- selective β2-receptor agonist , longer acting than isoproterenol (6–8 hr)
- for cats with feline asthma that experience frequent, severe bronchoconstrictive
episodes while on chronic glucocorticoid therapy (injectable terbutaline
administered at 0.01 mg/kg, SC); increase in the cat's heart rate to 240 bpm and
a 50% decrease in respiratory rate indicates a positive effect; can be given as
chronic oral therapy at 0.625 mg/cat, bid (¼ of a 2.5 mg tablet)
- not be used in cats with hypertrophic cardiomyopathy or glaucoma; may be
used concurrently with methylxanthine bronchodilators

d. Albuterol (salbutamol)
- β2-selective similar to terbutaline and is used systemically in dogs and horses

e. Clenbuterol
- β2-selective, treatment of recurrent airway obstruction in horses; conflicting
result with bronchoconstriction but significantly increase mucociliary transport in
horses with the disorder
- most common adverse effects are tachycardia and muscle tremors
- inhibits uterine contractions; used only during late pregnancy if this effect is
desired for obstetric manipulations
- also a repartitioning agent; it directs nutrients away from adipose tissue and
toward muscle (increased carcass weight, increased ratio of muscle to fat,
increased feed efficiency)
- banned in food animals due to significant health risks of its residue on humans
and should not be used in horses that may be sent to slaughter

2.2 Methylxanthines (Theophylline)

 Mechanism: 1) antagonism of adenosine: adenosine induces bronchoconstriction
in asthmatic animals and antagonizes adenylate cyclase that is responsible
responsible for the synthesis of cAMP, which controls bronchial smooth muscle
relaxation and inhibits the release of inflammatory mediators from mast cells; (2)
inhibit phosphodiesterase: increases intracellular cAMP, inhibit calcium
mobilization in smooth muscle, inhibit prostaglandin production, augment the release
of catecholamines from storage granules, and increase the availability of calcium to
contractile proteins of the heart and diaphragm; (3) decrease the release of
inflammatory mediators from mast cells and increase mucociliary transport
- adverse effects in humans warranted development of locally acting and safer
drugs
- variety of pharmacologic effects on various organ systems, including bronchial
smooth muscle relaxation, CNS stimulation, mild diuresis, and mild cardiac
stimulation

Theophylline
- injectable, aqueous solutions, elixirs, tablets, and capsules
- poorly soluble in water and often results in GI irritation when administered PO
- aminophylline is a theophylline salt that is 78–86% theophylline; more water
soluble and results in less GI irritation;oxytriphylline (a choline salt)
- rapidly and completely absorbed after oral administration
- animals are sensitive to high concentrations, especially after rapid IV
administration
- toxicity may be seen with concentrations <20 μg/mL; cardiac arrhythmias, CNS
excitement, tremors, convulsions, and GI irritation may be seen
- undergoes enterohepatic recirculation, so activated charcoal is recommended if
clinical signs are present, no matter how long after the drug was administered
- metabolism is inhibited by erythromycin, cimetidine, propranolol, enrofloxacin,
and marbofloxacin; concomitant therapy can result in theophylline toxicity;
metabolism is induced by rifampin and phenobarbital, which may necessitate
increasing the dose
- treatment of both cardiac and respiratory diseases in dogs and cats
- used in the management of intrathoracic collapsing trachea and various forms
of canine bronchitis, but it is less effective than glucocorticoids such as
prednisone
- used in horses in the management of recurrent airway obstruction, but efficacy
was often poor and their use has been replaced by β-agonist bronchodilators
- poor bronchodilator in cattle

2.3 Anticholinergics

Mechanism: act by reducing the sensitivity of irritant receptors and by inhibiting

vagally mediated cholinergic smooth muscle tone in the respiratory tract

a. Atropine
- used as a pre-anesthetic, to prevent bradycardia and reduce airway secretions,
and as emergency therapy of dyspneic animals with OP intoxication
 - also for acute bronchodilation in horses, in which a low IV dosage (0.014 mg/kg)
is more effective and less toxic than IV theophylline
- test dose of 0.022 mg/kg may also be used to determine prognosis in horses with
recurrent airway obstruction; if pulmonary function does not improve with a test
dose of atropine, successful management with bronchodilators is unlikely
- even low doses may cause tachycardia, ileus, neurologic derangement, and
blurred vision in horses

b. Glycopyrrolate
- twice as potent as atropine in people; does not cross the blood-brain barrier
- onset of action is slower than atropine, but its duration of effect is longer
- use in horses is sparse, but doses of 2–3 mg can be given IM, bid-tid

2.4 Glucocorticoids

Mechanism: inhibit the release of inflammatory mediators from macrophages and

eosinophils but do not inhibit the release of granules from mast cells; decrease
synthesis of prostaglandins, leukotrienes, and platelet-activating factor, which play
important roles in the pathophysiology of respiratory tract diseases; enhance the
action of adrenergic agonists on α2-receptors in the bronchial smooth muscle
- avoided in infectious respiratory diseases due to immunosuppression
- severe attacks of canine bronchitis, feline asthma, or recurrent airway
obstruction, parenteral injection of usually provides rapid relief
- oral prednisone is usually the drug of choice for chronic therapy in dogs
- cats and horses poorly metabolize prednisone to prednisolone
- cats are somewhat resistant to the effects of glucocorticoids, and dosages of
prednisone of 1.0 mg/kg/day may be necessary for chronic therapy of feline
asthma; 20 mg of methylprednisolone acetate can be administered IM to
asthmatic cats every 3 wk
- emergency treatment of dyspneic cats, a shock dose of an IV glucocorticoid
(prednisone sodium succinate, 5–10 mg/kg; or dexamethasone sodium
phosphate, 1–2 mg/kg) should be used
- prednisolone can be administered to horses, but small tablet sizes available
make it inconvenient, so equine formulations of oral dexamethasone (10 mg/450
kg) are recommended
- injectable formulation of dexamethasone can be given IV to horses with acute
bronchoconstriction and dyspnea

2.5 Cyproheptadine

Mechanism: serotonin antagonist

- may be used as an adjunct to glucocorticoids and bronchodilators to block
bronchoconstriction in chronically asthmatic cats
- serotonin antagonism in the appetite center stimulates appetite, so weight gain
may be a problem
- lethargy, depression, and increased appetite may occur within 24 hr of initiating
therapy

3. Expectorants and Mucolytics (having the ability to break down mucus) - drug that
enhances the expulsion of secretions from the respiratory tract. used to increase the
output of bronchial secretions, enhance the clearance of bronchial exudate, and
promote a productive cough

3.1 Saline Expectorants

Mechanism: stimulate bronchial mucous secretions via a vagally mediated reflex

action on the gastric mucosa

a. ammonium chloride
b. ammonium carbonate
c. potassium iodide
d. calcium iodide
e. ethylene diamine dihydroiodide

Iodine-containing products should not be administered to pregnant, hyperthyroid, or

milk-producing animals

3.2 Volatile Oils

Mechanism: directly increase respiratory tract secretions, efficacy in animals is

unknown

a. eucalyptus oil
b. oil of lemon

3.3 Guaifenesin (glyceryl guaiacolate)

Mechanism: centrally acting muscle relaxant that may also have an expectorant
effect; may stimulate bronchial secretions via vagal pathways
volume and viscosity of bronchial secretions does not change, but particle clearance
from the airways may accelerate
common component of human cold remedies in combination with dextromethorphan

3.4 N-acetylcysteine

Mechanism: mucolytic effect due to exposed sulfhydryl groups on the compound,

which interacts with disulfide bonds on muco-protein; may also increase the levels of
glutathione, which is a scavenger of oxygen free radicals
- helps to break down respiratory mucus and enhance clearance
- available as a 10% solution that can be nebulized
aerosolization of acetylcysteine can cause reflex bronchoconstriction due to irritant
receptor stimulation, so its use should be preceded by bronchodilator therapy

3.5 Dembrexine

Mechanism: effect is through an alteration of the constituents and viscosity of

abnormal respiratory mucus and an improved efficiency of respiratory clearance
mechanisms; also has an antitussive action and enhances concentrations of
antibiotics in lung secretions
- a phenolic benzylamine available in some countries for respiratory disease in
horses
 - supplied as a powder that is sprinkled on the feed at a dosage of 0.33 mg/kg, bid

4. Decongestants - substance that reduces the swelling from the respiratory tract

Mechanism: α-adrenergic agonist drugs cause local vasoconstriction in mucous

membranes, which reduces swelling and edema
- commonly used in people for allergic rhinitis, but they are rarely used for this
purpose in animals
- used topically as nasal decongestants in allergic and viral rhinitis, or systemically
in combination with antihistamines as respiratory tract decongestants
- antihistamines are effective for treatment of allergic rhinitis in people when
combined with the α-adrenergic agonist drugs, but their effectiveness in animals
has not been demonstrated
- topical α-adrenergic agonist drugs act within minutes with few adverse effects
- side effects:
a. extended use may cause rebound hyperemia and mucosal damage
b. systemic administration can result in hypertension, cardiac stimulation, urinary
retention, CNS stimulation, and mydriasis
c. systemic administration of antihistamines often causes sedation

5. Respiratory Stimulants

Doxapram

Mechanism: stimulates the medullary respiratory center and the chemoreceptors of the
carotid artery and aorta to increase tidal volume; other portions of the CNS are
stimulated only when high doses are administered
- used primarily in emergency situations during anesthesia or to decrease the
respiratory depressant effects of opiates and barbiturate
- recommended dosages are 1–5 mg/kg, IV, in dogs and cats, or 1–2 drops under
the tongue of apneic neonates
- adult horses, the dosage is 0.5–1.0 mg/kg, IV, while foals are dosed carefully at
0.02–0.05 mg/kg/min, IV

6. Inhalation Therapy
- latest approach to the management of inflammatory airway disease
- use of nebulizers or metered-dose inhalers (MDI)
- high drug concentrations are delivered directly to the lungs via nebulizers or
metered-dose inhalers (MDI), and systemic side effects are avoided or minimized
- onset of action for inhaled bronchodilators and anti-inflammatory drugs is
substantially shorter
- drugs available in MDI formulations include β 2 agonists, glucocorticoids,
ipratropium bromide, cromolyn sodium, and nedocromil

6.1 β2 agonists

Mechanism: relax smooth muscle and promptly increase airflow

Drugs:
 a. Albuterol (salbutamol)
- short-acting β2 agonist
- medications of choice for treating acute exacerbations of bronchoconstriction
- effective for symptomatic relief but do not control inflammation; monotherapy
may exacerbate airway disease
- tolerance may develop with chronic therapy

b. Salmeterol
- long-acting β2 agonist
- onset of action is slow (15–30 min), but its duration of action is >12 hr
- not recommended for use in acute bronchoconstriction, but daily use with
glucocorticoids provides better control of symptoms
- not available in an MDI in all countries

6.2 Glucocorticoids
- most potent inhaled anti-inflammatory drugs available
- early intervention with inhaled glucocorticoids improves asthma control,
normalizes lung function, and may prevent irreversible airway damage
- potential risk of adverse effects is well balanced by their efficacy in management
of chronic inflammation
- risk of systemic adverse effects, such as suppression of the hypothalamic-
pituitary axis, is less than with oral prednisone therapy

Drugs:
a. fluticasone - considered the most potent formulation with the longest duration of
action
b. beclomethasone
c. flunisolide
d. triamcinolone

6.3 Ipratropium bromide

- a quaternary derivative of atropine that lacks its adverse effects and is available
in an MDI (500 μg/actuation)
- used as an additional reliever medication to reverse bronchoconstriction when
inhaled short-acting β2agonists do not provide enough relief
- anticholinergic action also decreases mucous secretions
- anticholinergic drugs may be useful for treatment of asthmatic cats but there are
no published reports of the use of ipratropium in cats
- has shown efficacy for recurrent airway obstruction in horses
- not well absorbed after inhalation, so it does not cause systemic anticholinergic
effects

6.4 Cromolyn sodium and Nedocromil sodium

Mechanism: chloride-channel blockers that modulate mast cell mediator release and
eosinophil recruitment in humans, the clinical response to these drugs is less
predictable than the response to glucocorticoids
- no published reports of the use of cromolyn or nedocromil in asthmatic cats or
dogs with bronchitis; however, pretreatment with nedocromil sodium aerosols
attenuated viral-induced airway inflammation in Beagle puppies
 - further investigation of these drugs in asthmatic cats seems warranted given the
sensitivity of cats to serotonin released from degranulating mast cells

6.5 Suggested Treatment Regimens

a. Emergency management of dyspnea in cats and dogs2–4 puffs of albuterol

(salbutamol) should be given every 5 min until clinical signs resolve additional
therapy: oxygen and an rapid-acting glucocorticoid, IV

b. Feline asthma and chronic canine bronchitis use albuterol (salbutamol) as

needed for bronchodilation and 220 μg of fluticasone bid moderately affected
animals, a 5-day course of oral prednisone/prednisolone at 1 mg/kg may be
helpful several affected animals may require 1 mg/kg of
prednisone/prednisolone every other day.

c. Horses with recurrent airway obstruction environmental management and a

combination of bronochodilator and anti-flammatory therapy is recommended use
500 μg of albuterol (salbutamol) every 2 hr as needed and fluticasone at 2–4
μg/kg bid.
d. Beclomethasone has also been used 1–3 μg/kg, bid, but it causes more adrenal
suppression in horses than fluticasone at these doses

7. Antimicrobial Therapy
May or may not be necessary in the treatment of airway inflammatory diseases should
be started for cats with tracheo-bronchial cultures suggestive of a true bacterial infection
or those positive for Mycoplasma (isolated from normal dogs but not found in normal
cats)
a. doxycycline
b. azithromycin
c. fluoroquinolones
- secondary bacterial infection from Streptococcus zooepidemicus may
exacerbate inflammatory airway disease in horses
a. penicillin
b. ceftiofur
c. trimethoprim/sulphonamide

Vitamins
 Vitamins are essential organic nutrients, required in small amounts as catalysts for many
transformations and reactions in the body tissues as part of the enzyme complex.
Certain vitamins are also involved in producing blood cells, hormones, genetic material
and chemicals in your nervous system.

 Generally not synthesize by the body. Must be obtained by outside sources like diet,
rumen bacteria & sun.
  Required for growth, maintenance, reproduction and lactation.

 Requirements vary with species, size, growth rate, environment and metabolic function.

 Nutritional problems occur most commonly when animals are fed in excess and in
insufficient amount that will lead to the development of certain disease condition.

Classes: A. Fat Soluble Vitamins - vitamin that can be stored and accumulated in the liver and other fatty
tissues. These are not readily excreted from the body.
Example: Vitamins A, Vitamin D, Vitamin E and Vitamin K
B. Water Soluble Vitamins - vitamins travel in the blood and are stored in limited amounts. These are
readily excreted from the body through urine.
Example: vitamin C, choline, B complex: biotin, thiamin (B1), riboflavin (B2), niacin (B3)
Pantothenic acid (B5), pyridoxine (B6), folic acid/folate (B9) and cyanocobalamin (B12)

While cattle probably have a metabolic requirement for all the known vitamins, dietary sources
of vitamins C, K and the B-vitamin complex are not necessary in all but the very young.
Vitamin K and the B vitamins are synthesized in sufficient amounts by the ruminal microflora,
and vitamin C is synthesized in the tissues of all cattle. However, if rumen function is impaired,
as by starvation, nutrient deficiencies, or excessive levels of antimicrobials, synthesis of
these vitamins may be impaired.

Most commercial dog and cat foods are fortified with vitamins to levels that exceed minimal
requirements. There is no dietary requirement for vitamin C for dogs and cats because they
are able to synthesize it in the liver. Although dogs and cats can synthesize vitamin C in levels
sufficient to prevent signs of deficiency, supplementation may provide additional health
benefits because vitamin C functions as a free radical scavenger and an antioxidant in the
body.

There is also no dietary requirement for vitamin K for dogs and cats because intestinal
bacteria are able to synthesize it. However, any condition that alters the intestinal microflora,
such as antibiotic therapy, may result in vitamin K deficiency. NRC recommends 0.33 mg of
vitamins K/1,000 kcal ME in puppies, 0.45 mg of vitamin K/1,000 kcal ME in adult dogs, and
0.25 mg of vitamin K/1,000 kcal ME in kittens and adult cats.

Deficiencies of fat-soluble vitamins (A, D, and E in dogs; A, D, E, and K in cats) and some of
the 11 water-soluble B-complex vitamins have been produced experimentally. Water-soluble
vitamins are usually readily excreted if excess amounts are consumed and are thought to be far
less likely to cause toxicity or adverse effects when ingested in mega doses. Vitamin B12 is the
only water-soluble vitamin stored in the liver, and dogs may have a 2- to 5-yr depot. Fat-
soluble vitamins (except for vitamin K in cats) are stored to an appreciable extent in the
body, and when vitamins A and D are ingested in large amounts (10–100 times daily
requirement) over a period of months, toxic reactions may be seen.

Vitamin A
Occurs in animal tissues as retinol. It is an antioxidant synthesized from beta-carotene.
Essential for healthy eyes, skin, hair, mucous membranes and bone growth.

Function: development healthy skin and nerve tissue. Aids in building up resistance to
infection. Functions in eyesight and bone formation. ALL ANIMALS require a source of Vitamin
A. It is important in the ration of pregnant females.

Deficiency signs: retarded growth in the young, the development of a peculiar condition
around the eyes known as xerophthalmia, lacrimation, keratinization of the cornea, night
blindness and reproductive disorders characterized by abnormal epithelial cell growth,
susceptibility to pneumonia, abscesses of the sublingual gland, incoordination, impaired
reproduction, capricious appetite, and progressive weakness. Deficiency may develop if dried,
poor-quality roughage is fed for a prolonged period.

Sources: whole milk, carotene, animal body oils (cod fish and tuna), legume forages and can
be synthetically produced.

Trade and Other Names: Retinol, Aquasol-A, Vitamin AD, and Vitamins A and D

Indications and Clinical Uses: Used as a supplement for animals with deficiency.

Adverse Reactions and Side Effects

Excessive doses can cause bone or joint pain and dermatitis.

Drug Interactions
No drug interactions have been reported in animals.

Patient Monitoring and Laboratory Tests

Monitor for signs of toxicity if high doses are used.

Stability and Storage

Store protected from light at room temperature. Vitamin A, like other fat-soluble vitamins, is
insoluble in water but soluble in oils. It is subject to oxidation and should be kept in a tightly
sealed container.

Regulatory Information
Because of low risk of harmful residues in animals intended for food, no withdrawal time is
suggested.

Vitamin D

A steroid vitamin found as ergocalciferol (D2) and cholecalciferol (D3), both activated in
plants/animal skin by UV radiation. D3 primarily used as precursor for calcium regulation.

Function: is essential for the proper utilization of calcium and phosphorus to produce normal,
healthy bones. It increases calcium absorption from the GIT and helps control calcium
deposition in the bone; essential for development and maintenance of strong bone and teeth.

Deficiency: reduced bone marrow, stiff and swollen joints, stiffness of gait, irritability, and
reduced serum calcium and phosphorus. A deficiency will not develop if sun-cured hay is
consumed or the horse is exposed to sunlight. Deficiency in young could result to develop
rickets and for adult can develop a condition known as osteomalacia, w/c leads to weak, soft
bones and thin shelled eggs for chickens.

Excessive intake leads to nausea, headache, excessive urination, high blood pressure,
deposition of calcium in soft tissues leads to calcification of the kidney tubules, heart valves and
BV walls.

Sources: Whole milk, sun-cured hays, forage crops, fish liver oils, irradiated yeast.

Vitamin E

Active form is d-alpha tocopherol

Function: normal reproduction, good antioxidant that protects cell membranes and other fat-
soluble parts of the body from oxidation, play a protective role in the prevention of oxidation of
vitamin A and polyunsaturated fatty acids and stimulates immune response. It is often a
component of omega fatty-acid formulations used in oral dietary supplements.

Deficiency signs: poor growth, "crazy chick" disease, muscular dystrophy/ "white muscle"
disease in ruminants and sheep, "stiff lamb" disease (affects the nerves and muscles/ white
muscle disease in sheep and calves), male sterility, fetal resorption.

Sources: synthetic for poultry and swine, cereal grains and wheat germ oil, green forages,
protein concentrates, oil seeds (peanut and soybean oil).

Indications and Clinical Uses

Vitamin E is used as supplement and as treatment of some immune-mediated dermatoses and
hepatobiliary disorders. Vitamin E has been used as an oral treatment for discoid lupus in dogs;
however, efficacy for many skin diseases has been questioned.

Adverse Reactions and Side Effects

Vitamin E at high doses can cause coagulopathies. Coagulopathies are caused by a decrease
in vitamin K dependent coagulation factors.

Contraindications and Precautions

Use carefully in animals with coagulopathies.
Drug Interactions
Vitamin E may interact with anticoagulants. Vitamin E may exacerbate the anticoagulant effect
of warfarin.

Patient Monitoring and Laboratory Tests

Monitor for bleeding in animals treated with high doses.

Stability and Storage

Vitamin E, like other fat-soluble vitamins, is insoluble in water but soluble in oils. Store in a
tightly sealed container, protected from light, and at room temperature.

Regulatory Information
Because of low risk of harmful residues in animals intended for food, no withdrawal time is
suggested.

Trade and Other Names: Tocopherol, Alpha-tocopherol, Aquasol E, and generic brands

Vitamin K

Function: needed for the production of vitamin K dependent clotting factor in the liver. It
is a cofactor used to synthesize coagulation factors in the liver (factors II, VII, IX, and X). It is
essential for the formation of clotting factors by the liver: prothrombin, factor VII (proconvertin),
factor IX, and Factor X, all of which are important in blood coagulation. Menadione is the most
active form.

Deficiency causes blood clotting retardation it will lead to bruising and excessive bleeding.
Treatment for anticoagulant (warfarin) rodenticide poisoning.

Adverse Reactions and Side Effects

To avoid anaphylactic reactions, do not administer IV. Reactions from intramuscular injection,
such as hematoma, may occur in animals with coagulopathies.

Drug Interactions
Some drugs, such as cephalosporins, may decrease vitamin K–dependent clotting factors.

Patient Monitoring and Laboratory Tests

Monitoring bleeding times in patients is essential for accurate dosing of vitamin K-1
preparations. When treating long-acting rodenticide poisoning, periodic monitoring of the
bleeding times is suggested.

Stability and Storage

Vitamin K, like other fat-soluble vitamins, is insoluble in water but soluble in oils. Store in a
tightly sealed container, protected from light, and at room temperature.

Regulatory Information
No meat or milk withdrawal time is necessary.

Trade and Other Names: AquaMEPHYTON (injection), Mephyton (tablets),

Veta-K1 (capsules), Veda-K1 (oral and injectable), Vitamin K, Phylloquinone, and
Phytomenadione

Sources: green leafy forages, fish meal, liver, soybeans, rumen and intestinal synthesis, and
the synthetic compounds.

Vitamin C (Ascorbic acid)

Function: essential for the formation of collagen, helps to maintain skin integrity, absorb iron
from the gut and heal wounds, important in immune functions and has an effect on the
metabolism of calcium in the body.

Deficiency signs: none demonstrated in livestock. Human deficiency: scurvy (swollen and
painful joints and bleeding gums) and brittleness of bones.

Too much vitamin C can cause diarrhea and kidney stones and, as it increases iron uptake,
taking too much can also lead to iron overload.

Sources: citrus fruits, tomatoes, leafy vegetables and potatoes.

Thiamine (Vitamin B1)

- part of coenzyme needed for cellular respiration involved in final metabolism of

carbohydrates and many amino acids; essential for muscle and nervous system function, it
converts glucose to energy of the cell in the form of ATP.

Thiamine Deficiency: causes lesions of the central and peripheral nervous systems, weakens
the muscle (general wasting/beri-beri), heart and causes peripheral vasodilation, and GIT
disturbances. Polioencephalomalacia in ruminants, anorexia, weight loss, incoordination,
decreased blood thiamine, and increased blood pyruvate.

-under normal circumstances, the natural diet plus synthesis by microorganisms in the gut
probably meet the need for thiamine. However, needs may be increased by stress.

Large dose may cause headaches, insomnia, weakness and skin problems.

Sources: raw, whole grains and especially their seed coats and embryos; fresh green forage;
and yeast, milk and rumen synthesis.

Preparation: Thiamine hydrochloride, Vitamin B1 powder

Niacin (nicotinic acid)

Function: part of coenzymes needed for cellular respiration involved in the oxidation of fat
and protein. It is in the form of nicotinamide adenine dinucleotide (NAD) and nicotinamide
adenine dinucleotide phosphate (NADP) transport of hydrogen ions as NADP, NADPH;
electron transport, fatty acid, cholesterol synthesis. Niacin is involved in fat metabolism and
helps maintain the condition of your skin.

-early stages of niacin deficiency, simple physiologic changes such as muscle weakness and
poor glandular secretion may occur, but in severe niacin deficiency, actual tissue death
ensues.
-deficiency causes intense irritation and inflammation of the mucous membranes of the
mouth and other portions of the gastrointestinal tract, pellagra (dermatitis), anemia, skin
lesions

Sources: rice polishings, yeast, rice bran

Riboflavin (Vitamin B2)

Function: necessary for normal embryo development, important in the metabolism of amino
acids and carbohydrates. Normally combines in the tissues with phosphoric acid to form two
coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) involved
in cellular respiration.

Deficiency signs: poor reproduction characterized by small litters and deformed young (cleft
palate and club-footed) curly toe paralysis in chicks, digestive disturbances, general
weakness and eye abnormalities, catarrhal conjunctivitis in one or both eyes, accompanied by
photophobia and lacrimation. Impaired vision or blindness. Deficiency causes severe dermatitis,
vomiting, diarrhea, muscle spasticity, muscle weakness, coma, and decline in body
temperature, and then death. -although natural feeds plus synthesis within the gut normally
provide adequate riboflavin, limited evidence indicates an occasional deficiency when the diet is
of poor quality

Sources: milk and dairy by-products, yeast, green forages, well cured hay (especially alfalfa),
whole grains, wheat bran and synthetic riboflavin rumen synthesis.

Vitamin B12

- A coenzyme for reducing ribonucleotides to synthesize deoxyribonucleotides (DNA), a step

that is necessary in the replication of genes; essential for myelin synthesis. Coenzyme in
metabolic reactions, maturation of erythrocytes and important in nerve function.
- Deficiency causes pernicious anemia and demyelination of the large nerve fibers of the
spinal cord. Pernicious anemia and nerve disorders, macrocytic anemia, megaloblastic
anemia.

Folic Acid (Pteroylglutamic Acid)

-its most important use in the body is in the synthesis of purines and thymine, which are
required for DNA formation; coenzyme for hemoglobin formation. Also called vitamin B9 is
essential for the normal formation of the red blood cells, protein metabolism, growth and
cell division. Recently shown as very important for pregnant females to avoid birth
defects

Deficiency leads to the development of macrocytic anemia, megaloblastic anemia.

Sources: yeast, alfalfa meal, full-fat soybeans

Pyridoxine (Vitamin B6)

- Coenzyme in the transamination process for the formation of amino acids essential in the
synthesis of hormones and hemoglobin. It is also essential for energy production and normal
brain function. Essential for breaking down protein
-Dietary lack can cause dermatitis, decreased rate of growth, development of fatty liver, anemia,
and evidence of mental deterioration. Skin problems, esp. in and around the mouth and
neurological problems.

Pantothenic Acid (d-panthenol)

- Part of coenzyme involved in the oxidation of both carbohydrates and fats; aids in the
formation of hormones and neurotransmitters.
- Deficiency can cause retarded growth, failure of reproduction, graying of the hair, dermatitis,
fatty liver, and hemorrhagic adrenocortical necrosis. In poultry includes dermatitis and lesions
on the mouth and feet.

Biotin is a coenzyme needed for amino acid, carbohydrate and fatty acid metabolism. Biotin
deficiency in poultry includes dermatitis on foot and around eyes and beak. In sows includes
foot lesions and toe cracks.

Choline is part of coenzyme needed for metabolism

 Minerals
 Essential inorganic nutrients, required in small amounts.
 Most of the major minerals and trace elements are widely distributed in the herbage and
the other feeds eaten by the animal, and occur in sufficient quantities to meet animal
requirements.
 Required for growth, maintenance, reproduction and lactation.
 Provide rigidity and strength to skeletal structures, exoskeletons
 primary components of bones and teeth
 constituents of organic compounds such as proteins and lipids
 enzyme activators (coenzymes)
 osmoregulation, acid/base balance
 effect irritability of muscles and nerves

Macrominerals: required in large amounts.

• Calcium Ca • Sodium Na
• Phosphorous P • Chlorine Cl
• Potassium K • Magnesium Mg
• Sulfur S

Calcium

Dietary Ca is primarily absorbed from the intestine by active transport.

Function: major component of bones and teeth and essential in blood coagulation,
nerve and muscle function and milk and egg production. It is present in the body mainly in
the form of calcium phosphate in the bone. Excess quantities of calcium ions in extracellular
fluid can cause the heart to stop in systole and can act as a mental depressant

Deficiency signs: retarded growth, deformed bones in young animals (rickets), and soft
shelled eggs in poultry, osteoporosis in older animals and milk fever commonly seen in
swine. Low levels of calcium can cause spontaneous discharge of nerve fibers, resulting in
tetany. -essential for all stages of growth, gestation, and lactation
-these levels are adequate for maximal growth but they do not allow for maximal bone
mineralization. Maximal bone ash and strength can be achieved including 0.10-0.15% additional
calcium and phosphorus in the diet.

Clinical use: to prevent posterior paralysis in heavy milking sows.

-most of the phosphorus in cereal grains and oilseed meals is in the form of phytic acid
(organically bound phosphorus) and is poorly available, whereas phosphorus in protein sources
of animal origin, such as meat meal, meat and bone meal, and fish meal, is in organic form and
is highly available (pigs)
Phosphorus and Calcium supplement: monocalcium or dicalcium phosphate, defluorinated
phosphate, and steamed bone meal are excellent sources. Ground limestone is an excellent
source of calcium.

Sources: milk, oyster shells and limestone.

Phosphorus

- Phosphate is the major anion of intracellular fluid. Phosphates have the ability to combine
reversibly with many coenzyme systems and with multiple other compounds that are necessary
for the operation of metabolic processes.

Function: component of ADP, ATP, P-lipids, DNA, RNA, Phosphates serve as pH buffer
systems

Deficiency signs: similar to calcium deficiency, lack of appetite, poor reproduction and
unthrifty appearance.

Sources: dicalcium phosphate, bone meal, and low fluorine phosphates.

Sulfur

Function: the most important mineral for the proper development and maintenance of ruminal
microflora, because it may limit the synthesis of both cystiene and methionine which are
essential for the synthesis of microbial body-proteins.

Symptoms of sulfur deficiency are not very specific and are not easy to diagnose. Lower dry
matter intake, loss of weight, slow growth of wool in sheep, and sometimes death, are the
symptoms of a deficiency of this element. There is also a reduction in the microflora population
resulting in poor utilization of cellulose and poor protein synthesis

Fluorine

-Fluorine does not seem to be a necessary element for metabolism, but the presence of a small
quantity of fluorine in the body during the period of life when the teeth are being formed
subsequently protects against caries.

-Excessive intake of fluorine causes fluorosis, which manifests in its mild state by mottled teeth
and in its more severe state by enlarged bones.

Sodium Chloride

- These minerals are provided with common salts, which contain 40% sodium and 60% chloride.
Considered together because of a close biochemical relationship and are provided as common
salt (NaCl). Salt is needed to maintain a healthy appetite and to promote water consumption
naturally.
Function: play many roles including the maintenance of fluid balance, acid-base balance
normal flow of nerve impulses and muscular movements.

Deficiency signs: poor condition and depressed appetite, rapid loss of wt and a decline in milk
production. Animals show uncoordinated movements, a stiff walk, they shiver and are weak.

Sources: salt supplements and injectable products.

Potassium

- Practical diets contain ample amounts of these minerals from the grain and protein sources,
and supplemental sources are not needed.

Function: 3rd most abundant mineral element in the body. It is a major intracellular cation and
is involved in the osmotic regulation of tissue and in acid-base balance.

Deficiency signs: nonspecific and unlikely under most conditions but may have decreased feed
consumption and efficiency.

Sources: roughages. Grains are less than roughages

Magnesium

Used: Magnesium oxide supplementation has been used to prevent cannibalism, but controlled
studies do not support this practice.

Function: essential cofactor of many intercellular matabolic enzyme pathways, maintains

electrical potentials across nerve endings.

Magnesium
-Magnesium is about one sixth as plentiful in cells as potassium
-Magnesium is required particularly to carbohydrate metabolism
-Increased extracellular concentration of magnesium depresses nervous system activity as
well as skeletal muscle contraction
-Low magnesium concentration causes increased irritability of the nervous system, peripheral
vasodilation, and cardiac arrhythmias, especially after acute myocardial infarction

Deficiency in ruminants lead to a condition known as Grass tetany. Symptoms resemble those
of milk fever but the animal show more acute excitability, they stagger and have convulsions.

Sources: mineral supplements and ordinary feeds.

 A few elements are present in the body in such small quantities that they are called trace
elements. The amounts of these elements in foods are also usually minute. Yet without any one
of them, a specific deficiency syndrome is likely to develop. Three of the most important are
iodine, zinc, and fluorine.

Microminerals: required in small amounts.

Iodine (I) Manganese (Mn)

Copper (Cu) Molybedenum (Mo)

Iron (Fe) Zinc (Zn)

Selenium (Se) Cobalt (Co)

Copper (Cu)

Function: should be present in animal tissues for iron to be properly utilized, hemoglobin
formation and synthesis of keratin for fur and wool growth.
- The action of copper at high levels appears independent of, and additive to, the growth
stimulating effect of antibiotics.
- Copper sulfate at high levels in the diet results in very dark-colored feces.

Deficiency signs: poor pigmentation of feathers, stringy wool, sway back lambs, lack of
muscle coordination and anemia. Fertility is also affected, a lack of sexual activity is common,
and abortions and retained placentas often result.

Sources: forages and copper salts.

Manganese (Mn)

Function: Fetal development, udder development, milk production and skeleton development.
- Essential for normal reproduction and growth, the quantitative requirement for manganese is
not well defined. Manganese at 2-4 mg/kg in the diet is adequate for growth. Manganese toxicity
has been reported to produce albinism in some Siamese cats; a deficiency of manganese in
other species results in bone dyscrasia.

Iron

Essential part of blood and muscle. Function of iron in the body is in relation to the formation of
hemoglobin. Iron is absolutely essential for both the transport of oxygen to the tissues and the
operation of oxidative systems within the tissue cells.
Deficiency signs: seldom occurs in older animals, nutritional anemia associated with labored
breathing, excessive tiredness and pale skin

Because the amount of iron in milk is very low in suckling pigs it should receive supplemental
iron, preferably by IM injection of 100-200 mg in the form of iron dextran, iron dextrin, or
gleptoferron during the first 3 days of life.

Zinc

Zinc is an integral part of many enzymes, one of the most important of which is carbonic
anhydrase, lactic dehydrogenase and some peptidases. It is an important trace mineral with
many biological functions.

Function: Eliminates cholesterol deposits; aids in absorption of B-Vitamins, manufacture of

enzymes and insulin, and metabolism of carbohydrates; essential for growth; aids healing
essential for proper function of prostate gland; prevents prostate cancer and sterility; keeps hair
glossy and smooth.

Clinical used: Grain-soybean meal diets must contain supplemental zinc to prevent
parakeratosis
- Higher levels of zinc may be needed when dietary calcium is excessive.

Pharmacological levels: (1,500-3000 mg/kg) as zinc oxide have consistently been found to
increased pig performance during the post-weaning period.

Deficiency causes parakeratosis. This disease is manifested by slow growth, skin lesions and
hair loss.

Other symptoms of zinc deficiency in ruminants are inflamed membranes of the nose and
mouth, stiffness of joints, smaller testicles, and lowered libido. In horse can result to cracked
and brittle hooves. In poultry can result to poor feathering and short bones.

Cobalt (Co)

Function: Cobalt - is present in the vitamin B12 molecule, required as a nutrient for the
microorganisms in ruminants and thereby aids in rumen synthesis of Vitamin B 12. Because
swine cannot manufacture B12 from cobalt, the diets are supplemental with vitamin B12 instead.

Deficiency signs: lack of appetite, loss of weight, rough hair coat, anemia, decreased milk and
wool production and death in extreme cases.

Sources: legume forages and salt containing cobalt

Iodine

Function: stimulate the thyroid gland to secrete thyroxine necessary for carbohydrate
metabolism.
- Iodine is essential for the formation of thyroxine and triiodothyronine, the two thyroid hormones
that are essential for maintenance of normal metabolic rates in all cells of the body.
- The thyroid gland uses iodine to produce thyroxine, which effects cell activity and metabolic
rate.
- Stabilized iodized salt contains 0.007% iodine; when it is sufficient levels to meet the salt
requirement.

In calves: deficiency symptoms are stunted growth, enlarged thyroid gland, apathy, blindness,
hairlessness and a harsh coat

In cows: retained placentas and also impairs reproductive performance

In bulls: decline in sexual vigor and deterioration in semen quality.

Selenium

- The selenium content of soils and ultimately, crops is quite variable

Function: Making special proteins, called antioxidant enzymes, which play a role in preventing
cell damage by preventing the breakdown of oxygen at a cellular level (oxidation) when toxic
products including hydrogen peroxide and hydroxyl radicals are produced. These oxidizing
agents are powerful tissue poisons. And stimulatory role in the immune response and thereby
improving disease resistance

Selenium deficiency may cause white muscle disease, muscular dystrophy, reproductive
problems, and impaired immunity.

Deficiencies of Se and Vit. E can cause sudden death of young due to disease.

On the other hand, chronic selenium toxicity can cause partial or total hair loss (alopecia) in the
mane or tail, erosion of the long bones, and cracking and sloughing hooves. In acute toxicity,
also known as "blind staggers," the horse may go into severe distress or sudden death may
occur.

Chromium
- The trace mineral which is cofactor with insulin
 Drugs acting on the urinary system
Bacterial Urinary Tract Infections (UTI)

Bacterial UTI typically result from normal skin and GI tract flora ascending the urinary tract
and overcoming the normal urinary tract defenses that prevent colonization. It is the most common
infectious disease of dogs, affecting 14% of all dogs during their lifetime. It is less common in cats, and
occurs only infrequently in large animals. Young cats with feline lower urinary tract disease usually have
bacteriologically sterile urine. However, >50% of geriatric cats with urinary tract disease have a bacterial
UTI. Approximately two-thirds of those cats also have renal failure. Bacterial UTI in ruminants are
associated with catheterization or parturition in females and as both a cause and consequence of
urolithiasis in males. In horses, UTI are uncommon and typically associated with bladder paralysis,
urolithiasis, or urethral damage.

Unlike humans, veterinary patients are often asymptomatic, and UTI may be an incidental finding. In
intact male dogs, UTI frequently extends to the prostate gland. Due to the blood-prostate barrier, it is
difficult to eradicate bacteria from the prostate, and the urinary tract may be re-infected following
appropriate treatment, causing a systemic bacteremia, infecting the rest of the reproductive tract, or
causing an abscess within the prostate.

Antimicrobial Therapy
Ideal properties: Possess appropriate antimicrobial activity, achieve effective concentrations in urine,
easy for clients to administer, few adverse effects, and relatively inexpensive. Conduct urine culture and
sensitivity results are known, the bacterial MIC can be compared to the mean urinary concentration of
the drug and an appropriate antimicrobial chosen.

Amoxicillin and ampicillin

Bactericidal, relatively nontoxic and spectrum of antibacterial activity > penicillin G. Excellent
activity against staphylococci, streptococci, enterococci, and Proteus. Pseudomoncs and Enterobacter are
resistant. In dogs and cats amoxicillin is better absorbed from the GIT than ampicillin. Absorption of
ampicillin is affected by feeding, therapeutic success is easier to achieve with amoxicillin. They are weak
acids with a low Vd and do not achieve therapeutic concentrations in prostatic fluid of dogs or accessory
sex glands of large animals.

Amoxicillin+clavulanic acid

Increased spectrum against g- bacteria, clavulanic acid irreversibly binds to β-lactamases,

allowing amoxicillin to interact with bacterial pathogen. Excellent bactericidal activity against β-
lactamase producing staphylococci, E coli, and Klebsiella. Pseudomonas and Enterobacter are resistant.

Cefadroxil and cephalexin

1st generation oral cephalosporins. Cefadroxil is veterinary-labeled product while cephalexin is a

human formulation. Bactericidal and acidic drugs with a low Vd and are relatively nontoxic. Have >
stability to β-lactamases than PCN, > activity against staphylococci and gram-negative bacteria, excellent
activity against Staphylococcus, Streptococcus, E coli, Proteus, and Klebsiella. Pseudomonas,
enterococci, and Enterobacter are resistant. Adverse effects: vomiting and other GI signs.

Cefovecin

3rd generation cephalosporin approved for the treatment of UTI due to E coli and Proteus. SC
dosing, therapeutic concentrations are achieved for 2 weeks a treatment choice for fractious animals.

Cefpodoxime

Oral 3rd generation cephalosporin approved for use in dogs for skin infections e.g. wounds and
abscesses and extra-label use for the treatment of canine UTI. Has relatively long half-life in dogs, dosed
once daily.

Ceftiofur

Injectable cephalosporin approved for respiratory disease in horses and cattle and for treatment
of canine UTI caused by E coli and Proteus. It is metabolized to desfuroylceftiofur, with equivalent
activity to ceftiofur against E coli, but < active against Staphylococcus and has variable activity
against Proteus.

Fluroquinolones: Enrofloxacin, orbifloxacin, difloxacin, and marbofloxacin

 Fluoroquinolones are approved to treat UTI in dogs and cats. It is bactericidal, amphoteric drugs
with acidic and basic properties, very lipid soluble at physiologic pH and have a high Vd. Excellent
activity against staphylococci and g- bacteria, effective against Pseudomonas, variable activity against
streptococci and enterococci. Indicated for UTI in intact male dogs, have excellent penetration into the
prostate gland and abscesses.

Tetracyclines

Bacteriostatic and amphoteric drugs with a high Vd. Broad-spectrum, but because of plasmid-
mediated resistance, susceptibility is variable in staphylococci, enterococci, Enterobacter, E
coli, Klebsiella, and Proteus. In most tissues Pseudomonas are resistant. Excreted unchanged in urine, so
high urinary concentrations may result in therapeutic efficacy.

Doxycycline

Very lipid-soluble tetracycline, better tolerated in cats and reaches therapeutic concentrations in
the prostate, useful for some UTI.

Trimethoprim + sulfonamides

Combination of 2 very different drugs that act synergistically on different steps in the bacterial
folic acid pathway. Bactericidal and broad-spectrum agents, it inhibit both g+ and g- bacteria.
Potentiated activity against Streptococcus , Staphylococcus , Salmonella , Shigella, Vibrio, Hemophilus,
Pasteurella, E. coli and Pneumocystis carinii. Pseudomonas, Klebsiella, Proteus, Clostridium, and
Leptospira are most often highly resistant, as are rickettsiae. Widely used in the prevention and
treatment of local and systemic infections in all species.

Controlling Urine pH

The ideal urine pH should be 7–7.5 in dogs or 6.3–6.6 in cats. If the urine pH remains below
these values after diet modification, give potassium citrate at 80–150 mg/kg/day, PO, divided bid-tid to
increase the pH. Ammonium chloride (200 mg/kg/day, PO, divided tid) and dl-methionine (1,000–1,500
mg/cat/day, PO) are the urinary acidifiers of choice. Chronic urine acidification, and ensuing acidosis,
can be harmful and should not be instituted without complete evaluation of the animal.

Urinary Incontinence
Estrogen derivative diethylstilbestrol (DES) resembles estradiol. Inexpensive, first choice for
treating urinary incontinence in female dogs. Given orally, t-1/2 of 24 hours due to enterohepatic
recirculation and reaches peak plasma concentrations in 1 hour in dogs. Estrogen sensitize the urethral
sphincter to α-adrenergic stimulation, synergistic with α-agonists. It is given daily for 7–10 days and then
reduced to once weekly dosing, to avoid toxicity. Adverse effect: bone marrow suppression typified by
early thrombocytopenia and potentially fatal aplastic anemia, hematopoietic toxicity in cats, alopecia,
cystic ovaries, cystic endometrial hyperplasia, pyometra, prolonged estrus, and infertility.

Alpha agonists (phenylpropanolamine (PPA), ephedrine, pseudoephedrine, and phenylephrine)

act directly on smooth muscle receptors to increase urethral tone and maximal urethral closure
pressure. More clinically effective than DES, but the action is short lived, requiring 2-3x daily dose. PPA is
the most effective and produces fewer cardiovascular side effects. Adverse effects: excitability,
restlessness, hypertension, and anorexia.

In male dogs, testosterone injections are used to treat urinary incontinence but are generally
less effective than estrogen therapy in female dogs.

Urine Retention
Urine retention and a distended bladder are usually caused by hypocontractility of the bladder
or by urethral obstruction. Prolonged bladder distention leads to breakdown of the tight junctions
between detrusor muscle cells of the bladder, which prevents normal depolarization and contraction of
the detrusor muscles.

Phenoxybenzamine, an irreversible adrenergic antagonist may be indicated when manual

expression or voluntary voiding is nonproductive because of excessive urethral sphincter tone, it is often
seen in cats after relief of obstruction. Dosage for dogs or cats: 0.25 mg/kg, PO, bid.

Diazepam is a benzodiazepine sedative and a central muscle relaxant. Sedative does is sufficient
to allow for urethral sphincter relaxation. Dose: dogs, 0.2 mg/kg, PO, tid; cats, 0.5 mg/kg, IV. Diazepam
given PO may cause idiosyncratic acute hepatic necrosis in cats.

Bethanechol chloride is indicated for detrusor hyporeflexia or bladder atony. This cholinergic
agonist stimulates the initiation of detrusor muscle contraction. Dose: dogs, 5–25 mg/dog, PO, tid; cats,
2.5–7.5 mg/cat, PO, tid.

Fluid Therapy
Cardiac function, intravascular volume, and vascular tone integrity and patency are critical to
normal circulation. An abnormality in one or more of these components of circulation leads to
compensatory changes to maintain perfusion. The hemodynamic and cellular changes that develop as a
result of these abnormalities are called shock. As shock progresses, oxygen and substrate delivery to
the tissues becomes insufficient to meet energy requirements for cellular maintenance and repair. If
shock progresses and cellular energy demands cannot be met, the ensuing organ failure leads to death.
Early recognition of the type and stage of shock is vital to establishing a successful fluid therapy plan.

3 categories of shock: hypovolemic, cardiogenic, and distributive. Hypovolemic shock - blood

volume deficit ≥ 15%. Cardiogenic - heart fails as a pump. Causes: pulmonary emboli, cardiac
tamponade, valvular insufficiency, cardiomyopathy, and cardiac arrhythmias. Distributive shock - caused
by maldistribution of blood flow away from the central circulation as a result of peripheral vasodilation
or by systemic inflammatory diseases such as sepsis and anaphylaxis. Different types of shock may have
different hemodynamic profiles during the early and middle stages. Frequently, more than one type of
shock is present, with hypovolemia likely to play a role in each form. Rapid and aggressive fluid
resuscitation yields the best outcome. Effective fluid resuscitation plan depends on the understanding
the dynamics of fluid movement in different body fluid compartments.
 Major fluid compartments: intravascular, interstitial, and intracellular. Fluid movement from the
intravascular to interstitial and intracellular compartments occurs in the capillaries. A capillary
“membrane,” (capillary endothelial cells + sub-endothelial cell matrix) separates the capillary
intravascular compartment from the interstitial fluid compartment. The capillary “membrane” is freely
permeable to water and small molecular weight particles such as ions, glucose, acetate, lactate,
gluconate, and bicarbonate and gases such as oxygen and carbon dioxide diffuse freely through the
capillary endothelial cell to enter or exit the intravascular compartment. The interstitial compartment is
the space between the capillaries and the cell. Fluids support the matrix and cells within the interstitial
space. The intracellular compartment is separated from the interstitial space by a cell membrane. Cell
membrane is freely permeable to water but not small or large molecular-weight particles. Particle
movement between the interstitium and the cell occur through transport mechanism e.g. channel, ion
pump or carrier mediated mechanisms.

Fluids are in a constant state of flux across the capillary endothelial membrane, through the
interstitium, and into and out of the cell. The amount of fluid that moves across the capillary
“membrane” depends on a number of factors, including capillary colloid oncotic pressure (COP),
hydrostatic pressure, and permeability. The natural particles in blood that create COP are proteins
(globulins, fibrinogen and albumin). The hydrostatic pressure within the capillary (pressure forcing fluid
outward on the capillary “membrane”) is generated by the blood pressure and cardiac output. Fluid
moves into the interstitium when intravascular hydrostatic pressure is > COP, membrane pore size
increases, or intravascular COP < interstitial COP.

Fluid Resuscitation Plan

In hypovolemic shock, compensatory neuroendocrine responses are initiated for restoring

blood volume and meeting metabolic demands that occur during acutely decreased cardiac output
states, increasing ATP demands. When perfusion becomes compromised in spite of these mechanisms,
de-compensatory shock ensues. Adequate fluid resuscitation plan is necessary to optimize survival: l)
determine where the fluid deficit lies, 2) select specific fluids for the patient, 3) determine resuscitation
endpoints, and 4) determine the appropriate resuscitation technique.

DETERMINATION OF THE FLUID DEFICIT

Fluid deficit from the intravascular space is manifested by poor perfusion and inadequate tissue
oxygenation. This results in a lower vessel wall tension and stimulation of the baroreceptors and
sympathetic system. Clinical changes in heart rate, pulse intensity, capillary refill time, mucous
membrane color, level of consciousness, and rectal temperature are seen. Changes of these parameters
are used clinically to detect intravascular volume deficits. Most animals with an intravascular deficit also
have concurrent extra-vascular deficits.

Fluid deficit in the interstitial and intracellular spaces causes clinical signs of dehydration. 4–
5%: semi-dry oral mm, normal skin turgor, and eyes maintaining normal moisture. 6–7%: dry oral mm,
mild loss of skin turgor, and eyes still moist. 8–10%: dry mucous membranes, considerable loss of skin
turgor, eyes retracted, acute weight loss, and weak rapid pulse. 12%: very dry oral mm, complete loss of
skin turgor, severe retraction of the eyes, dull eyes, possible alteration of consciousness, acute weight
loss, and thready weak pulse.
 Two misleading clinical situations in the estimation of the degree of dehydration: 1) Chronically
emaciated animals may have metabolized the fat from around the eyes and the collagen in the skin,
resulting in poor skin turgor and sunken eyes despite normal hydration. 2) Animals with rapid fluid loss
into a 3rd body fluid space (space where local interstitial and intravascular fluid leak) have rapid fluid
shifts from the intravascular compartments into these spaces before clinical evidence of interstitial fluid
loss is seen. Both situations require evaluation of mucous membrane and eye moisture, PCV, and total
solids before dehydration can be estimated.

SELECTION OF FLUIDS

Fluids administered must concentrate within the body fluid compartment where the volume
deficit lies. Crystalloids are water-based solutions with small-molecular-weight particles, freely
permeable to the capillary and cell membrane, though as interstitial and intracellular volume
replacement fluid. Colloids are water-based solutions with a high molecular weight, too large to freely
pass across the capillary membrane, though as intravascular volume replacement fluid.

Crystalloids

Crystalloids consist primarily of electrolytes and buffers. When the sodium concentration of the
solution is equivalent to that of the cell, the solution is called isotonic e.g. LRS and 0.9% saline.
Intravascular administration of isotonic crystalloids will result in interstitial volume replacement and
minimal intracellular fluid accumulation. Over 75% of the isotonic crystalloid given IV can move into the
interstitial space within 1 hour in a normal animal.
Hypotonic crystalloids sodium concentration is less than the cell e.g. 5% dextrose in water and
0.45% saline, this will result in intracellular water accumulation and are not used as resuscitation fluids.
Balanced crystalloids e.g. LRS, Normosol-R, Plasmalyte-A contain molecules that act as buffers
e.g. acetate, gluconate, and lactate, they are converted to bicarbonate and raise the pH of the solution
to normal blood pH. It is used initially for specific clinical problems e.g. hyponatremia, hypernatremia,
hypercalcemia, hypochloremic metabolic alkalosis, head trauma, and oliguric renal failure. Normal saline
(0.9%) is isotonic but not balanced.
The particular crystalloid to administer is determined by the measured sodium and potassium
concentrations and by the osmolality of both the animal's serum and the fluid to be administered.
Most clinical problems will benefit from the use of balanced isotonic crystalloids as part of the
resuscitation fluid plan.

Sodium
When serum sodium estimations are normal, a balanced isotonic electrolyte solution can be
used for volume replacement. Serum sodium levels that are moderately to severely decreased (<130
mEq/L) or moderately to severely increased (>170 mEq/L) cause serum osmolality changes and result in
neurologic abnormalities. Do not to increase or decrease the sodium concentration too quickly. Sodium
concentrations should not be altered by >0.5 mEq/L/hr or 8–12 mEq/L/day, this allow neurons to adjust
over time and avoids cerebral edema or dehydration.
Animals with hyponatremia, should be replaced with isotonic saline (0.9%). Increased serum
Na+ values most commonly reflect a loss of solute-free water. The free water can then be replaced, if
necessary, using 2.5% dextrose in half-strength lactated Ringer's, 2.5% dextrose in half-strength saline,
0.45% saline, or 5% dextrose in water when hypernatremia persists. This must be done carefully, and
the Na+ concentration lowered slowly. Desmopressin may be required if hypernatremia persists after
appropriate fluid therapy, especially when the patient has hyposthenuria or head injury.
Potassium
When serum potassium estimates are normal, a balanced electrolyte solution can be used.
Hypokalemia can be difficult to recognize clinically. Few clinical situations warrant K+ supplementation
beyond the content of LRS or Plasmalyte-A, during initial volume replacement. Once the animal has
been stabilized, KCl should be added slowly to the fluids, administered at ≤0.5 mEq/kg/hr. Administer
KCl more rapidly when severe hyperkalemia (<2 mEq/L) is associated with respiratory distress from
paresis of the diaphragm or generalized lower motor paresis or paralysis. More commonly, 20–40 mEq
of KCl is added to 1 L of balanced isotonic crystalloids administered as maintenance fluids. Obtain serum
k+ values before supplementation and monitored closely during continued therapy.
In animals with hyperkalemia caused by oliguric renal failure, heat stroke, Addison's disease and
massive muscle breakdown require potassium-free solutions, such as 0.9% saline. After volume
replacement and fluid diuresis resolve the hyperkalemia, a balanced electrolyte solution should be
used. These solutions have a normal pH and promote potassium excretion.

Osmolality
Osmolality is defined as the number of solute particles per unit of solvent. Serum osmolality can
be calculated using the following formula:

Normal serum osmolality is 290–310 mOsm/L. Fluids that do not contribute significantly to
serum osmolality should be used for volume replacement.
Hyperosmotic crystalloids e.g. hypertonic saline, Normosol-M® with 5% dextrose, D5LRS or any
isotonic fluid that has glucose added. Except for hypertonic saline, the hyperosmolar glucose-containing
solutions are meant to be maintenance solutions used in animals in which fluids are not shifting rapidly
from the interstitium to the vascular compartment. They are usually not used as interstitial volume
replacement (dehydration) solutions.
Hypertonic saline e.g. 3%, 7%, or 7.5% provides a supra-normal concentration of sodium. The
effect is to rapidly draw water from the interstitial space into the intravascular space, rapidly expanding
the intravascular volume. It decreases cellular swelling and improve myocardial contractility. If the
patient has concurrent interstitial fluid deficits (dehydration) or a disease that results in free water loss
e.g. hyperthermia, diabetes, administration of hypertonic saline could result in severe hyperosmolality
with neurologic complications. Hypertonic crystalloid solution will leak into the interstitium <1 hour,
combining this with a colloid will offset the interstitial edema.

Colloids
When colloids is required, it must be decided whether a natural colloid e.g. plasma, albumin, or
whole blood or a synthetic colloid e.g. dextran, hydroxyethyl starch (HES), and stroma-free hemoglobin
is to be used. If the animal requires RBC, clotting factors, anti-thrombin III, or albumin, choose blood
products. But if the goal is to rapidly improve perfusion in an animal with adequate RBC, a synthetic
colloid can rapidly increase intravascular volume.
Dextrans are polysaccharides composed of linear glucose residues. They are produced by the
enzyme dextran sucrase during growth of various strains of Leuconostoc bacteria in media containing
sucrose. Dextrans are isotonic and can be stored at room temperature. Dextran is broken down
completely to CO2 and H2O by dextranase present in spleen, liver, lung, kidney, brain, and muscle at a
rate approaching 70 mg/kg every 24 hr. In normal dogs, dextran 70 increases plasma volume 1.38 times
(138%) the volume infused.
Dextran 70 increase buccal mucosal bleeding time and partial thromboplastin time and decrease
Von Willebrand's factor antigen and factor VIII coagulant activity, without clinical bleeding. Dextran
copolymerizes with the fibrin monomer, destabilizing clot formation. It elevates blood glucose during
dextran metabolism. It changes the total solids that does not reflect actual protein content and may
interfere with blood cross-matching. Moderate to life-threatening reactions in dogs have been rare.
Hydroxyethyl starch (HES/hetastarch) is polymeric molecule made from a waxy species of either
maize or sorghum and is composed primarily of amylopectin (98%). When hetastarch is infused at 25
mL/kg in healthy dogs, the initial increase in plasma volume is 1.37 times (137%) the volume infused.
Intravascular persistence is significantly > dextran 70, with 38% of hetastarch remaining compared with
19% of dextran 24 hour after infusion. Administration by constant rate infusion provide a constant
supply of larger molecular weight particles, maintaining and augmenting plasma COP and intravascular
volume in animals with albumin loss or increased capillary permeability.
Hetastarch favors retention of intravascular fluid and prevents washout of interstitial proteins.
In hypo-oncotic situations, it has a great advantage over other colloids because the larger molecules
remain intravascular, limiting pulmonary fluid flux. It is nontoxic and non-allergenic in dosages up to 100
mL/kg in dogs. Many cats have a moderate reaction e.g. nausea and occasional vomiting with rapid
infusion. However, when hetastarch is given slowly (over 5–15 min), this side effect is minimal.
Fluid Selection

Interstitial and intracellular volume deficits (dehydration) are replaced by the administration of
crystalloids. Intravascular volume (perfusion) deficits can also be replaced with crystalloids alone.
However, when large quantities of isotonic crystalloids are rapidly administered IV, there is an
immediate increase in intravascular hydrostatic pressure, a decrease in intravascular COP, and
extravasation of large fluid quantities into the interstitial spaces (edema). By administering colloids +
crystalloids during fluid resuscitation, less total fluid volume is required (crystalloids is reduced by 40–
60%), there is less tendency toward fluid overload, and resuscitation times are shorter.
Many conditions can increase capillary permeability and cause systemic inflammation e.g. CPV
diarrhea, pancreatitis, septic shock, massive trauma, heat stroke, cold exposure, burns, snake bite, and
systemic neoplasia. Hetastarch or stroma-free hemoglobin are the colloids of choice for intravascular
volume resuscitation when there is increased capillary permeability and loss of albumin through the
capillary membrane. Using crystalloids alone in animals that require large volumes for resuscitation or
that have increased capillary permeability will eventually result in significant interstitial edema.
Many of these animals also have 3 rd space fluid losses, most likely due to significant regional
inflammation, that result in massive fluid requirements and make it difficult to predict the volume
required for maintaining fluid balance.
DETERMINATION OF RESUSCITATION ENDPOINTS

There are no “standard” formulas for crystalloid or colloid infusion that will guarantee complete
volume resuscitation. Variables such as renal function, presence of a third body fluid space, brain injury,
lung injury, heart disease or failure, or closed cavity hemorrhage require that fluid resuscitation rate and
volumes be individualized for the patient. The endpoints (goal) typically reflect perfusion status, and
include heart rate, blood pressure, CVP (5–8 cm H 20), mm color (pink), CRT (2 sec), and pulse intensity.
An elevated blood lactate to <2 mmol/dL supports adequate tissue oxygenation. More advanced
endpoints: central venous oxygen saturation >70%, and a urine output of at least 1–2 mL/kg/hour.
Shock depletes cellular energy stores, causing cellular and organ dysfunction. Restoring the
circulation to “normal,” with normal oxygenation and perfusion parameters, may not be enough to
allow sufficient ATP production for repair as well as maintenance. When a patient is suspected of having
a disease process related to systemic inflammatory response syndrome such as vasodilation, increased
capillary permeability, or depressed cardiac output, resuscitation endpoints are chosen for supra-normal
resuscitation. The goal is to deliver oxygen and glucose to the cells in higher than normal
concentrations to promote sufficient energy production for both repair and maintenance of the cells.

Maintenance Fluid Plan

Hetastarch or Oxyglobin® can be administered as a constant rate infusion of 0.5–1 mL/kg/h in
dogs, or 0.25–1.0 mL/kg/h in cats, adjust the dose to maintain an adequate mean arterial pressure and
CVP. Reduce the amount of crystalloids administered with colloids by 40–60%.
The maintenance fluid plan: 1) replacement of IF volume (rehydration), 2) maintenance fluids
(for normal homeostasis), and 3) replacement of ongoing losses.
The volume of rehydration fluids required is determined by reassessing hydration parameters
after resuscitation, using the following formula:

Rehydration volume = % dehydration × kg × total body water (0.6). Administer over 4–12 hour
with replacement fluids such as Normosol-R®or Plasmalyte-A®.

Maintenance fluid requirements (larger animals: 40 mL/kg/day; smaller animals: 60 mL/kg/day)

is added to the rehydration volume. With prolonged parenteral fluid administration, usually over a
course of days, serum sodium may increase, and maintenance fluids e.g. 0.45% saline or 5% dextrose in
water may be needed to replace free water deficits.

Ongoing or increased fluid losses vary substantially and must be estimated and replaced.
Ongoing losses can be estimated by measuring urine and fecal output, nasogastric tube suction or
vomitus volume. Insensible losses, which can be increased with fever, or higher metabolic demands,
can increase the maintenance rate by 15–20 mL/kg/day.

There are situations, however, when supra-normal resuscitation can be detrimental. Increased
vessel wall tension can dislodge a life-saving clot in the vasculature of a traumatized animal, resulting in
significant hemorrhage. Brain and lung edema or hemorrhage can be worsened by aggressive and
sudden increases in hydrostatic pressure. Hypotensive resuscitation provides endpoints that are at the
lower limit of normal. The goal is to administer the smallest volume of fluids possible to successfully
resuscitate the intravascular compartment, while minimizing extravasation of fluids into the interstitium
(especially brain or lungs), titrating the amount of preload to minimize excess fluid load to a potentially
disabled heart, and reducing the probability of dislodging clots. Small-volume resuscitation techniques
should be used to reach hypotensive resuscitation endpoints.
DETERMINATION OF APPROPRIATE RESUSCITATION TECHNIQUE

Dogs in hypovolemic shock that require supra-normal endpoint values can benefit from large-
volume resuscitation techniques. Initial infusion: 20–50 mL/kg of balanced isotonic crystalloids,
followed by 5–15 mL/kg of hetastarch or dextran 70. When stroma-free hemoglobin is selected as the
colloid, the dosage is 5 mL/kg. Additional colloids can be administered using small-volume intravascular
resuscitation techniques if perfusion has not improved to the desired supra-normal endpoints after the
initial large volume dose of fluids.
Whole blood products can be administered by large-volume resuscitation techniques in
catastrophic hemorrhagic situations. However, initial administration of stroma-free hemoglobin will
allow for a slower administration of whole blood and less chance for transfusion reaction from rapid
whole blood administration.
Small-volume resuscitation techniques are recommended in the hypovolemic cat and any dog
with closed cavity hemorrhage e.g. head injury, pulmonary contusions or edema, cardiogenic shock, or
oliguric renal failure. Initial infusion: balanced isotonic crystalloids (10–15 mL/kg, dogs; 5–10 mL/kg,
cats). Either hetastarch or dextran 70 is then administered (5 mL/kg in dogs; 2–5 mL/kg in cats) over 1–5
min. The perfusion parameters are reassessed, and the initial bolus dose repeated as needed until the
endpoint of resuscitation is reached. When stroma-free hemoglobin is used as the colloid in dogs, the
dosage is 2–5 mL/kg. Stroma-free hemoglobin is not approved for use in cats, but it has been used
successfully at a dosage of 1–5 mL/cat (0.25–l.0 mL/kg) given slowly over 5 min.
Hypothermia, especially in cats, can significantly limit the cardiovascular response to fluid
resuscitation. Active external warming with circulating water blankets should be done once fluid
resuscitation has been initiated. Aggressive volume administration without active warming of
hypothermic cats can result in pulmonary edema despite continued hypotension.

Assessment of Resuscitation Efforts

When an adequate amount of fluids has been administered and reasonable resuscitation
endpoints have not been reached, several causes should be considered: inadequate volume
administration, ongoing hemorrhage, third body fluid spacing, heart disease, severe vasodilation,
vasoconstriction, hypoglycemia, hypokalemia, arrhythmias, or brain pathology. These variables should
be rapidly assessed and corrected. If a central venous pressure (CVP) line is available, it should be
checked to see if CVP is near the endpoints. If not, or if no CVP is available, a fluid challenge can be
given. This typically consists of a bolus (10–15 mL/kg) of crystalloids and a bolus (5 mL/kg) of hetastarch.
If the perfusion parameters improve with this challenge, then the likely cause of the nonresponsive
shock is inadequate volume, and colloids are titrated to reach the desired endpoints.
If fluid volume appears adequate and the patient is still hypotensive, vasopressors can be used.
Oxyglobin® can be given at the dosages listed above if it has not yet been used. If stroma-free
hemoglobin fails to increase the blood pressure, then dopamine is administered at 5–15 mg/kg/min as a
constant rate of infusion. This is weaned once the blood pressure has stabilized.

Monitoring Fluid Therapy

All animals receiving fluids should have a physical examination, including assessment of
hydration and body weight, at least twice per day. Overzealous administration of crystalloids can
manifest as increased respiratory rate and effort, crackles or wheezes upon auscultation, serous
discharge from the nares, chemosis, jugular vein distention or pulsations, shivering, edema,
hypertension (>140–150 mm Hg systolic), increased CVP (>8–10 cm H 2O), significant increase in body
weight (>12–15%), and rapid and/or dramatic decrease in PCV and total solids. In patients with urinary
catheters, urine output can be monitored and compared with fluid administration volumes. Monitoring
pulmonary capillary wedge pressures and cardiac output variables may be helpful in selected animals.
When parenteral fluid administration is to be discontinued, the animal should be able to
maintain hydration by voluntary drinking and eating or tolerate enteral supplementation (through a
feeding tube) or subcutaneous fluid administration. Tapering the volume infused IV over 24–48 hours
allows the renal medulla to reestablish the osmotic gradient and helps prevent excessive fluid loss
through diuresis.
Drugs Acting on the Gastrointestinal Tract
I. INTRODUCTION

Gastrointestinal disease or dysfunction is a common clinical problem in veterinary practice,

and accurate diagnosis is essential for effective therapy. Nonspecific therapy includes
correction of fluid and electrolyte imbalance, ensuring rest of the gastrointestinal tract to allow
healing, diet modification, and nutritional support.

A. CORRECTION OF FLUID AND ELECTROLYTE BALANCE

Prolonged vomiting or diarrhea produces dehydration, electrolyte loss, and disturbances in acid-
base balance that must be corrected by parenteral fluid therapy.

1. With severe vomiting, loss of sodium, chloride, potassium, hydrogen, and bicarbonate leads
to a metabolic acidosis.
2. If the pylorus is obstructed, duodenal bicarbonate is retained and the loss of gastric chloride,
potassium, and hydrogen leads to a metabolic alkalosis.

B. ENSURING REST OF THE GASTROINTESTINAL TRACT

Fasting for 24-48 hours is often effective in small animals suffering acute gastrointestinal
disturbances of vomiting and diarrhea. Fasting permits decreased gastric secretion and
increased time for mucosal healing (enterocyte regeneration) and results in fewer osmotically
active particles in the gut lumen.

C. DIET MODIFICATION

1. Bland diet. A bland, easily digested, low-fat diet such as 1 part boiled hamburger or
chicken with 4 parts of cooked rice should be offered after the 24-48 hour fast. Limiting
dietary fat is important because unabsorbed fatty acids are hydroxylated by colonic bacteria,
resulting in decreased absorption and osmotic retention of water, which increases fecal
water loss.

2. Lactose-free diet. Milk products should be eliminated from the diet if the animal suffers
from lactose intolerance or loss of mucosal brush border lactase as a result of invasive
enteritis.

3. Insoluble fiber. Fiber absorbs water and normalizes intestinal transit. Increasing the
insoluble fiber content of the diet is useful when treating constipation, chronic diarrhea, or
idiopathic colitis.

4. Gluten-free diet. Gluten-sensitive enteropathy has been observed in Irish setters. Clinical
improvement occurs with a cereal-free diet.
D. PROVISION OF NUTRITIONAL SUPPORT

Calories, protein, and vitamins should be supplied to maintain a positive energy and protein
balance. For example, the addition of medium-chain triglycerides to the diet of dogs with
intestinal lymphangiectasis provides calories because medium-chain triglycerides are absorbed
in the portal vasculature, not the lymphatics.

E. ALLEVIATION OF VISCERAL PAIN

1. Mild visceral pain may be alleviated by alimentary protectives or absorbants (e.g.,

aluminum or magnesium silicates, kaolin-pectin, bismuth salts). These agents may reduce
pain by reducing gastric acidity, coating inflamed mucosae, or absorbing noxious agents in
the lumen.

2. Severe visceral pain is alleviated by morphine or other µ-receptor opioid agonists that
inhibit pain reflexes at spinal and supraspinal sites within the CNS.
a. Opiates
(1) Morphine is administered intramuscularly in dogs and cats.
(a) Morphine’s duration of action is 6 hours in dogs and cats.
(b) High doses of morphine produce excitement in cats and horses.
(2) Butorphanol, an opioid agonist/antagonist similar to pentazocine, is administered
intravenously to horses for the control of colic pain. Its duration of action is 1-2
hours.
b. NSAIDs. Flunixin meglumine, dipyrone, or phenylbutazone are given intravenously
or intramuscularly to horses for the control of colic pain. Their duration of action is 1-8
hours, depending on the cause and severity of the pain.
c. Sedatives. Xylazine and detomidine produce sedation and analgesia in horses
suffering from colic. Their duration of action is 1-4 hours following intravenous or
intramuscular administration.

II. APPETITE STIMULANTS

Inappetence or anorexia is common in disease states, and the resultant malnutrition can
delay recovery and may exacerbate the underlying disease.

A. ENTERAL ALIMENTATION WITH LIQUID SUPPLEMENTS is useful in small animals –

delivered thru NGT

B. SMALL AMOUNTS OF PALATABLE FOOD should be offered at frequent intervals.

Warming the food may enhance appetite in carnivores.

C. VARIOUS DRUGS are used for the short-term stimulation of appetite.

1. Benzodiazepines (e.g., diazepam, oxazepam)

 a. Mechanism of action. Benzodiazepines increase GABA activity. The resultant anti-
serotonergic effect depresses the satiety center in the hypothalamus.
b. Therapeutic uses. Benzodiazepines are used for short-term stimulation of appetite
most frequently in cats, and less frequently in horses, dogs, and goats. After two to
three treatments, the effect of benzodiazepines on appetite is diminished.
c. Administration
(1) Diazepam is administered orally, intravenously, or intramuscularly once or twice
daily.
(2) Oxazepam is administered orally once daily.
d. Adverse effects include sedation and ataxia.

2. Cyproheptadine
a. Mechamism of action. Cyproheptadine acts as a serotonin and a histamine 1 (H1)
antagonist. It suppresses the satiety center in the hypothalamus.
b. Therapeutic use. Cyproheptadine stimulates appetite in cats and in humans, but not in
dogs.
c. Adverse effects. CNS excitement and marked aggressive behavior occur in 20% of
the cats administered cyproheptadine.

3. Glucocorticoids (e.g., prednisolone, dexamethasone)

a. Mechanism of action. The mechanism by which glucocorticoids stimulate appetite is
unknown. Stimulation of appetite may result from glucocorticoid-induced euphoria,
which in part results from the anti-inflammatory action of glucocorticoids.
b. Administration
(1) Small animals. Prednisolone or dexamethasone is administered intramuscularly
once daily or every other day.
(2) Large animals. Prednisolone or dexamethasone is administered intramuscularly
once daily.
c. Adverse effects
(1) Immunosuppression may delay recovery from the underlying disease
(2) Gastric ulcers may result from decreased gastric mucus production

4. Bitters are plant-derived compounds containing alkaloids, such as nux vomica.

a. Mechanism of action. Bitters stimulate salivation.
b. Therapeutic uses. The effect of bitters on appetite is questionable and they are seldom
used in this capacity; however, bitters are a component of tonics for appetite stimulation
in large animals.

5. Zinc is essential for the sensation of taste; therefore, zinc supplements may increase
appetite in zinc-deficient animals.

III. ANTACIDS

Reduced the hydrochloric acid content of the stomach by inhibiting acid secretion,
neutralizing acid, or coating and protecting the gastric mucosa.

A. ACID SECRETION INHIBITORS

1. Histamine2 (H2)-blockers e.g., cimetidine, ranitidine
a. Chemistry. H2-blockers are structurally similar to histamine.
b. Mechanism of action. H2 receptors stimulates the proton (acid) pump in parietal cells.
H2-blockers competitively block the H2 receptors on parietal cells, thereby decreasing
hydrochloric acid secretion.
c. Pharmacokinetics
(1) Absorption. H2-blockers are well absorbed by the gastrointestinal tract.
(2) Fate. They are widely distributed in body tissues with only 10%-20% bound to
plasma proteins. Up to 50% of the drug is metabolized by the liver.
(3) Excretion. Metabolites and the parent drug are excreted by the kidneys.
d. Therapeutic uses
(1) H2-blockers are used in dogs and cats with gastritis, gastric ulcers, esophagitis,
and gastrinomas.
(2) They are used to prevent destruction of replacement pancreatic enzymes by gastric
acid in dogs and cats with exocrine pancreatic disease.
(3) H2-blockers are used in horses with gastritis and gastric erosions.
e. Administration. Low doses are effective in dogs and cats because gastric hydrochloric
acid secretion is intermittent in carnivores.
(1) Cimetidine is administered orally, intramuscularly, or intravenously every 6-8 hours.
(2) Ranitidine is administered orally, intramuscularly, or intravenously every 12 hours.
f. Drug interactions. Cimetidine inhibits hepatic microsomal enzymes and may slow the
metabolism of drugs requiring hepatic metabolism (e.g., phenytoin, Phenobarbital).

2. Proton pump inhibitors e.g. omeprazole

a. Mechanism of action. Proton pump inhibitors reduce hydrogen secretion by inhibiting
the H+-K+ -ATPase pump on the luminal membrane of parietal cells. Binding to
adenosine triphosphatase (ATPase) is irreversible; therefore, cells must synthesize new
ATPase to restore HCl secretion.
b. Pharmacokinetics
(1) Absorption. Omeprazole is absorbed by the gastrointestinal tract.
(2) Fate
(a) Omeprazole enters gastric parietal cells, where it is protonated and trapped in
the acidic intracellular fluid. The protonated drug is the active form; thus,
ATPase in non-acid-producing cells is not affected.
(b) Because the drug slowly accumulates in parietal cells with repeated doses,
pharmacologic action is not correlated with plasma half-life.
(c) Omeprazole is metabolized by hepatic microsomal enzymes.
(3) Excretion. Omeprazole is excreted by the kidneys.
c. Therapeutic uses
(1) Omeprazole is used in dogs, cats, and horses to limit acid secretion in gastritis,
gastric ulcers, and esophagitis.
(2) It is used in the prevention and treatment of gastric erosions by NSAIDs.
d. Administration. Omeprazole is administered orally once daily.
e. Drug interactions. Omeprazole inhibits hepatic microsomal metabolism and may prolong
the actions of drugs requiring hepatic metabolism.

B. LOCALLY ACTING ANTACIDS

1. Preparations
a. Aluminum salts (e.g., aluminum hydroxide, aluminum carbonate, aluminum silicate) are
the most common preparations.
 b. Magnesium salts [e.g., magnesium oxide (milk of magnesia), magnesium trisilicate] have
a laxative effect in addition to their potent antacid activity.
2. Mechanism of action. Locally acting antacids neutralize gastric hydrochloric acid and inhibit
pepsin secretion.
a. Most are colloidal compounds that have a protective or adsorbent action on the mucosa
of the gastrointestinal tract following oral administration.
b. A mucosal cytoprotective action results from their ability to stimulate mucosal
prostaglandins (PGs).
3. Therapeutic uses
a. Locally acting antacids are administered as adjuncts to H2-blockers or proton pump
inhibitors in the treatment of gastric and duodenal ulcers.
b. They are used in nonspecific therapy of acute gastritis and gastroenteritis in small
animals.
c. Because aluminum salts increase fecal excretion of phosphate, they are used in the
treatment of hyperphosphatemia.
4. Adverse effects
a. Rebound HCl secretion. Aluminum salts do not raise the gastric pH above 4, so
there is no rebound hydrochloric acid secretion. Rebound hydrochloric acid secretion
may be a problem with magnesium salts, which can raise the gastric pH to 7.
b. Constipation. Aluminum salts increase fecal phosphate excretion, which tends to
produce constipation. Combination with laxative magnesium salts offsets this effect.
c. Impaired absorption of other drugs. Locally acting antacids may impair absorption of
other oral drugs for at least 2 hours.
5. Contraindications. Approximately 20% of the magnesium ions in magnesium salts are
absorbed and excreted by the kidneys. Impaired excretion may result in CNS depression;
therefore, magnesium salts should be avoided in the presence of renal disease.

C. GASTRIC PROTECTIVES

1. Preparations. Sucralfate is a sucrose sulfate-aluminum hydroxide complex.

2. Mechanism of action. Sucralfate polymerizes to a viscous gel at a pH less than 4. The
sulfate groups bind to proteins in ulcerated tissue and protect ulcers from acid and
pepsin.
3. Therapeutic use. Sucralfate is used in the treatment of gastric and duodenal ulcers in
dogs, cats, and foals.
4. Adverse effects. Constipation may occur with long-term therapy.

IV. DIGESTANTS

A. PANCRELIPASE

1. Chemistry. Pancrelipase consists of pancreatic enzymes (e.g., lipase, amylase, trypsin)

derived from porcine pancreatic tissue.
2. Therapeutic uses. Pancrelipase treats exocrine pancreatic insufficiency in dogs, cats, and
birds.
3. Administration
a. Pancrelipase powder preparations are administered orally, mixed with food.
b. Use of enteric-coated preparations or pretreatment with H 2-blockers prevents
pancrelipase destruction by gastric hydrochloric acid.
B. BILE ACIDS AND SALTS

1. Preparations
a. Bile acids (e.g., cholic acid, chenodeoxycholic acid)
b. Semisynthetic bile acid derivatives (e.g., dehydrocholic acid)
c. Sodium salts of bile acids
2. Mechanism of action
a. Bile acids stimulate choleresis (bile flow).
b. Bile salts emulsify dietary lipids, enhancing the digestion of fats and the absorption of
long-chain fatty acids.
3. Therapeutic uses. Bile salts and acids treat various maldigestion syndromes characterized
by steatorrhea e.g. pancreatitis, bile salt deficiency.

V. EMETICS

A. GENERAL CONSIDERATIONS

1. Vomiting reflex
a. Vomiting is triggered by the vomiting center, which receives central or peripheral
stimulation from the:
(1) Chemoreceptor trigger zone (via dopaminergic input)
(2) Gastrointestinal tract (via vagal and sympathetic afferent pathways)
(3) Vestibular apparatus (via cholinergic and histaminergic afferent pathways)
b. The vomiting reflex is developed in carnivores, primates, and swine. Horses, ruminants,
rodents, and rabbits do not possess this protective reflex and should never be
administered emetics.
2. Indications. Emetics are used in conscious dogs and cats to induce elimination of
noncorrosive poisons or prior to the induction of general anesthesia. They generally remove
less than 80% of the stomach contents.

B. CENTRALLY ACTING EMETICS

1. Apomorphine
a. Mechanism of action. Apomorphine induces vomiting by stimulating the chemoreceptor
trigger zone. It is not effective in swine.
b. Administration
(1) Intravenous administration of a low dose (e.g., 20 µg/lb) induces vomiting in dogs
within 1 minute. If vomiting does not occur, a second dose should not be given,
because the vomiting center is depressed following the initial stimulation of the
chemoreceptor trigger zone.
(2) Intramuscular, subcutaneous, or conjunctival administration is also effective.
c. Adverse effects. Apomorphine produces excitement in cats and should not be used in
this species.

2. Xylazine is an α2-adrenergic agonist that induces vomiting in cats following intravenous or

intramuscular administration. Vomiting occurs within 2-5 minutes and may be followed by
mild sedation for 30-90 minutes.
C. PERIPHERALLY ACTING EMETICS

1. Preparations
a. Sodium chloride is administered as crystals or a saturated solution.
b. Syrup of ipecac contains emetine alkaloid.
c. Copper sulfate (1%), zinc sulfate (1%), and H2O2 (3%, 1-2 ml/kg) are infrequently
used.
2. Mechanism of action. Peripherally acting emetics stimulate sympathetic and vagal afferent
receptors in the pharynx and stomach.
3. Therapeutic uses
a. H2O2 is commonly used by pet owners to induce vomiting in dogs following ingestion of
poisons.
b. Syrup of ipecac may induce vomiting within 15-30 minutes, but its action is more reliable
in humans than in dogs and cats.
4. Administration. Peripherally acting emetics are administered orally as a single dose, which
should not be repeated even if vomiting does not occur.

VI. ANTI-EMETICS

A. GENERAL CONSIDERATIONS

1. Prolonged vomiting leads to electrolyte and acid-base imbalances and dehydration.

2. Diagnosis and treatment of the primary cause of vomiting should precede administration of
the antiemetic. The most frequent causes of prolonged vomiting are:
a. Inflammation, distention, or the presence of chemicals or drugs in the gastrointestinal
tract
b. Labyrinthine disease or motion sickness
c. Inflammation, edema, or tumors of the CNS
d. Stimulation of the chemoreceptor trigger zone by drugs, bacterial endotoxins, or toxic
endogenous metabolites e.g. urea.

B. ANTIDOPAMINERGIC AGENTS

1. Phenothiazines e.g. acepromazine, chlorpromazine, promazine, prochlorperazine

a. Mechanisms of action
(1) Phenothiazines block dopamine receptors in the chemoreceptor trigger zone. At
high doses, they block dopamine receptors in the vomiting center as well.
(2) They have weak anticholinergic and antihistaminic actions.
b. Pharmacokinetics
(1) Absorption. Phenothiazines are well absorbed orally. They undergo significant first
pass metabolism.
(2) Fate. Phenothiazines are widely distributed to the tissues. They are metabolized by
the liver, primarily to glucuronide or sulfate conjugates.
(3) Excretion. Phenothiazines are excreted by the kidneys.
c. Therapeutic uses. Phenothiazines are broad-spectrum antiemetics used in dogs and
cats; however, their effectiveness is limited in arresting vomiting caused by severe
inflammation of the gastrointestinal tract or the inner ear.
d. Administration. Phenothiazines are administered orally or intramuscularly every 6 hours.
e. Adverse effects
 (1) Hypotension and bradycardia result from α-adrenergic blockade. α-Adrenergic
agonists (e.g., norepinephrine, phenylephrine) may be used to counteract these
effects, but epinephrine should not be used because of the possibility of epinephrine
reversal.
(2) Mild sedation may occur.

2. Metoclopramide
a. Mechanism of action
(1) Central action results from blockade of dopamine receptors in the chemoreceptor
trigger zone.
(2) Peripheral action results from stimulation of stomach and duodenum motility via
increased smooth muscle sensitivity to acetylcholine (ACh). Motility prevents the
gastric atony required for vomiting.
b. Pharmacokinetics
(1) Absorption by the gastrointestinal tract is rapid. Peak plasma levels are reached
within 2 hours.
(2) Fate. First-pass metabolism results in 50%-70% bioavailability. The drug is widely
distributed to the tissues, including those of the CNS.
(3) Excretion. Unchanged drug (25%) and conjugated metabolites (75%) are excreted
in the urine.
c. Therapeutic uses
(1) Metoclopramide is used to control severe vomiting in dogs and cats.
(2) It is used in the treatment of gastric motility disorders and esophageal reflux in dogs,
cats, and foals.
d. Administration
(1) As an antiemetic, metoclopramide is administered orally, subcutaneously, or
intramuscularly every 8 hours. It can also be administered by slow intravenous
infusion.
(2) In the treatment of gastric motility disorders and esophageal reflux, it should be
administered 30 minutes prior to feeding.
e. Adverse effects
(1) Gastric hemorrhage or perforation may occur in animals with gastric outlet
obstruction.
(2) Behavioral changes (e.g., excitement, disorientation) may occur in dogs and cats.

3. Butyrophenones (e.g., droperidol, haloperidol). These agents are neuroleptic drugs with
centrally acting antiemetic effects.
a. Mechanism of action. Butyrophenones create a long-acting blockade of dopaminergic
neurons in the chemoreceptor trigger zone.
b. Therapeutic uses. Hutyrophenones are used to control vomiting resulting from cancer
chemotherapy.
c. Administration. The butyrophenones are given orally or intramuscularly every 2-4 days.
d. Adverse effects. Butyrophenones may produce mild sedation and tranquilization.

C. ANTIHISTAMINES e.g. dimenhydrinate, diphenhydramine, promethazine

1. Mechanism of action. Antihistamines block histaminergic and cholinergic afferent pathways

from the vestibular organs to the vomiting center.
2. Pharmacokinetics
a. Absorption. Antihistamines are well absorbed by the gastrointestinal tract.
 b. Fate. Their distribution has not been studied in animals.
3. Therapeutic uses. Used to prevent motion sickness in dogs.
4. Administration. Antihistamines are administered orally every 8 hours.
5. Adverse effects. Mild sedation

D. ANTICHOLINERGIC AGENTS e.g. aminopentamide, propantheline, isopropamide,

Darbazine (isopropamide + prochlorperazine)

1. Mechanism of action. Anticholinergic drugs block cholinergic afferent pathways from the
gastrointestinal tract to the vomiting center.
2. Therapeutic uses. Anticholinergics are used in dogs and cats to treat vomiting and diarrhea.
a. Alone, anticholinergics are less effective than other antiemetics in the treatment of
vomiting.
b. Anticholoinergics combined with phenothiazines (e.g., Darbazine) control vomiting
resulting from severe gastroenteritis.
3. Administration to dogs and cats is as follows:
a. Aminopentamide is administered orally, intramuscularly, or subcutaneously every 8-12
hours.
b. Propantheline is administered orally every 8 hours.
c. Isopropamide is administered orally every 12 hours.
4. Adverse effects include xerostomia, xerophthalmia, loss of visual accommodation,
tachycardia, urine retention, paralytic ileus, and constipation.
5. Contraindications. Anticholinergics are contraindicated in patients with glaucoma.

E. MISCELLANEOUS ANTIEMETICS

1. Intestinal protectants and adsorbents e.g. kaolin, pectin, bismuth salts may reduce
vomiting caused by milk gastritis.

2. Locally acting gastric antacids (e.g., magnesium hydroxide, magnesium silicate, aluminum
hydroxide, aluminum silicate) may reduce vomiting caused by gastric hyperacidity.

VII. LAXATIVES AND CATHARTICS

A. GENERAL CONSIDERATIONS. Laxatives and cathartics are used for:

1. Relief of acute non-dietary constipation

2. Removal of poisons from the gastrointestinal tract

3. Prevention of tenesmus in advanced pregnancy or prolapse

4. Evacuation of the bowel prior to surgery or radiography

B. OSMOTIC CATHARTICS

1. Preparations
a. Magnesium sulfate (Epsom salt), magnesium oxide
b. Sodium sulfate (Glauber’s salt)
 c. Polyethylene glycol electrolyte solutions (Golytely, Colyte), isotonic mixtures of
polyethylene glycol, sodium sulfate, sodium bicarbonate, sodium chloride, and
potassium chloride
d. Sodium phosphate and sodium tartrate mixtures (Fleet enemas)

2. Mechanism of action. Osmotic cathartics are nonabsorbable or poorly absorbable salts or

polymers that osmotically retain water in the intestinal lumen. They have a rapid onset of
action that begins in the small intestine.

3. Therapeutic use. Osmotic cathartics are the cathartics of choice for elimination of poisons.

4. Administration
a. Magnesium sulfate and magnesium oxide are administered orally.
b. Sodium sulfate is administered orally or via a stomach tube as a 6% solution.
c. Polyethylene glycol-electrolyte solutions are administered orally prior to colonoscopy.
d. Sodium phosphate and sodium tartrate mixtures are administered rectally to dogs. In
cats, they produce hyperphosphatemia and should not be used.

C. IRRITANT CATHARTICS (e.g., castor oil, aloe, senna, cascara sagrada)

1. Chemistry. Irritant cathartics are plant derivatives.

2. Mechanisms of action
a. Castor oil is cleaved by pancreatic lipases in the small intestine to yield irritant
ricinoleates, which stimulate peristalsis and reduce fluid absorption.
b. Aloe, senna, and cascara sagrada contain glycosides that are hydrolyzed in the large
intestine to yield irritant anthraquinones. The anthraquinones stimulate smooth muscle
and increase colonic motility. Because they act in the large intestine, their onset of
action is slow.

3. Therapeutic use. Irritant cathartics are administered orally to relieve acute constipation in
small and large animals.

D. BULK LAXATIVES (e.g., methylcellulose, agar, psyllium, wheat bran)

1. Mechanism of action. Bulk laxatives contain hydrophilic colloids, which absorb water and
increase bulk. Bulk stimulates large bowel peristalsis.

2. Administration is oral; wheat bran is added to the diet. The laxative effect occurs within 1-3
days.

E. LUBRICANTS. Mineral oil (liquid petrolatum) and white petrolatum lubricate and soften
feces

F. SURFACTANTS. Docusate is an anionic surfactant that acts in the large bowel to hydrate
and soften feces by an emulsifying action.

VIII. ANTIDIARRHEAL

A. GENERAL CONSIDERATIONS
1. Indications. Acute diarrhea may respond to symptomatic therapy with antidiarrheal drugs,
but chronic diarrhea requires a definitive diagnosis and specific therapy.

2. Oral rehydration therapy represents a significant advance in treating diarrhea in the absence
of vomiting.
a. In addition to glucose or amino acids, or both, these solutions contain sodium chloride,
potassium chloride, sodium bicarbonate, and potassium phosphate.
b. Sodium-glucose- and sodium-amino acid-linked absorption by the enterocyte remains
intact even in the presence of moderate damage to the intestinal villi, providing the
driving force for water and electrolyte absorption from the lumen to replace fecal losses.

B. OPIATES

1. Preparations
a. Paregoric is a camphorated tincture of opium.
b. Diphenoxylate is a synthetic congener of meperidine. Lomotil is diphenoxylate plus
atropine.
c. Loperamide is a synthetic piperidine opioid.
d. Codeine

2. Mechanisms of action
a. Opiates inhibit ACh release. The resultant increased gastrointestinal rhythmic
segmentation and decreased propulsive motility slow the transit time of luminal contents
and increase absorption.
b. In addition, opiates directly stimulate absorption of fluid and electrolytes via µ-opiate
receptors in the CNS and intestinal mucosa.

3. Therapeutic use. Opiates are effective in the symptomatic treatment of acute diarrhea

4. Administration
a. Paregoric is administered orally 2-3 times daily to dogs and cats, once daily to calves
and foals.
b. Diphenoxylate is administered orally 2-3 times daily to dogs and cats.
c. Loperamide is administered orally 1-2 times daily to dogs and cats.
d. Codeine is administered orally 2-3 times daily to dogs and cats.

5. Adverse effects
a. Bacterial overgrowth in the intestinal lumen of animals with infectious diarrhea may
result from slowed intestinal transit time.
b. In cats, excitatory reactions render opiate use controversial.

C. ANTICHOLINERGIC AGENTS. Methscopolamine is used, as well as aminopentamide,

propantheline, and isopropamide, which are also effective as antiemetics.

1. Mechanism of action. Anticholinergic agents inhibit propulsive and nonpropulsive

gastrointestinal motility. They also inhibit normal, cholinergically mediated basal secretions
of the gastrointestinal tract.

2. Therapeutic uses
 a. Anticholinergic agents may be used to treat diarrhea; however, they are of questionable
benefit in this capacity because diarrhea is more commonly associated with hypomotility
than hypermotility.
b. Anticholinergic agents may be used to treat gastrointestinal spasm.

3. Administration
a. Methscopolamine is administered orally to dogs every 8-12 hours.
b. Administration of isopropamide, aminopentamide, and propantheline is discussed in VI D

D. PROTECTANT AND ADSORBENT AGENTS

1. Preparations
a. Kaolin-pectin suspensions [20% kaolin (hydrated aluminum silicate) and 1% pectin (a
polygalacturonic acid carbohydrate polymer)]
b. Bismuth subsalicylate

2. Mechanisms of action
a. Protectives and adsorbents adsorb toxins and provide a protective coating on inflamed
mucosa.
b. Bismuth subsalicylate has an anti-PG action in addition to its adsorbent properties.

3. Therapeutic use. Protectants and adsorbents are used for the symptomatic therapy of acute
diarrhea. Adsorbents may decrease fluidity of feces without actually decreasing fecal water
loss, thereby limiting their usefulness.

4. Administration
a. Kaolin-pectin suspensions are administered orally every 4-6 hours. Kaolin-pectin is
effective in dogs, cats, birds, horses, cattle, sheep, and swine.
b. Bismuth subsalicylate is administered orally every 6-8 hours. Bismuth subsalicylate is
approved for use in dogs, horses, cattle, and swine. Salicylates should not be
administered to cats.

5. Adverse effects. Bismuth subsalicylate may produce dark feces, which should not be
confused with melena.

IX. AGENTS USED IN THE TREATMENT OF INFLAMMATORY BOWEL DISEASE

A. SULFASALAZINE

1. Chemistry. Sulfasalazine is an enteric sulfonamide that consists of sulfapyridine and 5-

aminosalicylic acid (5-ASA) linked by a diazo bond.

2. Mechanism of action. Sulfasalazine is cleaved by bacteria in the large bowel to release

sulfapyridine and salicylate.
a. Salicylates have anti-inflammatory effects on the bowel mucosa.
b. Salicylates may inhibit PG synthesis in colonic mucosa.
3. Pharmacokinetics. Absorption of sulfapyridine and salicylate is minimal (less than 30% and
10%, respectively), allowing most of the dose to reach the colon.

4. Therapeutic uses. Sulfasalazine is used to treat chronic inflammatory bowel disease and
colitis in dogs and cats.

5. Administration. Sulfasalazine is administered orally 2-3 times daily.

6. Adverse effects are rare, but long-term use may cause sulfapyridine toxicity, especially
keratoconjunctivitis sicca. Salicylate toxicity may occur in cats.

B. OLSALAZINE

1. Chemistry. Olsalazine consists of two molecules of 5-ASA linked by a diazo bond.

Olsalazine is less toxic than sulfasalazine because it lacks the sulfonamide moiety.

2. Mechanism of action. After cleavage of the diazo bond by colonic bacteria, salicylates are
released.

3. Pharmacokinetics. Oral absorption of olsalazine is minimal, with over 98% of the dose
reaching the colon.

4. Therapeutic uses. Olsalazine is used for chronic inflammatory bowel disease in dogs and
cats.

5. Administration. Olsalazine is administered orally 2-3 times daily.

6. Adverse effects. Salicylate toxicity can occur in cats receiving long-term olsalazine therapy.

C. TYLOSIN

1. Chemistry. Tylosin is a macrolide antibiotic structurally related to erythromycin (see Chapter

11). Macrolides are organic bases that form salts with acids such as phosphate or tartrate.

2. Mechanism of action. Tylosin inhibits protein synthesis in susceptible bacteria by binding to

the 50S ribosome and blocking long-chain peptide synthesis. Its bacteriostatic action
suppresses bacterial overgrowth in chronic intestinal disease.

3. Pharmacokinetics
 a. Absorption and fate. Tylosin is absorbed from the intestine and widely distributed to
tissues except those of the CNS.
b. Excretion. Tylosin is excreted unchanged in bile and urine.

4. Therapeutic use. Tylosin is used to treat chronic colitis in dogs and cats.

5. Administration. Tylosin is administered orally 2-3 times daily with food.

6. Adverse effects. Tylosin may cause mild gastrointestinal disturbances (e.g., vomiting,
diarrhea).

D. METRONIDAZOLE

1. Mechanism of action
a. Metronidazole is an antiprotozoan nitroimidazole (see Chapter 13) and an antibacterial.
It is especially effective against anaerobes.
b. Metronidazole suppresses cell-mediated immune reactions.

2. Pharmacokinetics
a. Absorption and fate. Metronidazole is well absorbed by the gastrointestinal tract and
widely distributed.
b. Excretion. Hepatic metabolites and unchanged drug are excreted in urine and feces.

3. Therapeutic use. Metronidazole is used to treat colitis in dogs.

4. Administration. Metronidazole is administered orally 2-3 times daily.

5. Adverse effects are infrequent, but high or prolonged doses may produce neurotoxicity,
including tremors and ataxia.

6. Contraindications. Metronidazole should not be used in pregnant animals.

X. DRUGS FOR TREATMENT OF RUMINANT GASTROINTESTINAL DISORDERS

A. GENERAL CONSIDERATIONS
1. Development of rumen function begins at 3-6 weeks of age and is complete by 9-13 weeks
of age. In order to administer oral medication to lambs and calves, the nonfunctional
ruminoreticulum must be bypassed by inducing closure of the esophageal (ruminoreticular)
groove.

2. The normal intraruminal pH range is 5.5-7.

3. Innervation
a. Extrinsic contractions of the ruminoreticulum are controlled by vagal efferents from the
dorsal vagal nucleus in the CNS.
b. Intrinsic contractions are controlled by intramural plexuses.

4. Rumen microflora function depends on proper nutrient intake and normal ruminoreticular
motor activity.

B. AGENTS FOR INDUCING CLOSURE OF THE ESOPHAGEAL GROOVE

When stimulated, buccal and pharyngeal receptors activate a vagal reflex that closes the groove
within 2-5 seconds; effects last for 60 seconds. Milk, sodium bicarbonate (10% to calves), or
copper sulfate (5% to calves, 2% to lambs) may be used to induce esophageal groove closure.
Water is not effective.

C. RUMINOTORICS

1. Bitters (e.g., nux vomica, ginger, capsicum) stimulate salivation, which may enhance rumen
function; however, the efficacy of bitters is minimal. Bitters are administered orally.

2. Cholinergics (e.g., neostigmine, bethanechol) transiently increase the frequency, but not the
strength, of contractions in rumen atony. Cholinergics are administered subcutaneously.

3. Opiate antagonists (e.g., naloxone) stimulate extrinsic contractions when administered

parenterally. Opiate antagonists are useful for the treatment of endotoxin-induced rumen
stasis.

4. Rumen fluid transfer. Oral inoculation of viable rumen bacteria and protozoa is the most
effective means of restoring rumen function following correction of the primary cause of
stasis.

D. RUMEN ANTACIDS (e.g., magnesium oxide, magnesium carbonate, aluminum hydroxide,

calcium carbonate, ammonium carbonate)
1. Therapeutic use. Antacids treat mild cases of lactic acidosis resulting from carbohydrate
engorgement.

2. Administration. These agents are administered orally every 8-12 hours.

3. Adverse effects. Systemic alkalosis may result from overdose, especially of magnesium
oxide.

E. RUMEN ACIDIFIERS (e.g., vinegar, 4%-5% acetic acid)

1. Therapeutic uses
a. Rumen acidifiers may be used to treat simple indigestion, in which a constant inflow of
bicarbonate-rich saliva raises the pH of the rumen.
b. They are used in the treatment of acute urea poisoning, because they decrease
ammonia absorption via formation of ammonium ion and inhibit urease activity of rumen
microflora.

2. Administration. Rumen acidifiers are mixed with several liters of cold water and
administered via a stomach tube every 6-8 hours.

F. VISCOSITY-ALTERING (antibloat) AGENTS

1. Preparations include poloxalene, polymerized methyl silicone, mineral oil, and vegetable
(e.g., soybean, peanut, sunflower) oil.

2. Mechanisms of action. Viscosity-altering agents alter the surface tension of froth and break
up the gas bubbles.

3. Therapeutic use. Frothy (not free-gas) bloat requires viscosity-altering drug therapy.

4. Administration. Anti-bloat agents are administered via drench or stomach tube.

 Antimicrobial Drugs
INTRODUCTION

Antimicrobial therapy is based on the selective toxicity of a drug for invading organisms rather
than mammalian cells. Final eradication of organisms generally requires host immune
responses (e.g., phagocytosis), particularly with bacteriostatic antimicrobial drugs.

PRINCIPLES OF ANTIMICROBIAL THERAPY

Definitive antimicrobial choice should be based on isolated etiologic agent, antimicrobial

sensitivity, drug pharmacokinetics, adverse effects, least expensive and host factors. The
organism must be sensitive to the drug, and effective tissue concentrations of the drug should
be maintained until the organism is eliminated.

- Do Grams stain, culture, identification and antibiotic sensitivity testing before initiating
antimicrobial therapy.
- Dosage regimens and routes of administration should be selected to ensure
maintenance of therapeutic drug levels in affected tissues.

Empiric therapy should be based on local epidemiologic data and statistical probability e.g.
hospital, clinic data and their antimicrobial susceptibility pattern.

A single, narrow-spectrum antibiotic is usually more desirable than a less specific, broad-
spectrum agent.

Antimicrobial combination is indicated if needed e.g. bacterial endocarditis, tuberculosis,

mixed infection and fatal infections before laboratory data is available. This provides synergistic
effect and prevents emergence of resistance.

Effective antimicrobial therapy requires consideration of the total clinical problem.

Treatment may necessitate drainage of abscesses/ hematomas, debridement of devitalized
tissue, or removal of foreign bodies e.g. joint implant, prosthetic heart and irrigation of cavities.

High dose and prolonged therapy is necessary for bacterial endocarditis, osteomyelitis and
infections of devitalized tissues.

Prophylactic use of antimicrobials should be employed only when the identity of the invading
organism can be reasonably surmised. Example, staphylococcal infections of bone following
orthopedic surgery are prevented by administration of cephalosporins before or during
surgery.

Pharmacodynamics of antimicrobials is based on their kinetics of bacterial killing, post-antibiotic

effect (PAE), post-antibiotic leukocyte enhancing effect (PALE) as well as inoculum effect. PAE
is the period after exposure to and removal of antimicrobial agent during which inhibition of
bacterial growth persists.

a) Concentration-dependent antibiotics – bactericidal effect is dependent upon the

concentration of the antibiotic, “the higher the concentration of the drug, the greater is
the bactericidal effect”. During drug free period these antibiotics enhances WBC
phagocytosis and intracellular bacterial killing. The sub-MIC effect follows exposure to
supra-inhibitory concentration of the drug. Fluoroquinolones and aminoglycosides have
prolonged PAE. Aminoglycoside goal is to exceed 10x the MIC and for
fluoroquinolones 125x the MIC. This is best attained by dosing less frequently (once
daily dosing) than intermittently. For serious neutropenic patients whom PALE is not
working, this drug is most effective if given in combination with other antimicrobials.

b) Time-dependent antibiotics – bactericidal effect is dependent upon the length of time

the bacteria are exposed to the blood concentration which exceed 4x the MIC for at least
60% of the dosing time interval. This is best done by giving 1) constant infusion (IV)
after initial bolus dose, 2) multiple doses or by using drug with 3) longest half-life.
These include penicillins, cephalosphorins, monobactams, carbapenems, macrolides,
metronidazole, vancomycin, clindamycin and glycopeptides. Beta-lactam have
negligible PAE, carbapenems and macrolides have moderate PAE, all drugs exhibit
PAE on S. aureus, not all drugs exhibit PAE on Gram- bacilli.

ACQUIRED RESISTANCE TO ANTIMICROBIALS – due to frequent use of antimicrobials

Mechanisms of bacterial resistance

- Enzyme production. Organisms may produce enzymes (via constitutive or inducible
processes) that inactivate the drug. This is mediated by plasmid or chromosomal gene
production
- Decreased cell wall permeability. Cell wall permeability to the drug may be
decreased, limiting uptake by the organism.
- Active transport of the drug out of the cell may be increased.
- Alteration of the drug receptor or binding site may result in reduced drug affinity.
- Development of alternative pathways. The organism may develop alternate metabolic
or synthetic pathways to bypass the effects of the antimicrobial agent.

Development of resistance

- Mutation. Survival of the fittest. Bacterial chromosomal mutations confer resistance

either slowly (stepwise fashion with each succeeding generations of the mutant) or
rapidly (single step in which the bacterium is resistant after the initial mutation).
Mutation is a random event. Antimicrobials do not induce mutations but may
promote resistant strains of bacteria by suppressing susceptible good bacteria.
Susceptible strains are eliminated while resistant (R) strains are selected. R genes
develop by mutation (change of gene structure) and are transferred to other microbes
by plasmids (small DNA molecule that can replicate independently of the chromosome).
 - Conjugation. Conjugation is a type of reproduction in which genetic material is
transferred from bacteria to bacteria via a pilus (hair-like extension on the surface of
bacteria), which is encoded by a resistance transfer factor (RTF) on a plasmid.
(1) Infectious (transferable) drug resistance occurs when resistance factors (Rf) from
plasmid DNA, chromosomal DNA, or both encode for resistance to multiple
drugs and are rapidly transferred to the bacterial population.
(2) Conjugation, which occurs in certain Gram - bacteria, has been observed clinically
in enteric infections with Salmonella, Shigella and Escherichia coli.

- Transduction. The transfer of drug-resistant genes by bacteriophages (virus that

infect and replicates within a bacteria) may be important in the development of resistant
strains of Staphylococcus aureus.

- Transformation. DNA-carrying genes for drug resistance may be incorporated by

bacteria after its secretion or release following cof resistant organisms. Acquisition of
resistance by transformation is relatively infrequent.

II. SULFONAMIDES

A. CHEMISTRY

1. Structure. The sulfonamides are derivatives of p-aminobenzene sulfonic acid and are
structurally similar to p-aminobenzoic acid (PABA), an intermediate in the bacterial
synthesis of folic acid.

2. Characteristics. The sulfonamides behave as weak organic acids, which are poorly
water-soluble unless prepared as medium salts.
a. Concentrated solutions of the sodium salts of most sulfonamides are alkaline and
may be corrosive.
b. According to the law of independent solubility, the solubility of a sulfonamide is not
influenced by the presence of other sulfonamides in the solution; thus, sulfonamide
mixtures are used to increase solubility and reduce toxicity.

B. MECHANISM OF ACTION. Sulfonamides competitively inhibit dihydropteroate

synthetase, the enzyme that catalyzes the incorporation of PABA into dihydrofolic acid.

1. Folic acid is required for purine and DNA synthesis; without it, bacterial growth is
inhibited. Because they inhibit bacterial growth, sulfonamides are bacteriostatic agents.

2. Mammalian cells and some bacteria that use preformed folic acid are not affected by
sulfonamides. Bacteria that cannot utilize preformed folic acid for purine and DNA
synthesis are sensitive and inhibited with sulfonamides.

C. PHARMACOKINETICS

1. Absorption. Sulfonamides are well absorbed orally and widely distributed to tissues.

2. Fate
 a. Distribution. Transcellular fluid concentrations of the drug are 80% of the plasma
concentration. Binding to plasma albumin varies with each sulfonamide but generally
accounts for 50%-75% of the dose.

b. Metabolism. The type and extent of metabolism vary with the sulfonamide and the
animal species.
(1) Metabolism by acetylation at the p-amino group and glucuronide conjugation
occurs in most species; however, acetylation does not occur in dogs.
(2) Oxidation of the benzene and heterocyclic rings to quinine derivatives also occurs,
especially in dogs.

3. Excretion. Renal excretion of the unchanged drug and metabolites is via glomerular
filtration, active secretion, and passive tubular reabsorption. Re-absorption is pH-pKa
dependent.

D. SPECTRUM AND USES. Widely used in the prevention and treatment of local and
systemic infections in all species. Bacteriostatic, broad-spectrum agents with
antiprotozoal activity. Inhibit both g+ and g- bacteria, few Chlamydia , Nocardia , and
Actinomyces , and some protozoa such as coccidia and toxoplasma. More active
potentiated sulfonamides may include several species of Streptococcus , Staphylococcus ,
Salmonella , Shigella, Vibrio, Hemophilus, Pasteurella, E. coli and Pneumocystis carinii.
Pseudomonas, Klebsiella, Proteus, Clostridium, and Leptospira are most often highly
resistant, as are rickettsiae.

1. Sulfamethazine, sulfaguanidine and sulfaquinoxaline - used in cattle, sheep, and swine

in the control of respiratory and gastrointestinal infections and to promote growth in swine. It
is slowly excreted, and therapeutic levels are maintained in plasma for 24 hours with a
single dose.

2. Sulfadimethoxine - long-acting sulfonamide used in all species for the treatment of

systemic and soft tissue infections and coccidiosis. Sulfadimethoxine is more soluble and
less toxic than sulfamethazine. The plasma half-life is 10-15 hours.

3. Sulfathiazole - rapidly excreted sulfonamide used in swine and poultry as a feed or water
additive to treat respiratory and enteric diseases. In addition, sulfathiazole, along with
sulfamethazine and sulfapyridine, is used to treat acute infections in food-producing
animals.

4. Sulfachlorpyridazine - rapidly absorbed and rapidly excreted sulfonamide used in cattle

and swine for the therapy of respiratory and enteric infections, especially colibacillosis.

5. Sulfisoxazole and sulfamethoxazole - treat urinary tract infections in small animals.

They are rapidly excreted and very soluble; thus, high concentrations may be attained in
urine with minimal danger of renal crystalluria.
6. Sulfacetamide - only sulfonamide that can be prepared as a sodium salt at a neutral pH
and thus can be used in ophthalmic preparations.

7. Sulfasalazine - therapy of enteric diseases (e.g., colitis and inflammatory bowel

disease/IBD) in dogs and cats. It is cleaved by intestinal bacteria to sulfapyridine and 5-
aminosalicylic acid (5-ASA), which have antibacterial and anti-inflammatory actions,
respectively.

8. Potentiated sulfonamides - combinations of a sulfonamide + trimethoprim or

ormetoprim results in a synergistic action via sequential blockade of folic acid synthesis.
Trimethoprim and ormetoprim inhibit dihydrofolate reductase in bacteria (but not
mammalian cells) and thus block the formation of tetrahydrofolic acid, essential for purine
and DNA synthesis.
a. Potentiated sulfonamides have a broader spectrum of action, a reduced rate of
development of bacterial resistance and bactericidal against aerobic g- bacteria,
staphylococci, excellent against salmonella typhi, shigella, hemophilus influenza and
drug of choice for pneumocystis carinii. Used in the treatment of susceptible infections in
all species.
b. Preparations: sulfadiazine+trimethoprim, sulfamethoxazole+trimethoprim,
sulfadimethoxine+ ormetoprim & trimetophrim+sulfametrole

E. ADMINISTRATION

1. Oral administration. Sulfonamides are generally administered orally because absorption is

rapid. Slow-release boluses of sulfamethazine and sulfadimethoxine are available for
ruminants. These preparations provide blood levels for 48-72 hours with a single dose.

2. Intravenous administration is used for initial treatment of severe, acute infections.

3. Frequency of dosing varies with the individual sulfonamides.

F. BACTERIAL RESISTANCE. Bacteria that are resistant to one sulfonamide are resistant to
all.

MOA:

1. Increased PABA production

2. Decreased affinity of the sulfonamide for dihydropteroate synthetase
3. Bacterial metabolism of sulfonamide

G. ADVERSE EFFECTS
1. Renal crystalluria, the result of precipitation of sulfonamides in neutral or acidic urine, may
occur with large or prolonged doses or inadequate water intake, especially with the older,
less soluble sulfonamides (e.g., sulfathiazole). Sulfonamides therapy generally should not
extend beyond 5 days.

2. Keratoconjunctivitis sicca may be observed in dogs treated with sulfonamides such as

sulfadiazine, which contain the pyrimidine nucleus. The mechanism of the toxic effect on
lacrimal acinar cells is unknown.

3. Hypoprothrombinemia, thrombocytopenia, and anemia occur rarely and are probably

immune-mediated reactions. Sulfonamides should not be used in animals with pre-existing
bleeding disorders.

4. Hypersensitivity reactions include urticaria, angioedema, anaphylaxis, skin rashes, drug

fever, polyarthritis, hemolytic anemia, and agranulocytosis. Crystalluria with hematuria, and
even tubular obstruction. Acute toxic signs may seen after too rapid IV injection or if an
excessive dose is injected: muscle weakness, ataxia, blindness, and collapse. GIT upsets,
nausea and vomiting, may occur when sulfonamide levels are sufficiently high in the tract to
disturb normal microflora balance and vitamin B synthesis. Sulfonamides depress the
cellulolytic function of ruminal microflora. Prolonged treatment may cause bone marrow
depression (aplastic anemia, granulocytopenia, thrombocytopenia), hepatitis and icterus,
peripheral neuritis and myelin degeneration in the spinal cord and peripheral nerves,
photosensitization, stomatitis, conjunctivitis, and keratitis sicca. Mild follicular thyroid
hyperplasia may be associated with prolonged administration of sulfonamides to sensitive
species such as dogs, and reversible hypothyroidism can be induced after treatment with
high doses in dogs. Several sulfonamides can lead to decreased egg production and
growth. Topically, the sulfonamides retard healing of uncontaminated wounds.

III. FLUOROQUINOLONES – enrofloxacin ‘baytril max’, norfloxacin, ciprofloxacin, marbofloxacin

‘marbocyl’, danofloxacin ‘advocin’

A. CHEMISTRY
1. Structure. The fluoroquinolones consist of a carboxyl group, fluorine atom, and piperazine
ring attached to a quinoline ring.
2. Characteristics. Fluoroquinolones are weak acids and are lipophilic. Water-soluble salts are
used in parenteral preparations.

B. MECHANISM OF ACTION. The fluoroquinolones inhibit bacterial DNA gyrase sub-unit A,

an enzyme that controls DNA supercoiling as the replicating strands separate.

1. Inhibition of gyrase results in degradation of chromosomal DNA at the replicating fork.

2. Fluoroquinolones are bactericidal.

C. PHARMACOKINETICS

1. Absorption. Oral absorption of fluoroquinolones is rapid; for example, dogs achieve peak
plasma concentrations 1 hour after administration.

2. Fate
a. Distribution is wide and includes the CNS, bone, and prostate. The plasma half-life is
3 hours in dogs and 4 hours in cats.
b. Metabolism. Some hepatic metabolism occurs.

3. Excretion. Both the parent drug and metabolites are excreted in urine and bile. Renal
tubular active secretion results in high urinary concentrations.

D. SPECTRUM OF ACTIVITY. Although fluoroquinolones have broad-spectrum activity,

anaerobes tend to be resistant.

E. PREPARATIONS AND THERAPEUTIC USES. Enrofloxacin and ciprofloxacin are used in

the treatment of dermal, respiratory (pasteurella, hemophilus, mycoplasma), UTI and
prostatitis in dogs and cats .and GIT infections e.g. salmonella in food animals

F. ADMINISTRATION. Enrofloxacin and ciprofloxacin are administered orally twice daily, IM

is acceptable in dogs, but not in cats.

G. BACTERIAL RESISTANCE. Development of bacterial resistance is relatively rare.

Extended exposure to sub-therapeutic dosages may lead to the appearance of mutants that
resist fluoroquinolone binding to DNA gyrase.

H. ADVERSE EFFECTS include erosion of articular cartilage in young dogs. Fluoroquinolones

should not be administered to small and medium breeds <8yrs old or to large breeds for
the <18yrs old.

IV. BETA-LACTAMS: penicillins, cephalosphorins, cephamycins, carbapenems,

monobactams

PENICILLIN

A. CHEMISTRY. Penicillins comprise a beta-lactam ring and a thiazolidone ring.

1. Cleavage of the beta-lactam ring destroys antibiotic activity; some resistant bacteria produce
beta-lactamases (penicillinases).
2. Amidase cleavage of the amide bond side chain yields the 6-aminopenicillanic acid (6-APA)
nucleus used in producing semi-synthetic penicillins.

3. The carboxyl group attached to the thiazolidone ring is the site of salt formation (e.g.,
sodium, potassium, procaine, benzathine). Conversion to salt esters stabilizes the
penicillins and affects solubility and absorption rates.

B. MECHANISM OF ACTION

1. Penicillins bind to and inhibit the transpeptidase involved in the cross-linking of the
bacterial cell wall, the third and final step in cell wall synthesis. The weakened cell wall
ruptures, resulting in cell death.

2. Penicillins also inhibit other peptidases (penicillin-binding proteins) involved in cell wall
synthesis and block inhibition of autolysins.

3. Rapidly growing bacteria are most susceptible to the bactericidal effect of penicillin.

C. PHARMACOKINETICS

1. Absorption
a. Many penicillins are acid unstable e.g., penicillin G, methicillin, ticarcillin, are degraded
by gastric HCl and are poorly absorbed orally.
b. Acid-stable penicillins e.g., penicillin VK, ampicillin, amoxicillin, hetacillin, oxacillin,
cloxacillin, dicloxacillin, indanyl salt of carbenicillin are well absorbed orally.

2. Fate. Penicillins are widely distributed to tissues and transcellular fluids, except those of the
CNS and the eye.

3. Excretion. More than 90% of an administered dose is excreted unchanged in the urine by
glomerular filtration and active tubular secretion. The remainder is metabolized by the liver
to penicilloic acid derivatives, which may act as antigenic determinants in penicillin
hypersensitivity.

SPECTRUM OF ACTIVITY. The penicillins are primarily effective against G+ aerobes and
anaerobes. The broad spectrum, semi-synthetic penicillins are also effective against some
G- pathogens.
 Natural penicillins: Pen-G and Pen-V are active against both aerobic and anaerobic G+
bacteria, except Hemophilus, Neisseria and Bacteroides other than B fragilis, are inactive
against G- bacteria. Active against streptococci, pen-sensitive staphylococci,
Corynebacterium pyogenes, Clostridium spp, Erysipelothrix rhusiopathiae, Actinomyces
ovis, Leptospira canicola, Bacillus anthracis, Fusiformis nodosus, and Nocardia.

Semisynthetic β-lactamase-resistant penicillins: oxacillin, cloxacillin, floxacillin, and

nafcillin, have spectra similar to those noted above (although often at higher MIC) but also
include many of the β-lactamase-producing strains of staphylococci (especially S aureus
and S epidermidis ).

Semisynthetic β-lactamase unstable broad-spectrum penicillins: ampicillin and

amoxicillin are effective to a large number of g+ and g- bacteria (but not β-lactamase-
producing) are sensitive e.g. Staphylococcus, Streptococcus, Corynebacterium,
Clostridium, Escherichia, Klebsiella, Shigella, Salmonella, Proteus and Pasteurella . While
bacterial resistance is widespread, the combination of β-lactamase inhibitors and broad-
spectrum penicillins markedly enhances the spectrum and efficacy against both gram-
positive and gram-negative pathogens e.g. Sulbactam and Clavulanate potentiated
ampicillin/amoxicillin is an excellent example of such a synergistic association.

Anti- Pseudomonas and extended-spectrum penicillins: carbenicillin, ticarcillin,

imipenem and piperacillin are active against most of the usual penicillin-sensitive bacteria.
They often have a degree of β-lactamase resistance and are usually active against one or
more characteristic penicillin-resistant organisms. Yet, as a class, they remain susceptible
to destruction by β-lactamases. Active against Pseudomonas aeruginosa, Proteus,
Shigella, Citrobacter and Enterobacter spp. Streptococcus faecalis is often resistant to
these new extended-spectrum penicillins. Imipenem is relatively resistant to β-lactamase
destruction. Its spectrum includes a wide variety of aerobic and anaerobic microorganisms,
including most strains of Pseudomonas, streptococci, enterococci, staphylococci, and
Listeria. Anaerobes, including Bacteroides fragilis, are highly susceptible.

D. PREPARATIONS AND THERAPEUTIC USES

1. Natural penicillins – highly effective against gram+ cocci, except penicillinase producing
bacteria, meningococci, spirochetes & anaerobic cocci.
a. Penicillin G (benzylpenicillin G) is used in all species & most potent. Route: iv, im
b. Benzathine benzylpenicillin G e.g. Penadur-LA, slowly absorbed, provide therapeutic
level for 2-3 days. Route, im
c. Procaine penicillin G – slowly absorbed and provides therapeutic level for 1 day.
Route, im
d. Penicillin VK (phenoxymethylpenicillin VK) e.g. Sumapen, Megapen is administered PO
for long-term therapy of infections caused by gram+ organisms in dogs, cats, and
horses.
2. Semi- synthetic penicillins
a. Penicillinase-stable penicillins - reserved for severe infections caused by staphylococcal
beta-lactamase (penicillinase) producing organisms.
2.a Methicillin

2.b Oxacillin – im, iv, po

2.c Cloxacillin – im, iv, po

2.d Dicloxacillin – po

2.e Flucloxacillin – im, iv, po

2.f Nafcillin – im, iv, po

b. Amino-penicillins - broad-spectrum; spectrum of benzylpenicillin + >active on enterococci,

Listeria monocytogenes and Leptospira. Some strains of E. coli, salmonella, shigella, proteus
produces penicillinase and are resistant.
Ampicillin (iv, im, po), amoxicillin (iv, po) and bacampicillin (po) are active against many
Gram- aerobes (E. coli, Proteus, Haemophilus) as well as Gram+ pathogens. Used in all
species for the treatment of susceptible infections. They are acid-stable, but not penicillinase
resistant.

c. Carboxypenicillins – very broad spectrum - similar to aminopenicillins + active against

Pseudomonas, Providencia and Enterobacater.
Carbenicillin (po) and ticarcillin (iv, im) are used alone or in combination with gentamicin or
tobramycin in the treatment of infections caused by Pseudomonas species.

d. Ureidopenicillins – very broad - similar to aminopcn+carboxypcn + Klebsiella spp, route;

iv,im
Azlocillin (iv, im), mezlocillin (iv,im) and piperacillin have an extended spectrum of activity
against G- organisms e.g. Pseudomonas, Enterobacter, and Klebsiella spp. High cost limits
their use to the treatment of severe Gram-negative infections in dogs and cats.

e. Potentiated penicillins - used in small animals to restore and extend the spectrum of
antimicrobial action.
Clavulanic acid has minimal antibacterial action, but it inhibits many of the plasmid-encoded
and chromosomal beta-lactamases produced by penicillin resistant organisms e.g. strains of
staphylococci, gonococci, hemophilus, bacteroides, klebsiella & E. coli. Combined with
amoxicillin or ticarcillin in commercial preparations (clavamox, amoxiclav; iv, po).

Sulbactam, tazobactam - action is similar to clavulanic acid. Combined with ampicillin

(Unasyn, iv) or piperacillin (iv, im)

E. ADMINISTRATION. Penicillins are generally administered intramuscularly, if acid-stable,

orally 2-3 times per day.
1. Procaine penicillin G is slowly absorbed from intramuscular injection sites and may provide
therapeutic levels for 24 hours with a single dose.

2. Benzathine penicillin G is even more slowly absorbed over 48-72 hours, but blood levels
attained are relatively low.

3. Sodium or potassium salts of penicillin G may be administered intravenously or

intramuscularly every 4-6 hours.

F. BACTERIAL RESISTANCE

1. Inactivation of penicillins by bacterial production of beta-lactamases is the most common

mechanism of resistance.

2. Alterations in the structure of penicillin-binding proteins result in failure of the drug to bind.

G. ADVERSE EFFECTS

1. Allergic reactions to penicillin may occur in animals, especially cattle. Signs include skin
eruptions, angioedema, anaphylaxis, drug fever, serum sickness, vasculitis, eosinophilia,
and intrathecal administration may result in convulsions. Procaine salts of penicillin should
not be used in birds, snakes, turtles, guinea pigs, or chinchillas because these species are
sensitive to procaine.

2. Organ toxicity is rare. Cross-sensitivity between penicillins is well recognized. Intrathecal

administration may result in convulsions. The use of broad-spectrum penicillins may lead to
superinfection, and GI disturbances may occur after PO administration of ampicillin.
Potassium penicillin G should be administered IV with some caution, especially if
hyperkalemia is present. The sodium salt of penicillin G may also contribute to the sodium
load in congestive heart failure.

V. BETA-LACTAM: CEPHALOSPORINS

A. CHEMISTRY
1. Structure. Cephalosporins are beta-lactam antibiotics that have a 7-aminocephalosporanic
acid nucleus analogous to the 6-APA nucleus of penicillins.

2. Characteristics. Cephalosporins are weak acids that may be administered as a sodium salt,
monohydrate, or free base.

B. MECHANISM OF ACTION. Like the penicillins, the cephalosporins inhibit the third stage of
bacterial cell wall synthesis (i.e., the cross-linking of the peptidoglycan chain).
Cephalosporins are bactericidal.

C. PHARMACOKINETICS
1. Absorption. Most cephalosporins are unstable in gastric acid and must be administered
parenterally. Cephalexin and cefadroxil are acid-stable and are well absorbed orally.

2. Fate
a. Distribution. Cephalosporins are widely distributed, with excellent penetration of all body
tissues except cerebrospinal fluid.
b. Metabolism is minimal. Some cephalosporins (e.g., cephalothin, cefotaxime) are
deacetylated by the liver.

3. Excretion. Renal excretion is by glomerular filtration and active tubular secretion.

D. PREPARATIONS AND THERAPEUTIC USES

1. 1st generation – broad spectrum active to most g+ cocci, some g- bacilli and penicillin
resistant S. aureus but not against enterococcus & methicillin resistant S. aureus. Agents:
cephalexin, cefadroxil cephapirin, cephalothin, cefazolin, cephradine and cephaloridine: 1st
alternative to pcn for treating infections caused by E. coli, salmonella, proteus, klebsiella,
shigella, some anaerobes but inactive against pseudomonas, streptococcus fecalis.
Relatively sensitive to B-lactamase.

a. Used in all species: GIT, respiratory, urogenital, bone and soft tissue infections.
b. Useful for antibiotic prophylaxis due of their ability to penetrate tissues and body fluids.
2. 2nd generation – These agents have a broader activity on g- pathogens, except
pseudomonas. More resistant to B-lactamase, but not widely used in veterinary medicine.

True cephalosphorins - cefaclor, cefotiam, cefuroxime, cefamandole

Carbacephem/ oxacephem – flomoxef, loracerbef
Cephamycins – cefoxitin, cefmetazole, cefotelan

3. 3rd generation - e.g., ceftiofur ‘excede’, cefovecin ‘convenia’, ceftriaxone, cefsulodin,

cefotaxime, cefoperazone, moxalactam, ceftazidime (Fortum) have an extended activity
against g- organisms including pseudomonas. More enhanced resistance to beta-
lactamases and penetration to the BBB.

a. Used in the treatment of g- meningitis in small animals.

b. Ceftiofur is used in the treatment of respiratory disease in poultry, cattle and swine.

4. 4th generation – cefquinome ‘cobactan’, cefpodoxime, cefixime. Have extended spectrum

and B-lactamase resistance compared to the 3rd generation. Recommended for nosocomial
infections.

E. ADMINISTRATION. Most cephalosporins are administered every 8 hours.

F. BACTERIAL RESISTANCE. Bacterial beta-lactamase production may confer resistance,
although cephalosporins tend to be less susceptible than the penicillins.

G. ADVERSE EFFECTS

1. Nephrotoxicity may develop with prolonged administration; dosages should be adjusted in

the presence of renal disease.

2. Hypersensitivity and allergic reactions may occur. Cephalosporins may be used in penicillin-
intolerant patients; however, caution should be exercised because cross-reactivity can
occur.

VI. CARBAPENEMS: Spectrum – recommended for nosocomial infections caused by multiple-

resistant bacteria and complicated polymicrobial infections caused by mixture of aerobic g+&-
bacteria and anaerobic organisms. Insignificant activity against P. aeruginosa and not used
against methicillin resistant S. aureus.

Preparations: Imipenem+cilastin, ertapenem, meropenem, biapenem

VII. MONOBACTAMS: Spectrum – limited to g- bacteria including enterobacteriaceae,

aeromonas, N. gonorrhea, H. influenza & P. aeruginosa. Substitue for aminoglycosides in
combination therapy to avoid toxicity in the treatment of g- infections.

Agent: aztreonam

VIII. AMINOGLYCOSIDES & Aminocyclitols – ‘cin’ (aminoglycosides: avilamycin ‘surmax’,

tobramycin, amikacin, neomycin, gentamicin, streptomycin, kanamycin, apramycin ‘apralan’;
aminocyclitols: spectinomycin, neomycin)

A. CHEMISTRY
1. Structure. Aminoglycosides consist of two or three amino sugars joined to amino-cyclitol, a
hexose, by glycosidic bonds.

2. Characteristics
a. Numerous amino groups contribute to the highly polar and basic character of the
aminoglycosides.
b. Sulfate salts are water-soluble.

B. MECHANISM OF ACTION. The aminoglycosides bind to the 30S ribosome and inhibit the
rate of protein synthesis and the fidelity of messenger ribonucleic and mRNA translation,
resulting in the synthesis of abnormal proteins.
1. Aminoglycoside uptake by bacteria involves an energy-dependent step (EDP 1) that is
oxygen-linked. Uptake is inhibited by an anaerobic or acidic environment and by calcium
or magnesium ions.

2. Aminoglycosides are bactericidal.

C. PHARMACOKINETICS

1. Absorption. Aminoglycosides are not absorbed from the GIT.

2. Fate. Aminoglycosides are distributed to the ECF and to transcellular fluids e.g. pleural and
peritoneal fluids.
a. Penetration of the CNS and ocular tissue is minimal.
b. Aminoglycosides tend to accumulate in the renal cortex and otic endolymph,
predisposing these tissues to toxicity.

3. Excretion. Aminoglycosides are excreted unchanged in the urine by glomerular filtration.

Plasma half-lives are 1-3 hours in most species.

D. SPECTRUM OF ACTIVITY. Active against infections caused by aerobic g- bacteria in all

species.
Streptomycin and dihydrostreptomycin have relatively narrow spectra, and bacterial
resistance is becoming prevalent. Some staphylococci and g- bacilli are still susceptible e.g.
Actinomyces bovis, Pasteurella, E coli, Salmonella, Campylobacter fetus, Leptospira, and
Brucella. Mycobacterium tuberculosis is also sensitive to streptomycin.

Neomycin, framycetin, and kanamycin have broader spectra and their clinical use is
most often directed against G- bacteria e.g. E. coli and Salmonella, Klebsiella,
Enterobacter, Proteus, and Actinobacter.

Aminoglycosides with much broader spectra: gentamicin, tobramycin, amikacin,

sisomicin, and netilmicin are often highly effective against a wide variety of aerobic
bacteria e.g. P aeruginosa. Anaerobic bacteria and fungi are not appreciably affected;
streptococci are only moderately sensitive or quite resistant.

E. PREPARATIONS AND THERAPEUTIC USES

1. Streptomycin and dihydrostreptomycin are the oldest members of this class of antibiotics.
Their use has declined with the advent of broader spectrum aminoglycosides, such as
gentamicin and amikacin.
2. Neomycin is administered orally to treat enteric infections and topically to treat skin, ear, and
eye infections
3. Extended-spectrum aminoglycosides
a. Gentamicin and amikacin are effective against Pseudomonas, Proteus, Staphylococcus,
and Corynebacterium species, as well as g- aerobes. They are used in all species for
the treatment of septicemia and all susceptible infections of the skin, respiratory tract,
ear, eye, and urinary tract.
b. Tobramycin is similar to gentamicin but has more potent antipseudomonal activity.
c. Kanamycin has a spectrum of activity similar to that of gentamicin, except it is not
effective against Pseudomonas species. Kanamycin is used in dogs and cats to treat
gram-negative infections of the skin and soft tissue, urinary tract, and respiratory tract.

F. ADMINISTRATION

1. For systemic infections, aminoglycosides are administered intramuscularly or

subcutaneously every 8-12 hours.

2. For enteric infections, aminoglycosides are administered orally once or twice per day.

G. BACTERIAL RESISTANCE may be plasmid-mediated and may develop quickly.

Inactivation of aminoglycosides by bacterial enzymes is the most common form of
resistance.

1. The numerous amino and hydroxyl side groups are sites of attack by acetylases,
phosphorylases, and adenylases.

2. Amikacin is more resistant to enzymatic degradation than other members of this class.

H. ADVERSE EFFECTS. The aminoglycosides are relatively more toxic than other classes of
antimicrobials. Toxicity is reversible if treatment is stopped early. Aminoglycosides should
not be used with other ototoxic or nephrotoxic drugs (e.g., furosemide, amphotericin B).

1. Ototoxicity (>gentamicin) results from progressive damage to cochlear sensory cells

(causing deafness), vestibular cells (causing ataxia), or both.

2. Nephrototoxicity is caused by damage of the membranes of proximal cells, resulting in a

loss of brush border enzymes, impaired absorption, proteinuria, and decreased glomerular
filtration rate. Dosages must be adjusted for animals with decreased renal function.
3. Neuromuscular blockade (>neomycin) is a relatively rare adverse effect of aminoglycosides.
It is caused by prejunctional blockade of acetylcholine (ACh) release and decreased
postsynaptic sensitivity to ACh. Muscle paralysis and apnea are treated with calcium
gluconate.

VII. TETRACYCLINES – oxytetracycline ‘OTC’, chlortetracycline ‘CTC’, doxycycline

‘vibravet’, minocycline

A. CHEMISTRY. The tetracyclines are polycyclic compounds that are amphoteric and that
fluoresce when exposed to ultraviolet light. Most are prepared as the hydrochloride salt.
They form insoluble chelates with cations such as calcium, magnesium, iron, and aluminum.

B. MECHANISM OF ACTION. Tetracyclines, which are bacteriostatic, inhibit bacterial protein

synthesis by binding to the 30S ribosome and preventing attachment of aminoacyl transfer
ribonucleic acid (tRNA) to the mRNA-ribosome complex. They block the addition of amino
acids to the growing peptide chain.

C. PHARMACOKINETICS
1. Absorption. Oral absorption of tetracyclines ranges from 60%-90% of the administered
dose except for chlortetracycline, which is only 35% absorbed. Divalent or trivalent
cations impair absorption; thus, milk, antacids, or iron salts should be avoided 3 hours
before and after oral administration.

2. Fate
a. Distribution is wide and includes all tissues except those of the CNS. Doxycycline is
more lipid-soluble than tetracycline, chlortetracycline, and oxytetracycline; it penetrates
the CNS, eye, and prostate at therapeutic concentrations.
b. Metabolism is minimal in domestic animals. Plasma half-lives range from 6-12 hours for
most tetracyclines.

3. Excretion. Renal excretion by glomerular filtration is the major route of elimination for most
tetracyclines, but small amounts are excreted into feces via bile or diffusion from the blood
into the intestine. Doxycycline is unique in that intestinal excretion is the major route of
elimination (75%).

D. SPECTRUM OF ACTIVITY. Broad activity: includes G+ and G- aerobes and anaerobes,

rickettsiae, spirochetes, chalmydiae, mycoplasma, and some protozoa such as Anaplasma
species, amoeba and Haemobartonella species. All tetracyclines are about equally active
and typically have about the same broad spectrum activity. Strains of Pseudomonas
aeruginosa , Proteus , Serratia , Klebsiella , and Corynebacterium spp frequently are
resistant, as are many pathogenic E. coli isolates. Even though there is general cross-
resistance among tetracyclines, doxycycline and minocycline usually are more effective
against staphylococci.
E. PREPARATIONS AND THERAPEUTIC USES

1. Tetracycline, chlortetracycline, and oxytetracycline are used in the treatment of local and
systemic bacterial, chlamydial, rickettsial, and protozoal infections in cattle, sheep, horses,
and swine. These agents are also used as feed additives and growth promoters in cattle
and swine.

2. Doxycycline and tetracycline are used in the treatment of respiratory and urinary tract
infections in dogs and cats and as specific therapy for infections caused by Borrelia (Lyme
disease), Brucella, haemobartonella, and Ehrlichia species. These agents are also effective
in the treatment of psittacosis in birds.

F. ADMINISTRATION

1. Tetracyclines are administered orally or IV every 8-12 hours. Oral doses should be avoided
in adult ruminants and used with caution in horses.

2. If administered intramuscularly, special buffered solutions should be used to avoid pain

and local irritation.

G. BACTERIAL RESISTANCE may be plasmid-mediated and usually involves decreased drug

uptake or active transport of the tetracycline out of the bacterial cell.

H. ADVERSE EFFECTS

1. The tetracyclines (except for doxycycline) are potentially nephrotoxic and should be avoided
if renal function is impaired. They should not be used with methoxyflurane anesthesia
because acute renal failure may result.

2. Permanent staining of unerrupted teeth may occur in young animals. Formation of a

tetracycline-calcium phosphate complex in enamel and dentine is the probable cause.

3. Suprainfections of fungi, yeast, or resistant bacteria may occur in the gastrointestinal tract
with prolonged administration of broad-spectrum antibiotics such as the tetracyclines.

4. Phototoxicity and hepatotoxicity are rare side effects in animals.

5. Oral therapeutic doses may disrupt ruminal microflora in adult ruminants or colonic
microflora in horses.
VIII. CHLORAMPHENICOL and derivatives – ‘col’ e.g. thiamphenicol, florfenicol ‘nuflor’

A. CHEMISTRY. Chloramphenicol is an unusual natural compound because it contains

dichloracetate and nitrobenzene moieties as part of its structure.

1. Palmitate salts are water-insoluble and are administered orally.

2. Chloramphenicol sodium succinate is water-soluble for parenteral use.

B. MECHANISM OF ACTION. Chloramphenicol, a bacteriostatic agent, binds to the bacterial

50S ribosome unit to inhibit peptide bond formation and protein synthesis.

C. PHARMACOKINETICS

1. Absorption. Chloramphenicol is rapidly absorbed from the gastrointestinal tract.

2. Fate
a. Distribution. Chloramphenicol is widely distributed to all tissues, including those of the
CNS and eye.
b. Metabolism is hepatic, via glucuronide conjugation. In cats, 75% of the dose is
metabolized, and in dogs, 90% of the administered drug is metabolized.

3. Excretion. The elimination half-life is 1-1.5 hours in dogs and horses and 4-5 hours in cats.

D. SPECTRUM OF ACTIVITY. Chloramphenicol, a broad-spectrum antibiotic, is effective

against most anaerobic bacteria. G+ and G- bacteria and several anaerobes such as
Bacteroides fragilis , as well as Rickettsia and Chlamydia spp are susceptible. Of special
note is the efficacy against many Salmonella spp and the resistance of most strains of P.
aeruginosa . Florfenicol also has a broad antimicrobial spectrum.

E. THERAPEUTIC USES. Chloramphenicol is used in dogs, cats, horses, and birds for local
and systemic infections, inducing respiratory, CNS, and ocular infections, and enteric
infections caused by anaerobes and Salmonella species.

F. ADMINISTRATION. Chloramphenicol is administered orally every 6-8 hours to dogs, birds,

and horses, and every 12 hours to cats.
G. BACTERIAL RESISTANCE. Resistant bacteria inactivate chloramphenicol by producing
acetyltransferase and other metabolizing enzymes.

H. ADVERSE EFFECTS

1. Anemia
a. Dose-related and reversible non-regenerative anemia may occur in animals and
humans. Chloramphenicol may inhibit the uptake of iron by erythrocytes and slow their
rate of maturation in bone marrow.
b. Non-dose-related anemia may occur in humans. It is rare, but the resulting irreversible
aplastic anemia is often fatal. Because of the potential for residue-induced aplastic
anemia in humans, use of chloramphenicol is banned in food-producing animals.

2. Anorexia and diarrhea may occur with high or prolonged dosages, especially in cats
Suppress anamnestic immune responses, animals should not be vaccinated while being
treated with this antibiotic. Because of its ability to inhibit protein synthesis, excessive
topical application on wounds may delay healing.

In both male and female rats, chloramphenicol has adversely affected the structure and
functions of the gonads. In large animals, adverse signs are most often associated with
propylene-glycol-based preparations that, when infused rapidly IV, may result in collapse,
hemolysis, and death.

Notwithstanding the severity of the chloramphenicol-associated side effects noted above,

chloramphenicol is relatively safe, provided overdosage is avoided, courses of therapy are
limited to 1 week, the dose is reduced for newborn animals and for animals with impaired
liver function, and there is no evidence of a pre-existing bone marrow depression.

IX. MACROLIDES –‘cin/sin’ e.g. tilmicosin ‘pulmotil’, tylosin ‘tylan’, tulatromycin ‘draxxin’,
azithromycin, oleandomycin, kitasamycin, spiramycin ‘suanovil’, erythromycin, rosasomycin,
enramycin ‘enradin’

A. CHEMISTRY. The macrolide antibiotics are basic, lipid-soluble compounds consisting of

deoxy sugars attached to a lactone ring. They are prepared as sulfate salts or as esterified
salts of stearate, tartrate, estolate, or lactobionate.

B. MECHANISM OF ACTION. Macrolides inhibit bacterial protein synthesis by binding to the

50S ribosome, preventing translocation of amino acids to the growing peptide chain.
Macrolides are bacteriostatic.

C. PHARMACOKINETICS
1. Absorption. Enteric-coated preparations protect the antibiotic from gastric acid destruction,
allowing oral absorption. Oral absorption is also possible when the stable, esterified salts
are used.

2. Fate. Macrolide antibiotics are widely distributed to all tissues except those of the CNS.
Tilmicosin is concentrated in lung tissue at levels sixty times higher than serum levels.

3. Excretion
a. Erythromycin is metabolized by the liver and excreted in bile.
b. Tylosin and tilmicosin are excreted unchanged in bile and urine.

D. SPECTRUM OF ACTIVITY. The antimicrobial activity of macrolides is primarily against g+

aerobes and anaerobes and Mycoplasma species.

E. PREPARATIONS AND THERAPEUTIC USES

1. Erythromycin
a. Erythromycin is an alternative to penicillin for the treatment of infections caused by
Gram-positive aerobes and anaerobes in dogs, cats, and horses.
b. It is the drug of choice for the treatment of enteritis caused by Campylobacter jejuni in
dogs and foals and for Rhodococcus equi pneumonia in foals.
2. Tylosin
a. Tylosin is used in cattle, sheep, and swine for the treatment of local and systemic
infections caused by mycoplasma, Gram-positive bacteria, and some Gram-negative
pathogens (e.g., Pasteurella, Haemophilus) also Brachyspira/Serpulina hyodysenteria
(swine dysentery). It is also used as a growth promoter in these species.
b. Tylosin is used in dogs and cats for the treatment of chronic colitis.

3. Tilmicosin is used only in cattle for the treatment of respiratory disease caused by
Pasteurella species.

F. ADMINISTRATION

1. Erythromycin is administered orally or intramuscularly three times daily to dogs, cats, and
foals.

2. Tylosin is administered intramuscularly or orally once or twice daily to swine, calves, lambs,
dogs, and cats.

3. Tilimicosin is administered subcutaneously to cattle every 72 hours.

G. BACTERIAL RESISTANCE to macrolide antibiotics may be chromosomal or plasmid-
mediated and results from decreased drug binding by the 50S ribosome.

H. ADVERSE EFFECTS

1. Erythromycin and tylosin have relatively few side effects.

a. Mild GIT upset may result from oral doses.
b. Pain and irritation at intramuscular injection sites may occur.
c. Edema of the rectal mucosa with mild anal prolapse may be seen in swine following
intramuscular administration of tylosin.
d. Severe diarrhea may occur if erythromycin is administered orally to adult ruminants or if
tylosin is administered orally or parenterally to adult cattle and horse.

2. Tilmicosin produces cardiovascular toxicity in species other than cattle.

X. LINCOSAMIDES – lincomycin, clindamycin

A. CHEMISTRY. Lincomycin and clindamycin are derivatives of a sulfur-containing octose with

an amino acid-like side chain. They are prepared as hydrochloride or phosphate salts,
which are water-soluble, or clindamycin palmitate for oral administration.

B. MECHANISM OF ACTION. The lincosamides, which are bacteriostatic, bind to the bacterial
50S ribosome to inhibit protein synthesis. Because this is the same binding site of
chloramphenicol and the macrolides, combination therapy should be avoided.

C. PHARMACOKINETICS

1. Absorption. Oral absorption is 50% for lincomycin and 90% for clindamycin.

2. Fate
a. Distribution is wide, with excellent penetration of bone and soft tissues, including tendon
sheaths. CNS levels are low unless the meninges are inflamed.
b. Metabolism. Lincosamides are metabolized by the liver (60%, lincomycin; 90%,
clindamycin).

3. Excretion. Unchanged drug and metabolites are excreted in the urine, bile, and feces.
Elimination half-lives are 3-5 hours in dogs and cats.
D. SPECTRUM OF ACTIVITY. The lincosamides are active against g+ aerobes and
anaerobes, Toxoplasma and some Mycoplasma species. The antibacterial activity of
clindamycin is greater than that of lincomycin, especially against anaerobes.

Lincomycin has a limited spectrum against aerobic pathogens but a fairly broad spectrum
against anaerobes. Clindamycin is a more active analog with somewhat different
pharmacokinetic patterns. Many g+ cocci are inhibited by lincosamides, but most g-
organisms are resistant, as are most mycoplasmas. Bacteroides spp and other
anaerobes are usually susceptible. Clostridium difficile strains appear to be regularly
resistant.

E. THERAPEUTIC USES

1. Lincomycin is used in swine for the control and treatment of swine dysentery and the
treatment of staphylococcal, streptococcal, and some mycoplasma infections.

2. Clindamycin is used in dogs and cats for periodontal disease, osteomyelitis, dermatitis, and
deep soft tissue infections caused by Gram-positive organisms. It is used for treating
toxoplasmosis in dogs and cats.

F. ADMINISTRATION

1. Lincomycin is administered intramuscularly to swine once daily or added to the drinking

water.

2. Clindamycin is administered orally or intramuscularly twice daily to dogs and cats.

G. BACTERIAL RESISTANCE. Altered drug binding by bacterial ribosomes is the usual form
of resistance. Cross-resistance between lincosamides and macrolides is common.

H. ADVERSE EFFECTS

1. In horses, rabbits, hamsters, and guinea pigs, lincosamides are contraindicated because
they may produce a severe, often fatal diarrhea caused by altered gastrointestinal flora.

2. In dogs, cats, and swine, side effects are. Neuromuscular blockade may occur at high
doses or when lincosamides are administered with anesthetics.
XI. MISCELLANEOUS ANTIBACTERIALS

A. AMINOCYCLITOLS (spectinomycin, apramycin ‘apralan’)

1. Chemistry. Aminocyclitols are chemically related to the aminoglycosides.

2. Mechanisms of action. Aminocyclitols bind to the 30S ribosome and inhibit protein
synthesis. Unlike the aminoglycosides, aminocyclitols are bacteriostatic.

3. Pharmacokinetics. The pharmacokinetics of aminocyclitols are similar to those of the

aminoglycosides.
a. Absorption. Less than 10% of the dose is absorbed orally.
b. Fate. Parenterally administered spectinomycin distributes to the extracellular fluid
(ECF).
c. Excretion. Aminocyclitols are excreted unchanged by the kidney.

4. Spectrum of activity. Aminocyclitols are effective primarily against Gram-negative aerobes

and Mycoplasma species.

Apramycin is used to control g- infections, particularly Escherichia coli and salmonellae in

calves and piglets. It also is active against Proteus , Klebsiella , Treponema , and
Mycoplasma spp . There is little cross-resistance within the aminoglycosides, and
plasmid-mediated resistance is yet to be confirmed. Apramycin is poorly absorbed after
administration PO (<10%). It is rapidly absorbed from parenteral injection sites. Plasma
levels peak within 1-2 hr of IM administration. Apramycin distributes only into the
extracellular fluid and is excreted unchanged in the urine (95% within 4 days). The
elimination half-life in calves is ~4-5 hr. Apramycin is toxic in cats but is considered safe in
most other species (3-6 times the recommended oral dose rarely produces toxicity). The
oral dose rate is 20-40 mg/kg, sid for 5 days. The parenteral dose rate is 20 mg/kg, bid. The
withdrawal time in pigs and calves (Europe) is 28 days after oral use.

The structure of spectinomycin differs from that of the aminoglycosides, but it also binds to
bacterial ribosomes and interferes with protein synthesis. However, the effect is
bacteriostatic rather than bactericidal. Spectinomycin can be inactivated by an enzyme
coded for by an R factor, but mutant resistance due to diminished ribosomal binding is
perhaps more common. It is active against several strains of streptococci, a wide range of
g- bacteria, and Mycoplasma spp ; most Chlamydia spp are resistant. It is poorly absorbed
from the GI tract but is rapidly absorbed after IM administration, with blood levels peaking
within 1 hr. Like aminoglycosides, spectinomycin penetrates tissues rather poorly and
distributes principally into extracellular fluid. Metabolic transformation of spectinomycin is
limited, and 80% can be recovered unchanged in the urine over 24-48 hr. About 75% is
eliminated by glomerular filtration in ~4 hr. At usual doses, no major toxic reactions have
 been reported. It is administered both PO at 20 mg/kg, bid, and IM at 5-10 mg/kg, bid .
Withdrawal time for pigs is usually ~3 wk.

5. Preparations and therapeutic uses

a. Spectinomycin is used in dogs, cats, horses, swine, and poultry for the treatment of
enteric and respiratory disease.
b. Apramycin is used in swine and calves for the treatment of enteric diseases especially
colibacillosis.

6. Bacterial resistance. Resistant mutants fail to bind aminocyclitols to the 30S ribosome.
Plasmid-mediated resistance, manifested as the production of degrading enzymes, is less
common.
7. Adverse effects. No significant toxicity is associated with clinical use of spectinomycin or
apramycin.

B. METRONIDAZOLE – dimetridazole, ronidazole, tinidazole

1. Mechanism of action. Metronidazole is taken up by anaerobic bacteria and protozoa and

reduced to a cytotoxic metabolite that disrupts DNA. Metronidazole is bactericidal at
concentrations equal to or slightly higher than the minimal inhibitory concentration. The
precise mode of action is unclear, but it seems that after the drug enters a susceptible
organism it is first reduced and then binds to DNA, causing loss of the helical structure,
strand breakage, and impairment of DNA function. Only susceptible organisms (bacteria and
protozoa) appear to be capable of metabolizing the drug.

2. Pharmacokinetics
a. Absorption. Metronidazole is well absorbed orally.
b. Fate
(1) Distribution. Metronidazole is widely distributed and penetrates the CNS.
(2) Metabolism. One-third to one-half of the administered drug is metabolized by
oxidation and conjugation in the liver.
c. Excretion. Metabolites and the unchanged drug are excreted in the urine and feces.

3. Spectrum of activity. Metronidazole is bactericidal against most obligate anaerobes and is

active against protozoa, including Amoeba, Giardia, Histomonas and Trichomonas species.

4. Therapeutic uses. Metronidazole is used in dogs, cats, and horses for the treatment of
severe infections caused by anaerobic pathogens, especially pelvic, genitourinary, and
respiratory tract infections and brain abscesses. Dimetridazole use in the treatment of
Serpulina hyodysenteria (bloody stools), Giardia, Balantidium, Histomonas and aerobic and
anaerobic g+ bacteria.
5. Adverse effects. High or prolonged, dosages may produce neurotoxicity (i.e., nystagmus,
ataxia, seizures).

C. RIFAMYCINS (rifampicin)

1. Mechanism of action. Rifampin inhibits DNA-dependent RNA polymerase, preventing

initiation of RNA synthesis. It is bactericidal.

2. Pharmacokinetics
a. Absorption. Rifampicin is absorbed orally.
b. Fate. It is rapidly distributed to cells and tissues. Its distribution to cells makes it
effective against intracellular infections.
c. Excretion. Rifampin is metabolized by the liver and excreted primarily in bile.
Metabolites may impart a red color to the urine, feces, and saliva.

3. Spectrum of activity. Rifampin is bactericidal for mycobacteria (tuberculosis) and g+

pathogens (Brucella, Staphylococcus) and Chlamydia.

4. Therapeutic uses. Rifampin is combined with erythromycin in the treatment of R. equi

infections in foals.

5. Bacterial resistance may develop quickly. Alterations in the structure of DNA-depenedent

RNA polymerase prevent rifampin from binding to the organism.

6. Adverse effects are rare. Hepatotoxicity may occur in animals with preexisting liver disease.

D. PLEUROMUTILINS – tiamulin, valnemulin (2x as active)

1. Mechanism of action. Tiamulin binds to the 50S bacterial ribosome to inhibit protein
synthesis. Its mechanism of action and spectrum of activity are similar to those of the
macrolides such as tylosin.

2. Pharmacokinetics
a. Absorption. Tiamulin is well absorbed orally.
b. Fate. It is widely distributed and metabolized by the liver.
c. Excretion. Elimination of metabolites occurs via the feces (70%) and urine (30%).

3. Spectrum of activity. Tiamulin is active against Gram-positive cocci, mycoplasma,

spirochetes, and Gram-negative pathogens e.g, Haemophilus.
4. Therapeutic uses. Tiamulin is used in poultry and swine for the control and treatment of
pneumonia (Hemophilus), dysentery (Brachyspira/Serpulina hyodysenteria), ileitis
(Lawsonia inracellularis), colitis (Brachyspira pilosicoli), and enzootic pneumonia/CRD
(Mycoplasma). Synergistic with tetracyclines.

5. Adverse effects. Irritant metabolites in the urine may cause dermatitis with erythema and
pruritus in pigs confined in overcrowded areas. Do not give to horses, rabbits and guinea
pigs (fatal diarrhea)

E. VANCOMYCIN

1. Mechanism of action. Vancomycin blocks the second step of bacterial cell wall synthesis by
inhibiting polymer release from the cell membrane. It is bactericidal.
2. Pharmacokinetics
a. Absorption. Vancomycin is not absorbed orally.
b. Fate. It is distributed to the ECF and transcellular fluids.
c. Excretion. It is excreted unchanged by glomerular filtration.

3. Spectrum of activity. Vancomycin is effective against most g+ organisms but not on g-

bacteria.

4. Therapeutic uses. Vancomycin is a reserve antibiotic used IV for methicillin-resistant S.

aureus infections of bone and soft tissue in dogs and cats and antibiotic induced
enterocolitis caused by Clostridium difficile.

5. Adverse effects. Ototoxicity and nephrotoxicity occur with large dosages or prolonged
administration.

F. BACITRACIN

1. Mechanism of action. Bacitracin inhibits the second step of cell wall synthesis and is
bactericidal.

2. Pharmacokinetics. Bacitracin is not absorbed orally. It is too nephrotoxic for systemic use.

3. Spectrum of activity. Similar to pcn, effective against >g+, g- (less) bacteria and
spirochetes.

4. Therapeutic uses
 a. Bacitracin is used in ointments and solutions and is frequently combined with polymyxin
B or neomycin or both to treat topical infections.
b. It is also added to swine and poultry rations to prevent and treat enterocolitis caused by
Clostridium difficile (alternative to vancomycin) and to promote growth.

G. POLYMYXINS B & E (colistin)

1. MOA: Polymyxin interacts with phospholipids in the bacterial cell membrane to produce a
detergent-like effect and membrane disruption. It is rapidly bactericidal, > activity on g-
bacteria (enterobacter: E. coli, Salmonella, Pasteurella, Bordetella, Shigella,
Pseudomonas) than g+ bacteria but no proteus activity.

2. Pharmacokinetics. Polymyxin B is not absorbed orally and is too nephrotoxic for systemic
use.

3. Therapeutic uses
a. Polymyxin B is used topically to treat Gram-negative infections of the skin, eye, and ear
in all species. It is usually combined with bacitracin for broad-spectrum antibacterial
effects.
b. Polymyxin B and E is administered orally to cattle and swine for the treatment of Gram-
negative enteric infections.

4. Adverse effects. Polymyxin does not produce systemic toxicity when administered topically
or orally. Parenterally it causes nephrotoxic, neurotoxic and allergic (rare) reactions.

5. Not to be used with sulfonamides, tetracyclines, chloramphenicol and carbenicillin,

H. NITROFURANS e.g., nitrofurantoin, nitrofurazone, furazolidone

1. Mechanism of action. Nitrofurans are reduced by bacteria to reactive intermediates that

inhibit the enzyme systems of carbohydrate metabolism. They may also block mRNA
translation. Nitrofurans are broad-spectrum (coccidia, trypanosoma, trichomonas,
mycoplasma, salmonella, E. coli, klebsiella, proteus, G+ bacteria and anaerobes) and
bacteriostatic.

2. Pharmacokinetics
 a. Absorption. Nitrofurantoin is absorbed orally.
b. Excretion. It is rapidly excreted by glomerular filtration and active secretion. Peak urine
levels are achieved less than 1 hour after administration.

3. Therapeutic uses
a. Nitrofurantoin is occasionally used in the treatment of lower urinary tract infections in
dogs and cats. It is most effective in an acid urine.
b. Nitrofurazone is used topically as an antibacterial ointment, powder, and water-soluble
wound dressing in all species.
c. Furazolidone and nitrofurazone against coccidiosis, E.coli, mycoplasma and salmonella
in poultry and swine.

4. Adverse effects are rare.

a. Nausea, vomiting, and diarrhea may occur in dogs and cats following oral administration.
b. Oral administration of nitrofurans is contraindicated in food-producing animals because
nitrofurans have been shown to be potential carcinogens in laboratory animals.

XII. ANTIFUNGAL AGENTS

A. GRISEOFULVIN

1. Chemistry. Griseofulvin is a cyclohexane benzofuran antibiotic derived from Penicillium

griseofulvum. It is insoluble in water.

2. Mechanism of action. Griseofulvin is actively taken up by growing dermatophytes

(ringworm). It binds to microtubules to inhibit spindle formation and mitosis. Griseofulvin is
fungistatic and its action is slow-infected cells must be shed and replaced with uninfected
cells.

3. Pharmacokinetics
a. Absorption. Oral absorption is increased by high-fat foods and by preparations
consisting of microsized particles.
b. Fate. Griseofulvin distributes to the keratin precursor cells of the skin, hair shafts, and
nails.
c. Excretion. It is metabolized by the liver by demethylation and glucuronide conjugation
and excreted in urine.

4. Spectrum of activity. Griseofulvin is effective against dermatophytes e.g. Microsporum and

Trichophyton species.

5. Therapeutic uses. Griseofulvin is used in dogs, cats, and horses for multifocal
dermatophyte infections.
6. Administration. Griseofulvin is administered orally twice per day to dogs and cats and once
daily to horses for 4-6 weeks.

7. Adverse effects are rare. Leukopenia and anemia may occur as an idiosyncratic reaction in
kittens.

B. KETOCONAZOLE

1. Chemistry. Ketoconazole is an imidazole antifungal for systemic use. Other imidazoles

used only topically for dermatophyte or yeast infections include miconazole and
clotrimazole.

2. Mechanism of action. Ketoconazole inhibits the synthesis of ergosterol in fungal

cytoplasmic membranes by blocking cytochrome P-450 enzymes. It is fungistatic.

3. Pharmacokinetics
a. Absorption. Ketoconazole is absorbed orally.
b. Fate. It is widely distributed, except to the CNS.
c. Excretion. It is metabolized by the liver and excreted in bile.

4. Spectrum of activity. Ketoconazole is effective against most pathogenic fungi responsible

for systemic infections (e.g., Blastomyces, Coccidioides, Cryptococcus, and Histoplasma
species). It is also effective against candidiasis (yeast infections) and griseofulvin-resistant
dermatophytes.

5. Therapeutic uses
a. In dogs, cats, horses, and birds, ketoconazole is used to treat systemic mycoses and
severe yeast infections.
b. In dogs and cats, high dosages are used to treat hyperadrenocorticism.

6. Administration. To treat systemic mycotic infections, ketoconazole is administered orally,

twice per day for 3-6 months.

7. Adverse effects
a. Anorexia, vomiting, and diarrhea may occur.
b. Suppression of adrenal or gonadal steroids may also occur, but the effects are transient
at dosages employed in antifungal therapy.

C. AMPHOTERICIN B
1. Chemistry. Amphotericin B is a polyene macrolide that is stabilized with sodium
desoxycholate as a colloidal suspension.

2. Mechanism of action. Amphotericin B binds to the ergosterol of fungal cell membranes to

form pores or channels, which results in leakage of cell contents. Amphotericin B is
fungicidal.

3. Pharmacokinetics
a. Absorption. Amphotericin B is not absorbed from the gastrointestinal tract.
b. Fate. After intravenous administration, it is slowly distributed to most tissues, except
those of the CNS, eye, and bone.
c. Excretion. Elimination is biphasic, with serum half-lives of 24-48 hours and 1-2 weeks.
Less than 5% of the unchanged drug is excreted in the urine.

4. Spectrum of activity. Amphotericin B is effective against most organisms causing systemic

mycoses (e.g., Aspergillus, Blastomyces, Coccidioides, Cryptococcus, Histoplasma species)
and candidiasis..

5. Therapeutic uses
a. Amphotericin B is used to treat systemic fungal infections in dogs, cats, horses, and
birds. Combination with ketoconazole reduces toxicity.
b. Amphotericin B is used with flucytosine in the treatment of CNS, bone, and ocular
infections.

6. Administration. Amphotericin B is diluted in 5% dextrose and administered intravenously.

Treatment frequency and duration vary with the type of infection.

7. Adverse effects. Renal toxicity is a serious side effect.

a. Amphotericin B produces renal vasoconstriction, decreased glomerular filtration, and
damage to tubular epithelium.
b. Renal function must be monitored weekly during therapy [e.g., by evaluating blood urea
nitrogen (BUN) levels].

D. FLUCYTOSINE

1. Chemistry. Flucytosine is a fluorinated pyrimidine that is deaminated by fungi (not

mammalian cells) to 5-fluorouracil (5-FU), a potent antimetabolite.

2. Mechanism of action. Flucytosine, which is fungicidal, inhibits thymidylate synthetase,

thereby inhibiting DNA and RNA synthesis in susceptible fungi.
3. Pharmacokinetics
a. Absorption. Flucytosine is well absorbed orally.
b. Fate. It is widely distributed, including to the CNS.
c. Excretion. It is excreted unchanged in urine.

4. Spectrum of activity. Flucytosine is effective against Cryptococcus, Candida, and

Aspergillus.

5. Therapeutic uses
a. Flucytosine is combined with amphotericin B for synergistic action in the treatment of
cryptococcosis (especially meningeal cryptococcosis) in dogs and cats.
b. It is used alone in treating aspergillosis and candidiasis in psittacine birds.

6. Administration. Flucytosine is administered orally 3-4 times a day for a minimum of 4

weeks.

7. Adverse effects. Toxicity is low. Mild gastrointestinal disturbances and, more rarely, bone
marrow suppression have been reported.

Antiparasitic Agents

I. INTRODUCTION

Antiparasitics are drugs that reduce parasite burdens to a tolerable level by killing parasites or
inhibiting their growth. The ideal antiparasitic has a wide TI (toxic dose at least 3x therapeutic
dose), is effective after only one dose, is easy to administer, is inexpensive, and does not leave
residues (an important consideration for use in food-producing animals).

A. MECHANISMS OF ACTION

1. Paralysis of parasites by stimulating or inhibiting the release or action of putative

neurotransmitters

2. Alteration of metabolic processes

a. Inhibition of fumarate reductase
b. Inhibition of folic acid synthesis or metabolism
c. Inhibition of thiamine utilization
d. Uncoupling of oxidative phosphorylation
e. Inhibition of chitin formation in arthropods
f. Stimulation of insect juvenile hormones
3. Alteration of parasite reproduction
a. Inhibition of replication in protozoans
b. Inhibition of egg production in nematodes

B. DISADVANTAGES of antiparasitics include:

1. Expense
2. Development of resistant strains
3. Inhibition of host immunity

C. CURRENT TRENDS include the use of broad-spectrum drugs or combination therapy to

increase efficiency.
f

II. EXTERNAL ANTIPARASITICS (INSECTICIDES)

A. INTRODUCTION

1. Uses. Insecticides are used on animals to control mites, fleas, ticks, and flies, in the
environment to control flies and other insects, and on feedstuffs.

2. Toxicity. Individual animals vary in response to insecticides.

a. Age. Young animals are most susceptible.
b. Health. Healthy animals are least likely to experience adverse effects.
c. Stress e.g., extremely hot or humid weather, can increase susceptibility to insecticide
toxicity.
d. Species. Some species are especially sensitive to insecticides.
(1) Horses tend to develop urticaria and hyperemia following application of insecticides.
(2) Cats are very susceptible to cholinergic stimulants.

3. Formulations influence the degree of toxicity, the duration of action, and the convenience of
application.
Table 13-1. Putative neurotransmitters of various parasites

NEUROTRANSMITTERS
PARASITE
Excitatory Inhibitory

Nematodes ACh GABA, histamine

Cestodes 5-HT ACh

Trematodes 5-HT ACh, DA, NE

Arthropods ACh GABA, octopamine

ACh = acetylcholine; DA = dopamine; GABA = -aminobutyric acid; 5-HT = serotonin; NE =

norepinephrine

a. Sprays, dips, and shampoos are suitable when conditions are above freezing.
b. Pour-ons and dusts can be used when conditions are below freezing.
c. Oil sprays should be applied to the haircoat but not the skin, in order to avoid systemic
absorption.
d. Feed additives that are absorbed are effective against bloodsucking parasites. Whether
they are absorbed or not, they are effective against both the larval and pupal stages of
ectoparasites in the feces.
e. Collars and ear tags are available.

B. ORGANOPHOSPHATES. Hundreds of organophosphates are available as insecticides.

The withdrawal of chlorinated hydrocarbons from the market is increasing the importance of
these agents.

1. Preparations
a. Thio compounds include coumaphos, cythioate, fenthion, malathion, chlorpyrifos,
diazinon, famphur, phosmet, and pirimifos.
b. Oxy compounds include dichlorvos, tetrachlorvinphos, and trichlorfon.

2. Mechanism of action. The organophosphate insecticides inhibit acetylcholine (ACh)

breakdown by inhibiting acetylcholinesterase (AChE) irreversibly (see Chapter 2 V A). The
thio compounds must be metabolized to oxy compounds in order to inhibit AChE.

3. Pharmacokinetics
a. Absorption. Organophosphates are lipid-soluble; thus, they are well-absorbed through
the skin and gastrointestinal tract.
b. Excretion. The organophosphates pose no residue problems.

4. Administration. Organophosphates are applied to animals topically or administered orally.

5. Adverse effects
a. Toxicity (see Chapter 15 III 1)
(1) Acute toxicity
(a) Clinical signs include SLUD (salivation, lacrimation, urination, and defecation),
dyspnea, fasciculation, ataxia, and convulsions.
(b) Treatment involves decontamination and administration of atropine sulfate.
Pyridine aldoxime methiodide (2-PAM, an AChE reactivator) may be
 administered along with atropine (see Chapter 15 III 1 4). 2-PAM should not be
used alone to treat organophosphate overdose.
(2) Drug toxicity. Some organophosphates (e.g., chlorpyrifos, dichlorvos) can cause
severe peripheral nerve damage by inducing demyelination.
b. Drug interactions may occur with drugs that activate cholinergic receptors, skeletal
muscle relaxants, and chlorinated hydrocarbons.

C. CARBAMATES

1. Preparations. Frequently used carbamates include carbaryl and propoxur.

2. Mechanism of action. Carbamates inhibit AChE via carbamylation. Their effects are more
reversible than those of the organophosphates.

3. Pharmacokinetics. The pharmacokinetics of the carbamate insecticides are not well-

understood.

4. Adverse effects include toxicity. Carbamate poisoning is similar to acute organophosphate

poisoning. Atropine sulfate is an effective antidote. 2-PAM should not be used to treat
carbamate poisoning for two reasons:
a. Carbamate binding to AChI is reversible.
b. 2-PAM itself inhibits cholinesterase.

D. CHLORINATED HYDROCARBONS

1. Chlorinated ethane derivatives (e.g., DDT, methoxychlor) are very effective synthetic
insecticides. However, because of the environmental hazard posed by DDT residues, DDT
has been banned by the Environmental Protection Agency (EPA) since 1972.
a. Mechanism of action. These insecticides increase cytosolic calcium (Ca 2+)
concentrations via two mechanisms.
(1) They prevent the closure of sodium (Na+) channels, leading to an increase in
intracellular Na+ concentrations. Subsequently, the intracellular Ca2+ concentration is
increased through the action of the Na+ -Ca2+ antiporter (exchanger).
(2) They block Ca2+ -ATPase to inhibit sequestration of Ca2+.
b. Pharmacokinetics
(1) Absorption. Both DDT and methoxychlor are highly lipid soluble. Fat in feed
promotes absorption (and, therefore, increases toxicity); however, obese animals are
more resistant to insecticide toxicity.
(2) Fate
(a) DDT is metabolized into DDD and DDE.
(i) DDD is further metabolized into DDA, which is water soluble and is excreted
in the urine
(ii) DDE is lipid soluble and cannot be further metabolized. DDE is permanently
stored in the adipose tissue of animals, causing residue problems.
 (b) Methoxychlor is a biodegradable derivative of DDT that does not cause the
severe residue problems associated with DDT.
c. Adverse effects
(1) Toxicity. Acute toxicity in animals is rare; however, overdose (e.g., 10 mg/kg DDT)
can cause CNS excitation that may lead to convulsions.
(a) Detoxification. Activated charcoal should be administered to remove the toxicant
from the gastrointestinal tract.
(b) Symptomatic therapy
(i) Anticonvulsants can be administered for seizures. Phenobarbital, in addition
to controlling seizures, induces microsomal enzymes, increasing the
metabolism of chlorinated hydrocarbons.
(ii) Artificial respiration may be needed in cases of asphyxia.
(2) Drug resistance in arthropods may be a significant problem.
(3) Environmental concerns. DDT and methoxychlor present little risk of acute toxicity in
animals; however, DDT poses a hazard to the environment by persisting in the food
chain.
(a) Eggshell thinning results from the ability of DDT to block the estrogen receptors
that mediate the deposition of Ca2+ into the eggshell.
(b) Toxicity to aquatic life

2. Hexachlorocyclohexanes [e.g. lindane (r-BHC)] are used primarily to control screwworm

and ear tick infestations in cattle, horses, swine, sheep, and goats.
a. Mechanism of action. Lindane antagonizes -aminobutyric acid (GABA) receptors.
b. Pharmacokinetics. The pharmacokinetics of the hexachlorocyclohexanes are not clear.
c. Adverse effects. Lindane is one and one half times more toxic than DDT. Young
animals, especially calves, are extremely sensitive to lindane poisoning.
(1) Signs of toxicity are similar to those produced by DDT (e.g., tremors, ataxia,
convulsions, prostration, tachypnea).
(2) Treatment of poisoning is nonspecific.

E. INSECT GROWTH REGULATORS

1. Preparations include cyromazine (larvadex), fenoxycarb, and methoprene (‘frontline’:

fipronil+methoprene).

2. MOA: Cyromazine alter the deposition of chitin into the cuticle rather than its synthesis.
Fenoxycarb and methroprene mimic the actions of the juvenile hormones of insects. These
preparations maintain the larvae in an immature stage and interfere with reproductive organ
differentiation.

3. Pharmacokinetics. The pharmacokinetics of these agents are not well understood.

4. Therapeutic uses and administration.

a. Fecal maggot control. Cyromazine is administered in the feed to control fecal maggots
in poultry, houseflies, mosquitoes and blow fly larvae in sheep.
 b. Flea control
(1) Fenoxycarb and methoprene are sprayed in households and on animals to prevent
eggs, pupae, and larvae from developing into adult fleas. These drugs are effective
for at least 21 weeks. Methoprene is also available as a flea collar for dogs.
(2) Fenoxycarb and methoprene are mixed with pyrethroids to kill adult fleas.

5. Adverse effects. These products are safe when used as directed.

F. BOTANICALS

1. Rotenone
a. Chemistry. Rotenone is an alkaloid derived from the root of the derris plant.
b. Mechanism of action. Rotenone inhibits cellular respiratory metabolism by blocking
electron generation from reduced nicotinamide adenine dinucleotide (NADH). As a
result, oxidation of lactate, glutamate, and other substances is reduced and nerve
conduction is adversely affected.
c. Therapeutic uses
(1) Rotenone is used to kill fleas, lice, ticks, and mites. It has fast “knockdown” action
on all arthropods, with little persistence.
(2) Rotenone is also used to kill unwanted fish in ponds and lakes.
d. Adverse effects include local irritation and CNS disturbances (e.g., excitation,
convulsions, depression).

2. Pyrethroids
a. Preparations include pyrethrins, allethrin, cypermethrin, lambdacyhalothrin, and
permethrin.
b. Chemistry
(1) Pyrethrins are alkaloids of pyrethrum (chrysanthemum), which is one of the oldest
insecticides known to man.
(2) The other pyrethroids, which are synthetic, are more resistant to breakdown.
c. Mechanism of action
(1) Pyrethroids block nicotinic receptors.
(2) Pyrethroids increase GABA release.
d. Pharmacokinetics. The pharmacokinetics of the pyrethroids are not well understood.
e. Therapeutic uses. Pyrethroids exert a rapid “knockdown” effect but have little residual
activity. The “knockdown” effect may or may not be fatal; therefore, these agents are
usually combined with other insecticides or a synergist (e.g., piperonyl butoxide) to
increase insecticidal activity. Synergists inhibit induction of the microsomal enzymes
that degrade pyrethroids.
f. Adverse effects. Pyrethroids are generally safe, but may cause allergy, nausea and
vomiting, and headache.
G. OTHER INSECTICIDES

1. Amitraz is a formamidine insecticide cleared for use on dogs, pigs, and cattle.
a. Mechanism of action. Amitraz activates octopamine receptors in arthropods.
b. Pharmacokinetics. The pharmacokinetics of amitraz are not well understood.
c. Therapeutic uses
(1) Amitraz is used to eliminate mites, lice, and ticks in dogs, swine, and cattle. No pre-
slaughter withdrawal period is necessary in cattle, and it can be used on lactating
dairy cattle without incurring a withdrawal period for milk following application.
(2) Three to six bi-weekly treatments may be used to control demodectic mange.
d. Adverse effects. In animals, amitraz activates α 2-adrenergic receptors. Therefore, the
adverse effects of amitraz are similar to the pharmacological effects of xylazine (e.g.,
sedation, bradycardia, hyperglycemia, gastrointestinal stasis). α 2-Adrenergic
antagonists (yohimbine) can be used as an antidote.
e. Contraindications
(1) Amitraz should not be applied to swine within 3 days of slaughter.
(2) Amitraz may cause fatal colon impaction in horses.

2. Lufenuron (Program)
a. Mechanism of action. Lufenuron inhibits chitin synthesis. (Chitin is an essential
constituent of flea eggshells and the exoskeleton of immature fleas.)
b. Pharmacokinetics. Following oral dosing, lufenuron is distributed to the adipose tissues
and then back into the blood stream, reaching therapeutic concentrations in 6-12 hours.
Therapeutic blood levels are maintained for over 32 days.
c. Therapeutic uses. Lufenuron is used in dogs and cats older than 6 weeks of age to
control fleas. It is effective against eggs and immature fleas, but has no proven effect on
adult fleas.
d. Administration. Lufenuron is administered orally once monthly. Doses should be given
with or immediately following the meal.
e. Adverse effects. At recommended doses, lufenuron has no side effects or
contraindications. It is safe in young animals (i.e., those older than 6 weeks of age), in
reproducing and lactating dogs and cats and their offspring, and when used in
conjunction with other insecticides.

3. Avamectins and like acting agents: ivermectin (ivomec/heartguard), doramectin (dectomax),

selamectin (revolution), moxidectin (cydectin/pro-heart), abamectin (virbamax), fipronil
(frontline), milbemycin - GABA agonist: control ecto and endoparasites including whipworm,
lungworm, eyeworm, microfilaria and demodex mites, but excluding tapeworm and flukes. Safe
for pregnant animals.

4. Neonicotinoids - modeled after natural nicotine. Three compounds available for veterinary
use: dinotefuran, imidacloprid, nitenpyram
 MOA: agonists on the postsynaptic acetylcholine receptors in insects; inhibits cholinergic
transmission, resulting in paralysis and death.
 Imidacloprid- applied as spot-on; used to control fleas and lice on both dogs and cats.
  Nitenpyram- administered PO; used to kill fleas in dogs and cats
 Dinotefuran- derived from in acetylcholine; 3rd generation topical spot-on; control fleas

III. ANTINEMATODAL AGENTS (NEMATOCIDES) may be broad spectrum or narrow

spectrum (Table 13-2).

A. BENZIMIDAZOLES

1. Thiabendazole is the prototypical agent. It is approved for use in ruminants and horses.
a. MOA: Thiabendazole inhibits fumarate reductase, which catalyzes the formation of
succinate from fumarate. Interference with succinate formation leads to the inhibition of
adenosine triphosphate (ATP) formation.

Table 13-2. Classification of antinematodal agents

BROAD SPECTRUM NARROW SPECTRUM

Benzimidazoles Phenothiazine

Nicotine-like compounds Piperazine

Organophosphates Toluene

Antibiotics Thenium closylate

b. Pharmacokinetics
(1) Absorption. Thiabendazole is lipid soluble. As a result of poor dissolution in
digestive fluids, thiabendazole may be poorly or erratically absorbed from the
gastrointestinal tract.
(2) Metabolism and excretion. Hydroxylation on position 5 is followed by conjugation.
The 5-hydroxy metabolites are excreted as urinary glucuronide and sulfate. In cattle,
excretion is complete within 3 days.
c. Therapeutic uses
(1) Ruminants. Thiabendazole is effective against major gastrointestinal nematodes. It
is not effective against whipworms, lungworms, or filariae.
(2) Horses
(a) Thiabendazole is effective against strongyles, but large doses are needed to kill
Strongylus vulgaris. It is not effective against immature strongyles.
(b) Thiabendazole is used to treat intestinal threadworms and pinworms.
(c) Thiabendazole has some degree of larvicidal and ovicidal activity; however, it is
not effective against bots.
d. Adverse effects. Because fumarate reductase does not exist in mammals,
thiabendazole is one of the safest antinematodal drugs.
2. Other benzimidazoles
a. Preparations include albendazole, fenbendazole, flubendazole, mebendazole,
oxfendazole, oxibendazole, netobimin, thiophanate, and febantel (a pro-benzimidazole
that is converted to fenbendazole and oxfendazole in animals).

MOA: Benzimidazoles inhibit tubulin polymerization; it is believed that the other

observed effects, including inhibition of cellular transport and energy metabolism, are
consequences of the depolymerization of microtubules. Inhibition of these secondary
events appears to play an essential role in the lethal effect on worms. Benzimidazoles
progressively deplete energy reserves and inhibit excretion of waste products and
protective factors from parasite cells; therefore, an important factor in their efficacy is
prolongation of contact time between drug and parasite. Cross-resistance can exist
among all members of this group because they act on the same receptor protein, β-
tubulin, which is altered in resistant organisms such that none of the benzimidazoles can
bind to the receptor with high affinity.

b. Chemistry. All of these preparations, with the exception of febantel, have a side chain
that prevents hydroxylation of position 5. Therefore, these compounds are more potent
than thiabendazole, and dosages are usually less than those of thiabendazole.
c. Pharmacokinetics
(1) Absorption. Gastrointestinal absorption varies, depending on the water solubility of
the compound.
(2) Metabolism. The degree of metabolism is related to the 5C substitution.
(3) Excretion. The majority of benzimidazoles (except thiabendazole) are excreted
unchanged in feces.
(a) Drug residues persist for 1-3 weeks. They approach the low limit of detection in
2 days; however, residues in the liver are detectable for 2 weeks.
(b) The pre-slaughter withdrawal period in cattle is 27 days for albendazole, 8 days
for fenbendazole, and 7 days for oxfendazole.
d. Therapeutic uses
(1) Ruminants. Albendazole, fenbendazole, and oxfendazole are effective against major
gastrointestinal worms (in both the adult and larval stages). In addition, they are
effective against lungworms, eyeworm and tapeworm. However, they are ineffective
against filariae.
(2) Horses. Fenbendazole, mebendazole, oxfendazole, oxibedazole, and febantel have
activity similar to that of thiabendazole. In addition, they are effective against
ascarids, eyeworm and tapeworm.
(a) Fenbendazole is effective against Habronema.
(b) Mebendazole is active against lungworms at dosages of 15-20 mg/kg/day for 5
consecutive days.
(3) Dogs and cats. Fenbenazole, mebendazole, oxibendazole, and febantel are
effective against ascarids, hookworms, tapeworm and whipworms.
(a) Febantel is the only agent approved for use in cats.
 (b) Three to five consecutive daily dosages are usually necessary.
(4) Mebendazole is used for the treatment of trichinosis, particularly at the muscular
stage of Trichinella spiralis.
(5) These agents have more larvicidal and ovicidal activity than thiabendazole.
(6) Triclabendazole – effective for immature and mature liver fluke, no activity against
roundworm and tapeworm, use for acute fascioliasis.
e. Drug resistance. Cross-resistance occurs among all benzimidazoles.
f. Adverse effects. These agents are generally safe, although albendazole and
oxfendazole may be teratogenic. Hepatotoxicity may occur in dogs (partially as a result
of repeated administrations for 3-5 consecutive days).

B. NICOTINE-LIKE NEMATOCIDES

1. Levamisole is approved for use in ruminants and pigs.

a. MOA: Levamisole paralyzes worms by causing depolarizing neuromuscular blockade.
b. Pharmacokinetics:
(1) Absorption is excellent following gastrointestinal, topical, or parenteral administration.
(2) Excretion. The plasma half life is 4 hours, and the drug is eliminated from the body
in 2 days.
(a) Forty percent of the dose is excreted in the urine within 12 hours.
(b) The pre-slaughter clearance periods in pigs and cattle are 3 days and 7 days,
respectively.
c. Therapeutic uses
(1) Ruminants. Levamisole is effective against most mature gastrointestinal worms,
eyeworm and lungworms, but it has marginal activity against Strogyloides and
immature gastrointestinal worms.
(2) Pigs. It is effective against ascarids, intestinal threadworms, lungworms, nodular
worms, and kidney worms.
(3) Dogs. The use of levamisole as a microfilaricide for canine heartworms is an extra
label use.
d. Adverse effects. Levamisole is one of the most toxic anthelmintics. It has a low safety
margin, especially when given by injection.
(1) Signs of levamisole poisoning include parasympathetic stimulation, convulsions,
CNS depression, and asphyxia, which is primarily the result of respiratory muscle
paralysis.
(2) Atropine cannot counteract levamisole-induced depolarizing blockade of skeletal
muscle; therefore, it is not an antidote for levamisole overdose.
(3) Co-administration of levamisole and pyrantel, another nicotine-like nematocide,
increases toxicity.

2. Butamisole is a derivative of levamisole

a. Therapeutic uses. Butamisole is an injectable used to treat whipworms and hookworms
in dogs. Butamisole has microfilaricidal activity against heartworms; therefore, it may
cause anaphylactic reactions when inadvertently used in microfilaremic animals.
b. Contraindications. Butamisole is contraindicated in severely debilitated animals or those
with renal or hepatic disorders.

3. Pyrantel and morantel

a. Chemistry
 (1) Pyrantel, which is inactivated in aqueous solution upon exposure to light, should be
stored in tight, light-resistant containers. The drug should be used soon after
preparation of a drench solution or suspension.
(2) Morantel, the methyl ester of pyrantel, forms stable solutions.
b. Preparations
(1) Pyrantel tartrate is approved for horses and pigs.
(2) Pyrantel pamoate is approved for horses and dogs.
(3) Morantel tartrate is approved for cattle.
c. MOA: Like levamisole, pyrantel and morantel paralyze worms by causing depolarizing
neuromuscular blockade.
d. Pharmacokinetics
(1) Absorption
(a) Pyrantel tartrate is water soluble; therefore, gastrointestinal absorption is
excellent following oral administration. Peak plasma concentrations occur 2-3
hours after dosing.
(b) Pyrantel pamoate is poorly soluble in water, limiting gastrointestinal absorption.
Therefore, pyrantel pamoate is good for treatment of bowel worms (e.g.,
pinworms).
(c) Morantel tartrate is absorbed rapidly from the abomasums and small intestine.
Peak plasma concentrations occur 4-6 hours after dosing.
(2) Metabolism and excretion. The absorbed pyrantel and morantel are rapidly
metabolized and excreted, mostly via the feces, but also via urine. Pre-slaughter
withdrawal requirements are 1 day for pyrantel tartrate in swine and 14 days for
morantel in cattle.
e. Therapeutic uses
(1) Horses. Pyrantel is effective against strongyles, ascarids, and pinworms, but not
against bots.
(2) Pigs. Pyrantel is effective against ascarids, nodular worms, and stomach worms.
(3) Dogs. Pyrantel is effective against all GIT nematodes, but its activity against
whipworms is erratic.
(4) Ruminants. Morantel is effective against stomach worms, nodular worms, and other
principal intestinal worms.
f. Adverse effects. At recommended doses, adverse effects are not common. Emesis
may occur in dogs and pigs.
g. Contraindications. Because morantel and pyrantel have the same mechanism of action
as levamisole, these agents should not be used concurrently.

C. ORGANOPHOSPHATES

1. Preparations. Dichlorvos, trichlorfon, and coumaphos are widely used.

a. Dichlorvos and trichlorfon are approved for use in horses, pigs, and dogs. Dichlorvos
is rather unsafe in cattle and poultry.
b. Coumaphos is approved for use in cattle.

2. MOA: The organophosphate nematocides inhibit ACh breakdown by irreversibly inhibiting

AChE.
3. Pharmacokinetics
a. Dichlorvos is a lipophilic liquid that is incorporated into polyvinyl chloride resin pellets.
As these pellets traverse the gastrointestinal tract, dichlorvos diffuses into the intestinal
fluid, allowing the drug to come into contact with nematodes. The pellets release
approximately 50% of the drug in 48 hours. When passed into the feces, the pellets still
contain approximately 50% of the original dose of dichlorvos, enough to kill fecal fly
larvae.
b. Trichlorfon is a white crystal with poor water solubility that must be converted to
dichlorvos to be effective. Trichlorfon is metabolized rapidly after oral dosing and may
inhibit AChE for 2-3 weeks.
c. Coumaphos. The pharmacokinetics of coumaphos are not well understood.

4. Therapeutic uses. Organophosphates are effective against the major gastrointestinal

parasites.
a. Dichlorvos
(1) Pigs and dogs. Dichlorvos is effective against whipworms, nodular worms,
Strongyloides, hookworms, and ascarids in pigs and dogs. It has little or no
activity against migrating larvae of ascarids and hookworms.
(2) Horses. Dichlorvos is effective against bots, strongyles,, ascarids, and pinworms.
b. Trichlorfon is used mainly in horses. Is spectrum of activity is similar to that of
dichlorvos. It is one of the safest organophosphates and thus can be used in fish ponds.
c. Coumaphos is used in cattle to control stomach worms, whipworms, and Cooperia. To
improve safety, the drug is given orally as a feed supplement at the rate of 2 mg/kg/day
for 6 consecutive days.

5. Adverse effects
a. Toxicity
(1) Acute. Stimulation of cholinergic receptors may induce the SLUD syndrome.
(2) Chronic. Organophosphates may cause demyelination, inducing chronic
neurotoxicity.
b. Acute death may result from respiratory paralysis and cardiovascular arrest.

6. Contraindications. Organophosphate nematocides are not to be given to weak animals,

those exposed to other anticholinesterase agents, or those with gastrointestinal disorders.

D. ANTIBIOTICS

1. Ivermectin is an antibiotic extracted from Streptomyces avermitilis.

a. Mechanism of action. Ivermectin activates the GABA A-receptor-chloride channel
macromolecular complex, thus inhibiting neurotransmission in both arthropods and
animals. It may also increase the release of GABA from nerve terminals.
b. Pharmacokinetics
(1) After administration, more than 95% of the dose is metabolized in the liver. The
plasma half-life is 3 days in cattle.
 (2) Ivermectin remains in tissues with long persistency; one dose is usually effective for
2-4 weeks. Pre-slaughter clearance periods are 18 days in swine and 35 days in
cattle. Ivermectin should not be administered to milking dairy cattle.
c. Therapeutic uses and administration
(1) Ruminants. Ivermectin is effective against all major gastrointestinal worms and
lungworms and eyeworm. The standard dose is 0.2 mg/kg administered orally or
subcutaneously.
(2) Horses. It is effective against bots, stomach worms, strongyles, pinworms, eyeworm
and ascarids. The dose and route of administration are the same as for ruminants.
(3) Pigs. Ivermectin is effective against major gastrointestinal worms, lungworms, and
kidney worms. It is not effective against Trichinella during the muscular stage.
The standard dose is 0.3 mg/kg administered subcutaneously.
(4) Dogs
(a) Ivermectin is effective against ascarids, hookworms, and whipworms at a dosage
of 0.2 mg/kg. However, this dose may not be safe in some breeds (e.g., collies)
and is therefore not approved for dogs.
(b) It is effective as a microfilaricide (50 µg/kg) and heartworm preventive (6-12
µg/kg). The use of ivermectin as a microfilaricide is an extra label use.
(5) All species. Ivermectin is effective against all ectoparasites. It is used especially to
control mites.
d. Adverse effects. Ivermectin has a high safety margin in ruminants, horses, and swine,
and is safe for use in pregnant animals and breeders.
(1) Local irritation may occur following subcutaneous administration to swine.
(2) CNS depression. At high doses, ivermectin may evoke CNS depression as
evidenced by listlessness mydriasis, ataxia, recumbency, and coma. Although
ivermectin enhances the activity of the GABA system, the GABA receptor antagonist
picrotoxin does not work as an antidote.

2. Milbemycin is isolated from Streptomyces hygroscopicus.

a. Mechanism of action. The mechanism of action is the same as that of ivermectin.
b. Pharmacokinetics. Following oral administration, approximately 90% of the dose passes
through the gastrointestinal tract unchanged. The remaining approximately 10% is
absorbed and subsequently excreted in the bile. Therefore, nearly the entire dose is
eliminated in the feces.
c. Therapeutic uses. Milbemycin is approved for use in dogs only and is effective against
the infective larvae of Dirofilaria immitis, hookworms, whipworms, and ascarids.
Milbemycin at the recommended dose of 0.5 mg/kg can be used in all dog breeds,
including collies, and is safe in pregnant dogs and breeders.
d. Adverse effects. Milbemycin has a high safety margin in dogs; however, at high doses,
milbemycin may evoke CNS depression as evidenced by pyrexia, ataxia, and
recumbency.

E. MISCELLANEOUS ANTINEMATODAL DRUGS

1. Phenothiazine, the oldest antinematodal drug, was discovered in 1938.

a. MOA: The mechanism of action is not well understood. Phenothiazine may inhibit the
enzyme system involved in carbohydrate metabolism. Very high concentrations of
phenothiazine may inhibit cholinesterase.
 b. Pharmacokinetics
(1) Absorption. The gastrointestinal absorption of phenothiazine may be erratic;
generally, up to 50% of the dose is absorbed.
(2) Metabolism and excretion. Phenothiazine may be converted to phenothiazine
sulfoxide in the intestinal epithelium. Phenothiazine and phenothiazine sulfoxide are
further metabolized into two brown-red dyes, phenothiazone and thionol, which
may be evident in urine and milk.
c. Therapeutic uses. Phenothiazine has excellent efficacy against small strongyles, and
at high doses, it has good efficacy against large strongyles. It is mixed with piperazine
and trichlorfon as a tube formulation for use in horses.
d. Adverse effects. Phenothiazine may evoke dullness, weakness, anorexia, oliguria, colic,
constipation, fever, tachycardia, and signs of hemolysis (e.g., icterus, anemia,
hemoglobinuria).
e. Contraindications. Phenothiazine should not be used in pregnant, constipated, or weak
animals.

2. Piperazine
a. Preparations. Piperazine is available in adipate, citrate, hydrochloride, tartrate, or
phosphate form.
b. Chemistry. Piperazine is inactivated by moisture, carbon dioxide, and light; therefore,
containers should be tightly closed and protected from light.
c. MOA: Piperazine is a GABA-receptor agonist that inhibits neurotransmission
(hyperpolarization), resulting in paralysis of worms.
d. Pharmacokinetics
(1) Absorption. Piperazine salts are well absorbed from the gastrointestinal tract.
(2) Metabolism and excretion. Some piperazine is metabolized in the liver and the
remainder (30%-40%) is excreted in the urine. Urinary excretion of piperazine starts
as early as 30 minutes after dosing, and is complete within 24 hours.
e. Therapeutic uses. Piperazine is effective against ascarids and nodular worms in all
species; however, its use is limited in ruminants, because ascarids are not a significant
problem in this species. Thiabendazole is combined with piperazine to increase
ascaricidal activity.
f. Adverse effects. Piperazine is a very safe drug, but large doses may produce vomiting,
diarrhea, and ataxia.

3. Toluene
a. Chemistry. Toluene is an organic liquid.
b. Pharmacokinetics
(1) Absorption. Toluene is absorbed well from the gastrointestinal tract following oral
administration.
(2) Metabolism and excretion. It is metabolized into benzoic acid within 24 hours of
administration and is excreted in the urine.
c. Therapeutic uses and administration. Toluene is approved for use in dogs and cats.
Because it is irritating to the oral mucosa, toluene is administered in gelatin capsules.
(1) It is effective against ascarids and has limited activity against hookworms. To
enhance efficacy, toluene may be combined with n-butyl chloride (another mild drug
effective against ascarids and hookworms).
(2) Toluene is used in combination with dichlorophen (an anticestodal drug).
d. Adverse effects. Toluene may cause anorexia, vomiting, diarrhea, tremors, and ataxia.
4. Thenium closylate (Canopar)
a. Chemistry. Thenium closylate is a nicotine-like quaternary drug that is soluble in water.
b. Mechanism of action. Like levamisole and pyrantel, thenium closylate paralyzes worms
by causing depolarizing neuromuscular blockade.
c. Pharmacokinetics. When administered orally, thenium closylate is poorly absorbed from
the gastrointestinal tract because of its quaternary structure.
d. Therapeutic uses. Thenium closylate is used strictly in dogs to control hookworms. It
is effective against adult worms, immature worms, and fourth stage larvae. It has no
activity against other worms.
e. Adverse effects. Thenium closylate has a wide margin of safety because
gastrointestinal absorption is limited.
(1) Vomiting. Approximately 20% of dogs treated with the drug experience vomiting.
(2) Rarely, sudden death may occur following dosing with thenium closylate.

IV. DRUGS FOR HEARTWORM PREVENTION AND THERAPY

A. INTRODUCTION. Treatment and prevention of heartworm involve three aspects:

1. Removal of adult heartworms requires an adulticide.

2. Interruption of the life cycle requires a microfilaricide. Treatment to eliminate microfilariae

should be initiated 3-4 weeks after the adulticide treatment.

Life cycle: Heartworm infection is caused by a filarial organism, Dirofilaria immitis . At least 70
species of mosquitoes can serve as intermediate hosts: Aedes, Anopheles , and Culex are the
most common vectors. Patent infections are possible in numerous wild and companion animal
species e.g. wolves, coyotes, foxes, California gray seals, sea lions, and raccoons. In
companion animals, it is seen primarily in dogs and less commonly in cats and ferrets and has
been reported in most countries with temperate, semitropical, or tropical climates, including the
USA, Canada, and southern Europe.

Infected mosquitoes are capable of transmitting HW infections to man, but there are no reports
of such infections becoming patent.

Mosquito vector species acquire the 1st stage larvae (microfilaria/(L1) while feeding on an
infected host. Development of microfilaria to the 2nd larval stage (L2) and to the infective 3rd
stage (L3) occurs within the mosquito in ~1-4 wk, depending on environmental temperatures.
This development phase requires the shortest time when the ambient temperature is >30°C.
When mature, the infective larvae (L 3) migrate to the labium of the mosquito. As the mosquito
feeds, the infective larvae (L3) erupt through the tip of the labium with a small amount of
hemolymph onto the host’s skin. The larvae migrate into the bite wound, beginning the
mammalian portion of their life cycle. A typical Aedes mosquito is only capable of surviving the
developmental phase of small numbers of HW larvae, usually <10 larvae/ mosquito.

In canids and other susceptible hosts, infective larvae (L3) molt into a 4th stage (L4) in 2-3
days. After remaining in the subcutaneous tissue for close to 2 months, they molt into young
adults (L5) that migrate through host tissue, arriving in the pulmonary arteries ~50 days later.
Adult worms (males, ~15 cm in length, females, ~25 cm) develop primarily in the pulmonary
arteries of the caudal lung lobes over the next 2-3 mo. They reside primarily in the pulmonary
arteries but can move into the right ventricle when the worm burden is high. Microfilariae (L1)
are produced by gravid females ~6-7 months post-infection.

Adults typically live 3-5 years, while microfilariae may survive for 1-2 years while awaiting a
mosquito intermediate host.

a. Microfilaricidal treatment reduces the incidence of glomerulonephritis induced by masses

of microfilaria.
b. Microfilaricidal treatment reduces the possibility of an anaphylactic reaction to
diethylcarbamazine (DEC) in microfilaria-positive dogs.
c. Microfilaricidal treatment eliminates the source of heartworm infection (minor reason for
eliminating microfilaria).

3. Prevention of infection requires a larvicide (kills L1).

B. ADULTICIDES kill both immature (L5) and adult heartworms.

1. Thiacetarsamide (Caparsolate) is the only adulticide available commercially.

a. Chemistry. Thiacetarsamide is a trivalent arsenic compound.
b. Mechanism of action: Thiacetarsamide denatures metabolizing enzymes by binding to
the sulfhydryl groups of cysteine residues.
c. Pharmacokinetics
(1) Distribution. The drug is widely distributed in the body, but is concentrated in the
liver and kidneys.
(2) Metabolism and excretion. Thiacetarsamide is metabolized in the liver. Following
intravenous injection, thiacetarsamide has an elimination half-life of approximately 45
minutes and a clearance rate of approximately 200 ml/kg/min. After administration,
85% of the dose is eliminated within 48 hours, primarily in the feces (66%). Some of
the dose is excreted in the urine as well.
d. Administration. The dosage is 2.2 mg/kg intravenously, twice daily for 2 days.
e. Adverse reactions. Thiacetarsamide has a narrow margin of safety; therefore,
dosages must be accurately determined to avoid serious adverse effects. In case of
overdose, dimercaprol (BAL) can be used as an antidote.
(1) Tissue sloughing and phlebitis may occur if thiacetarsamide is injected into the
perivascular space. Local injection of a glucocorticoid may inhibit the reaction.
(2) Vomiting. Dogs may vomit after thiacetarsamide administration. Only persistent
vomiting, which may be indicative of hepatotoxicity, warrants concern.
 (3) Hepatotoxicity affects approximately 20% of animals receiving thiacetarsamide.
Should severe liver damage occur, thiacetarsamide should be discontinued and
supportive treatment for liver disease should be instituted as needed.
(4) Renal toxicity may occur after thiacetarsamide therapy. Renal casts alone are
generally not an indication that thiacetarsamide treatment should be interrupted;
however, blood urea nitrogen greater than 100 mg/dl and albuminuria are indications
that treatment should be discontinued for at least 4 weeks.
(5) Thromboembolic pneumonia may result as dead heartworms accumulate, usually
in the caudal lung lobes. Adult heartworms begin to die within days of
thiacetarsamide treatment and continue to die over a 3-week period. To minimize
mortality, animals should be kept on strict rest, usually for 1 month following
therapy.
(a) Signs include coughing, dyspnea, hemoptysis, fever, anorexia, and lethargy.
(b) Treatment. Aspirin and glucocorticoids may be used for 2 weeks to treat
thromboembolic pneumonia. Antibiotics may be administered to prevent
secondary bacterial infection.

2. Melarsomine (Immiticide) – new and given IM

a. Chemistry. Melarsomine is also a trivalent arsenical compound.
b. Mechanism of action. Its mechanism of action is the same as that of thiacetarsamide
(L5 and adult).
c. Pharmacokinetics
(1) Absorption. Following intramuscular injection, melarsomine has a mean absorption
half-life of 2.6 minutes and a peak concentration in blood at 8 minutes.
(2) Distribution. Melarsomine is found in both plasma and red blood cells, whereas
thiacetarsamide is found only in red blood cells.
(3) Excretion. Melarsomine is retained in the body five times longer than
thiacetarsamide. The body clearance is approximately three times lower for
melarsomine than thiacetarsamide.
d. Administration. The advantage of melarsomine over thiacetarsamide is that
melarsomine can be administered intramuscularly.
(1) The usual dosage is 2.5 mg/kg once daily for 2 days.
(a) The first injection should be administered in the right lumbar muscles and the
second in the left.
(b) This two-dose schedule completely eliminates all worms from 60%-81% of dogs.
The regimen can be repeated in 4 months to increase the efficacy to 98%.
(2) For dogs with severe infection, a single dose (2.5 mg/kg) is followed by the full two-
dose treatment 1 month later. The initial single dose kills 88% of male and 17% of
female worms, hence providing some relief of clinical signs while reducing the risk of
complications from pulmonary embolism. This regimen removes all worms from
approximately 85% of dogs.
e. Adverse reactions
(1) Mild localized edema may occur following intramuscular injection.
(2) Hepatotoxicity and renal toxicity may be milder than thiacetarsamide.
(3) Thromboembolic pneumonia may be as severe as that seen with thiacetarsamide
treatment.
(4) Overdose may result in distress, restlessness, pawing, salivation, vomiting,
tachycardia, tachypnea, dyspnea, abdominal pain, hindlimb weakness, and
recumbency. Severe cases terminate in circulatory collapse, orthopnea, coma, and
death. Toxicity can be reversed by intramuscular injection of 3 mg/kg dimercaprol
 (BAL) within 3 hours of the onset of symptoms. However, dimercaprol may reduce
the efficacy of melarsomine.

C. MICROFILARICIDES – kills L2-L4

1. Agents. Microfilaricidal use is an extra label use for ivermectin and milbemycin; however,
these are the only two drugs that may be safely and effectively used for this purpose. These
agents are discussed in detail in III D.

2. Administration
a. Ivermectin - one dose at 50 µg/kg administered orally or subcutaneously. This drug is
contraindicated in collies.
b. Milbemycin. One dose at 0.5 mg/kg is administered orally; treatment may be repeated
in 2 weeks. This drug can be safely used in collies.

3. Adverse reactions. Transient weakness, pale membranes, intestinal hyperperistalsis, and

tachypnea may be seen following administration of a microfilaricide, suggesting a mild
cardiovascular shock resulting from reactions to dead microfilariae. The higher the
microfilaria count, the greater the chance of encountering noticeable adverse effects.

D. LARVICIDES - kills L1

1. Diethylcarbamazine (DEC) kills HW L1, thereby eliminating stages L2-L5 of the heartworm
life cycle.
a. Chemistry. DEC is a piperazine derivative.
b. Mechanism of action. Like piperazine, DEC is a GABA-receptor agonist.
c. Pharmacokinetics
(1) After oral administration, plasma levels peak at 3 hours and fall to zero in 48 hours.
The therapeutic level of DEC has to be maintained by daily dosing.
(2) Ten to thirty percent of the dose is excreted as the unchanged drug in urine. The
rest is excreted as metabolites.
d. Administration. DEC citrate (2.5-3 mg/lb/day) is administered orally daily during and 2
months after the mosquito season.
e. Adverse reactions
(1) Adverse reactions are minimal if there are no microfilariae in the bloodstream. DEC
causes potentially fatal anaphylactic reactions in microfilariae-positive dogs. It has
been suggested that DEC liberates substances from microfilariae that constrict the
hepatic vein.
(2) At high doses (i.e., greater than 50 mg/kg), DEC may induce vomiting and gastric
mucosa irritation.

2. Ivermectin (Heartgard) is a larvicide that kills HW L 1. It is administered orally at dosages of

6-12 µg/kg once monthly. The first dose is given within 1 month following the last exposure
to mosquitoes. Because it takes 2.5 months for L 4 larvae to develop into L5 larvae, the
elimination of larvae in the L4 stage once monthly is effective.
3. Milbemycin (Interceptor). Kills L1-L4, when used as a larvicide, milbemycin is administered
orally once monthly (0.5 mg/kg) following the same principles as those for ivermectin
administration.

V. ANTICESTODAL AGENTS

A. GENERAL INFORMATION

1. These agents kill tapeworms, as opposed to arecoline, an obsolete taeniafuge that only
paralyzes them.

2. Worms killed by these drugs may be digested by the host animal; therefore, they may not be
evident in the feces.

3. Control of intermediate hosts (e.g., fleas for Dipylidium and rodents for Taenia is necessary.

B. DICHLOROPHEN

1. Mechanism of action. Dichlorophen causes uncoupling of oxidative phosphorylation to

deplete ATP.

2. Pharmacokinetics. Gastrointestinal absorption of dichlorophen, a lipid-soluble drug, is

greatly enhanced when it is combined with toluene (an organic solvent).

3. Therapeutic uses. Dichlorophen is used to treat Taenia infestations in dogs and cats. Its
efficacy against Echinococcus and Dipylidium is variable.

4. Administration. Dichlorophen is best given orally after an overnight fast. As with all of the
anticestodal agents, purgation is unnecessary.

5. Adverse effects. No side effects have been reported, other than salivation if the animal bites
the gelatin capsule.
C. BENZIMIDAZOLES (see III A). Mebendazole, fenbendazole, oxfendazole, and albendazole
are effective against mature Taenia and Echinococcus in dogs and cats, and Moniezia in
ruminants. They may kill intermediate cysts of Taenia in infected sheep and cattle. These
agents are not effective against Dipylidium. Mebendazole and albendazole are used to
control hydatid cysts in humans.

D. PRAZIQUANTEL (Droncit, Canex ‘praziquantel + pyrantel’)

1. Mechanism of action. Praziquantel causes paralysis and digestion of tapeworms as well

as irreversible focal vacuolization and disintegration of integument. The exact
mechanism of action is unknown, but these activities may be mediated by an increase in
intracellular Ca2+ concentration, attributable to increased Ca2+ influx.

2. Pharmacokinetics
a. Absorption. Praziquantel is completely absorbed within 30-120 minutes of oral dosing.
b. Distribution. It is distributed throughout the body, including the CNS.
c. Metabolism and excretion. Praziquantel is metabolized to unknown compounds in the
liver and excreted primarily in the urine. The elimination half-life is 3 hours in dogs.

3. Therapeutic uses. Praziquantel is effective against all species of tapeworms and kills
both adults and juveniles. However, its activity against hydatid cysts is erratic.

4. Administration
a. Praziquantel is approved for use in dogs and cats, and has been used in birds and
other animals. Use in large animals may not be economically feasible.
b. Praziquantel may be administered orally or subcutaneously. Fasting is not necessary.

5. Adverse effects. safest anticestodal

a. Overdose induces anorexia, vomiting, salivation, diarrhea, and lethargy in less than 5%
of animals receiving the drug.
b. no teratogenic or embryotoxic effects.

E. EPSIPRANTEL (Cestex), a praziquantel analog, is approved for use in dogs and cats.
Epsiprantel is administered orally. Unlike praziquantel, epsiprantel is absorbed poorly after
oral administration and most of the drug is eliminated in the feces (less than 0.1% of the
drug is recovered in the urine after dosing).
Praziquantel and epsiprantel are closely related analogs that have high efficacy against
cestode parasites at relatively low dose rates but no effect on nematodes. Praziquantel
exerts its antiparasitic effects by interfering with the regulation of intracellular Ca 2+
concentrations, impairing both motility and function of the suckers of the cestode. In
vivo studies have indicated that it induces spastic paralysis of the parasite; thus,
 praziquantel acts, as many anthelmintics, primarily on neuromuscular coordination.
Praziquantel is rapidly and almost completely absorbed from the GI tract. After absorption,
the drug is distributed to all organs; it is believed to reenter the intestinal lumen via the
mucosa and bile of dogs. Praziquantel is rapidly hydroxylated into inactive forms in the liver
and secreted in bile. It has a wide safety margin.

Praziquantel PO is highly effective against cestodes of ruminants (eg, Moniezia spp ,

Stilesia ), horses (Anoplocephala perfoliata ), and poultry. The PO (5 mg/kg) or SC (5.8
mg/kg) administration of praziquantel in dogs and cats is 100% effective against Taenia spp
and Echinococcus granulosus (both adult and immature forms). Praziquantel at a dosage of
40 mg/kg is also effective against Schistosoma infections in cattle (and humans).

Epsiprantel at 5 mg/kg is used specifically for the treatment of the common tapeworms of
dogs and cats, including adult E granulosus .

VI. ANTITREMATODAL DRUGS

A. ALBENDAZOLE is approved for use against mature liver flukes (e.g., Fasciola hepatica) in
cattle. Albendazole requires a 27-day preslaughter withdrawal period. Because
albendazole is a teratogen, it cannot be used in pregnant cattle during the first 45 days of
gestation or in female dairy cattle of breeding age.

B. PRAZIQUANTEL is effective against lung flukes in dogs. It is also effective against liver
flukes, however it is too expensive for use in ruminants.

C. CLORSULON (Curatrem)

1. Mechanism of action. Clorsulon inhibits 3-phosphoglycerate kinase and

phosphoglyceromutase in the glycolytic pathway, depriving the flukes of a metabolic energy
source.

2. Pharmacokinetics. Clorsulon is lipid soluble. After oral dosing, it is absorbed rapidly. Peak
levels occur within 4 hours, and blood levels of clorsulon peak 8-12 hours after
administration. The pre-slaughter withdrawal period is 8 days and the milk withdrawal
period is 4 days.

3. Therapeutic uses. Clorsulon is the most effective drug against F. hepatica, killing both
mature and immature flukes in ruminants. However, its activity against F. magna is poor.
4. Adverse effects. When used as directed, adverse effects are rare. Clorsulon is safe in
pregnant and breeding animals.

D. RAFOXANIDE – against immature and mature liver fluke

E. TRICLABENDAZOLE (fascinex) – against all stages of liver fluke, safe for pregnant
animals, non-teratogenic.

VII. ANTIPROTOZOAL DRUGS

This discussion focuses on anticoccidial drugs and metronidazole. With the exception of
metronidazole, other antiprotozoal drugs are not safe for use in animals.

A. ANTICOCCIDIAL DRUGS

1. Introduction
a. Financial implications of coccidiosis. Coccidiosis, a prevalent disease in calves,
piglets, and poultry causing significant losses: impaired feed conversion, slow growth,
and the poor quality of carcasses at processing.
b. Therapeutic approaches:
(1) Poultry. Most of the anticoccidial drugs discussed in this section are used in
chickens.
(a) Broilers are not vaccinated against coccidian because latent infection may retard
growth. Amprolium, the non-withdrawal anticoccidial drug, is administered 1
week prior to slaughter.
(b) Layers are vaccinated against coccidian. Outbreaks are usually treated with a
sulfonamide, amprolium, toltrazuril, diclazuril on an as-needed basis.
(2) Mammals can be treated with sulfonamides, ormetroprim, amprolium, decoquinate,
or Na+ ionophores, toltrazuril.
c. Resistance to anticoccidial drugs is minimized by using two or more drugs sequentially.
Overemphasized switching may decrease immunity; therefore, it may be self-
defeating.
(1) Shuttle program. Different anticoccidial drugs are used in a single grow-out.
(2) Rotation (switch) program. Different anticoccidials are used between two grow-
outs.
d. Life cycle of avian coccidian: A coccidial infection differs from bacterial and viral
infections because coccidia are “self-limiting” and usually stop multiplying before killing
the bird. Coccidiosis is caused in poultry by a one-celled parasite of the genus Eimeria.
The life cycle of Eimeria takes about 4-7 days to complete. It begins when active
“oocysts” are picked up by the bird and swallowed. An “oocyst” is a capsule with a thick
wall protecting the parasites. They “sporulate” or become infective if moisture,
temperature, and oxygen become conducive to growth. After a bird eats the oocysts,
coccidia imbed in the intestinal lining and multiply several times, damaging tissue. A
single sporulated oocyst can have a big impact when eaten by a chicken. Each oocyst
has 4 sporocysts in it, and each sporocyst has 2 sporozoites in it. The digestive tract
releases the 8 sporozoites from the oocyst, and they move into the cell lining of the
digestive tract. Inside the cell, the parasite divides and invades more cells. There may be
several generations of asexual multiplication; however, this stage is self-limiting and
eventually stops. Finally, a sexual stage occurs in which male and female organisms
 unite and form new oocysts that are protected by a thick wall. The bird sheds the oocyst
in its droppings. These new oocysts can infect other birds.

2. Agents

a. Decoquinate
(3) Chemistry. Decoquinate is a quinolone.
(4) MOA: Decoquinate may block DNA synthesis by inhibiting DNA gyrase.
(5) Pharmacokinetics. The pharmacokinetics of decoquinate are not well understood.
The pre-slaughter withdrawal period is 5 days when used in broilers.
(6) Therapeutic uses
(a) Decoquinate is approved for use in calves, young goats, and broilers for the
prevention of coccidiosis. It is not effective for treating clinical coccidiosis.
(b) It should be effective against all species of avian Eimeria on the first sporozoite
stage. Use is limited because of its tendency to induce drug resistance
(attributable to its action on such an early stage of the asexual cycle of the
coccidia).
(c) It is effective against bovine Eimeria, E. bovis, and E. zuernii and caprine E.
christenseni and E. ninakohlyakimovae.

(7) Toxicity. No adverse effects are seen when the drug is used as directed.

b. Na+ ionophores
(1) Preparations include monensin, salinomycin, and lasalocid. These antibiotics are
used exclusively as anticoccidial drugs.
(2) MOA: Na+ ionophores facilitate the transport of Na + into cells, elevating intracellular
Na+ concentrations. As a result, certain mitochondrial functions (e.g., substrate
oxidations) and ATP hydrolysis are inhibited.
(3) Therapeutic uses
(a) Ionophores are effective against all Eimeria species in chickens, cattle, and
sheep.
(i) Monensin (elancoban) is approved for use in cattle and sheep.
(ii) Lasalocid is approved for use in cattle, sheep, and chickens for prevention of
coccidiosis. In chickens, it attacks the first generation of trophozoites and
schizonts. The pre-slaughter withdrawal period for lasalocid is 5 days in
chickens.
(iii) Salinomycin (salocin/intervet)is approved for use in chickens only. The pre-
slaughter withdrawal is not required.
(b) Ionophores are also used as growth promoters.
(4) Adverse effects. These drugs may cause severe cardiovascular side effects. In
animal cells, intracellular Na+ further exchanges for extracellular Ca 2+, thereby
increasing intracellular Ca2+ concentrations. In addition, these drugs may directly
facilitate Ca2+ transport into the cells. High intracellular Ca 2+ levels in cardiac and
skeletal muscle cells are responsible for the toxic effects of these drugs in animals.
Do not use with tiamulin.
(5) Contraindications. Horses and turkeys are very sensitive to Na + ionophores.
Accidental consumption by these animals can be fatal.
c. Amprolium – (Amprol/Merial)
(1) Chemistry. Amprolium is a quaternary compound.
(2) Mechanism of action. Amprolium prevents coccidia from utilizing thiamine by
blocking thiamine receptors.
(3) Pharmacokinetics
(a) Amprolium is poorly absorbed after oral administration.
(b) No preslaughter withdrawal period is necessary.
(4) Therapeutic uses. Amprolium is the only anticoccidial agent that can be used in
laying birds and cattle for both the prevention and treatment of outbreaks.
(a) It is effective against the first generation of trophozoites and schizonts.
(b) Amprolium is rarely used alone, because E. maxima, E. mivati, and other species
are resistant; combination with sulfa drugs increases the efficacy of amprolium
against these organisms in chickens.
(5) Adverse effects. Amprolium is a safe drug when used as directed. Thiamine
deficiency may occur in the host following overdose.

d. Nicarbazin (maxiban: ‘nicarbazin+narasin/elanco), narasin (monteban/elanco)

(1) Chemistry. Nicarbazin is a mixture of 4,4’-dinitrocarbanilide (DNC) and 2-hydroxy-
4,6-dimethylpyrimidine (HDP).
(2) Mechanism of action. Nicabazin’s mechanism of action is unknown.
(3) Pharmacokinetics
(a) Absorption. DNC and HDP are absorbed separately from the digestive tract.
DNC is absorbed more rapidly but disappears more slowly from the tissues than
HDP.
(b) A 4-day withdrawal period is required before broilers are markted.
(4) Therapeutic uses. Nicarbazin is approved for use in chickens to prevent coccidiosis
outbreaks.
(a) It is effective against all Eimeria species.
(b) Its peak activity is on second-generation trophozoites.
(5) Toxicity
(a) Nicarbazin may bleach brown-shelled eggs, cause mottled egg yolks and poor
hatchability, and impair egg production.
(b) Medicated broilers may be more susceptible to heat stress.

e. Robenidine
(1) Pharmacokinetics. The pharmacokinetics of robenidine are not well understood.
(2) Mechanism of action. The mechanism of action is undetermined. Its peak activity is
on the first generation schizonts.
(3) Therapeutic uses. Robenidine is approved for use in chickens to prevent outbreaks
of coccidiosis. It is effective against all Eimeria species.
(4) Adverse effects. Robenidine imparts an unpleasant taste to the flesh of broilers if
therapy is not terminated 5 days before slaughter. The taste is imparted to eggs
when birds are fed at dosages equal to or greater than 66 ppm. The ability of
humans to taste robenidine is apparently genetically linked.

f. Sulfonamides have the longest history of use as anticoccidial drugs. These agents are
discussed in detail in Chapter 11 II.
(1) Preparations. Sulfonamides used most frequently as anticoccidial agents include
sulfadimethoxine, sulfachloropyrazine, sulfaquinoxaline (Noxal,pfizer), and
ethopabate [not a sulfa drug, but also a p-aminobenzoic acid (PABA) antagonist].
 (2) Therapeutic uses. These drugs are used for both the prevention and treatment of
coccidiosis outbreaks in all species.
(a) They are more effective against the intestinal than cecal species of coccidia.
(b) Their peak activity is against the second-generation schizonts.
(c) Use of these drugs does not impair immunity development.

g. Antifolate compounds
(1) Preparations include ormetoprim and pyrimethamine. Pyrimethamine is not
approved for food animal use.
(2) Mechanism of action. These drugs block the conversion of dihydrofolate into
tetrahydrofolate, thereby inhibiting thymidine synthesis in protozoans and bacteria.
(3) Pharmacokinetics. After oral dosing, therapeutic levels of ormetoprim are
maintained for over 24 hours.
(4) Therapeutic uses. Ormetoprim and pyrimethamine are synergestic with sulfa drugs;
when combined with a sulfonamide, they are used to treat coccidiosis outbreaks and
toxoplasmosis. The pre-slaughter withdrawal period for sulfonamides plus
ormetoprim is 5-10 days in chickens.

h. Toltrazuril (baycox, cevazuril), diclazuril, (clinacox) – prevention and treatment of

coccidiosis in poultry and piglets. Effective in all stages of the parasite.

B. METRONIDAZOLE

1. Chemistry. A nitroimidazole antiprotozoal and antibacterial agent, metronidazole is

sparingly soluble in water.

2. Mechanism of action. A ferredoxin-linked metabolite of metronidazole disrupts DNA

synthesis in protozoans and bacteria.

3. Pharmacokinetics
a. Absorption. The oral bioavailability of metronidazole in animals varies from 50%-100%.
If given with food, absorption is enhanced in dogs, attributable to increased bile
secretion that helps dissolve metronidazole. Peak blood levels occur within
approximately 1 hour of dosing.
b. Distribution. Metronidazole is rapidly and widely distributed after oral absorption
because it is highly lipid soluble.
c. Metabolism and excretion. Metronidazole undergoes hydroxylation and conjugation in
the liver. Both metabolites and unchanged drug are eliminated in the urine and feces in
24 hours. Elimination half-lives of metronidazole are 4-5 hours in dogs and 3-4.5 hours
in horses.

4. Therapeutic uses. Metronidazole is a broad-spectrum antiprotozoal drug that is effective

against giardiasis, histomoniasis, babesiosis, trichomoniasis, and amebiasis. It is approved
as a human drug and has been used largely in small animals.

5. Toxicity. Metronidazole may induce lethargy, weakness, ataxia, rigidity, anorexia, vomiting,
diarrhea, reversible leucopenia, and hepatotoxicty. Because metronidazole affects DNA
 synthesis, it may have teratogenic and carcinogenic effects.

6. Drugs against trypanosomiasis – suramin, homidium bromide, pyrithidium bromide,

diminazene aceturate

7. Drugs used in the treatment of babesiosis – diminazene aceturate, quinoronium sulfate,

phenamidine isothionate

8. Drugs for anaplasmosis – imidocarb propionate, tetracycline

9. Drugs for leukocytozoonosis – treatment is poor, prevention is much better: pyrimethamine

and sulfadimethoxine

10. Drugs for toxoplasmosis – clindamycin, pyrimethamine