Pharm Notes

Drugs Acting on the Autonomic Nervous System – Weber
Effector Tissues Sympathetic Response – fight/flight Parasympathetic Response – rest/digest

Heart 1 – general excitation M2 receptors – general inhibition
SA node  HR/force/velocity/automaticity  HR, force, velocity
Atria
AV node AV block possible
His-Purkinje system
Ventricles Irritability – susceptible to arrhythmias
Blood vessels – arteriole 1 – contraction; 2 relaxation M3 – relax (no innervation)
Coronary 1 – contraction; 2 relaxation M3 – relax (dogs); contract (pig)
Cutaneous, mucosal 1 – contraction; 2 relaxation M3 – relax
Cerebral 1 – contraction; 2 relaxation M3 – relax
Skeletal muscle 1 – contraction; 2 relaxation M3 – relax
Splanchnic 1 – contraction; 2 relaxation M3 – relax
Renal M3 – relax
1 – contraction; 2 relaxation
Genital M3 – relax
1 – contraction
Veins
GIT General inhibition General excitation
Smooth muscle 1 relax;  – relax M3 -  motility/tone
Sphincters  – contraction Relax
Secretions  
Gallbladder/ducts relax contracts
Bronchioles
Smooth muscle 2 relaxation M3 – contract
Glands  
Eye
Radial muscle, iris 1 = mydriasis – pupil dilation M – miosis – pupil constriction
Sphincter muscle, iris M – contract (near vision)
Ciliary muscle  – relax (far vision)
Urinary Bladder Urinary Retention M – urination
Fundus 1 – relax M – contract
Trigone, sphincter  – contract M – relax
Sweat Glands Profuse, watery secretions
M – most species
2 – horse
Salivary Glands  – dry mouth M – watery salivation
Piloerector muscles  – contract
Kidney renin release 1 – increase
1 – decrease
Uterus 2 – relaxation M – contract
Adrenal Medulla Nn – secretion (Epi > NE)
Autonomic Ganglia Nn – ganglionic discharge Nn – ganglionic discharge
Liver 2 – glycogenolysis and
gluconeogenesis
Pancreas
Islet cells 2 – ; 2 –  secretion
Acini  -  secretion M -  secretions
Fat cells 1 – lipolysis
Adrenergic Nerve 2 –  NE release +/- NE release
Terminals 2 –  NE release
Platelets 2 - aggregation
Muscarinic receptors (on effector organs in the

parasympathetic system)
 M1, M2, M3, M4, M5
 M2 on the heart, M3 on blood vessels and
exocrine glands.
o Don’t need to know M1, M4, M5.
 Don’t have good pharmacological receptors that can
distinguish between the subtypes.
 We will be concerned with muscarinic agonists and
antagonists in general - these are 'dirty' drugs - they
have wide spread effects and do not target specific
organs.
Norepinephrine and Epinephrine

 -adrenergic (1, 2)
o 1 receptor (NE>Epi) - on blood vessels
(vasoconstriction)
 -adrenergic (1 - heart, 2 - smooth muscle, blood vessels, 3 - leptin, controls metabolism  lipolytic effect,
anti-obesity drugs).
 We have good tools to distinguish among these different subtypes (selective activation or blockage by agonists
and antagonists).
o 1 receptor (Epi>NE) - on the heart
o 2 (Epi >>> NE) - on blood vessels (vasodilation)
Baroreceptor Reflex
 Found in aortic arch and in the carotid sinus (where blood pressures are high)
 Rapid response to changes in blood pressure
 Information from receptors go to medullar via afferent fibers
 Vagus nerve (parasympathetic) takes information from the brain to the heart
 Sympathetic nerve fibers go from medulla to ganglia and then to blood vessels .
Cholinergic Agonists
Drug Receptor Notes
Selectivity
Direct-acting agonist Non-selective Carbachol has a similar structure to Ach but has a longer duration of
 Acetylcholine cholinergic action.
 Carbachol (N=M) Shouldn’t be used systemically because it targets the heart and stops
it. It is commonly used in ophthalmic preparation – acts on M
receptors and causes pupil constriction (near vision)
Direct-acting agonist Nicotinic Common toxicity from animals chewing cigarettes or neonicotioids.
 Nicotine selective Acts on Nm receptors at motor end plate and in the ganglion
(N>>M) (activates parasympathetic and sympathetic system).
Parasympathetic stimulation dominates in the gut (increases
motility/secretions) and in the heart (heart rate drops). Sympathetic
stimulation dominates in vasculation (vasoconstriction).
Direct-acting agonist Muscarinic Stimulates muscarinic receptors through the parasympathetic system
 Muscarine selective to drop the heart rate.
 Bethanechole (M>>N)
 Pilocarpine
Indirect acting-agonists Non-selective ACh esterase inhibitors primarily act at the neuromuscular junction,
(ACh esterase inhibitors). (N=M) prolonging the presence of Ach in the synaptic cleft which causes
Irreversible: prolonged activation of Nm receptors and contraction of the myocyte.
 Organophosphate
or carbamate Edrophonium should be used when there is weak neurotransmission
insecticides (muscle weakness).
Reversible:
 Edrophonium
 Neostigmine
Cholinergic Antagonists
Drug Receptor Selectivity Notes
Atropine Muscarinic selective  Inhibits muscarinic receptors.

Ipratropium antagonist  Atropine is a common pre-anesthetic drug (decreases secretions)
(M>>N) & causes bronchodilation (prefer to use a  agonist that does not
cause a decrease in HR).
Hexamethonium NN blocker (ganglionic  Low doses – block ganglionic transmission in the sympathetic
Trimethaphan blocker) and parasympathetic system.
(NN >NM>>M)
 High doses – get interference with the motor system
 Can be used to treat hypertension.

Tubocurarine NM blocker  Tubocurarine and Pancuronium inhibit NM receptors and cause
Pancuronium (neuromuscular muscle paralysis. Should be used with an analgesic
blocker)
(NM>NN >>M)  Succinylcholine activates NM receptors causing depolarization of
Succinylcholine the muscle cell, and has slow disassociation from the receptor,
polarization is prevented and causes muscle paralysis.
Adrenergic Agonists
Drug Receptor Selectivity Notes
Epinephrine    Equally activates all  and  receptors.

 stimulation causes vasodilation in vascular beds supplying
skeletal muscle
 1 stimulation in arterioles causes
 Net effect = decreased TPR (decreased diastolic pressure too) 
less vagal firing  increases HR
Norepinephrine     1 stimulation in arterioles causes vasoconstriction  increases
TPR  increases diastolic BP.
 stimulation increases HR  increased SV  increased CO 
increase in pulse pressure.
Isopreterenol   -selective, equally stimulates both 1 and 2 receptors but does
not really stimulate  receptors
 stimulation causes vasodilation in vascular beds supplying
skeletal muscle  huge decrease in TPR  decrease in diastolic
pressure  feedbacks and causes massive increase in HR 
increase CO  increases pulse pressure.
 Used in emergencies to support cardiac function, causes some

vasodilation.
Dopamine D  Lots of D1 receptors in renal vasculature. Stimulation here causes
dilation and increased renal perfusion (good during times of shock).
 Vasodilator in the renal vasculature (good for shock treatment) to
preserve renal blood flow/function
 High doses will also stimulate 1 receptors causing an increase in

HR supporting cardiac function and blood pressure and maybe
some 2 stimulation causing minor vasodilation throughout entire
body decreasing TPR  decrease diastolic pressure
Dobutamine   Good for cardiac support in crashing animal.

 Doesn’t cause a lot of vasoconstriction compared to epinephrine.
Phenylephrine   Selective agonist for 1.

 High doses also stimulate 2 receptors.
 Should be used when there is lots of vasodilation
locally/systemically.
 Side effect of systemic administration is that blood pressure gets
quite high.
Clonidine,   2 agonists
Xylazine  Reduce pain sensation.
Terbutaline   2 agonists
Albuterol  Can use during asthma to cause bronchodilation
Mirabegron   Human 3 agonist.
 Anti-obesity drug – causes animal to burn fat
 Used for poor bladder control

Adrenergic Antagonists
Drug Receptor Notes
Selectivity
Alpha Prazosin   1 selective antagonist
Antagonist  Causes vasodilation of arterioles
 Anti-hypertensive
Phenooxybenzamine   1 selective antagonist
 Binds to 1 receptors covalently (somewhat irreversible)
and lowers blood pressure – takes a while to get the
blood pressure back up
Phentolamine   Not selective
 Shouldn’t be used to reverse sedation
Tolazine   2 selective
 Used to reverse sedation
Mixed Labetalol   Need to watch for asthma if you give to a heart failure
Antagonists Carvedilol dog
 Affects RAAS and vasodilation
Beta Metoprolol   Treats heart failure
Antagonists Acebutolol  Antagonising 1 receptors decreases HR  decrease in
Atenolol pulse pressure.
 Causes decreased renin release from the kidney
Propranolol, Timolol   Not selective.

 Blocking 2 receptors on smooth muscle can be
problematic in certain situations (uterine contractions
during pregnancy).
 Shouldn’t be given to asthmatics – prevents
bronchodilators from working.
Butoxamine   2 selective
 Not important
Cardiac Drugs – Weber
Important Concepts
Preload
 Filling pressure into the heart, comes from peripheral venous system feeding into central venous system.
Venous pressure determines filling in the heart, more filling = more contractility = increases stroke volume.
 Preload from the pulmonary system forces the left side of the heart to fill during diastole.
o Pulmonary hypertension can cause an isolated effect to force the L-side of the heart to contract more.
Afterload
 Resistance that the heart meets in the arteriole system
 Higher afterload = heart needs to generate more force in order to pump blood (seen in hypertension/stiffening
of arteries).
Two Types of Heart Failure
1. Pressure Overload
 Cats and humans
 Caused by increased systolic pressure – due to hypertension/stiffening of arteries
 Heart must work harder to pump blood  leads to myocardial concentric hypertrophy (muscle is added
inwards and heart lumen gets very small while the while gets very thick).
 Hypertrophic cardiomyopathy (HCM)
2. Volume Overload
 Dogs
 Usually a problem during diastole (filling of the heart – preload)
 Happens when there is valvular regurgitation
 High preload forces more blood into heart during diastole, this causes heart to expand outwards to
accommodate the larger volume.
 Results in eccentric hypertrophy – adding muscle outwards forms a large heart with a thin wall.
 Dilated cardiomyopathy (DCM)
Cardiac Insufficiency/Failure
Reduced Stroke Volume & Cardiac Output secondary to:

 Reduced preload
o Hypovolemia: less blood for heart filling
o HCM: heart wall is thickened and lumen is much smaller, less room for filling
o Pericardial effusion: fluid in the pericardial cavity prevents the heart from filling, results in cardiac
tamponade.
 Increased afterload
o Hypertension: heart must work hard to pump against a high blood pressure
o Aorta or Pulmonary Stenosis
 Impaired contractility
o DCM
 Inadequate valve function
o Residual blood volume left in the heart due to back flow
 Abnormal Heart Rates
 Bradycardia: slow heart rate – Third degree AV block
 Tachycardia: fast heart rate – atrial fibrillation, ventricular tachycardia – not enough time during diastole for
filling.
Symptoms
L-ventricular Failure
 Blood not moving from the heart into the peripheral systemic circulation well, causing blood to accumulate in
the pulmonary circulation
 Blood accumulates in lungs
 Pulmonary edema
 Poor peripheral perfusion – cold limbs, fainting when standing/exercise, generalized confusion, decreased
kidney perfusion
R-ventricular failure
 Blood backs up in the central venous compartment (systemic blood circulation)
 Ascites and subcutaneous edema
 Hepatojugular reflex: if you palpate the liver and really push on it you create a wave of blood within the venous
compartment that travels to the jugular vein and causes distension. The distension is severe in animals with R-
sided heart failure.
Chronic Heart Failure

 Cardiomegaly
Failure on one side eventually leads to failure on the other side

Arrhythmias (especially tachycardia) often accompany heart failure.
Atrial Flutter – stuck in a loop of excitation, get disorganized atrial contraction. Get a lot of P waves after the QRS
complex.
Atrial Fibrillation – completely disorganized electrical activity, basically no contraction at all. Get a bunch of noise
between QRS complexes.
Ventricular Tachycardia - contraction/excitation is a looping pattern, ventricles empty too fast and improper filling
during diastole. Appears as very wide QRS complexes.
Ventricular Fibrillation – completely disorganized electrical paddles, need to use electrical paddles to reset electrical
current of the heart. No ventricular emptying at all and no cardiac output.
Heart Failure Drugs

Drug Use Mechanism of Effect Notes

Action
Digoxin Heart failure Inhibits Na/K Positive inotrope  Increases force/strength of
Atrial ATPase pump in Negative chronotrope contraction
(digitalis toxin fibrillation all cells  Na – reduces pacemaker  Decreases HR and
isolated from becomes firing conduction speed
foxglove) increased  Negative dromotrope  More cost effective
excess Na leaves compared to pimobendan
cell via Na/Ca Increases  Secondarily leads to
exchanger  Ca parasympathetic tone increased peripheral
builds up  and decreases perfusion (eg. Increased
increased sympathetic tone by renal perfusion and urine
contractility. enhancing output).
baroreceptor  Highly toxic – can affect
sensitivity neural conduction in the
entire body and CNS.
Side effects:  Therapeutic Index = 2 (if you
 Death double the dose you’ll kill the
 Anorexia patient).
 V&D  Hypokalemia can
 AV block or potentiate toxicity 
ventricular further prevents Na/K pump
arrhythmias from working.
 Hypokalemia can  Give aldosterone antagonists
precipitate  cause hyperkalemia
arrhythmias which will force the Na/K
pump to work (inhibiting
effects of digoxin).

Dobutamine Acute treatment 1 agonist Positive inotrope  Emergency use only
of severe heart  Arrhythmogenic
failure  Exerts actions on 1
receptors directly on the
heart.
Pimobendan Heart failure Phosphodiesterase Increased cAMP:  May enhance sensitivity of
(PDE) inhibitor in  Positive inotrope cardiac contractile proteins
VetMedin™ heart and blood (increased to calcium.
vessels – causes contractility and  Reduces afterload heart
cAMP to rise. HR) needs to work against
 Vasodilator  Induces a sense of well
PDE normally (arterial) – being
takes cAMP and reduces TPR  Increases appetite
breaks it down to (afterload)  Increases survival and
inactive AMP. reduces morbidity in dogs
with DCM or mitral valve
Counteracts the insufficiency.
excessive
sympathetic
stimulation you get in
heart failure
Metoprolol HCM Slows HR -blocker  Allows more time during
(selective 1 Relaxes ventricular decreased HR diastole, improves filling
antagonist) wall  diastolic Improved CO  Anti-hypertensive  inhibits
filling improved sympathetic stimulation of
Carvedilol renin secretion
(mixed 1/1 Mixed blockers 1  Blocks effects of
antagonist) causing vasodilation compensatory overactivation
in vessels – reduces of the heart by the
afterload heart needs sympathetic nervous
to work against. system.
 Watch for asthma – caused
by 2 antagonism  less
vasodilation =
vasoconstriction of vessels
in lungs
Enalapril Heart failure ACE inhibitor Reduces angiotensin 1. Causes vasodilation –
Benazepril Hypertension (prevents II reduces venous and arterial
formation of Ang II Vasodilation pressure (preload and
from Ang I) (arterioles) afterload) and therefore
Reduces aldosterone edema
release 2. Prevents aldosterone
Prevents bradykinin release, decreasing Na+
(vasodilator) from retention thus decreasing
being broken down. fluid retention and edema.
Valsartan Heart failure AT1 receptor Vasodilation (smooth
Losartan antagonists muscle in arterioles) Enalapril - decreases clinical
Inhibits actions of Reduces aldosterone symptoms and extends survival
angiotensin II release from the time by 92% in dogs
adrenal cortex
Nitroglycerin Heart failure Exogenous Vasodilation of ALL  NG – venodilator (reduces
Nitroprusside sources of nitric the vascular beds pressure in venous system,
oxide  activates Reduced preload reducing edema in body
guanylyl cyclase cavities)
increasing cGMP  NP – arteriolar/venodilat or
causing vascular (reduces preload and
smooth muscle afterload).
relaxation
 Only use acutely, watch
out for extreme
hypotension.
 Tolerance develops
quickly.
Prazosin Heart failure 1 adrenergic Arteriolar dilation  Cheap
Hypertension receptor antagonist Reduced afterload
Hydralazine Heart failure Unclear Arteriolar and venous  Causes smooth muscle
Hypertension May involve dilation (reduced relaxation in
decreased preload and afterload) arterioles/venules.
vascular smooth  Not really used in vet med.
muscle calcium
*All the above drugs may cause excessive hypotension, reflex tachycardia and activation of the RAAS system.
Diuretics used to reduce hypertension in animals with heart failure. Helps to reduce edema and improve animals
quality of live. Beware of causing excessive loss of venous return and hypokalemia which potentiates digoxin action
leading to toxicity and alone causes muscle spasming in the heart.
DO NOT use positive inotropes (digoxin/pimobendan) in cats with HCM – makes heart work harder, use a -blocker
(gives heart more time in diastole to fill, counteracts excessive sympathetic stimulation) and diuretic instead (always
use diuretic for edema).
Anti-arrhythmic Drugs
Class and Drug Examples Mechanism of Effect Use
Action
Class I Voltage gated  Decreases Na+ current  Mainly ventricular
 Quinidine Na+ channel  Decreases phase 0 tachycardia and arrhythmias
 Procainamide inhibitor potential, makes  Supraventricular arrhythmias
 Lidocaine depolarization to action
potential slower with a
Class 1A: targets all smaller amplitude.
cardiac cells  Prolongs QRS phase (and
Class 1B: targets damaged QT interval)
ventricular myocytes  Reduces HR and
Class 1C: targets all cardiomyocyte excitability
cardiac cells, some
preference for conduction
cells
Class II 1 adrenergic  Negative chronotrope,  Supraventricular tachycardia,

 Metoprolol antagonists dromotrope and inotropic particularly where excessive
 Atenolol effect sympathetic stimulation is
the cause
Class III K+ channel  Decreases K+ current  Refractory ventricular
 Amiodarone inhibitor  Prolongs repolarization tachycardia (re-entry)
 Bretylium and reduces HR
 Sotalol
Class IV Ca+ channel  Decreases Ca+ current  Supraventricular tachycardia
 Verapamil inhibitor  Negative chronotrope  HCM
 Diltiazem
Class I Anti-arrhythmic Drugs
Class Drug Na+ K+ Autonomic Hemodynamic Clinical Use

Channel Channel Effects Effects
Blocker Blocker
1A Quinidine* + + Decreases Tachycardia  Oral, IV, IM -
vagal firing Negative supraventricular and
(increases inotrope (weaken ventricular arrhythmias
HR) contractility)
1 adrenergic Hypotension
antagonist
Procainamide + + Ganglionic Hypotension  Oral, IV, IM -
and NMJ Mild negative supraventricular and
blocker inotrope ventricular arrhythmias
 Dogs do not have acetyl
transferase to activate it so
it does not work well.
1B Lidocaine* + – – –  IV - ventricular arrhythmias
 Only targets damaged
ventricular myocytes
(ectopic cells)
 Theoretically safe
Tocainide + – – –  Oral - ventricular
Mexiletine arrhythmias
Phenytoin + – – Hypotension (IV)  Digitalis associated
arrhythmias
 Anticonvulsant
 Good against digitalis
toxicity
1C Fecainide + + – –  Oral - supraventricular
arrhythmias
 Proarrhythmic in ischemic
heart disease
 Targets conduction cells
Class II, III, IV Anti-arrhythmic Drugs

Class Drug  K+ Na+ Ca+ Clinical Use
Adrenergic Channel Channel Channel
Antagonist Blocker Blocker Blocker
II Propranolol  + Oral, IV – supraventricular and ventricular
Metoprolol  Oral – supraventricular
Atenolol
Esmolol IV – supraventricular (half-life = 2 mins)
III Amiodarone  + + Oral – ventricular
Non-
competitive
Bretylium  YES IV – ventricular
Sotalol  Oral – ventricular
III Verapamil + Oral, IV – supraventricular (pacemaker

Diltiazem cells)
Amiodipine + Oral – hypertension (works in vasculature)
 60% of the sodium filtered by the glomerulus is recovered by the proximal tubule. (60% of the
water also reabsorbed here). Anything that keeps the sodium in the filtrate will keep water in
the filtrate and has a diuretic action.
 25% of the filtered sodium load is reabsorbed in the thick ascending tubule. Drugs that act
Diuretic Drugs – Weber
here will have a fairly good diuretic effect (later in the collecting duct)
 7% of filtered sodium load is reabsorbed from the distal tubule. Inhibiting sodium reabsorption
here has a much 'lower' diuretic effect.
 3% of filtered sodium load is reabsorbed by the collecting duct. Anything that acts here is a
WEAK diuretic.
Classes of Diuretics
Class and Drug Mechanism of Use Notes

Action
Loop Diuretics Inhibits  Acute relief of severe  Major go to drug
Furosemide Na/K/Cl edema  Initial natriuretic effect
symporter in  Can be used chronically  Increased volume of NaCl enriched fluid to
the thick with caution/monitoring late distal tubule/collecting duct
Diuretic Drugs – Weber
ascending  Heart failure  Stimulates Na+ exchange for K+, results in
loop of Henle a strong kaliuretic effect (loss of Ca/Mg in
blood)
Thiazides Inhibits Na/Cl  Chronic diuretic therapy  Not widely used in Vet Med
Hydrochlorothiazide symporter in  Heart failure  Inhibits sodium reabsorption in the distal
early distal tubule (7% of filtered load)
convoluted  Natriuresis and diuresis
tubule  Na+ exchange for K+ in distal
tubule/collecting duct
 Less kaliuresis than with furosemide
 Less need to worry about hypokalemia
 Less efficacy that loop diuretics
K+ sparing Aldosterone  Heart failure where  Not very effective because they act in the
Spironolactone antagonist elevated aldosterone is distal tubule where there is little sodium
a problem reabsorption (7%).
 Use in combination with  Mineralocorticoid receptor antagonist
a K+ depleting diuretic (aldosterone receptor) – prevents sodium
to combat hypokalemia retention
 Prevents transcription of Na channel and
pump genes of the late distal tubule and
collecting duct
 Prevents hypokalemia – may be used in
combination with other diuretics
 Combination therapy with pimobendan in
dogs with DCM, effective in mitral valve
failure
 Anti-steroid hormone side effects.
Osmotic Mannitol is  IV administration only
Mannitol freely filtered  Emergency use
in glomerulus
and
osmotically
prevents water
from being
reabsorbed in
the proximal
tubule
*Side effects of using diuretics is hypokalemia – loss of potassium in the distal tubule in exchange for Na
Anesthesia – Duke
Lecture 1 – Sedation and Anticholinergic Drugs

Terminology
 Pre-anesthetic preparation: get animal ready for anesthetic, pre-medicate with certain drugs to make animal more
tractable.
 Induction: moving from a state of consciousness to unconsciousness
 Maintenance: prolonging the duration of anesthesia for duration of the procedure. Want it to be as short as
possible
 Local Anesthesia: AKA analgesia
 General Anesthesia: controlled and reversible intoxication of the CNS to produce a sleep like state.
 Balanced Anesthesia: AKA multimodal, hits all the possible pathways.
Mechanism of Action
 Largely unknown
 Must be lipophilic drug to have action within the CNS
 Interaction with inhibitory pathways: GABA in brain, glycine in spinal cord
 Change Ca and K ion channel function
3 Components of the Anesthetic State:
1. Analgesia – pain relief

 Opioids, NSAIDs, local anesthetics, ketamine, 2 agonists
2. Muscle Relaxation – needed before surgery

 High doses of anesthetics reduce muscle tone
 Peripheral neuromuscular blocking drugs if you need NO muscle tone at all
 Drugs that act on spinal cord can reduce muscle tone
 Benzodiazepines, guaifenesin, 2 agonists
3. Narcosis/Amnesia – don’t want animal to remember what they went through

 Isoflurane, sevoflurane, propofol, alfaxalone, ketamine
Stages and Planes of Anesthesia
Stage 1 •Voluntary Excitement
Stage 2 •Involuntary Excitement

•Plane 1 - light
Stage 3 •Plane 2 - surgical depth (used for most procedures)
•Plane 3 - deep (warning that stage 4 is close)
Stage 4 •Cardiopulmonary arrest
Depth of anesthesia is dynamic – meaning it can change depending on what part of the procedure is being done.
Painful maneuvers cause an increased stress response (ANS) detected by monitoring blood pressure, heart rate,
respiratory rate and stress hormones. Animals tend to get lighter when something painful is being done (intubation,
ovarian ligament traction, incision).
Anesthesia – Duke
Pre-anesthetic Drugs
Drug Mechanism of Action Effect Notes
Tranquilizers Phenothiazine Inhibitory action on Sedation to calm  Common in
(Acepromazine) dopamine receptors animal and reduce VetMed. Causes
1 receptor blockade anxiety mild sedation when
Half-life: 10-20 hours. Anesthetic sparing used alone. Often
Mild anticholinergic effect combined with
and antihistamine Hypotension  1 opioids in dogs/cats.
effect antagonist in vascular Used in horses, but
Anti-emetic at smooth muscle not ruminants or
chemoreceptor trigger Hypotension exotics. Slow time
zone – administer 15- Overdose will cause to onset of effect,
20 minutes before catalepsy (rigidity, not even after IV. 30-
opioids in dogs. comatose) 40% anesthetic
NO analgesia sparing effect.
 Half-life: 10-20
hours.
Butyrephone  Licensed for use in
(Azaperone – Stresnil) swine
Sedatives 2 agonists 2 receptors found Sedation and reduces  Very popular in

Dexmedetomidine presynaptic and anxiety. VetMed
Medetomidine postsynaptic on the Often used with opioids  Individual receptor
Xylazine vasculature and Analgesia distribution can
Clonidine causes hypertension **Side effects: account for species
through peripheral and individual
vasoconstriction. vasoconstriction and differences.
increased blood  Might get some a1
pressure – reflex stimulation
bradycardia possible (xylazine) which
causes arousal,
excitement, and
restlessness.
 Strong anesthetic
sparing effect
 Reversible drugs
 Overdoses cause
coma.
Benzodiazepines GABA agonist Anticonvulsant, spinal  First use for seizure

cord mediated muscle control
relaxation, retrograde  When given alone
amnesia can cause
Sedation and reduced excitement,
anxiety more evident in disinhibition and
humans dysphoria
 Can be used in
exotic animals and
for compromised
dogs and cats
 Diazepam
metabolite is active
 Reversible drug
Anesthesia – Duke
Diazepam Lipid soluble, high protein binding
(Valium) Adheres to plastic syringes (takes 12 hours) and sensitive to light
degradation.
In propylene glycol – painful IM injection and erratic absorption
Crosses placenta and reaches fetus, doesn’t cross back.
Midazolam Water soluble because imidazole ring closes at plasma pH to form a lipid
soluble drug
2-3 times more potent then diazepam
1-6 mins action IM, transmucosa
Popular in exotic anesthesia.
Flumanezil Benzodiazepine antagonist at site on GABA receptor
No side effects
Increases muscle tone to normal, allows better respiratory movements and
lung ventilation
Useful for exotic anesthesia
Used to reverse midazolam
30-60 mins action IV, IM.
Anticholinergics Acts on muscarinic/cholinergic sites NOT nicotinic receptors.
Can cause bradycardia leading to cardiac arrest
Used to prevent:
Increases in vagal tone and sudden bradycardia
Excessive secretions, drooling
Not routinely used in herbivores  reduces gut motility, secretions
become thicker because only water producing cells are affected.
Increases workload by increasing HR and reducing diastolic filling time
Increase intra-ocular pressure through mydriasis  don’t use in animals
with glaucoma
Don’t use with a2 agonists unless blood pressure has been lowered with
other drugs (isoflurane)  causes blood pressure to go through the roof.
Use if there is excessive parasympathetic action (HR is low) or if blood
pressure is low and has been HR dependent.
Atropine Atropine has shorter length of action compared to glycopyrrolate (30-40
Glycopyrrolate mins compared to 2 hours)
Atropine is faster acting IV (CPR drug), cross into the CNS and raises HR
higher then glycopyrrolate
Glycopyrrolate has strong action to dry secretions.
Trazadone SSRI – atypical antidepressant

Some a1 receptor blocking action, possible hypotension
Oral administration (not high-dose IV), may be given before a vet visit
Similar to using acepromazine
Can be combined with an opioid.
Anesthesia – Duke
Lecture 2 – Injectable Anesthesia
Need a high concentration of drug to rapidly reach the site of action (the brain) to have a titratable effect.
Routes of Administration
Intramuscular Less precision for dosing
Difficult to titrate effect
Best for wildlife anesthesia
Subcutaneous/rectal/oral Not suitable for anesthesia – doesn’t reach a high enough concentration in the brain to
have good action
Too slow, unreliable
Intraperitoneal Risk of depositing drug in gut
Laboratory animals
Intravenous Accurate, titratable, rapid-acting
Injectable anesthetics act in 20-60 s following injection
Rapidly achieves surgical plane of anesthesia – bypasses stage I and II of anesthesia
Requires restraint and ideally an IV catheter
In large animals we give the full calculate dose at once, in small animals we can give a
little bit of a time.
Drug movement influences anesthetic recovery. The release of drug back into the central compartment from can go back
to the brain and produce a sedative effect = hangover.
The redistribution of the drug form the brain produces recovery from anesthesia. Metabolism finishes recovery and
dictates the hangover effect.
Anesthetic maintenance using injectable drugs:
Total IntraVenous Anesthesia (TIVA) – using injectable drugs to maintain anesthesia, usually a combination of drugs to
produce the triad of anesthesia (narcosis, analgesia, muscle relaxation).
Partial IntraVenous Anesthesia (PIVA) – using injectable drugs, give an infusion and supplement it with inhalational
anesthesia.
Bolus – top up anesthesia when you see the animal is giving light
Infusion – give a loading dose (bolus) to bring up plasma concentration to therapeut ic range then maintain with an
infusion.
Continuous Rate Infusion – not changing rate

Variable Rate Infusion – rate is changing
Recovery time usually increases with the duration of infusion – the drug half-life changes depending on length of infusion.
Drug Notes
Barbiturates  Pentobarbital = euthanasia solution
Anesthesia – Duke
 Phenobarbital = anti-seizure medication
 GABA agonist
 Alkaline solution – tissue irritant
 Cannot be mixed with other drugs in syringe – causes precipitation
 Sensitive to other condition which change action of cytochrome P450 enzymes.
Thiopental  GABA agonist
 Accumulation can occur (longer recovery)– avoid in sighthound breeds
 Irritant if deposited outside vein – use a catheter to ensure deposition into vessel
 Comes as a powder – make 2.5% solution for small animals, 5-10% for large animals
Propofol  In a lipid emulsion – that can grow bacteria
(Akly l Phenol)
 GABA agonist
 Onset is 40-90 secs, and one dose lasts 5-10 minutes
 Redistribution important for recovery and metabolism is very rapid  little accumulation
 Can be used for induction
Alfaxalone  A neurosteroid - GABA agonist
 Onset is 15-45 secs, lasts 5-10 mins
 Recovery through redistribution, rapid metabolism  little accumulation
 Used for induction in cats, dogs, reptiles, fish
 Recoveries often accompanied by excitatory movements (sound sensitive).
Ketamine  Interrupt information reaching higher centres in the brain
 NMDA receptor antagonist
 CNS voltage dependent Na/K/Ca channels
 Depression of CNS acetyl choline receptors
 Some action at GABA receptors
 Depression of nociceptive cells in spinal cord
 Cataleptoid state with slow nystagmus = can see head bobbing
 Muscle rigidity with higher doses  not good for surgery, always use in combination with
something else.
 Some reflexes maintained (gag, swallow)
 No eye rotation in dogs, cats
 Intense somatic analgesia, less visceral analgesia
 Sub-anesthetic doses used to sedate some animals
 Neither an anti or pro-convulsant.
 Comes in a racemic mixture – S is more active
 IM, IV, SQ
 Onset is 30-90 secs, lasts 10-20 minutes
 Auditory and visual stimuli disturbed during recovery to cause emergence delirium
 Used with other drugs to reduce side effects  a2 agonists, benzodiazepines ,
acepromazine
 Used for induction, maintenance, analgesia
 Elimination half -life is 60 minutes (dog), 80 minutes (cat)
 Cat excrete drug as active metabolite through the kidney
 Use in combination with hydromorphone and dexmedetomidine = kitty magic
Guaifenesin  Large animals for mild sedation – need to use large volumes for large animals
 Muscle relaxation – acts on neurons in spinal cord, doesn’t act on diaphragm
 Not an analgesic  rarely used alone
 High doses cause extensor rigidity and relaxation then cardiac arrest
 Can be used after xylazine and ketamine to top up the sedation in horses/cattle
 Used with 5% dextrose to prevent hemolysis
 Irritant to tissues
Lecture 3 – Inhalational Anesthesia

Inhalational Drugs:
Anesthesia – Duke
 Drug supplied as a liquid and is vaporized into a form that can be inhaled. The vaporizing gas is oxygen. Entry
to the body is via the lungs and pulmonary circulation (uptake) and distributed to the brain.
 Controllable – anesthetic depth can be rapidly changed, provides oxygen and the ability to ventilate lungs.
 IH drugs don’t accumulate and recovery is rapid.
 Safe
 Produce more cardiovascular depression (hypotension)
Uptake and distribution is regulated by changing the inhaled concentration using the vaporizer dial. Cardia c output, lung
ventilation and physical properties of the drug will affect uptake.
The drugs effect on the brain is related to partial pressure not concentration. The value does not change with barometric
pressure.
Vaporizer dials are in % output of the total gas leaving the vaporizer. The actual % output will vary with the atmospheric
pressure and altitude, but the partial pressure output will be the same.
Anesthetic gas moves down partial pressure gradients from one compartment into another until an equilibrium occurs
(maintenance). Recovery reverses the gradient so the drug leaves the body.
The more fat soluble the drug is the slower the uptake and elimination. These are more potent then drugs that are not
fat soluble. Eg. Nitrous Oxide > Desflurane > Sevoflurane > Isoflurane
Minimum Alveolar Concentration = the alveolar concentration (partial pressure) of an anesthetic agent which prevent s
50% of a population from responding to a noxious stimulus. Is a measure of potency of an IH drug. This value changes
with the use of other drugs, hypothermia, age, and species.
 If you use a drug alone you need to you 1.5x the MAC value to guarantee that the animal does not wake up 
rough idea of where to set the vaporizer dial.
The more lipid soluble the drug the more potent it becomes and the MAC value is lower, but it has slower uptake and
elimination.
How the Body Affects Uptake
1. Lung Ventilation
 A higher minute ventilation increases uptake
 Artificially ventilating the lungs increases uptake
 Isoflurane and sevoflurane uptake improve if lung ventilation is augmented
2. Lung Perfusion (cardiac output)

 Low CO increases the ability of alveoli to reach a higher partial pressure  allows a larger gradient to form
 Uptake will be faster with low CO states
 Excited animals are hard to ‘mask induce’ anesthesia using IH drug  they have a high cardiac output which
slows induction & need to use more drug
Elimination and Metabolism

 80-90% of the drug needs to be eliminated for full recovery.
 Turn off vaporizer and let oxygen displace any IH drug in breathing system
 Lipid soluble drugs stay in fatty tissues longer and may produce a hangover effect
 Rapidly eliminated IH drugs can cause emergence delirium = animals wake up disinhibited
o Have sedative ready to give IV in case of emergence delirium
o Talk to patient, give them TLC – remember you are at risk of bites and scratches.
 Modern drugs have minimal metabolism
PIVA
 IH drugs have little analgesia and can depress the cardiovascular system
 Can give drugs as a bolus/infusion to help reduce the IH concentration required  anesthetic sparing effect
o can use remifentanil or dexmedetomidine
 Useful for debilitated animals or animals undergoing invasive procedures (surgery).
Anesthesia – Duke
Halogenated Ethers – ends with flurane, reduced flammability/analgesia, less lipid soluble, higher MAC, rapid elimination
(little hangover), easy to change depth of anesthesia, minimal metabolism.
Drug Use/Notes
Isoflurane MAC 1.2% in dog
Rapid uptake/elimination, very little metabolism
Pungent smell  may elicit coughing and breath holding
Stable compound
Extremely common in VetMed
Sevoflurane Fluorinated ether
MAC 2.4% in dog, 3% in cat
Rapid uptake and elimination
Not pungent smelling
5% metabolized
 Can produce Fl ions which can be nephrotoxic
 Rapid elimination via lungs, helps to reduce amount of Fl ions so not clinically a problem
 Can be broken down to carbon monoxide in older breathing systems.
Desflurane Fluorinated methyl ether
Very rapid uptake and elimination
High MAC
Boiling point close to room temperature
Requires an expensive vaporizer
Not used in VetMed
Nitrous Oxide Not potent
MAC 188% in dog (use 60% inhaled)
Delivered as a gas
Acts on NMDA receptors and possibly opioid receptors
Used for analgesic properties – child birth and dentistry
Bone marrow depression if inhaled for >24 hrs or long term (drug abusers, not OR staff using waste
gas scavenging)
Waste Gas Scavenging

 Avoid inhalation of trace amounts of IH drug
 Reports of headaches, tiredness, nausea
 Check equipment functions correctly
 Divert waste gases to outside of building or use a charcoal adsorber.
 Do not place building exhaust close to intake vent
 Do not put scavenging hose into a recirculating ventilation system
 Avoid spills, fill vaporizers when few staff are around.
Pregnancy and ORs

 No proof that IH drugs cause problems in trace amounts
 Follow basic rules of exposure limitation  try to avoid it if possible
 Can use masks that absorb volatile compounds.
Lecture 4 – Support Drugs

General anesthetics depress the respiratory, vasomotor and thermoregulatory centres in the brain. It causes
hypotension, hypothermia, and hypoventilation (hypercapnia, hypoxemia)
Analgesic Drugs
 Nociceptive pathways can be stimulated during anesthesia (sympathetic nervous system stimulation)
Anesthesia – Duke
 May require higher doses of anesthetic drugs
 Better to provide a good quality analgesic
 Ketamine is the only general anesthetic with analgesic properties.
Fluid Therapy
 Surgical fluid rate
o Dog - 5 ml/kg/hr
o Cat – 3 ml/kg/hr
 Replace losses due to evaporation at body surfaces, bleeding from surgical sites, urine production.
 To treat hypotension  increases venous return and cardiac output
 Types of fluids to use:
1. Isotonic crystalloid solutions – Lactated ringers, Normosol-R
 Used for volume replacement and for maintenance fluids
 Stays in circulation for 20 minutes then diffuses into ECF compartment
 Need 3 units per 1 unit of blood loss
2. Colloids
 Larger molecules provide oncotic pressure (“water holding capacity”) similar to albumin
 Stays in circulation longer than crystalloids
 Starches, or gelatin based
 Need 1 unit pet 1 unit of blood loss
3. Blood products – whole blood, plasma, packed RBCs
 For severe blood loss (>20%)
Respiratory Stimulants
 Not often used during anesthesia  best to ventilate lungs using anesthetic breathing system and oxygen
o Drugs can cross into the CNS and wake animal up during procedures
 Possible indications:
o Neonates following C-section  resuscitation, gets them breathing
o Field situations where there are no apparatus to ventilate lungs
o Some tests for laryngeal paralysis
 Doxapram
o Directly stimulates respiratory centre in the brain
o Increases tidal volume and respiratory rate
o Can be given IV, IM, buccal
o Onset is immediate, effect lasts 1-2 minutes
o Also stimulates vasomotor centre to increase blood pressure
o Increases plasma catecholamine concentration
Hypotension During Anesthesia

 Usually caused by vasodilation
o Anesthetic drugs depress vasomotor centre  decreases sympathetic tone  causing vasodilation
o Anesthetic drugs directly relax vascular smooth muscle and skeletal muscle
 Reduced cardiac output
o Depress cardiac contractility
o Reduce venous return (relaxation of great veins)
o Position of animal can affect venous return
Treatment for Reduced CO

 Fluid therapy
 1 adrenergic receptor stimulation
o Catecholamine drugs (dobutamine, epinephrine for emergencies)
o Have a short half-life
o Usually give as an infusion
Treatment of Excessive Vasodilation

 1 adrenergic receptor stimulation to cause vasoconstriction
Anesthesia – Duke
o be careful not to cause too much vasoconstriction and limit renal vascular supply or skeletal muscle
perfusion
 Useful for pathological conditions causing excessive vasodilation/hypotension  shock, sepsis, anaphylaxis
 Short elimination lives, infusions required
 Phenylephrine (1 action only)
 Norepinephrine (mainly 1, some 1)
 High infusion rate of dopamine (mainly 1, some 1)
 Epinephrine (1, 1 and 2)
 Ephedrin
o Vasopressor and inotrope
o Mixed action, quite inexpensive
o Long duration (10-15 minutes) so can be used as bolus or infusion
o Has direct effect and 1, but releases endogenous norepinephrine (1 and 1)
o Repeat bolus injections can exhaust the ability to replenish norepinephrine  use up the bodies stores
of NE
o Preserves tissue perfusion
Skeletal muscle tone is reduced under anesthesia. Some procedures require no muscle tone at all (Eg. Intra-ocular
surgery) Centrally acting drugs reduce muscle tone but still allow eye rotation. Need to use a peripheral-acting
neuromuscular blocker (NMB).
NMBs
 Not lipophilic  do not cross into CNS or placenta
 No sedative/analgesic properties
 Never used alone in animals  animal will remain conscious, must be used with anesthesia
 Paralyzes all skeletal muscles
o Must ventilate lungs for animal
o Cannot monitor muscle tone/action normally
o Must ensure full reversal before recovery  ensure full recovery of muscle tone
Drugs Use
Depolarizing NMB Succinylcholine  Relaxes laryngeal muscles and allows endotracheal
 Acts similar to ACh intubation – animals aren’t hard to intubate, so not
 Remains on receptor longer really used for this
 Depolarization (contraction)  Fast onset of action (20 s)
then flaccid paralysis  Lasts short time in most species, except the dog
 Broken down by plasma  May be combined with euthanasia drugs to prevent
cholinesterase limb paddling in horses.
 No reversal drug available
Non-depolarizing NMB Atracurium  Spontaneously broken down in the body
Anesthesia – Duke
 Longer time to onset (1-2  Store in refrigerator
minutes, lasts 15-20 minutes)  Duration of action increases with hypothermia
 Competitive inhibition with
Ach
 NMB stays on receptor – Rocuronium  Liver metabolism
prevents Ach from binding  Duration does not change with change in body
 Reversible  increase temperature
number of Ach molecules by  May increase heart rate (ganglionic effect?)
blocking acetylcholinesterase
(neostigmine).
 Increases Ach all over the
body, including nicotinic and
muscarinic sites  may need
atropine to prevent
undesirable side effects
(bradycardia, drooling).
Histamines, Anticonvulsants and Behaviour and Respiratory Drugs – Chicoine
Histamine
H1 receptor
 High affinity – activated at low histamine doses
 Smooth muscle contraction  bronchioles > GIT > urinary tract
 Smooth muscle relaxation  vasodilation in arterioles, capillaries and venules
 Hypotension, dyspnea, edema in the skin.
H2 receptor
 Lower histamine affinity, but prolonged duration
 Importance in HCl secretion from parietal cells
H3 receptor
 Located on CNS neurons, modulate NT release – can have paracrine activation of receptors
 Limited veterinary relevance (for now)
H4 receptor
 Allergic/inflammatory response?
 Limited veterinary relevance (for now)
Histamine has a role in allergic reactions – typically local cutaneous response. Antigen cross-links with IgE on mast
cells and causes degranulation (histamine release). Causes inflammation (redness, swelling, pain, heat, loss of
function). Anaphylaxis can occur with severe systemic activation of H1 receptors. Get hypotension and
bronchoconstriction (respiratory distress). Histamine is a NT in the CNS. Peripherally histamine release stimulates
sensory neurons causing pruritus and pain (insect bite).
H1 blocking pharmacodynamics - used to reduce inflammation and itchiness.

 Reversible, competitive inhibition
 Drugs compete with histamine for H1 receptor binding, can be countered by high histamine concentrations.
 Limited oral bioavailability, but lipid soluble with a high volume of distribution
 Hepatic metabolism results in active metabolites.
 Can induce hepatic microsomal enzymes  increased clearance after repeated dosing
 Elimination may be inhibited by P-gp substrates
 Low doses cause sedation, high doses cause CNS excitement
 May also inhibit muscarinic receptors  parasympatholytic signs (similar to atropine)
o Reduces salivation, increased HR, mydriasis (pupil dilation).
1st Generation H1-blockers (anti-histamines)  DROWSY anti-histamines

 Ethylene Diamine Family: Pyrilamine, Tripenlennamine HCl
 Ethanolamines: Diphenhydramine (Benadryl), Dimenhydrinate (Gravol), Clemastine (Tavist)
 Alkylamines: Chlorphiramine (human cold drug used in VetMed) – antidepressant that inhibits serotonin
reuptake.
 Piperazines: Trimeprazine (Vanectyl-P  contains prednisone for skin allergies), Hydroxyzine (Atarax)
2nd Generation H1-blockers

 More selective for peripheral H1 receptors  No CNS effects like 1st generation
 Longer half life and dosing intervals
 Zwitterions, more P-gp substrates  less CNS distribution and effects (NON-drowsy).
 Piperazines  Cetirazine (Zyrtec) not common in VetMed, Loratidine (Claritin)
3rd Generation H1-blockers

 Contains only the active enantiomer or metabolite
 Decreases adverse events and increases efficacy.
 Faster acting, higher potency.
Clinical Uses of H1-blockers for Allergic Reactions
 Can be used to modulate allergic reactions, but won’t stop allergies – more useful if administered BEFORE the
histamine release (contact with allergen).
 Limited efficacy for atopic dermatitis – may decrease pruritus for a limited time, individuals respond differently
to drug – might just cause sedation.
 Limited efficacy for bronchoconstriction
 Antidote for phenothiazine tranquilizer
 Alternative therapy for anaphylaxis, insect bites – doesn’t replace EPI
 Therapy for mast cell tumors – prevents degranulation and resulting pruritus, doesn’t treat tumor itself
Other Inflammatory Mediators
Cyproheptadine (periactin)
 Blocks H1 and serotonin receptor
 Used for photic headshaking in horses – serotonin increases with day length
 Appetite stimulants in cats – serotonin blocker effect
Cromolyn sodium – mast cell stabilizing agent
Leukotrienes, prostaglandins, dopamine, kinins, etc.
Anticonvulsants
Dogs tend to get idiopathic epilepsy (genetic component), cats have seizures but usually not idiopathic (brain
abnormality). Cats tend to respond to the same medications anyways.
Anti-Epileptic Therapy Recommended when:

 Signalment fits idiopathic epilepsy
 Seizures occur more then once a month, or if frequency is increasing or duration/severity is worsening
 If postictal signs are severe or lasting >24 hrs
 If status epilepticus occurs (very prolonged seizures that do not stop on their own)
Challenges of Therapy:
 Cannot cure epilepsy – need chronic administration, there will be side effects and a problem with tolerance
 Individual response to treatment varies
 Owner compliance is an issue
 Therapeutic drug monitoring is required – expensive, tough sell to client, can be used to optimized dose for
individual therapy
 Not many veterinary approved drugs
o Phenobarbitol (Epiphen) in Canada  efficacy of 85% (having less then 1 seizure a month, no cluster
seizures).
o KBr (potassium bromide) in USA  causes severe liver reactions
o Benzodiazepines  use while seizure is occurring, not chronically.
Objective: raise the seizure threshold by stabilizing neuron membrane potential  reduce duration and severity of
seizures. Can enhance inhibitory NT (GABA, glycine), or reduce excitatory NT (glutamate).
Want to hyperpolarize the cell – do this by activating postsynaptic K+ or Cl channels OR reducing pre and postsynaptic
Na/Ca channels.
Phenobarbital (Epiphen)
 Slow onset, long lasting
 Barbiturate with anti-epileptic effects when used at sub-anesthetic doses
 Good oral bioavailability, moderate Vd
 BID dosing – more frequent than the half-life so accumulation occurs
 Steady-state concentrations reached after 5-7 half lives.
 Switching brands doesn’t really matter – make sure you are using approved generic drug products (not
compounded!!)
o Sometimes minor changes in PK may have significant clinical effects in dogs
Phenobarbital in Dogs/Cats
Dogs Cats
Adverse Effects Sedation/lethargy, PUPD Same as dogs except rarely causes
Polyphagia (avoid obesity – lipid soluble so it hepatotoxicity.
accumulates in the fat). Also causes temporary facial swelling,
Ataxia at beginning of therapy (10-15 days) allergic reaction (low platelets/WBC
Blood dyscrasias - changes in blood cell parameters count), and blood clotting disorders.
Decrease in T4 concentration  hypothyroidism
Hepatotoxicity (increases ALT, ALP, abnormal bile
acid stimulation test, decreased albumin, urea,
cholesterol).
Pharmacokinetics Long half-life 37-89 hours (2-3 days) Non-linear kinetics (increase in dose
Induces cytochrome P450 enzymes in liver  NOT proportion to increase in drug
increases clearance, decreases plasma exposure) - minor changes in doses can
concentrations and half-life. result in large fluctuations in blood levels
Potassium Bromide (KBr)

 No documented drug interactions
 Extremely long half life = 24 days  takes 4 months for dog to reach steady state, use a loading dose to bring
up concentration during first week then drop down to a maintenance dose.
 Renal elimination: chloride reabsorption NO hepatic metabolism
 Influence of diet
o High salt diets will decrease plasma KBr  Cl and Br compete for proximal tubule transporter – Br has
a hard time being reabsorbed from filtrate so is excreted in urine and need higher and higher doses to
maintain concentrations.
o Cardiac diets will increase plasma KBr  Cl restricted diet there is little competition and all the Br is
reabsorbed and plasma concentrations go up
 Treatment of overdose: 0.9% NaCl IV maintenance rate over 12 hrs
 Not recommended in cats – 50% of all cats will show adverse reactions (severe coughing a nd
bronchial asthma due to allergic reactions)
 Adverse Effects in Dogs:
o Sedation
o V/D and constipation
o Increased hunger/thirst – b/c KBr is a salt
o Pelvic limb weakness or stiffness  looks like an old arthritic dog
o Pancreatitis (rare, but severe)
o Skin reactions  pruritic lesions
o Occasional behavioural changes  depression, aggression, attention seeking, aimless pacing
Diazepam (Valium)
 Used to treat status epilepticus (uncontrolled seizures) in cats/dogs
 Not used for long term seizure control, used to stop seizures while they are happening.
 IV  crosses BBB rapidly
 Rectal (F = 50% so double the dose), intranasal (F=80%), Oral (F=very low)
o Rectal administration easier at home  beware of misuse
 Highly metabolized by liver to active metabolites  nordiazepam and oxazepam - 10% activity of diazepam
 Also, used for some behavioural disorders, appetite stimulant and pre-anesthetic.
 Adverse Effects:
o Lethargy, sedation, ataxia
o Polyphagia (wt gain)
o Hyperactivity
o Seizures may occur after abrupt discontinuation of chronic diazepam administration
o Fulminant hepatic necrosis in cats  check liver enzymes before and 5d after treatment, then at 6
months
“New Anticonvulsants” = Benzodiazepines, Gabapentin/pregabalin, levetiracetam, zonisamide, imepitoin, topiramate

 Needs to be administered with phenobarb or KBr anyways
 No evidence these are better then the old drugs
 Efficacy studies were not done well: new drugs were always administered with old ones, non-controlled, small
sample size, often not blinded, imprecise outcome measures (owners)
Gabapentin
 Structural analogue of GABA
 Tolerance may develop – 4-8 months of use (honeymoon period)
 Blocks Ca channels  causes hyperpolarization
 Combine with phenobarb or KBr in dogs
 Frequent administration in dogs 10 mg/kg 3-4x daily  run into compliance issues
 TDM not necessary due to low incidence of side effects
Pregabalin (Lyrica)
 Gets metabolized to GABA analogue
 2-4 mg/kg TID with phenobarb or KBr in dogs
 mean reduction 50% of seizures
 mild adverse side effects
Adverse Effects of GABA Analogues
 uncommon
 mild sedation
 transient ataxia
 unpredictable efficacy
Levetiraetam (Keppra)
 Helps for a while, then dogs develop tolerance
 Used with phenobarb and KBr
 After 120 d of therapy, phenobarb refractor dogs had a decrease in seizure frequency
o Some dogs had an increased seizure frequency
 10-20 mg/kg 3x daily orally
o start at 10 mg and work up as animal adapts to drug
o decrease dosage in renal impaired patients
 No identified drug interactions
Imepitoin (Pexion)
 European
 Low affinity for benzodiazepine binding site of GABA receptor
 Effective but not as good as phenobarb
 Can use when animal develops phenobarb hepatotoxicity or tolerance
Therapeutic Drug Monitoring

 Peak occurs 4-6 hours after the dose was given
 Trough = immediately before the next dose.
 Timing is NOT critical if you simply want to assess if you are in the therapeutic range
 Timing is important in determining individual patient PK
If outside the therapeutic range (low)

 Might be adequate for that patient
o Leave it if seizure control seems adequate
 May have to adjust the dose
o First check owner compliance
o See if it is due to enzyme induction
If inside the therapeutic range

 Responsive (animal has good seizure control)
o No need to adjust the dose, recheck in 6 months
 Unresponsive (animal still having seizures)
o Increase dose or frequency
o Try a combination treatment: Phenobarb + KBr or a 2 nd generation “newer” anticonvulsant
Adjusting the Dose

 First – empiric dose adjustment  trial and error
 Requires only single plasma sample
 Assumes linear pharmacokinetics (not the case with enzyme induction/inhibition or cats)
𝑡𝑎𝑟𝑔𝑒𝑡 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

𝑁𝑒𝑤 𝐷𝑜𝑠𝑒 = 𝑂𝑙𝑑 𝐷𝑜𝑠𝑒 𝑥
𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛

𝑁𝑒𝑤 𝐼𝑛𝑡𝑒𝑟𝑣𝑎𝑙 = 𝑂𝑙𝑑 𝐼𝑛𝑡𝑒𝑟𝑣𝑎𝑙 𝑥
𝑡𝑎𝑟𝑔𝑒𝑡 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
Estimating the Patients Phenobarb Half-life

 Two blood samples needed within 24 hours – at peak and trough
 Allows you to better predict responses to dose changes
 Assess changes in PB metabolism overtime
 If half-life decreases over time (enzyme induction) you may need to switch therapy
 If there are signs of toxicity check if half-life has increased (enzyme inhibition).
𝑝𝑒𝑎𝑘 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
ln( 1 0.693
𝑡𝑟𝑜𝑢𝑔ℎ 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
𝐾𝑒𝑙 = 𝑇 =
𝑇𝑡𝑟𝑜𝑢𝑔ℎ −𝑇𝑝𝑒𝑎𝑘 2 𝑘𝑒𝑙
Changes in Phenobarbital Metabolism

 CYP450 induction  reduces plasma concentration and seizures may reoccur
 CYP450 inhibition  grapefruit juice, increases plasma concentration, watch for sedation and hepatotoxicity
Behaviour Modifying Drugs

Always rule out any underlying medical causes of inappropriate behaviour. Pharmacotherapy should always
be accompanied by behavioural and environmental modifications.
Common Behavioural Disorders

 Cats – urine spraying and aggression
 Dogs – separation anxiety, aggression, loud noise phobias, compulsive behaviours
Anxiety
 Serotonin – 5-HT receptors
o comfort/wellbeing, role in impulse control
 Norepinephrine – adrenergic receptors
o Fight/flight Monoamines
 Dopamine – D1/D2 receptors
o role in motivation and drive, can lead to stereotypies in high amounts
 GABA – GABA receptors
o Causes animal to be less reactive
 Glutamate – NMDA receptor
o Role in learning/memory
 Acetylcholine - muscarinic/nicotinic receptors
o Excitatory NT, role in compulsive behaviours
Monoamine oxidase is in pre-synaptic terminal and breaks down monoamines
Antidepressants
 Tricyclic antidepressants: clomipramine, amitriptyline

o Inhibits the reuptake of serotonin and NE
o Treatment of: separation anxiety, aggression, urine marking, general anxiety, excessive vocalization,
phobias and compulsive behaviours.
o Used as sole treatment or with anxiolytics – 4-6 weeks before full therapeutic effect
o Side effects: mild sedation (anti-histaminic), dry mouth, urine retention and constipation (anti-
muscarinic), tachycardia, hypotension, arrhythmias (adrenergic).
 Selective serotonin reuptake inhibitors: fluoxetine (Prozac)

o Treatment of: anxiety states
o Sole treatment or combined with anxiolytics – 3-4 weeks before full therapeutic effect
o Side effects: mild sedation, GI irritation, excessive vocalization, seizures
 Serotonin agonist/reuptake inhibitor: trazadone

o At low doses, antagonizes postsynaptic 5-HT2, H1 and 1 receptors
o Agonistic effect at 5HT1 receptors, may impact GABA receptors
o Can be used in combination with other SSRI or TCAs safely
o Dogs – half life is 3 hours, oral bioavailability is 85%
 Monoamine oxidase inhibitor: selegiline (Anipryl)

o Stops breakdown of all the monoamines at the pre-synaptic junction
o Approved to treat canine cognitive dysfunction (pituitary Cushing’s disease – causes increased ACTH
and cortisol
o Used as sole treatment  metabolized to amphetamines
o Side effect: GI irritation (decreased appetite, V/D), lethargy
o Generally considered ineffective
Serotonin Syndrome = too much serotonin

 Beware of toxicity of drugs above
 Autonomic signs – tachycardia, hypertension, hyperthermia, diarrhea
 Neurological signs – tremors, myoclonus, hyperreflexia
 Mental signs – restlessness, paradoxical anxiety, confusion, agitation, coma at high doses
 Metabolic acidosis, renal failure, DIC
 Treatment – supportive (IV fluids, external cooling’s, benzodiazepines)
Anxiolytics – inhibits anxiety
 Benzodiazepines: diazepam (valium), midazolam (IM injection).

o Binds GABA receptor, stabilizes membrane charge
o Treatment of anxiety: fear, phobias, urine spraying
o Used as sole treatment or in combination with antidepressants
o Can interfere with learning/memory
o Side effects: sedation, ataxia, increased appetite, paradoxical excitation, hepatic necrosis.
 Azipirones: buspirone (Buspar)

o 5HT1 partial agonist, dopaminergic antagonist effects  increases serotonin, decreases dopamine
o Treatment of anxiety states and urine spraying
o Generally used as sole treatment
 More helpful in multi-cat households and in females
 Improvement in 55% of cats, but may relapse
o Benefits – not sedating (doesn’t affect learning ability)
o No CYP-mediated drug interactions
o Drawbacks: frequent dosing required (TID), transdermal not good (poor bioavailability)
o Side Effects: decreased inhibition, vomiting, more affectionate towards owner, tachycardia
 Feline Facial Pheromones

o Analogue of naturally occurring facial pheromones – spray/diffuser
o Calms anxious cats, reduces urine spraying – does not actually work
 It didn’t reduce RR or HR or improve the behavioural score
 Didn’t reduce stress scores
Treatment of Inappropriate Urination in Cats – none of the below drugs are approved in cats
 Tricyclic Antidepressants - clomipramine
 SSRIs – fluoxetine
 Benzodiazepines – diazepam, midazolam
 Buspirone – 5HT receptor blocker and dopamine antagonist effects
 Pheromones
Antipsychotics
 Phenothiazines: acepromazine, chlorpromazine

o Acepromazine:
 Injectable and oral forms – poor oral efficacy
 Licensed for small and large animals
 D2 antagonism (and a1 receptor antagonism)
 Used for sedation and motion sickness
o Chlorpromazine, Fluphenazine
o Adverse effects:
 Hypotension
 Extrapyramidal signs from excessive antagonism of dopaminergic receptors.
 Involuntary muscle movements
 Treatment – IV diphenhydramine – H1 blocker with anticholinergic effects
 Muscle rigidity
 Penile prolapse
 Ataxia, prolapsed 3rd eyelid
 CYP mediated interactions
Other CNS Depressing Drugs
 Mirtazepine (Remeron)
o Noradrenergic and 5HT1 antidepressant
o Antagonist of 5HT2 and 5HT3 and H1 receptors
o Anti nausea, stimulates appetite
 Dextromethorphan (antitussive)
o NMDA antagonist – decreases glutamate effect (excitatory NT)
 Reserpine
o NE reuptake inhibitor, leads to NE depletion
o Drug of abuse in horses
o Hypotension that lasts a few weeks
o Potentially fatal interactions with other hypotensive drugs (a2 agonists – xylazine, dexmeditomidine).
 Narcotic antagonist: naloxone (for opioid overdoses)
Respiratory Drugs
Goal of Therapy for Inflammatory Airway Disease

 Maintain pulmonary function
 Prevents recurrent episodes of dyspnea
 Improve animals quality of life
 Effective therapy is species specific:
o Cat are very responsive to serotonin from mast cells  causes bronchoconstriction
o Dogs/horses are response to COX (PG - prostaglandin) pathway products
Significant benefit of using anti-inflammatories and bronchodilators together
𝑝𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝑔𝑟𝑎𝑑𝑖𝑒𝑛𝑡
𝐴𝑖𝑟 𝐹𝑙𝑜𝑤 𝑅𝑎𝑡𝑒 = 𝑅𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 = 8 𝜋𝑛𝑟4𝐿
𝑎𝑖𝑟𝑤𝑎𝑦 𝑟𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒
Resistance is mostly determined by the radius of the tube

 Radius =  Resistance =  Airflow
2 adrenergic agonists (isoproterenol, ephedrine, clenbuterol) stimulates:
1. 2 adrenergic receptors are located on bronchial smooth muscle

 stimulation causes:  activity of adenylyl cyclase = cAMP
 cAMP causes:
o vasodilation of smooth muscle
o reduces bronchoconstriction by antagonising bronchoconstriction causing adenosine receptors
o blocks release of inflammatory mediators from mast cells
2. -receptors on mast cells decreasing release of inflammatory mediators

3. increases mucociliary clearance  clears inflammation and debris from airways
Epinephrine
 Stimulates  and  receptors causing producing vasopressive and cardiac effects
 Reserved for use in emergencies – during intense bronchoconstriction (anaphylaxis shock)
 Shouldn’t be used for chronic therapy due to its non-specific stimulation of other receptors (increases, HR, RR,
mydriasis) and short duration of action.
Isoproterenol
 Potent  receptor agonist – non-selective  stimulates both 1 and 2 receptors equally
 stimulation has profound cardiac effects making it unsuitable for long term bronchodilation use.
 Available in an injectable or inhalational form
 Short duration of action < 1 hour
Clenbuterol (Ventipulmin ®)
 Injectable or syrup form
 2 agonist for recurrent airway obstruction causes vasodilation at a low dose
 Need to use with an anti-inflammatory and some kind of environmental modification
 Banned in food animals due to welfare issues and because residues are detected in tissues months/years later
and can cause toxicity to humans.
 May cause tachycardia, muscle tremors or is tocolytic (relaxation of uterus)
 Clenbuterol is often misused at a high dose because it
o Increases skeletal muscle blood flow bringing more nutrients causing muscle mass to increase.
o Lipolysis  breaks down fat stores, makes FFA available for skeletal muscle
 2 selectivity is lost at higher doses  see 1 effects also (increased HR, lipolysis, increase muscle flow due
to 2 vasodilation)
Salbutamol aka albuterol (Ventolin®)

 Blue inhaler for acute asthma attacks  aerosol route with rapid onset and little systemic effects
o The drug gets down into the lungs to the bronchioles (site of action).
 Used in cats/horses
 Should only be used for acute bronchoconstriction
o Chronic use causes –receptor down regulation
Salmeterol (Advair, Serevent)  longer acting 2-agonists
Methylxanthines
 Not used much due to adverse effects  cardiac and CNS stimulation, diuresis
 Phosphodiesterase inhibitors that relaxes bronchial smooth muscle
o cAMP which antagonizes adenosine
 Anti-inflammatory effects
o  inflammatory gene expression
o  mast cell / eosinophil degranulation
 Respiratory Effects: theophylline > caffeine > theobromine
 Cardiovascular Effects: theophylline > caffeine > theobromine
 CNS Excitation: caffeine > theophylline > theobromine
Theophylline
 Human formulations – injectable and aqueous solutions, tablets/capsules
 Aminophylline is a theophylline salt that is 78-86% theophylline
o More water soluble  less GI irritation, good oral bioavailability
 Cytochrome P450-mediated metabolism
o Inhibited by erythromycin, cimetidine, propanolol, fluoroquinolones
  plasma concentration and toxicity
o Induced by rifampin and phenobarbital
  plasma concentration  may need to increase dose
o Need therapeutic drug monitoring  narrow margin of safety, plasma concentration fluctuates with
other drug interactions.
Anticholinergics
 Inhibits vagally mediated parasympathetic smooth muscle tone  bronchodilation
 Asthmatic humans may have excessive stimulation of cholinergic receptors
 In experimental feline asthma, long-term antigen exposure causes increased muscarinic receptor response to
acetylcholine
Atropine
 Test the dose for RAO horses, may cause colic or ileus
 Increases HR and mydriasis
Glycopyrrolate
 Used during anesthesia mostly
Ipratropium bromide
 Mostly used in human med
 Atrovent inhalant, multiple generics
Glucocorticoids
 Old therapy of RAO in horses, feline asthma and canine
bronchitis: high dose, long term chronic treatment with oral
glucocorticoids
o Oral steroid that attenuates (depresses) the
inflammatory response
o Suppress generation of cytokines and  recruitment of
airway eosinophils
 What are some of the concerns about chronic glucocorticoid
administration?
o Negative feedback to hypothalamus will stop production
of endogenous CRH (corticotropic releasing hormone) thus preventing ACTH production and cortisol
secretion from the adrenal cortex.
 Is dose dependent: low doses (replaces corticoids), high doses (reduces inflammation), very high doses
(causes immunosuppression).
 Inhibits phospholipase A and phospholipase C  less arachidonic production  less prostaglandin
production, less leukotrienes and then less thromboxane
 Airway effects:
o  severity of airway inflammatory symptoms
o  airway response to allergens
o might prevent airway remodelling  prevents chronic thickening
o  airway radius =  airflow
 Not really a bronchodilator, is a steroid that just prevents inflammatory airway disease signs.
 Use the lowest effective dose to minimize potential side effects.
Prednisone
 Is bioactivated to prednisolone in the body
 Cats/horses have limited oral bioavailability of prednisone  administer prednisolone instead (active form)
 Give prednisone/prednisolone to dogs: 1 mg/kg orally EOD
 Give methylprednisolone acetate to cats: 10-20 mg IM for 2-4 weeks (watch for diabetes!)
 Give dexamethasone for horses
Fluticasone (Flovent®)
 Inhalant glucocorticoids – less systemic absorption, decreases hypothalamus -pituitary axis suppression
 Most potent, longest acting, not cheap
 Available as 50, 125 and 250 mcg per puff (a lot less drug then what is taken orally)
Beclomethason (Rivenase®)
Budesonide (Pulmicort®)
Anti-leukotriene Drugs
 Leukotrienes – draw in a lot of WBCs and other inflammatory mediators
 Leukotriene receptor antagonist and 5-lipoxygenase inhibitor drugs used for chronic therapy of asthma in
humans
 Not a bronchodilator, is an anti-inflammatory drug – used for chronic therapy of inflammation (like steroids)
– not used for acute bronchoconstriction
 Lukast Family:
o Zafirlukast (Accolate®)
o Montelukast (Singulair®)
 Not very useful in cats – their inflammatory airway disease and bronchoconstriction are not usually leukotriene
mediated
Antitussives
 Minimizes coughing
 We want to minimize non-productive coughs
 Contributors to coughing: glottis, bronchi, mechanical stimuli, inflammation, drug adverse effects (ACE
inhibitors)
o ACE inhibitors (pril drugs) – lowers the threshold of irritation required to elicit a cough, prevents the
breakdown of bradykinin and increases coughing
Opioids
 Suppresses cough center in the medulla oblongata
 Mediated through both  and  receptors
  agonists
o Morphine
o Codeine (methylmorphine)
 increased oral bioavailability and decreased
analgesia compared to morphine but equal
antitussive effects
o Hydrocodone (Hycodan®) w/ homatropine
 Stops parasympathetic muscarinic receptors
  agonist
o Butorphanol (Torbutrol)
 Best for dogs
 1-5 mg oral tablets
 dose = 0.55 mg/kg every 6-12 h (frequent administration)
 poor oral bioavailability, so higher dose then equine IV injection
Tramadol
 Used a lot in companion animal practice – no licenced vet formulations
 Agonist for multiple opioid receptor types, plus 2 and 5-HT receptors
 Antitussive activity of M1 and/or M2
 Likely not as effective as butorphanol
 Not a go to anti-tussive drug
Dextromethorphan (Robitussin®)
 Not a true opioid, no and  receptor binding
 Is the non-addictive D-isomer of levorphan (an addictive opiate)
 NMDA receptor antagonist – not related to antitussive effect
 Not sure if it is a true effect or a placebo effect
Buckley’s
 Contains a ton of herbal ingredients: camphor, menthol, Canada balsam, pine needle oil, tincture of capsicum
The “Phlegm” Drugs – makes the cough more productive

 Expectorant: increases mucus hydration to volumes that are more easily expelled by coughing (Guaifenesin)
 Mucokinetics – increase mucus transportability by cough, improves mucociliary escalator (Ambroxol)
 Mucolytics: reduces mucus viscosity by cleaving muc in disulfide bonds (N-acetylcysteine)
 Mucoregulators: reduce mucus hypersecretion (Anticholinergics)
Doxapram
 Respiratory stimulant  directly stimulates the respiratory centre in the brain.
 Can use in neonatal animals (the calf that is having trouble and you don’t have a respirator)
 Anesthesia uses
 No licensed veterinary formulations
Appetite, Nausea/Vomiting, GIT Motility Modifying Drugs – Gurpreet
Appetite Modifying Drugs
Regulation of food intake

 Monogastric vs ruminants
 Food intake mainly regulated by hormones
o Mainly insulin (regulates glucose in the body)
o Also lecthins, ghrelin among many others
Causes of obesity in companion animals

 The animals with risk factors for obesity include: neutered males, inactive/indoors, inappropriate feeding, high
energy dense foods
 Easier to prevent obesity, than to treat it  weight management is key (need to improve diet and physical
activity and improve client education)
 Weight loss should not be more then 1-2% of body weight per week
 If you lose too much too fast you lose the essential fats in the body
Causes of weight loss in companion animals (inappetance/anorexia/hyporexia)

 Poor quality/low caloric density food
 Anorexia
 Dysphagia = difficulty swallowing
 Regurgitation/vomiting
 Maldigestive disease – pancreatic insufficiency
 Malabsorptive disease – small intestinal disease
 Malassimilation – organ failure
 Cancer cachexia – wasting of the body for a reason we don’t know – TNF- mediated
 Stress (lactation, cold, pregnancy, fever/inflammation, hyperthyroidism)
 Diabetes
 Lower motor neuron disease
Ruminants
 Forestomach (dorsal ruminal sac) houses a lot of cellulose rich material and a lot of water. The water in this sac
dilutes incoming drugs – dose-dependency doesn’t really work here.
 Massive saliva secretion which further dilutes the ruminal contents
 Food stimuli via autonomic reflexes control ruticulo-rumen motility
 Dopamine is not central for food intake
Dog/Cat
 Has a simple stomach
Hunger vs Satiety
 Daily caloric needs
 Prandial stimulation of taste receptors, gastrointestinal and hepatic chemoreceptors (dorsal ruminal sac) and
mechanoreceptors (reticulum) sends signals to the paraventricular nucleus (hypothalamus), central nucleus
(amygdala). The reflexes sense the signal and respond by increasing eating, reducing eating or allowing normal
eating behaviour.
 Peripheral auto-endocrine response
Anorexic Agents - suppresses food intake

 Cholecystokinin, serotonin, a2 agonists, uro-cortin-corticotropin releasing factor, bombesin-like peptide,
glucagon-like peptide 1, peptide-YY, orlistat, dirlotapide
 2 Main Anorexic Agent (that actually reduce weight)
o Dirlotapide
o Orlistat
Dirlotapide (Slentrol®)
 Selective microsomal triglyceride transfer protein inhibitor (MTPI)
o MTP enzyme normally catalyzes the assembly of lipoproteins to form chylomicrons in the intestinal
mucosa
o Inhibits lipoprotein assembly and secretion into the bloodstream – thus the fat never reaches the body
stores
o Reduces intestinal fat absorption and causes increased release of satiety signal (peptide YY) from lipid
filled enterocytes
 Oral solution used for obesity management in dogs (>1 y.o)
 Not for cats  causes hepatic lipidosis
 ADME:
o Food enhances absorption
o Plasma protein bound
o Enterohepatic circulation (so less metabolism by the cats – poor glucoronidators, so needs a lessened
dose)
o Non-linear kinetics
o Accumulation
 Contraindications – corticosteroids, liver disease, hyperadrenocorticism (Cushings)
o Don’t use in patients with above problems – drug has a metabolic effect
 Adverse Side Effects – V/D, anorexia, lethargy, liver TSA elevation
 Reduces absorption of fat soluble vitamins (A, D, E and K)
Orlistat
 Reversible pancreatic lipase inhibitor, undigested triglycerides accumulate
 Prevents intestinal fat absorption
 Off-label use, is a human drug and expensive ($$$)
 ADME:
o Minimal absorption but efficacy is good due to luminal action in stomach and small intestine.
o >99% lipoprotein and albumin bound
o Two metabolites (weak activity)
o Fecal excretion in 3-5 days and/or biliary excretion
Orexigenic Agents – enhances food intake

 NE (a1 receptor agonist), glutamate, BDZ (GABA receptors), opioid agonists, pancreatic polypeptides (NP -Y),
melanocyte concentrating hormone, mirtazapine, cyproheptadine (serotonin antagonists)
Benzodiazepines – enhance food palatability

 Diazepam (Valium®), Oxazepam (Serax®)
 Take caution if patient has renal disease – reduce dose by 25-50%
 Avoid oral dosing due to risk of acute hepatic necrosis
 Diazepam
o GABAa agonist – dampens neural conduction (CNS acitivity - this reduces anxiety but doesn’t explain
the food enhancement activity – we aren’t really sure why this happens
o ADME:
 Oral peak within 30 min-2 hours, rectally slow
 Bioavailability is 80% due to active metabolites (nordiazepam, temazepam, and oxazepam) –
thus its effectively long acting.
 Can be injected IV – great for cats (but watch out for hepatotoxicity)
 Dissolved in propylene glycol – so needs to be injected slowly or might get thrombophlebitis
 Undergoes glucuronidation – T½ in cats is 21.3 hrs vs 2-3 hrs in dogs
o Precautions – cats (hepatoxicity), renal disease, hypotension from rapid IV
 Oxazepam
o Oral alternative to diazepam, slightly longer acting
o Active metabolites
o Glucuronidation  adjust dose in cats
o Adverse Side Effects: ataxia, sedation, fatal idiosyncriatic hepatotoxicity in cats
Cyproheptadine (Periactin®)
 Serotonin antagonist antihistamine
 Not recommended for patients with hepatic lipidosis
 5-HT2 antagonist, H1 anti-histamine in ventromedial hypothalamus, Ca channel blocking
 Used offlabel
 Indicated primarily in cats, can be useful in management of serotonin syndrome
 ADME:
o Well absorbed
o T½ = 13 h in cats
o Liver metabolism, renal excretion
 Adverse Side Effects:
o Sedation, paradoxical hyperexcitability, anti-cholinergic effects, lowers seizure threshold, paradoxical
agitation in cats, hemolytic anemia in cats (rare)
o Mild depression, anorexia or lethargy in horses.
Mirtazapine (Remeron®)
 Pre-synaptic 2-receptor antagonist resulting in NE increase
 Serotonin receptor antagonist
Emetics and Anti-Emetic Drugs
Vomiting Reflex
 Protective
 Involuntary
 Well developed across species, especially carnivores
o Herbivores have less chance of eating toxic foods
 Associated with prodromal feeling (salivation, nausea)
 Bulimea nervosa = purging disorder
 Dogs – not a regulated reflex
o Dopamine, histamine
 Control:
o Peripheral receptors – irritation, inflammation, distension
o Vestibular apparatus – motion sickness
o Vomiting Centre – in the brain
o Chemoreceptor Trigger Zone – present outside the BBB
 Responsible to produce instant vomiting – quick vagal stimuli
 Associated with ACh, dopamine, serotonin, and histamine receptors
Neurotransmitters of Emesis
Acetylcholine (muscarinic receptors) and substance P (NK-1 receptors) act on the emetic center. The CRTZ is
stimulated by dopamine (D2 receptors), α 2-adrenergic drugs (NE receptors), serotonin (5-HT3 receptors), acetylcholine
(M1 receptors), enkephalins, and histamine (H1 and H2 receptors).
α-Adrenergic receptors in the CRTZ are important in inducing emesis in cats. α 2-Adrenergic agonists (eg, xylazine) are
more potent emetics in cats than in dogs.
5-HT1A antagonists (eg, buspirone) and α 2-adrenergic antagonists (eg, acepromazine, yohimbine, mirtazapine)
suppress vomiting in cats.
CRTZ D2 dopamine receptors are not as important in mediating humoral emesis in cats as they are in
dogs. Apomorphine, a D2 dopamine receptor agonist is a more reliable emetic in dogs than cats, and
D2 dopamine receptor antagonists (eg, metoclopramide) are not very effective antiemetic drugs in cats.
Histamine H1 and H2 receptors are found in the CRTZ of dogs but not cats. Histamine is a potent emetic in dogs but
not cats, and H1 antagonists (eg, diphenhydramine) are ineffective for motion sickness in cats.
Muscarinic M1 receptors are found in the vestibular apparatus of cats. Mixed M1/M2 antagonists (eg, atropine) inhibit
motion sickness in cats.
Substance P binds to NK-1 receptors, which are found in the gut and the emetic center of the CNS. Substance P
induces emesis, and selective substance P antagonists (eg, maropitant) are potent antiemetics in both dogs and cats
with a broad spectrum of activity against a variety of emetic stimuli.
Emesis
 Induced to empty anterior GIT for general anesthesia or ingestion of non-corrosive poisons.
 Generally removes 80% of stomach contents
 Most reliable emetic drugs act centrally to stimulate the vomiting centre, either directly or via the CRTZ
Emetics
Peripherally Acting Emetics

 Distension of pharynx, esophagus, stomach or duodenum by warm water (dilutes poisons), saturate saline, oral
3% H2O2 (risk of foam aspiration)
 Some contain alkaloid or emetine may be fatal in cats
 If repeated use fails, perform gastric lavage with charcoal
Hydrogen peroxide (3%) applied to the back of the pharynx stimulates vomiting via the ninth cranial nerve.
Small doses (5–10 mL) of hydrogen peroxide can be administered via oral syringe until emesis occurs. It should
be administered cautiously, especially in cats, because aspiration of hydrogen peroxide foam causes severe
aspiration pneumonia. When small amounts are administered, 3% hydrogen peroxide is relatively nontoxic.
Stronger concentrations (eg, hair dye peroxide) are more toxic.
Other products have been used but are not recommended to induce emesis in dogs and cats. Syrup of ipecac is
no longer recommended for "home use" in people or animals. The active ingredient is emetine, a toxic alkaloid,
which produces vomiting by acting as a stomach irritant. If repeated use fails to induce emesis, then gastric
lavage is necessary to remove the emetine to prevent additional toxicosis. Although sometimes
suggested, sodium chloride (salt) and powdered mustard should not be used. Mustard is rarely effective and
can be inhaled and cause lung damage, whereas salt toxicity can easily occur if overdosed and can result in fatal
cerebral edema.
Centrally Acting Emetics
 Apomorphine
o Non-electively stimulates D2 in CTZ, suppresses vomiting centre so repeating doses may be ineffect ive
o Higher doses cause CNS depression
o Low oral bioavailability
o Emesis within 20 minutes
o Apomorphine
 Xylazine
o 2 agonist, sedative analgesic
o Used in cats to induce emesis
Apomorphine is an opioid drug that acts as a potent central dopamine agonist to directly stimulate the CRTZ.
Therefore, it is less effective in cats than in dogs. It can be administered PO, IV, or SC; the IM route is not as
effective. It can also be applied directly to conjunctival and gingival membranes, using the tablet formulation,
which can easily be removed once emesis is initiated. Vomiting usually occurs in 5 –10 min.
Although apomorphine directly stimulates the CRTZ, it has a depressant effect on the emetic center. Therefore, if
the first dose does not induce emesis, additional doses are not helpful. Because the vestibular apparatus may
also be involved in apomorphine-induced vomiting, sedate and motionless animals will not vomit as readily as
active animals. Excitement that results from apomorphine in cats can be treated with the opioid
antagonist naloxone.
Xylazine is an α2-adrenergic agonist used primarily for its sedative and analgesic action. It is a reliable emetic,
particularly in cats, in which it stimulates the CRTZ. Because xylazine can produce profound sedation
and hypotension, animals should be closely monitored after administration.
Anti-Emetics
Protracted vomiting is physically exhausting and can cause dehydration, acid -base and electrolyte disturbances,
and aspiration pneumonia. Antiemetic drugs are used to control excessive vomiting once an etiologic diagnosis
has been made, to prevent motion sickness and psychogenic vomiting, and to control emesis from radiation and
chemotherapy. Antiemetics may act peripherally to reduce afferent input from receptors or to inhibit efferent
components of the vomiting reflex response. They may also act centrally to block stimulation of the CRTZ and
emetic center.
Antihistamine Drugs: Diphenhydramine, Dimenhydrinate, Promethazine
 Crossover with phenothiazines and anti-muscarinics
 H1 antagonists
 Sedative side effect, sometimes excitation in cats
 Less effective in animals
Phenothiazine Tranquilizers (Acepromazine, Metoclopramide)

 Broad spectrum  antagonizes D2, 1, M1 and H1
 Causes sedation, involuntary motor activity, vasodilation (due to peripheral 1 blockade)
Acepromazine
 Helps in controlling intractable animals
 Alleviates itching
 Antiemetic during motion sickness and as pre-anesthetic
 Adverse Side Effects: hypotension, bradycardia, CV collapse, hemodynamic instability , penile
protrusion in horses resulting in permanent paralysis of retractor muscle, excitement, restlessness,
sweating, trembling, tachypnea, tachycardia, seizures, recumbency
 Monitor for toxicity – ataxia, sedation, hypotension
 Use epinephrine or phenylephrine to control hypotension
 BDZ or diazepam to control seizures
 Doxapram antagonizes CNS depressant effects
Metoclopramide (Reglan®)
 Broad spectrum
 More potent as anti-emetic (dogs) than a prokinetic
 Poor anti-emetic in cats
 Low doses: D2 antagonism
 Peripheral GIT – increase emptying of stomach and upper duodenum
 High Doses : 5HT3 antagonism
Antimuscarinic drugs (Atropine, Methscopolamine, Isopropaminde)

 M1 antagonists
 Help with motion sickness (vestibular)
 CRTZ induced
 Transderm-Scop not very effective in dogs/cats, causes excitement in cats
 Xerostomia (dry mouth), reduced gastric emptying, ileus, urinary retention, constipation
Serotonin (5-HT) Antagonists (Ondansetron)

 5HT3 antagonists – works very well for the vomiting centre
 Used against cancer chemotherapy induced vomiting  given IV/oral 30 min before cancer drug administration
 Expensive
NK-1 Receptor Antagonists (Maropitant = Cerenia®)

 Functions of NK1 Receptors
o Regulates vascular tone
o Regulates vascular permeability
o Regulates bronchial tone and mucus production
o Tachycardia
o CNS: locomotor, grooming, aggression in cats
o Emetic centre
Maropitant
 Used for motion sickness (vestibulitis), and vomiting caused by cancer treatments, pancreatitis, enteritis,
cisplatin, copper sulfate, apomorphine, ipecac, parvo.
 Crosses BBB and selectively blocks NK1 receptors in the nucleus tractus solitaries (emetic center)
 Rapid and complete SC absorption
 Low oral BA due to first pass effect
 No dose adjustments required for renal failure patients
The phenothiazine tranquilizers are α 2-adrenergic antagonists and antagonize the CNS stimulatory effects
of dopamine and decrease vomiting from a variety of causes, including motion sickness in cats. These drugs also have
antihistaminic and weak anticholinergic action. Phenothiazine tranquilizers used as antiemetics include
acepromazine, chlorpromazine, and prochlorperazine. Potential adverse effects include hypotension due to α -
adrenergic blockade, excessive sedation, extrapyramidal signs, and a lowering of the seizure threshold in animals with
epilepsy. Extrapyramidal signs can be counteracted with an antihistamine (eg, diphenhydramine).
The anticholinergic drugs block cholinergic afferent pathways from the GI tract and the vestibular system to the
vomiting center. Alone, they are less effective than the other emetics. Aminopentamide is approved for use in dogs and
cats in the USA as an injectable formulation and oral tablets. It should be more efficac ious in the treatment of motion
sickness in cats than in dogs, because muscarinic M1 receptors are found in the vestibular apparatus of cats.
Aminopentamide has low efficacy for other causes of vomiting.
The antihistamines can block both cholinergic and histaminic nerve transmission responsible for transmission of the
vestibular stimulus to the vomiting center of dogs. The commonly used histamine (H1) blocking drugs
are diphenhydramine and dimenhydrinate (diphenhydramineplus 8-chlorotheophylline). They may cause mild sedation,
especially diphenhydramine, but paradoxical CNS stimulation may also occur, presumably from anticholinergic effects.
Metoclopramide exerts its antiemetic effects via three mechanisms. At low doses, it inhibits dopaminergic
transmission in the CNS, whereas at high doses, it inhibits serotonin receptors in the CRTZ.
Peripherally, metoclopramide increases gastric and upper duodenal emptying. Metoclopramide is a useful antiemetic
for dogs. Because CRTZ D2 dopamine receptors are not very important in mediating humoral emesis in
cats, metoclopramide is less effective in cats than in dogs. It is used to control emesis induced by chemotherapy,
nausea and vomiting associated with delayed gastric emptying, reflux gastritis, and viral enteritis. Th ere is tremendous
individual variability in metoclopramide pharmacokinetics, and oral bioavailability is only ~50% because of a significant
first-pass effect. At high doses or with rapid IV administration, metoclopramide causes CNS excitement
by dopamine antagonism (similar to the phenothiazine tranquilizers). Extrapyramidal signs can be counteracted with an
antihistamine such as diphenhydramine. Metoclopramide should not be administered if a GI obstruction or perforation
is suspected.
The serotonin antagonists ondansetron, granisetron, and dolasetron are specific inhibitors of serotonin subtype 3
receptors in the CRTZ. These receptors are located peripherally on vagal nerve terminals and centrally in the area
postrema of the brain. Cytotoxic drugs and radiation damage the GI mucosa, causing release of serotonin. These are
the most effective antiemetics used in people undergoing radiation and chemotherapy, and they have been used in
cats and dogs receiving chemotherapy. Although very effective at controlling vomiting associated with chemotherapy
and drug-induced vomiting, these drugs do not prevent or relieve nausea, which may be more debilitating than
vomiting. They are not effective for emesis caused by motion sickness. All serotonin subtype 3 antagonists ha ve been
associated with prolongation of the QT interval in people. Adverse effects of dolasetron include ECG changes (PR and
QT prolongation, QRS widening) caused by dolasetron metabolites that block sodium channels.
Butorphanol is an effective antiemetic for dogs receiving cisplatin chemotherapy. It causes only mild sedation. It is
believed to exert its antiemetic effect directly on the vomiting center.
Maropitant is a neurokinin 1 (NK-1) receptor antagonist approved to treat and prevent emesis in dogs and cats.
Substance P is a regulatory peptide that binds to the NK-1 receptors and induces emesis. NK-1 receptor antagonists
are believed to provide antiemetic activity by suppressing activity at the nucleus of the solitary tract, where vagal
afferents from the GI tract converge with inputs from the CRTZ and other regions of the brain involved in the control
and initiation of emesis. Despite its selectivity for the NK-1 receptor, maropitant blocks apomorphine, cisplatin, and
syrup of ipecac–induced vomiting in dogs, which suggests that activation of the nucleus of the solitary tract is a final
common step in the initiation of emesis. Despite being very effective antiemetics in people, NK -1 receptor antagonists
have little effect on chemotherapy-associated nausea in people or hydromorphone-induced nausea in dogs.
Maropitant injectable is approved for vomiting in cats ≥16 wk old and acute vomiting in dogs ≥8 wk old at 1 mg/kg/day.
Maropitant tablets are approved for acute vomiting in dogs ≥8 wk old (2 mg/kg), and to prevent vomiting due to motion
sickness in dogs ≥16 wk older (8 mg/kg). Dogs should not be fed for 1 hr before giving maropitant. The best time to
give maropitant is 2 hr before travelling, with a small amount of food. The tablets should not be wrapped tightly in fatty
food such as cheese or meat, because this may keep the tablets from dissolving and delay the effect of maropitant.
Adverse effects are rare with maropitant, but the most common ones are excessive drooling, lethargy, lack of appetite,
and diarrhea. Maropitant injections may also cause a stinging sensation; this can be minimized by keeping the
injectable solution refrigerated and, once the drug is drawn up, injecting right away at the refrigerated temperature. A
few dogs may vomit after treatment. Giving maropitant with a small amount of food will help avoid this.
Gastric Motility Modifying Drugs
Gastric Reservoir Relaxation

1. Receptive Relaxation – mechanical stimuli in in pharynx stimulates vagal centre and inhibits vagal fi ring
2. Adaptive Relaxation – distension in the stomach stimulates tension receptors which stimulate the vagal centre
to inhibit vagal firing
3. Feedback Re-relaxation – nutrients in the intestine stimulate CCK and the vagus centre to cause relaxation
allowing food to move aborally
Peristaltic Wave – tonic contractions of the corpus of the stomach pushes food from the reservoir. Also get backflow from
the antrum.
Agents that Control Gastric Motor Function

Excitatory Agents – increases gastric motility
 Increases Calcium  ACh, Serotonin, Opioid Peptides, Substance P
 Increased ACh and Substance P  CCK, bombesin
 Inhibits adenylate cyclase  opioid peptides
Inhibitory Agents – decreases gastric motility

 Increases cAMP/cGMP  VIP, beta agonists, glucagon, nitric oxide
 Inhibits release of ACh and Substance P  somatostatin, alpha agonists
Prokinetics increase GI motility

 Upper GI prokinetics
o Metoclopramide
o Domperidone
o Erythromycin (motilin agonist in upper GI at low doses)
 Lower GI prokinetics
o Cisapride
o Tegaserod
o Bethanchol
o Neostigmine
 General Prokinetics
o H2 receptor antagonists (cimetidine, ranitidine)
o Lidocaine
Metoclopramide
 D2 and 5HT3 antagonist  may cause D2 extrapyramidal side effects
 5HT4 agonist
 Increases release and sensitivity to Ach
 Less effect on distal segments
 Dogs – little effect in gastroparesis or chronic regurgitation, more commonly used an an anti -emetic
 Cats – IV infusion, Cattle – IM for pyloric stenosis, Horses – CRI
 Side Effects: neurological behaviour changes, abdominal pain, prolactin secretin
Domperidone (Motilium®, Equidone®)

 Similar to metoclopramide
 Does not readily cross BBB, lesser CNS effects
 Used in horses to preent and treat fescue toxicity and agalectia
 Do not administer with antacids (omeprazole, cimetidine)
Cisapride
 Off label use
 5HT4 agonist
 5HT3 antagonist  cardiarrhythmic side effects
 Cats – directly stimulates smooth muscle motility of stomach, small intestine and colon, accelerating transit times.
Useful for cats with chronic constipation.
 Also used in dogs and horses
 Precaution – ketoconazole may increase plasma concentrations of cisapride by inhibiting CYP450 enzymes
 Side Effects – cardiac arrhythmias due to K channel blockade causing prolonged QT interval
Tegaserod (Zelnorm®)
 Partial 5HT4 agonist
 Little effect on 5HT3 or dopamine receptors
 Stimulates coordinated motility
 Increases gastric emptying and small bowel transit
 Banned in 2007
Bethanechole (Urecholine®)
 Off-label use
 Cholinergic M1 agonist – produces nonspecific smooth muscle stimulation
 More pronounced effect on ileocecoclic region in cattle
 Side Effects – nonspecific cholinergic stimulation (salivation, lacrimation), diarrhea
Neostigmine (Prostigmin®)
 Inactivates AChE inhibiting ACh degradation, prolongs action by making ACh available for cholinergic receptors
 Horses – use is discouraged due to risk of colic
 Side Effects – diarrhea, salivation, respiratory difficulty, muscle twitching
 Used for treatment of neuromuscular disease – myasthenia gravis
Erythromycin
 Antibiotic with activity that non-specifically stimulates motility at low doses
 Long term use may cause vomiting and regurgitation
 Activates motilin receptors in stomach and proximal small intestine via endogenous motilin of ACh in upper GIT
 Calves – increase rumen motility
 Horses – not very effective, increased incidence of diarrhea likely due to microflora disturbances
Lidocaine
 Suppresses sympathetic tone transmission
 Prevents sympathetic reflexive spinal and peritoneal inhibition of sympathetic stimulation
 Direct excitation of intestinal smooth muscle
 Suppresses central hyperalgesia by blocking neural transmission
 Anti-inflammatory effects in intestinal re-perfusion injury
 Horses – to reduce post-operative ileus via IV infusion
 Side Effects – muscle fasciculations, ataxia, seizures – motor for these and reduce infusion rate accordingly
Newer Drugs
 Mosapride – 5HT4 agonist used PO in horses
 Opiate Agonist (Naloxone) can restore postoperative ileus in ponies but also antagonizes analgeis effect as it
crosses BBB
Idiopathic Megaesophagus  Bethanechole
Gastric Emptying Disorders  used Cisapride, Erythromycin, Ranitidine
Intestinal Transit Disorders  uses Cisapride, Tegaserod, Metoclopramide
Colonic Motility Disorders  Cisapride, Ranitidine
Metoclopramide is a central dopaminergic antagonist and peripheral 5-HT3 receptor antagonist and 5-HT4 receptor
agonist with GI and CNS effects. In the upper GI tract, metoclopramide increases both acetylcholine release from
neurons and cholinergic receptor sensitivity to acetylcholine. Metoclopramide stimulates and coordinates esophageal,
gastric, pyloric, and duodenal motor activity. It increases lower esophageal sphincter tone and stimulates gastric
contractions, while relaxing the pylorus and duodenum. Inadequate cholinergic activity is incriminated in many GI
motility disorders; therefore, metoclopramide should be most effective in diseases in which normal motility is
diminished or impaired. Metoclopramide speeds gastric emptying of liquids but may slow the emptying of solids. It is
effective in treating postoperative ileus in dogs, which is characterized by decreased GI myoelectric activity and
motility. Metoclopramide has little or no effect on colonic motility.
Metoclopramide is primarily indicated for relief of vomiting associated with chemotherapy in dogs, as an antiemetic for
dogs with parvoviral enteritis, and for treatment of gastroesophageal reflux and postoperative ileus. GI obstruction,
such as intussusception in puppies with parvoviral enteritis, must be excluded before initiating metoclopramide therapy.
Its prokinetic action is negated by narcotic analgesics and anticholinergic drugs, such as atropine. Drugs that dissolve
or are absorbed in the stomach, such as digoxin, may have reduced absorption. Bioavailability may be increased for
drugs absorbed in the small intestine. Because of accelerated food absorption, metoclopramide therapy may increase
the insulin dose required in animals with diabetes.
Metoclopramide readily crosses the blood-brain barrier, where dopamine antagonism at the CRTZ produces an
antiemetic effect. However, dopamine antagonism in the striatum causes adverse effects known collectively as
extrapyramidal signs, which include involuntary muscle spasms, motor restlessness, and inappropriate aggression.
Concurrent use of phenothiazine and butyrophenone tranquilizers should be avoided, because they also have central
antidopaminergic activity, which increases the potential for extrapyramidal reactions. If recognized in time, the
extrapyramidal signs can be reversed by restoring an appropriate dopamine:acetylcholine balance with the
anticholinergic action of an antihistamine, such as diphenhydramine hydrochloride given IV at a dosage of 1 mg/kg.
Cisapride is chemically related to metoclopramide, but unlike metoclopramide, it does not cross the blood-brain barrier
or have antidopaminergic effects. Therefore, it does not have antiemetic action or cause extrapyramidal effects
(extreme CNS stimulation). Cisapride is a serotonin 5-HT4 agonist with some 5-HT3 antagonist activity, so it enhances
the release of acetylcholine from postganglionic nerve endings of the myenteric plexus and antagonizes the inhibitory
action of serotonin (5-HT3) on the myenteric plexus, resulting in increased GI motility and increased heart
rate. Cisapride is more potent and has broader prokinetic activity than metoclopramide, increasing the motility of the
colon, as well as that of the esophagus, stomach, and small intestine. Cisapride is especially useful in animals that
experience neurologic effects from metoclopramide. Cisapride is very useful in managing gastric stasis, idiopathic
constipation, and postoperative ileus in dogs and cats. Cisapride may be especially useful in managing chronic
constipation in cats with megacolon; in many cases, it alleviates or delays the need for subtotal colectomy. Cisapride is
also useful in managing cats with hairball problems and in dogs with idiopathic megaesophagus that continue to
regurgitate frequently despite a carefully managed, elevated feeding program. In comparative studies of GI motility in
people and animals, cisapride is clearly superior to other treatments.
Initially, the only adverse effects reported in people were increased defecation, headache, abdominal pain, and
cramping and flatulence; cisapride appeared to be well tolerated in animals. As cisapride became widely used in
management of gastroesophageal reflux in people, cases of heart rhythm disorders and deaths were reported to the
FDA. These cardiac problems in people were highly associated with concurrent drug therapy or specific underlying
conditions. In veterinary medicine, adverse reactions to clinical use of cisapride have not been reported. Cisapride for
animals can only be obtained through compounding veterinary pharmacies.
Domperidone is a peripheral dopamine receptor antagonist that has been marketed outside the USA since 1978. It is
available in Canada as a 10-mg tablet. Currently, it is available in the USA only as an investigational new drug (1% oral
domperidone gel) to treat agalactia in mares due to fescue toxicosis. Domperidone regulates the motility of gastric and
small-intestinal smooth muscle and has some effect on esophageal motility. It appears to have very little physiologic
effect in the colon. It has antiemetic activity from dopaminergic blockade in the CRTZ. But because very little
domperidone crosses the blood-brain barrier, reports of extrapyramidal reactions are rare; however, if a reaction
occurs, the treatment is the same as for reactions to metoclopramide. Domperidone failed to enhance gastric emptying
in healthy dogs in one study. In other studies, however, domperidone was superior to metoclopramide in stimulating
antral contractions in dogs but not cats, and it improved antroduodenal coordination in dogs. Because of its favorable
safety profile, domperidone appears to be an attractive alternative to metoclopramide.
Macrolide antibiotics, including erythromycin and clarithromycin, are motilin receptor agonists. They also appear to
stimulate cholinergic and noncholinergic neuronal pathways to stimulate motility. At microbially ineffective doses, some
macrolide antibiotics stimulate migrating motility complexes and antegrade peristalsis in the proximal GI
tract. Erythromycin has been effective in the treatment of gastroparesis in human patients in whom metoclopramide or
domperidone was ineffective. Erythromycin increases the gastric emptying rate in healthy dogs, but large food chunks
may enter the small intestine and be inadequately digested. Erythromycin induces contractions from the stomach to the
terminal ileum and proximal colon, but the colon contractions do not appear to result in propulsive motility.
Therefore, erythromycin is unlikely to benefit patients with colonic motility disorders.
Human pharmacokinetic studies indicate that erythromycin suspension is the ideal dosage form for administration
of erythromycin as a prokinetic agent. Other macrolide antibiotics have prokinetic activity with fewer adverse effects
than erythromycin and may be suitable for use in small animals. Both erythromycin and clarithromycin are metabolized
by the hepatic cytochrome P450 enzyme system and inhibit the hepatic metabolism of other drugs,
including theophylline, cyclosporine, and cisapride. Nonantibiotic derivatives of erythromycin are being developed as
prokinetic agents.
Ranitidine and nizatidine are histamine H2-receptor antagonists that are prokinetics in addition to inhibiting gastric
acid secretion in dogs and rats. Their prokinetic activity is due to acetylcholinesterase inhibition, with the greatest
activity in the proximal GI tract. Cimetidine and famotidine are not acetylcholinesterase inhibitors and do not have
prokinetic effects. Ranitidine and nizatidine stimulate GI motility by increasing the amount of acetylcholinesterase
available to bind smooth muscle muscarinic cholinergic receptors. They also stimulate colonic smooth muscle
contraction in cats through a cholinergic mechanism.
Ranitidine causes less interference with cytochrome P450 metabolism of other drugs than does cimetidine,
and nizatidine does not affect hepatic microsomal enzyme activity, so both drugs have a wide margin of safety.
IV lidocaine is used in the treatment of postoperative ileus in people and has been shown to be useful in treating ileus
and proximal duodenitis-jejunitis in horses. It is thought to suppress firing of primary afferent neurons, as well as to
have anti-inflammatory properties and direct stimulatory effects on smooth muscle. It is also thought to suppress the
primary afferent neurons from firing, as well as have anti-inflammatory properties and direct stimulatory effects on
smooth muscle. Most horses respond within 12 hr of starting an infusion.
Anti-thrombotic and Hematopoietic Drugs - Hiebert
Antithrombotic and Hematopoietic Drugs
Hemostasis – prevention of blood loss, but also maintaining blood in a liquid state and eventual clot destruction
Primary Hemostasis – injury, vessel constricts, platelets adhere and form a

platelet plug
Secondary Hemostasis – coagulation mechanism activated, results in fibrin

deposition – forms stable platelet plug
Fibrinolysis – clot dissolved
Antithrombotic Drugs – prevents thrombosis but not so much that

hemorrhage occurs
Thrombosis – formation of a solid blood clot in a blood vessel
Embolism – clot or other material that is free to move in the circulation
Pulmonary Embolism – blood clot that breaks off and travels to pulmonary arteries
Post-thrombotic Syndrome – venous stasis, valves dysfunctional, breakdown of lymphatic vessels, swelling, pain,
dermatitis, ulcers
Needs for Therapy

 Cardiac, arterial or venous thrombosis
 DIC
 Inflammation
 Pancreatitis
 Neoplasia
Tenase Complex (8 and 9 activate 10)

 Produces active enzyme cofactor Xa
 Phospholipid layer and calcium associates with cofactor IXa
 Cofactor VIIIa converts factor X to Xa
Prothrombinase Complex (5 and 10 activate prothrombin to thrombin)

 Prothrombin (II) converted to thrombin (IIa)
 Cofactor Va and Cofactor Xa (active enzyme) attached to phospholipid bilayer by calcium
Anticoagulants – prevent coagulation

Thrombolytics – increase clot breakdown (fibrinolysis
Anticoagulants
Drug Mechanism of Action Notes
Calcium chelators  Bind calcium and remove it from  Excellent for blood collection
 sodium citrate the system  Needed in many places of the
 sodium oxalate coagulation cascade
 EDTA
 Sodium fluoride
Heparin  Direct anticoagulant  Harvested from animal tissues –
 Enhances the action of usually pigs
antithrombin III or heparin cofactor  Produced in mast cells as a
II (inhibitors of coagulation) proteoglycan
 Inhibits factor IIa, Xa and IXa and  Is a glycosaminoglycan
Xia  Very negatively charged
 Heterogenous – lots of variation in
chain length and charge density –
 When given orally it binds to lots of different groups on it
endothelial cells and has anti-  Best known for anticoagulant
thrombotic activity activity – stabilizes molecule,
binds histamine in mast cells
 Given IV, SQ, or PO
 High MW binds to antithrombin
and can inhibit both factor Xa and
thrombin (better at inhibiting
thrombin compared to low MW
heparins)
Fondaparinux (low MW heparin)  Binds directly to anti-thrombin  Pentasaccharide binds to anti-
thrombin then there is a better fit
for factor Xa (better fit to inhibit
Xa)
Small molecule direct thrombin  When given IV directly inhibit  Proxabind – monoclonal Ab for
and Xa inhibitors thrombin and factor Xa reversal of Dabigatran
 Hiruidin, bivalirudin (IV)  Antidote for Xarelto – not
approved by FDA
NOACs
 Dabigatran – Pradaxa (IIa  Bleeding
inhibitor)  Bleeding and liver injury
 Rivaroxabana-Xarelto (Xa
inhibitor)
Coumarin Derivatives  Interfere with the use of Vit K and  Preventative medicine
 Dicoumarol Vit K dependent factors (II, VII, IX,  Warfarin = rodenticide
 Warfarin X and protein S and protein C)  Dicoumarins produces in spoiled
 Interferes with Vit K recycling in sweet clover
the liver – need Vit K to add GGC  This affects the tenase and
onto factors and it binds calcium – prothrombinase complex –
so get abnormal factors produced prevents them from attaching to
that cannot bind calcium phospholipid surface so you
cannot make factor Xa or
thrombin
 After administration of
warfarin/dicoumarol the first factor
to disappear will be Factor VII
(measured by PT – extrinsic
pathway) so extrinsic pathway is
affected first
Fibronolytic system
 depend on formation of plasmin which destroys the fibrin clot
 plasmin is formed by urokinase, streptokinase and tissue plasminogen activator
Streptokinase  Binds plasminogen and  Bacterial source
converts to plasmin  Side effect – bleeding (broke down vessels)
Tissue  Not used quite as much
plasminogen  Used in VetMed
activator  Treats stroke in humans
 Normally released from endothelial cells
 Recombinant
 Side effect – bleeding (broke down vessels)
 Effect is doubled in presence of fibrin
Platelet Function: adhesion, aggregation, clot retraction, induce coagulation, tissue repair, inflammation, angiogenesis

Aspirin  Inhibits COX1 and COX2 and prevents  Reduces the ability of the platelet to
production of thromboxane from arachidonic stimulate/activate other platelets 
acid. preventing platelet aggregation
 Prevents primary hemostasis
Clopidogrel  Binds to receptor that ADP binds to on  ADP that is produced by activated platelet
platelet surface and cannot enhance neighbouring platelets 
preventing platelet aggregation
 Prevents primary hemostasis
Vascular Wall Drugs

 Anti-inflammatory drugs
 Vasodilators
Hematopoietic Drugs – increase RBC and WBC production

Erythropoietin  Arterial blood monitored for oxygen  Increases RBC production
content in the kidney, if oxygen is too  Used in chronic kidney disease where EPO
low the peri-tubular interstitial cells in production is reduced
the kidney produce EPO which goes  Also, used in myelodysplasia (bone marrow
to bone marrow and enhances not producing enough cells – cancer, etc).
erythropoiesis  Performance-enhancing drug
rhG-CSF  Increases WBC production
 Used in cancer patients
Granulocyte Colony  Used in canine cyclic hematopoiesis – they
Stimulating Factor have cyclic neutropenia (every 14 days there
is a low level of neutrophils)
GM-CSF  Acts synergistically with IL-3  Used in myelodysplasia
Granulocyte
Macrophage Colony
Stimulating Factor
(Sargramostim)
IL-3  Acts synergistically with EPO and GM-  Increased RBC/WBC production
(Oprelvekin) CSF
Chicoine 2
Drugs Affecting Gastric Acid Secretion
Gi Ulcers
 Painful
 Leads to blood loss
 Melena (digested blood in feces)
 If it perforates the stomach or abomasum leads to peritonitis and guaranteed death
 Common in thoroughbred race horses
Ulcer Healing Requires

 Angiogenesis in the granulation tissue at the base of the ulcer
 Growth factors for epithelial and endothelial cell growth (VEGF)
 Epithelial cell division at ulcer margins
ProtectionMechanisms
1. Mucus Layer Coating Cells – prevents acid from contacting the epithelium
2. Tight Junctions b/w Cells – prevents acid from getting into submucosal tissue
3. Bicarbonate in Mucous – neutralizes any acid that gets to it
4. Rapid Turnover of Mucosal Cells – there are lots of healthy new cells that don’t get old, die off and wear
away – prevents acid from getting in
5. Pepsinogen is inactive when secreted
Receptor activation increases translocation of H/K ATPase pumps into apical membrane
Stimulators of HCl Secretion:

 Parasympathetic stimulation (vagal nerve) releases ACh that binds muscarinic receptors
o Can we use Atopine to block muscarinic receptors to decrease HCl secretion?
 These drugs are not specific to one localized muscarinic receptor type – acts throughout the
body  likely not a good therapy for gastric ulcers
 Gastrin Receptors
o Gastrin binds gastrin receptor and upregulates receptors (most importantely H2 receptors)
o Gastrin also binds entero-endocrine cells and causes release of histamine
 H2 Receptors
Inhibitors of HCl Secretion:

 Prostaglandins and Somatostatin
o Block the pathway that results in upregulating H/K ATPase pumps
o Stimulates increased mucus secretion and vascularization = cytoprotective – helps to protect epithelial
cells lining the stomach
Acid Rebound
 Happens when we abruptly stop anti-ulcer therapy (PPIs, H2 blockers)
 Increased serum gastrin and/or upregulation of the H2 receptors
 Increase in parietal cell mass may occur with the chronic use of H2-blockers and proton pump inhibitors
 Increases sensitivity to histamine
 Rapid increase in HCl production
 Be careful when weaning animals off these medications

Chicoine 2
Antacids  Neutralizes stomach acid to form  Doesn’t fix the ulcer
water and neutral salt  Fixes the acid temporarily (short-term)
(AlOH, MgOH, CaCO3)  Usually not absorbed systemically
Maalox, Tums, Rolaids  Pros  cheap, effective very quickly
 Cons  changes pH, doesn’t treat
underlying issue
 Not used a lot in VetMed – if we have
an ulcer we want to fix it, not just treat
the symptoms
 Symptomatic type therapy
Sucralfate  Disassociates in gastric acid to  Relatively safe – few adverse drug
sucrose octasulfate (coats the ulcers) reactions in normal patients
and AlOH (antacid)  Hard to demonstrate the benefits of this
 Increases mucosal PGE synthesis  drug – may interfere with absorption of
increases blood flow and mucous other drugs (due to coating)
production  Symptomatic type therapy
H2 Receptor Antagonists  Blocks gastric acid secretion from  All human drugs, none of these are
parietal cells by blocking the H2 licensed for veterinary use
receptor therefore minimizing HCl  Less H2, less cAMP, less proton pumps
production and Cl secretion
 Orally absorbed – low bioavailability in
horses and ruminants (need higher
doses – impractical from $$
perspective)
 Lipid soluble
 Short T½
 CYP inhibition: decrease metabolism of
other drugs
Cimetidine (Tagamet) Cimetidine – may increase gastric motility
(pro-kinetic). Don’t give with food or
antacids – can mess with drug absorption.
Also inhibits CYP enzymes in the liver. If
Ranitidine (Zantac) you give this with other drugs that are
metabolized in the liver you block its
metabolism and decrease clearance
Famotidine (Pepsid) Famotidine – can be given with food or
antacids
Proton Pump Inhibitors  Most effective at stopping acid  Gives ulcers time to heal on their own
secretion by blocking the proton  Short T½ but long effect  irreversible
pumps inhibition of proton pumps – so doesn’t
 Protons cannot get into gastric lumen need to stay in the plasma for a long
Omeprazole (Gastroguard) time – it can be cleared from the body
 only licenced for horses, but the proton pumps are still inhibited
extralabel use in  High dose – to treat ulcers
dogs/cats  Low dose – prevents ulcers
 Relapse when off therapy  rebound
HCl secretion and return of ulcers
 Adverse Effects: reduced gastric acid 
hypergastrinemia (excess gastrin
secretion)  mucosal cell hyperplasia
 rugal hypertrophy and carcinoids
(precancerous cells)
 CYP enzyme inhibition: if you use
cimetidine and PPI at the same time
they both inhibit CYP enzymes
decreasing clearance of eachother
 Con: $$$$$$$ - limits the use
Chicoine 2
 May decrease CSF production when
injected into IV or ventriculocisternal 
possibly due to inhibition of carbonic
anhydrase
Misoprostal  Synthetic PGE analogue  Evidence of efficacy as a preventative
 Stimulates bicarbonate and mucous for NSAID induced ulcers in dogs
secretion  Doesn’t prevent methylprednisolone –
 Increases mucosal blood flow  may induced GI hemorrhage & ulceration
stimulate healing  Best for preventing the ulcer from
 Decreases vascular permeability occurring
 Increases cellular proliferation and  Useful in animals that have history of
migration  to heal the ulcers ulcers in the past
 Not the best evidence
 Not cheap
 Few adverse effects
Corn Oil  60% linoleic acid – 2 double bonds  Cheaper than Gastrogard ®
 Decreases acid output in horses (only  Safe
on grass fed diets, not grain fed diets)  Easy to administer
 Significantly increases PGE2 and  Not an appropriate drug for gastric
sodium outputs  may treat ulcers ulcers – early studies are not
reproducible
 No difference b/w corn oil group and
placebo group
Antidiarrheal Drugs
 Many types of diarrhea
 Protectants and Adsorbents
o Kaolin-Pectin
o Activated Charcoal  absorbent for toxins then elimination in feces
Chicoine 2
 Bismuth Subsalicylate (Pepto-Bismol) coating agent and aspirin (anti-PGE)  anti-inflammatory effect, need
frequent administration.

Treatment of Diarrhea
Anticholinergic Drugs  Decreases intestinal  Doesn’t work that well because diarrhea isn’t
motility and secretions usually caused by increased intestinal
motility
 May actually worse diarrhea  shutting
down segmentation prevents mixing of food
and the digesta just slides through the
intestine
 Systemic Side effects  tachycardia,
mydriasis, dry mouth
Hyoscine Butylbromide  Antispasmodic and  Rapid onset 5-10 minutes, duration 3-4
(Buscopan ®) anticholinergic for horses hours
 Used for intestinal pain in colic and to
facilitate rectal exams
 No evidence of efficacy as an antidiarrheal
 Transient tachycardia and decreased gut
sounds
 Decreased gut sounds are one of the
prognostic factors in assessing colic – is a
main diagnostic tool.
Opioids  Acts on  receptors in  Great for hyposecretion or osmotic types of
GIT diarrhea – increased transit time allows
 Anti-secretory and anti- more water reabsorption and less is lost in
Loperamide (Imodium ®) motility the feces
Paregoric – tincture of opium  Decreases propulsive  No respiratory depression or analgesia
intestinal contractions, (doesn’t cross the BBB)
increases segmentation  Don’t use in cases of infectious diarrhea
(prolongs the time the (especially toxic types)  the increased
food stays in the transit time may result increased toxin
intestines) absorption
 Increases the tone of GI  Don’t use in ABCB-1 deletion 
sphincters heterozygotes – drug in BBB accumulates
 Stimulates absorption of because of inactive P-glycoprotein causing
fluid and electrolytes CNS effects
Antimicrobials  Useful in certain cases of  Antimicrobials are frequently the cause of
diarrhea where there is a diarrhea. Oral administration messes with
known bacterial the normal flora
causes and systemic  Beware of OTC calf scour boluses  has
impact (septicemia, very tetracyclines and sulfonamides (no longer
sick animal) available as of 2018)
 Not to useful, not many diarrheas are
actually microbe associated.
Chicoine 2
NSAIDs  Decreases inflammation  Metacam has label claim for supportive
of GIT therapy of calf diarrhea in combination with
Ketoprofen  Decreases secretion fluid therapy.
Flunixin associated with  Flunixin – only useful for blood present in the
inflammation feces
 Might just make the  Increased appetite, faster rate of gain but
animal feel better – so couldn’t prove a decrease in diarrhea
they eat more, etc.  Not useful for all species and all ages –
 Antipyretic effects? doesn’t apply to puppies and kittens
 Central analgesia?  Risk of renal adverse events and
dehydration
Treatment of Constipation
Lubricants  Particularly useful if there is an impaction
 Not a routine therapy for constipation
Mineral oil (cattle/horses)
Mineral oil + white petroleum
(hairball remedy)
Motility Modifying Drugs  Doesn’t work, can be dangerous
(Prokinetics)  NONE should be used for constipation
 Might not increase motility at the right region
Metoclopramide of the GIT
Cisapride  All have their own adverse effects
Erythromycin
Cimetadine
Ranitidine
Stimulant Laxatives  Irritate the mucosa or  ExLax irritates the lining of the colon 
intrinsic nerves causing dangerous!
Phenolphthalein (ExLax) motility  May cause excess fluid loss and messes
Bisacodyl (Dulcolax)  Inhibits Na/K ATPase with electrolyte absorption
pump causing  Not the best choice for constipated patients
increased Na in GIT
tract which osmotically
pulls water in and helps
flush out fecal material
Hyperosmotic Laxatives  Osmotically active to  Useful when we want to clean out the distal
draws fluid into GI colon
Sodium phosphate enemas lumen to stimulate  Useful for colonoscopy
Lactulose motility  Works very well, very quickly
Polyethylene glycol  Not for therapy of routine constipation
 Contraindication: Sodium phosphate enemas
may lead to hyperphosphatemia in Cats
Bulk Laxatives  Non-absorbed cellulose  Best for treating constipation

material will increase  Look at animals diet to see if they need to
Hydrophilic colloids - Metamucil the bulk of fecal change if they are routinely constipated
Fibre: prunes, pumpkins material  Fairly safe
 Easy to administer
Stool Softeners  Breaks up the  Likely not a primary therapy for treating
compacted fecal constipation
Docusates material, water moves
into the feces and its
easier to pass
Chicoine 2
Probiotics  Bacteria or yeast  No reports of adverse effects
added to food with the  Very in price
purpose of regulating  Biggest downside – owners need to use
the intestinal flora these continuously
 Doesn’t work well – likely does not change
the normal flora
 Might change nutrient production – impacts
motility and secretion and the normal
intestinal microflora
 Might stimulate the enteric immune system
Treatment of Chronic Colitis
5-amino-salicyclic acid  NSAID effects  Poor absorption from the GIT – stays in the
GIT without systemic absorption
 Still risky in cats
 Symptomatic therapy for colitis
Sulfasalazine  Anti-lipoxygenase  Sulfapyridine and mesalamine joined by an
activity azo bond
 Decreased IL1  General anti-inflammatory effects
 Decreased PGE
synthesis
 ROS scavenging
activity
Antimicrobials  Does metronidazole actually exert anti-
inflammatory effects  might be changing
Metronidazole gut flora which changes by products of
Tylosin fermentation which may have anti-
inflammatory activity
 Tylosin  anti-inflammatory effect,
antimicrobial effect and may effect motility in
colon and intestines
Glucocorticoids  Anti-inflammatory and/or  Give prednisolone formulation to cats/horses
immunosuppressive  Entocort has an oral pill form that is not
Prednisone/Prednisolone effect uncoated until it gets into the ileum / colon 
Budesonide (Entocort) prevents systemic side effects due to
absorption in duodenum and jejunum
 Fatty Acids  try to minimize inflammation in
Fatty acids GIT (omega 3s)
 At very high doses glucocorticoid drugs are
immunosuppressive, at low doses they are
Immunosuppressive Drugs anti-inflammatory.
 Immunosuppressive drugs have lots of nasty
Azathioprine (dogs) side effects – only use them if you absolutely
Chlorambucil (cats) need to
Exocrine Pancreatic Insufficiency: Pancrealipase (Pancrease V = Pank-Aid)

 Supplement of exocrine pancreas enzymes  lipase, amylase, proteases
Chicoine 2
 Used to treat exocrine pancreatic insufficiency
 Why are enzymes not digested in the stomach?
o Coated enzymes? Dose of enzymes?
o Mix with food 20 minutes before feeding dog
o H2 receptor antagonists may increase the amount of enzyme that reaches the duodenum
 Can try to modulate acid in the stomach that is responsible for degradation of these enzymes – then more of
these enzymes would get through to the small intestine
Pancreatitis - leakage of pancreatic enzymes into the bloodstream

 Octreotide (Sandostatin) is a synthetic somatostatin analog – inhibits secretion of prodigestive hormones
(gastrin, secretion, VIP, motilin, glucagon, insulin, acid and pepsin production, intestinal motility and GI blood
flow.
 No evidence for this in VetMed
 Evidence is only experimental
 Does not replace supportive therapy (fluids, anti-emetics)
Hepatitis and Liver Disease – hepatocellular damage, issues with bile secretion, etc.
 No specific therapy for hepatitis that is considered generally effective
 Limited trials for treatment efficacy in veterinary patients
 Antioxidant substances are popular in chronic disease  vitamin E, Milk thistle extract
 Be sceptical about all of these drugs – warn clients that these might not work
 Most don’t have any adverse effects at the clinically relevant dose
Uro-deoxycholic Acid
 Is a bile acid
 For cholestasis (decreased bile flow)
 Impairs cholesterol uptake and synthesis
 Reduces hepatotoxic effects of bile acids
 Aids in clearing cholesterol gallstones
 Limited adverse effects
SAMe
 Nutritional supplement for hepatocytes
 Increases hepatic concentrations of glutathione (antioxidant)
 Hepatic glutathione often deficient in severe hepatic disease
 Safely used in acute/chronic cases
 Food interactions – feeding reduces bioavailability
Copper Chelators
 D-penicillamine
o GI signs including vomiting arecommon
o Associated with pyridoxine deficiency
 Trientine
o Safer than penicillamine
o Only available as bulk chemical/compounded
 Zinc
o Blocks intestinal absorption of copper
o Various salts available
o Adverse effects – mostly GIT signs
 May have copper toxicosis shortly after administration
Chicoine 2
Veterinary Chemotherapy Know major classes how they work and
side effects. Only know indications on
Why bother learning about veterinary chemotherapy? veterinary approved chemotherapeutics
 New drugs always coming out
 Animals live longer
 More animals with clients and more clients willing to treat their animals
 Many chemo drugs can be used in general practice
 Older drugs are still mainstays
 Even if you refer chemo patients, you need to discuss options with your clients
Caveats of Veterinary Chemotherapy
Drugs rarely cure cancer

 99.9% kill rate – but it is not 100%
 Lots of cancerous cells will remain in the tumour
Pharmacokinetics and doses are not well known

 Usually using human drugs – lots of inter and intra species variability
 Difficult to predict the drug concentration in the tumour
 Drug interactions may not be known
 Used in older animals, possible with liver/kidney disease
Narrow Therapeutic Window

 NOT SAFE – these drugs are meant to kill cells (tumour cells) but spare the rest of the body
o Cytotoxic drugs – more adverse effects
 Can’t just raise and lower the doses
 Dosed based on body surface area (mg/m 2)
o Correlates better with metabolic rate (decreased metabolic rate per unit of body weight)
o Large dogs are more likely to overdose if dosed based on BW - increased adverse effects
o Problems:
 Small dogs may now be overdosed
 Large dogs may now be under-dosed
 Other factors that could predict toxicity:
 Distribution
 Clearance
 Wide range in pharmokinetics parameters for individual animals
 Animals with tumors are inappetant and lose lots of weight – so be careful when dosing – in most
cases we dose to effect
Cancer cells develop resistance to chemotherapeutics

 Similar to antimicrobial resistance – develop efflux pumps and inactivate drugs
 Multiple drugs used in protocol
 Worst Drug Rule – use the most cytotoxic drug 1st
Quality vs Quantity of Life

 Lots of owners do not want to put their animals through chemotherapy
 Treatment may make the animals more disease free, but may reduce survival
 Client may prolong survival and just let the disease progress
 Have a discussion with owners
Cell Cycle
 All cells in the body are going through the cell cycle
 Not happening in the cancer cells
 Chemotherapeutic cells target dividing active cells – not specific so will target all active cells
 Cycle Non-specific – kills at all phases
 Cycle Specific – kills cells during replication but spares the resting cells (Go)
 Phase Specific – kills cells during a specific cellular phase (DNA synthesis phase or Mitosis phase)

Chicoine 2
Aklylating  Cross-links the DNA strands  Proteins are translated but may be inactive or
Agents: Nitrogen  Causes abnormal base pairing, truncated
Mustard misreading of genetic code and  Toxic to rapidly growing normal cells (bone marrow,
excision of bases GI epithelial cells, hair)
 Prevents DNA replication and  Bone Marrow – myelosuppression, reduces
RNA transcription leading to cell production of WBC and neutrophils (we want to
death measure these). Neutrophils are critical for fighting
 Cell Cycle Nonspecific – most infections – causes animal to be
active when DNA is replicating immunocompromised.
(G1 and S phase)  Thrombocytopenia also common leading to clotting
disorders
 Nadir = lowest point of neutrophil counts = most
critical time of immunosuppression, blood sample at
this time to see how bad it is. This dictate dosing and
blood sampling.
Cyclophosphamide Prodrug – metabolised in the liver  Used for many tumor types.
to very active metabolites:  Carcinomas, sarcomas, feline lymphoproliferative
diseases, mammary carcinoma and lymphoma
1. Hydroxyphosphamide  Implications in dogs with hepatic dysfunction  dog
2. Aldophosphamide cannot metabolize cyclophosphamide into active
Phosphoramide metabolites and it won’t have much of an effect
Acrolein (sterile cystitis)  Cats – marrow suppression is delayed but prolonged
and typically severe  other medications may be
better
 Toxicity:
 Dose-dependent bone marrow toxicity – we
can lower the dose to minimize myelosuppression
 Hemorrhagic Cystitis (sterile) from acrolein in
30% of dogs – is a chemical cystitis. Can
minimize with furosemide (loop diuretic) or Mesna
(binds acrolein forming non-toxic products).
These work by increasing urination which rids of
the acrolein, so it is not sitting in the bladder
causing damage.
 GI: vomiting due to stimulation of chemoreceptor
trigger zone, destruction of gastric mucosa,
diarrhea
 Alopecia
Chlorambucil  Used more in smaller dogs and cats
(Leukeran ®)  Similar to cyclophosphamide – less potent, less toxic
$$$$  Decreased myelosuppression, vomiting
 Used more in immune mediated conditions for cats
Melphalan  Used to treat plasma cell tumours and myeloma
 Extremely myelosuppressive – very bone marrow
toxic
Ifosfamide  Hepatic biotransformation to  Used for sarcomas and lymphoma
active metabolites  Must be administered with mesna – will likely cause
hemorrhage cystitis
Nitrosoureas  Cross-links the DNA  These drugs end in “mustine”
 Lipid soluble – very good oral bioavailability
 Enters cell passively – no efflux pump resistance
 Crosses BBB – used anecdotally for brain tumours
 Myelosuppressive and may cause thrombocytopenia
Stretozocin  Targets and is toxic for  Used for insulinomas
(Zanosar®) pancreatic -cells  Extremely nephrotoxic (may cause tubular necrosis
inhibiting glomerular filtration) – need to administer
with lots of IV fluids to continuously flush this drug out
 Can result in Type I diabetes – used in research
Chicoine 2
 Vomiting common
 Not a common therapeutic in VetMed
Platinum Based Drugs

Cisplatin  Platinum binds to DNA bases  Used for solid tumors (osteosarcoma, carcinomas,
and cross links it is inhibiting mast cell tumours)
DNA synthesis  Dose every 3-4 weeks
 Max effect during the S phase  Extremely nephrotoxic – dose limiting factor
(when cells are dividing)  Don’t use in cats – causes rapidly fatal pulmonary
edema
 Vomiting and diarrhea may occur
 Can be used in conjunction with surgery or
amputation
 Effective intra-lesionally for sarcoids and other skin
tumours in horses – injected right into lesion to induce
remission.
Carboplatin  2nd generation platinum  Drug of choice
(Paraplatin®) derivative  Can be used in Cats
 Less nephrotoxic than cisplatin
 Causes thrombocytopenias
 Myelosuppression
Tx for mesothelioma – causes remission, can prolong
life a little bit (discuss cost/benefits with owner)
Bisphosphonates  Inhibits osteoclasts  reduces  Used in dogs with osteosarcoma (tumor with PTH
bone resorption like effects  bone lysis)
 Very painful
 May be analgesic for chronic osteolytic bone pain – by
slowing down the rate of bone resorption  leads to
more bone deposition
 Used for hypercalcemia of malignancy
 Nephrotoxic
 IV administration, once a month
Antimetabolites
 Inhibits nucleic acid synthesis by binding to cellular enzymes responsible for purine (A,G) or pyrimidine (C,T)
synthesis
 Active in the S phase of DNA replication
 Blocking synthesis of base pairs = slows down DNA replication
Methotrexate  Binds and inhibits dihydrofolate  Used in some combination chemotherapy protocols
reductase  Major adverse effects including anorexia, nausea,
 DHFR necessary for DNA purine vomiting
synthesis  Myelosuppression: nadir @ 6-9 d
 Low doses for rheumatoid arthritis in people –
unknown mechanism – immunosuppressive actions
5-Fluorouracil  Inactivates thymidylate  Used in equine medicine for squamous cell
synthetase – required for carcinomas
synthesis of thymine  Do not use in cats – neurotoxic and hepatotoxic
 Used topically of IV – systemic use limited due to
neurotoxic
Gemcitabine  Cytidine analogue  May cause thrombocytopenia and pulmonary toxicity
 Stops DNA replication  Used in some lymphoma protocols
Chicoine 2
Cytarabine  Metabolized to an active  Not commonly used
metabolite that inhibits DNA  Used in lymphoma protocols
polymerase blocking DNA  Very suppressive to bone marrow
synthesis  Needs to be metabolized to produce active
metabolites that block DNA polymerase
 Causes nausea and vomiting
Rabafosadine  Active metabolites increase  Indicated for lymphoma in dogs
(Tanovea-CA 1®) permeability and accumulation  Conditional approval for Veterinary Use
of metabolites in blood  Double prodrug converted twice  1st metabolite is
mononuclear cells somewhat active, but the 2nd metabolite (PMEG) is
 Inhibits multiple DNA very active
polymerases (DNA synthesis),
resulting in S-phase arrest and
induction of apoptosis
 Inhibits proliferation of mitogen-
stimulated lymphocytes
Enzyme Chemotherapy
L-asparaginase  Breaks down asparagine to  High MW enzyme made by E.coli
(Kidrolase®) aspartic acid  Used in lymphoma protocols, melanoma, mast cell
 Interferes with protein synthesis tumour therapy
(G1 phase)  Hypersensitivity reactions can occur – might use
antihistamines to minimize immune response
 Minimal myelosuppression
Tyrosine Kinase  Inhibits tyrosine kinase, platelet  Approved for dogs for cutaneous mast cell
Inhibitors derived growth factor receptor sarcomas (with or without regional lymphnode
and stem cell factor receptor involvement )
Toceranib  Anti-proliferative effect on  Blocking tyrosine kinase receptors = stops
(Palladia®) endothelial cells angiogenesis to and within the tumours
 Induce cell cycle arrest and  Starves tumours of oxygen and nutrients  induces
apoptosis in tumour cell lines apoptosis and cell death
expressing activating mutations  C-kit tumours are more susceptible to Palladia – not
in the split kinase RTK, c-kit easy to characterize C-kit status in tumours
 Dosed based on body weight depending on adverse
effects or progression of mast cell tumour
 Very good drug label – use it
Vinca Alkaloids
 Binds tubulin protein, interferes with microtubules needed for chromosome migration during mitosis (M phase
specific)
 Derived from periwinkle plant
Vincristine  Used in lymphoma protocols and other tumours
(Oncovin®)  Adverse Effects:
 Tissue necrosis if given perivascularly
 Peripheral neuropathy: bound tubulin interferes
with axonal function
 Constipation
 Not usually myelosuppressive but can cause
neutropenia
 Increases platelets from megakaryocytes (treatment
for IM thrombocytopenia)
Chicoine 2
Vinblastine  Used for lymphosarcoma and disseminated mast cell
neoplasia
 No cross resistance between vinblastine and
vincristine if a tumour develops resistance to
vinblastine, it will still be resistant to vincristine (and
vice versa) Used for lymphosarcoma and
disseminated mast cell neoplasia
 No peripheral neuropathy
 Higher incidence of leukopenia and myelosuppression
compared to vincristine
Anti-tumour Antibiotics
Doxorubicin  Intercalates between bases of  Used for lymphosarcoma, osteosarcoma, mammary
(Adriamycin®) DNA, blocking RNA transcription carcinomas, and other tumours
and protein synthesis  AKA “red death”
 Binds to cell membranes and  Kills through the cell cycle, but especially during the S
alters ion transport phase (DNA synthesis)
 Generates free oxygen radicals  Given by slow IV infusion
which are toxic to cell  Plasma concentrations persist for 20-30 hours
membranes  Metabolized by the liver; 50% excreted in the bile, and
by the kidney.
 Hepatic dysfunction = Decrease the dose if
bilirubin is increased
 VERY toxic – if injected outside a vein may result in
amputation
 Adverse Effects:
 Perivascular administration results in severe
tissue necrosis
 Acute myelosuppression
 Cardiotoxic
 Due to iron buildup in cardiomyocyte
mitochondria
 Acute: ECG changes, cardiac arrest
 Chronic: DCM, CHF
 Related to total dose
 Alopecia
 GI toxicity
 Hypersensitivity reaction from mast cell
degranulation
Mitoxantrone  Similar mechanisms as  Used for a wide variety of tumours – rescue therapy
doxorubicin for lymphoma (if tumour is resistant to doxorubicin)
 No cross resistance  Minimal renal elimination, almost 100% eliminated via
the bile – better for patients with renal insufficiency
compared to doxorubicin
 Not cardiotoxic
 ADR: myelosuppression, GI effects.
Taxane Drugs
Paclitaxel (Taxol®)  Polymerizes and renders  Activity against many tumours in humans
useless the microtubular  Derived from bark of Pacific Yew tree
network  Adverse Effects: Hypersensitivity reactions
 Stops M phase  Drug carrier (cremophor base) causes pruritis,
anaphylaxis, hypotension, edema
 Pre-treat with steroids, cimetidine, and anti-histamines
 Extremely myelosuppressive
 P-gp substrate – test ABC-B1 before treating
Chicoine 2
Immunosuppressive Drugs
Why use immunosuppressive drugs?

 Treats immune-mediated disease, reduces clinical signs
 Often involves life-long therapy, has side effects
 Hard to cure them – we don’t know why the immune system is attacking the body when it shouldn’t be
 Immune system is overactive – some component is attacking normal host cells
Immune-Mediated Disease
 IMHA, systemic lupus erythematosus, IBD, immune mediated polyarthritis, immune mediated thrombocytopenia,
myasthenia gravis, atopic dermatitis, pemphigus foliaceous
Effects
 Continuum of effects
 Immunomodulating – favours one immune response while minimizing another
 Mild immunosuppression
 Severe myelosuppression
Glucocorticoids
Why use these for oncology patients?
 Lyses lymphoid cells
 Decreases inflammation caused by cancer or chemotherapeutics
 Decreases adverse effects of drugs
o The adverse effects caused by glucocorticoids still happens
o Not as bad as what the cancer is causing
 Stimulates appetite and attitude
 Decreases cachexia from TNF
 Steroids themselves can cause muscle wasting
Characteristics
 Non-specific response
 Inhibits phospholipase – prevents conversion of phospholipids to arachidonic acid  no PGE production and
leukotriene production
 Low doses = physiological effects (basically replacing cortisol)
 Anti-inflammatory then immunosuppressive effects depending on dose
 Altered leukocyte migration and function
 Decreased function of monocytes/macrophages – due to decreasing IgG receptors (less stimulated by Ab), no
phagocytosis
 Decreased lymphocyte function – decreases T cells, at high doses decreases B cells, NK cells, etc
 Veterinary Formulations – prednisone, prednisolone, dexamethasone, isoflupredone
 Short acting = succinate formulation
 Long acting = acetate formulation
 Immunosuppressive Therapy – start aggressively, taper off slowly
NSAIDS
 COX is increased in some tumours – molecular target for cancer therapy
o Make get increased PGEs, make increase blood flow stimulating tumor growth
 Not really sure why NSAIDs are helpful – doesn’t knock out chemotactic pathways
o May prevent PGE formation, less blood flow, less tumour growth
Drug Notes
Immunosuppressive Drugs
Chicoine 2
Azathioprine (Imuran®)  Oral or injectable purine anti-metabolite
 Metabolized in liver to active and inactive metabolites
 Variety of immunosuppressive uses in dogs
 Cats more susceptible to myelosuppression
 Rebound “hyper-immune” response possible if drug rapidly discontinued
Chlorambucil (Leukeran ®)  Aklylating agent that cross-links DNA
 Similar to cyclophosphamide but less potent and less toxicity
 Myelosuppression and vomiting
 Expensive so used for cat and small dogs
 “Steroid-sparing” drugs for cats
 Used for:
 Lymphocytic/plasmacytic infiltrative disease – IBD
 Indolent ulcers
 Pemphigus
 Atopy
Cyclosporine (Atopica®)  “Immunomodulating” Therapy
 Inhibits cytoplasmic calcineurin phosphatase, prevents induction of genes coding for
cytokines and receptors
 Decreases IL2 and cytokines production results in inhibition of:
 T cell activation, chemotaxis
 Antigen presenting cells (Langerhans)
 Mast cell and eosinophil infiltration
 Veterinary liscensed oral forms:
 Capsule (dogs), solution (cats)
 Oral bioavailability is highly variable: formulation dependent  oral solutions
are highly variable
 Same dose doesn’t work for all patients – need to tailor to the individual
 Topical Form Indicated for Opthalmic Issues
 Keratoconjunctivitis sicca
 Chronic superficial keratitis in dogs
 Indications for Atopic Dermatitis in Dogs
 Indications for Cats:
 Control of feline allergic dermatitis
 Eosinophilic granuloma/indolent ulcer
 Plasmacytic stomatitis
 Vomiting
 GIT disorders and diarrhea
 Gingival hyperplasia
 Secondary infections rare, may occur
 Drug Interactions – P-gp and CYP substrate
Tacrolimus (Protopic®)  Similar function to cyclosporine
 Used for atopy, but expensive
Apoquel (oclactinib)  Janus Kinase Inhibitor
 Blocks intracellular communication
 Inhibits pruritogenic and pro-inflammatory cytokines on JAK 1 and 3 enzymes,
 Minimal effect on cytokines involved in hematopoiesis
 Indications: control of pruritus, associated with allergic dermatitis and for control of
atopic dermatitis in dogs over 12 months old
 Immunosuppression (secondary infection, demodecosis)
 Low incidence of V/D
Immunostimulants
Chicoine 2
Imprestor®  Recombinant pegylated bovine granulocyte colony-stimulating factor protein
(Pegbovirastim )  PEG (polyethylene glycol) attached to protein and decreases protein clearance
 Increases the number of circulating neutrophils to counter neutropenia during
periods of transient physiological stress (peri-parturient period)
 Label Claim – reduction in incidence of clinical mastitis in first 30 days of
lactation
 No change in milk composition or performance
 Relative Risk Reduction = 25-50%
 Administered by SC injection
 Adverse Side Effects: rare but occasionally fatal idiosyncratic hypersensitivity
reactions (vulvar swelling, dyspnea, edema).
Pharmacology of Anthelminthic Control

Chicoine 2
Benzimidazoles  Binds to -tubulin  The more drug exposure the more the parasite is effected –
subunit on thus usually requires a longer course of therapy
microtubule in  Generally, very safe in mammals – binds but rapidly
parasites dissociates from tubulin
 Disrupts parasite  Broad Spectrum: GI and lung nematodes, some cestodes
cell shape, and trematodes
division, motility,  Differences in effect is likely due to differences in
secretion, pharmokinetics (not PD)
absorption  Absorption – generally poor, not water soluble, poor oral F
(does this matter), rumen is reservoir (more of the drug is
absorbed)
 Does the drug need to get in the blood stream? Not
all parasites are in the GI lumen, they may migrate
into vessels. In general, it’s not a bad idea to get drug
into blood stream.
 Distribution – generally high but varies
 Metabolism & Excretion – extensive hepatic metabolism
(CYP enzymes) (then further metabolism in lung/intestines).
Some of the metabolites are active (sulphoxide, sulphone).
 Lots of 1st pass metabolism – may contribute to poor oral F
Fenbendazole  Licensed for use in: horses, cattle, swine, chicken, and dogs
 Label Claims: wide range of nematodes (esp adult GI worms and lungworms)
 Commonly used off-label in:
 Small ruminants (sheep/goats) – big problem, they really want these drugs!
 Cats – useful for variety of nematode infections and giardia. Popular
treatment for clinical disease associated with lung worm (Aeleurostrongylus)
 Birds/reptiles/exotics
Fenbental (Drontal ®)
 Fenbendazole pro drug
(Drontal Plus®)
 Also contains pyrtantal and praziquantel, liscensed in dogs
Albendazole  Oral suspension licensed for cattle
(Valbazen®)  Indications:
 Adult flukes (Fasciola hepatica)
 Adult tapeworms
 Some GI and lung nematodes
 Possible early teratogenicity in developing embryo – don’t use within 21 days of
breeding
Triclabendazole  Not used routinely
(Fascinex ®)  Chlorine atom attached
 Active against adult and juvenile Fasciola hepatica
 Also active against a bunch of other flukes (F. gigantica, F. magna, Paragonimus)
 Used in humans as a flukacide
Emergency Drug Release: licensed in USA, but was brought to Canada
Know Key Things: what drugs kill certain parasites, what are the adverse effects?
Chicoine 2
Macrocyclic  Activates (opens) glutamate-gated Cl channel  Cl enters cell (hyperpolarization)  Acute
Lactones flaccid paralysis of worm’s pharyngeal muscles and somatic muscles – can’t ingest
nutrients or move  flushed out of hosts GIT
 At high concentrations, the drug may bind with GABA receptors
Avermectins  Produced by fermentation by Streptomyces in soil
Ivermectin  Endectocide (kills internal and external parasites)
Doramectin  Effective against most nematodes and arthropods
 Exceptions: demodex mites, HW adults.
Selamectine
Abamectin  HW prevention dose is very small
 Minimal activity against cestodes and trematodes
 Differences in potency b/w avermectins – likely not due to chemical structure, likely caused
Milbemycins by big differences in pharmacokinetics.
Moxidectin  Oral, topical or injectable products – watch out for animal or other animals from licking
Milbemycin product off
 Oral or transcuticular absorption of ML by parasite from the treated host
 Very lipid soluble with high Vd (wide distribution to many tissues) – can penetrate skin of
host and parasite – allows us to use topical products
 Some hepatic metabolism, mostly excretion via bile and feces.
 T ½ = 1-3 weeks
 Low clearance
 Watch withdrawal times – typically very long
 NOT for use in dairy cows
 Generally, very safe but adverse effects more significant than benzimidazoles
 Toxicity: associated with GABA release in CNS  neuro signs (ataxia, seizures)
 Treatment: supportive care (fluid, oxygen)
 IV lipid emulsion – draws fat soluble drugs out of tissue into the blood – minimizes
distribution and facilitates elimination
 Normally little distribution to CNS except in:
 ABC-B1 mutant dogs
 Decreased P-gp function = increases drug to brain
 Resistance:
 Resistance reported in multiple parasite species – sheep, emerging in
cattle/horses, widely reported in cyathostomes and large strongyles
 Resistance mechanisms:
 Induction of parasite efflux pumps (P.gp)
 Changes in glutamate gated Cl channels
 Test for resistance parasites: fecal egg count reduction (resistance if <95%
reduction)
 Ecological Impact:
 Avermectins persist in feces for prolonged periods
 Metabolism might be helpful to mitigate this risk
 Topical Tips:
 Apply to skin, not hair
 Watch for skin/hair condition
 Careful with temperature (cattle) – less absorption in cold
 Flammable
AVERMECTINS
Ivermectin  Used in sheep, horses, cattle, pigs, dogs
(Ivomec®)  Oral tablet in dogs – at the HW prevention dose
 Topical or oral drenches – has variable doses
 Injectable form = standard dose is 0.2 mg/kg
 If found in milk is CATASTROPHIC – will have milk residues
Eprinomectin  Pour-on formulation (Eprinex®) for use in dairy cattle with no milk withholding time
 Milk Maximum Residue Level established
 Not a risk to public health
(different  Long-Range® (extended release SC injection)
formulations)  2 different solvent carriers – one has rapid absorption, one has slow absorption
Chicoine 2
 4-5 months of activity against some worms
 4 month meat withdrawal period
 NOT for use in dairy cows
 Has flip-flop kinetics
Doramectin  Similar spectrum as ivermectin
(Dectomax®)  Injectable (cattle and swine)
 Pour on (cattle)
Selamectin  Monthly topical formulation for dogs and cats
(Revolution®)  Fleas, mites (not demodex), nematodes, HW prevention
 Not frequent or high enough to kill demodex
 Less affinity for P-gp than Ivermectin
 Safer for ABC-B1 mutants – but still not necessarily safe
 Less distribution to CNS
MILBEMYCIN
Moxidectin Cydectin Pour-On (beef and dairy cattle)
 Similar spectrum as ivermectin/doramectine
 Not quite as effective against lice compared to ivermectin
 Quest/Quest plus oral gel (horses)
 Moxidectin (plus praziquantel)
 Effective against all kinds of nematodes and some tapeworms
 Advantage Multi (dogs, cats, ferrets)
 Monthly topical
 Only drug liscensed for use in ferrets in Canada
 Moxidectin + imidacloprid
 HW preventative, fleas, ear mites, and GIT nematodes
 ProHeart6 (dogs)
 HW preventative gives 6 months of control
 $$$$$
Milbemycin Monthly Tablets:
 Milbemax tablets (cats)
 Milbemycin & praziquantal
 HW prevention, hookworm, roundworm, tapeworm
 Interceptor tablets (cats/dogs)
 Just Milbemycin
 HW prevention, hookworm, roundworm, whipworm
 Sentinel tablets (dogs)
 Milbemycin & lufenuron
 HW prevention, hookworm, roundworm, whipworm, fleas
 Trifexis tablets (dogs)
 Milbemycin & spinosad
 HW prevention, hookworm, roundworm, whipworm, fleas
OTHER DEWORMERS
Piperazines  Very old OTC dewormer for lots of animals (not ruminants)
AKA  Good for large roundworms (ascarids) – no effect on migrating larvae
Diethylenediamine  Mechanism: anticholinergic at parasite NMJ but probably causes hyperpolarization of NMJ
 Leads to flaccid paralysis and worms are swept out of host GIT
 Generally safe
 Not commonly used in practive
 Formulations:
 Oral solution – medicated water (food animals)
 Oral tablets (dogs/cats)
Chicoine 2
Pyrimidines  Mechanism: depolarizing NMJ and activates nicotinic receptors
 Leads to spastic paralysis
 Good for nematodes (maybe some cestodes)
 Horses – resistance in small strongyles
Pyrantel®  Very safe

 Contains pamoate salte or tartrate salt
 Pamoate Formulations:
 Drontal (cats) / Drontal plus (dogs)
 Dolpac (chewable tablet for dogs)  pyrantel/oxantel/praziquantel
 Heart-Gard Plus (chewable tablet, dogs)
 Pyrantel + Ivermectin  why are they both in this?
 Ivermec dose very low only to kill heartworm
 Exudus – oral paste for horses
 Strongid – oral paste or oral suspension (horses)
 Used extralabel in small animals
 Effective against large strongyles
 Tartrate Formulations:
 Pro-Banminth premix (swine) – prevents Ascaris suum
Emodepside  Profender ® = Emodepside & Praziquantel (topical solution for cats)
 Mechanism: induces intracellular signal transduction in parasite pharynx and body wall
muscles resulting in flaccid paralysis
 Spectrum = roundworms, hookworms, tapeworms (praziquantel)
 Very safe, including in pregnant queens
 Mild GIT signs is the most common adverse event
 Good for nematodes that are resistant to Ivermectin, benzimidazoles, levamisole.
Praziquantel  Anti-cestode (tapeworm) drug for dogs, cats, horses, cattle
 Minimal activity against nematodes
 Mechanism = increases Ca in ICF causing spatic paralysis
 Found in combination with many anti-nematode drugs
 Available by itself: Droncit injectable/tablet
Nitroscanate  Tablets for dogs

(Lopatol®)  Spectrum = roundworms, hookworms, tapeworms
 Poor GIT absorption
 Increased absorption when given with food – prolongs transit time in the GIT
 Adverse Effects: vomiting
 Safe in pregnant dogs and young puppies
Melarsomine  Dogs only
(Immiticide®)  Kills adult Dirofilaria immitis heartworms
 When adult worms die you can get caval syndrome, embolism
 Arsenical = a toxin – mechanism not known
 Administered by deep IM injection in epaxial muscles (L3-L5) ONLY
 NASTY DRUG – if injected in the wrong place causes toxicity = narrow margin of safety
 Not administered commonly, read package insert before use
 Risk/Benefit Assessment: Do you leave the worms? Do surgery to remove the worms?
Coccidiostats and Antiprotozoal Drugs

Know that these drugs exist, Sulfonamides important (talked about more in antimicrobial section) and
Ionophores important, other ones quickly mentioned
Drug Notes
Coccidiosis  Coccidia = primarily Isospora and Eimeria species
Treatments  Protozoal Infections: cryptosporidium, giardia, sarcocystis, toxoplasma, babesia
Chicoine 2
 Most of these drugs are used in food animals, sometimes used off label in small
animals
 Can act on various stages of the coccidian life cycle
 Extracellular stages (sporozoites, merozoites)
 Intracellular stages – stop or inhibit development
 Coccidiostat = arrests development of parasite. Allows the immune system to clear
the infection.
 Coccidiocide = kills most of the coccicdial stages
 May vary between static/cidal depending on duration of treatment, dosage, species of
coccidian.
 Label Claims:
 Treatment of coccidiosis
 Aids in the control/prevention of coccidiosis
 Reduction in fecal shedding
Sulfonamides  Analogue of PABA – precursor in folate synthesis (antibacterial, anti-coccidial effect)
 If we block PABA it shuts down their pathways and makes them folate deficient
 Two with Coccidian Label Claims:
 Sulaquinoxaline (oral solution for poultry)
 Sulfamethazine (oral bolus or solution for calves, sheep, poultry).
Potentiated  Inhibits Dihydrofolate Reductase – inhibiting folate synthesis
Sulfas  Quinnoxine-S® - Sulfa + Pyrimethamine  good affinity for protozoal DHFR, has
poultry indications
 Trimethoprim sulfa also effective against coccidian – product available in Canada but
not liscensed for this use
Amprolium  Thiamine analogue – stops all the paths in coccidian that are thiamine dependent
 Important for prevention of coccidial disease but not effective for clinically infected
Amprol ® animals
Ampromed®  Oral solutions and feed mixes available for poultry and calves
 Has the potential to cause thiamine deficiency in mammals
 Only happens when the dose is increased above the clinically significant level
 Clinical Signs of Thiamine Deficiency: polioencephalomalacia (often fatal)
 Treatment with thiamine may be successful especially early on in the disease.
Ionophores  Only drug that can be used as prophylaxis for coccidian in poultry and cattle
 Has generalized inhibitory action against all coccidial stages
 Mechanism of Action: acts by Na/K pump activation and disruption of electrolyte
Monensin balance. Also get metal cation transport into cell causing osmotic damage.
Lasalocid  Not great for treatment of clinical disease
Salinomycin  Label Indications: broilers/turkeys, calves, sheep, rabbits
Narasin  Why calves only? No clinical disease present in older cows/bulls
Maduramycin  Toxicity – VERY toxic in non-target species
 Can cause significant toxicity and death in mammals (especially horses, also
dogs)
 Same mechanism as above, except effects the cardiac and skeletal muscle
cells
 Common Reasons for Toxicity:
 Accidently feed ionophores feed to the horses
 Incorrect ionophores concentration in the feed
Monensin  Monensin CRC Boluses – slow release boluses administered orally, sits in the rumen,
slowly administers Monensin over MONTHS
 Label Claims (other then coccidian control):
 Kills Gram+  changes the by-products of fermentation  increases
propionate, decreases methane  this improves feed efficiency
Chicoine 2
 Improved feed efficiency in feedlot cattle and increased weight gain of cattle
on pasture
 Aids in reducing bloat in cattle grazing on legume pasture
 Reduction in fecal shedding of MAP in mature cattle in high risk Johne’s
disease herds, only useful in combination with improved biosecurity.
 Decreased incidence of acute rumen lactic acid production after grain
overload – due to shifting of bacteria in rumen - not on label but works
 Dairy Specific Label Claims
 Aids in prevention of subclinical ketosis in lactating dairy cattle
 Reduced milk fat in lactating dairy cows
 Minimizes loss of body condition during lactation in dairy cows
 Improves feed efficiency of milk protein production in lactating dairy cows
Toltrazuril  Registered for use in piglets, lambs and calves
 Reduces shedding and treatment of clinical infection
 Prolonged withholding time (48-70 days)
 Off label use in puppies/kittens/poultry for coccidiosis
 Indications
 Treatment of preclinical coccidiosis in neonatal piglets
 Prevention of C/S of coccidiosis and reduced shedding in lambs
 Prevents C/S of coccidiosis and reduction of coccidian shedding in calves.
Ponazuril  Toltrazuril metabolite
(Marquis®)  Registered for treatment of EPM (Sarcocystis neuronii) in horses
 Prolonged treatment course for several weeks
 Dial a dose syringes – oral formulation
Clindamycin  Lincosaminde (macrolide) antibacterial drug
 Used for treatment of clinical toxoplasmosis in dogs/cats
 Large Vd – reaches high concentrations in the CNS
Veterinary Pesticides
What is a pesticide?
 Pesticide = insecticides and ectoparasiticides
 Regulation of pesticide products in Canada controlled by Health Canada under Pest Management Regulatory
Agency
 Pest Control Product (PCP) Number – allows us to easily identify which products are pesticides.
Primary differences for veterinarians when prescribing/selling drugs and pesticides

 DO NOT use pesticides extra-label (ILLEGAL!!)
 DO NOT dispense partial packages – the package will no longer contain all of the label information
Chicoine 2
 Smaller Margin of Safety: pesticides are less safe compared to drugs
Drugs vs Pesticides
 PCP vs DIN
 Veterinary drug products can have effects on external arthropods/insects:
o Ivermectin for sarcoptes mange
o Selamectin for fleas, mites ticks
 Why are these considered drugs and not pesticides?
o To be classified as a drug it needs to have systemic absorption. It gets to the parasite via distribution
of the drug
o Pesticides get to the parasite just from topical application, stays on or just inside the skin. Does not get
into blood stream
Ectoparasiticide Formulations – administered topically (ear tags, collars, immersion baths, topical dusts, shampoos)

Organophosphates Acetylcholinesterase  Highly toxic to mammals
inhibitors  Muscarinic effects 1st , then nicotinic – leads to spastic
Binding to AChE paralysis killing the parasite
(irreversible)  Delayed neuropathy
 Environmental concerns – applied topically to each animal,
not much environmental exposure
 Formulation: Diazinon ear tags (horn flies and face flies in
cattle)
Carbamates Competitive inhibitor of  Still toxic, but less toxic to mammals then
AChE (reversible) organophosphates
Carbaryl®  Formulation: carbaryl dusting powder to control mites,
fleas, ticks, lice, flies in many food animal species
Amitraz Inhibits Monoamine  Toxicity: activation of 2 receptors – can occur w/ oral
Oxidase ingestion and dermal exposure
 Treats demodecosis and prevents ticks
Monoamines =  Formulations: topical  PrevenTic collars, Mitaban dip,
serotonin, NE, dopamine just recently removed from CDN market
 If animal licks it or eats collar = toxicity
Pyrethrins and Most open Na+ channels  Pyrethrins: chrysanthemum plant extract
Pyrethroids (depolarization and  Pyrethroids: synthetically modified compounds
remain open) or other  Includes: permethrin, cypermethrin, cyflutherin
NT functions  Highly lipid soluble
Ionic current  Topical formulations stay in stratum corneum (not
Cylence® manipulation absorbed systemically)
Vetolice®  Formulations: shampoo, spray, dips, dust, ear tags
 Active against ectoparasites (fleas, ticks, flies, lice, mites)
 Has label claims for ticks but efficacy depends on tick
burden, time of year, etc
 Toxic in cats: due to oral ingestion (grooming) of topical
product and poor hepatic glucuronidation
Chicoine 2
Neonicotinoids Activates insect nicotinic  Like nicotine, more stable (less degradation at synapses)
receptors (depolarizes  Non-ionized at physiological pH – so crosses the BBB
and Na+ channel remain  Does not at on vertebrate nicotinic/muscarinic receptors
open, cell cannot  Environmental impact: honey bees
repolarize and neural
transmission stops)
Imidiaclopride  Topical formulation for dogs/cats (Advantage/K9 Advantix)

 Minimal transdermal absorption, but it migrates across the
skins surface
 Kills adult and larval fleas and lice, limited activity for ticks
 Generally safe
Nitenpyram
 Oral tablet flea adulticide in dogs/cats
(CapstarVM)
 Administered daily if fleas observed on animals
 100% oral bioavailability
 Effective against fipronil-resistant (Frontline®) fleas
 Very safe
Insect Growth Analogues of hormones  NON-pesticide; carried in pet stores no in vet clinic
Regulators which are required for  Arrested development at larval stage
larval development to  NO effect on adult insect
become adult  Little toxicity in mammals – different hormones
Methroprene-collar  Takes weeks to see effect
Pyriproxifen ®  Administer with adulticide
Insect Development Inhibit chitin synthesis or  Used to control fleas at egg/larval stage
Inhibitors utilisation blocking  NO effect on adult insect
development of insect
exoskeleton
Lufenuron®:
ProgramVM – cats  Monthly oral suspension or SC injection (6 month duration)
SentinelVM – dogs  With milbemycin to kill adults

Spinosad Nicotinic ACh receptor  Derived from soil fungus (actinomycete)
agonist (depolarizes and  For flea control in dogs/cats, ticks at high doses
prevents neural  Significant drug interactions with Macrocyclic Lactones
Trifexis® transmission)  Inhibitor of P-gp
Comfortis ®  Be careful when using with a P-gp substrate
Isoxazoline Antagonists of GABA  Effective for control of fleas and ticks (maybe mites)
and glut-gated Cl-  Contraindicated in patients with seizures: lose some
channels (lack of inhibition
hyperpolarization =  Oral tablet licenced in Canada in dogs:
excess neural activity)  Fluralaner = BravectoVM (every 3 months)
 Afoxaolaner = NexGardVM (monthly)
 Dosed based on animal size (weight)
Phenylpyrazoles Blocks Cl- movement  Not important to remember
through GABA and  Treat fleas and ticks in dogs/cats
Fipronil glutamate gated  Not available in Canada, widely used in USA
(FrontlineVM) channels
Chicoine 2
Antifungals
Fungal Infections
 Difficult to treat
 Long duration of therapy
 High doses
Types of Fungal Infections

 Superficial Mycoses
o Affect skin, hair and nails
o Use topical or systemic therapy depending on severity
 Systemic (Invasive) Mycoses
o Involve the internal organs
o Primary vs opportunistic
o Eg. Blasto in the lungs
o Requires systemic therapy
Chicoine 2
Targets for Antifungal Therapy
1. Cell Membrane (fungi use ergosterol instead of cholesterol – can use drugs that target ergosterol synthesis or
incorporation & will not target host cells)
2. DNA Synthesis
3. Cell Wall (fungi have chitin cell walls – so can target chitin synthesis)
Drug Mechanisms of Notes

Action
Amphotericin B Binds to sterols in  Broad spectrum
cell membrane,  No effect on bacteria/rickettsia
(old) alters membrane  Mammalian cells contain sterols
permeability so toxicity is likely (not very safe)
causing ICF K+  IV use only (must be administered
to leak out in clinic)
(hyperpolarizes  For invasive fungal infections not
the cell) responding to other therapy or
where cost is an issue
 Very toxic (cats): nephrotoxic
(GFR), anorexia, vomiting,
anemia
 Avoid in cats with renal failure,
monitor kidney function closely
Azole Antifungals  Suffix: “azole”
 Eg. Ketoconazole, itraconazole, fluconazole, voriconazole
 All human formulations used extra label
 Except itraconazole licenced for use in cats
Mechanism of Action: Binds CYP450 and inhibits synthesis of ergosterol
Adverse Effects: may impact the normal function of mammalian CYP450
 May prevent cholesterol synthesis and the synthesis of steroid hormones from cholesterol (cortisol,
reproductive steroid hormones)
 Significant drug interactions – cyclosporine
Can be used to treat hyperadrenocorticism (Cushings) therapy – minimizes cortisol being produced (lots of better
drugs to treat Cushings)
Pharmokinetics/Pharmodynamics
 Oral tablets/suspension, topical creams
 Possibly concentration independent fungistatic agents – blood concentration does not matter, need to
exceed the MIC
 Goals of dosing: maintain 1-2x the MIC for entire dosing interval
 BID might be more effective, SID dosing often on product label
Fungal Resistance
 Failure to accumulate the drug – if drug doesn’t get into the fungal cell
 Decreased influx, increased efflux
 Change in drug interaction with the target enzymes in ergosterol synthesis pathway
Ketoconazole  Treats infections caused by: yeast, systemic fungi, dermatophytes
$  Adverse Effects: low
Nizorol® dandruff  Hepatic toxicity: acts on CYP enzymes, monitor liver enzymes, watch for drug
shampoo interactions
 GIT: nausea, vomiting, anorexia. Drug dependent, adverse GI effects lower
when given with food
Itraconazole  Licensed for use in cats (feline dermatophytosis)
 Expensive, but safer and generally more effective
$$$  Compounded form is VERY sketchy: does NOT reach high concentrations in plasma
 Pharmokinetics:
  F when given in fasting state (maximizes plasma conc) – better absorbed in
acidic media
 High Vd, accumulates in hair/skin
 Comparison to Ketoconazole: more potent, similar ADR but less severe (esp. in Cats),
similar CYP450 metabolism and drug interactions
Chicoine 2
 Clinical Uses:
 Dermatophytes
 Blastomycosis (dogs) – systemic fungal infection
 Crptococcus (cats)
 Horses: guttural pouch mycosis, nasal aspergillosis, fungal keratisis
Fluconazole  Good oral F, crosses BBB (not as highly protein bound)

 Limited hepatic metabolism, mostly excreted in urine
$$$$$$  Good to use in animals with hepatic dysfunction
 Generally very safe – mild GI ADR
 Clinical Uses:
 Fungal meningitis (candida, cryptococcus)
 Limited activity against systemic fungi (blasto, Histoplasma, sporothrix)
 No activity against Aspergillus
Voriconazole  Very broad spectrum

 Hepatic metabolism and excretion in bile
 100% oral F
 Possibly not safe in cats
Topical Azoles Miconazole & Clotrimazole
 Liscensed for topical use against superficial skin/ear mycotic infections in small animals
 Product often contain antibiotic, steroid and anti-mycotic
 Steroid might cause the problem – systemic absorption leading to hyperadrenocorticism
 Systemic use leads to:
 Rapid hepatic enzyme induction (increased clearance) – increases the dose you
need to use. Induces enzymes responsible for their own metabolism.
 Serious adverse events
Enilconazole (Imaverol®)
 Only for veterinary use
 Indicated for dermatophyte skin infection in dogs/horses – turns into a shampoo that
you wash the dog with
 Generally a very safe topical product
Miscellaneous Terbinafine (OsuriniaVM)
Antifungals Iodophores – iodine, betadine
Silver sulfadiazine (in Baytril Otic)
Toothpaste – for ringworm infection – not sure what it does, but worth a shot
Griseofulvin  Typically used in equine mycotic infection
 Just pulled off the market
 Deposited in keratin of skin and hair
 Takes a long time before you can buildup concentrations at site on infect ion – need to
give for a long time.
 Mechanism of Action: disrupts structure of the fungal cell’s mitotic spindle (stops cell
division)
 Only effective against Dermatophytosis in dogs, cats, horses
 NOT for systemic use
 Pharmokinetics:
 Hepatic metabolism and elimination
 Short-half life in dogs/cats than humans
 Absorption highly variable
 Increased F when given with high fat meal or when formulated as very fine
particles
 Adverse Effects: especially common in cats
 Hematological abnormalities
 Teratogenicity
 Anorexia, depression, V/D
Chicoine 2
Antimicrobials
Antimicrobial Therapy – The Basics of USING Antimicrobials

Antibiotics = substance produced naturally by bacteria, and active against other bacteria
Antimicrobial = substance (natural or synthetic) that is active against microbes, including bacteria, fungi, protozoa
Questions to ask yourself:

1. Does the diagnosis warrant antimicrobial therapy?
 Viral infections usually do not require antibiotics
 Use signalment, clinical signs etc. to determine if antimicrobials would be useful
2. What organisms are lik ely to be involved?
 Gram positives  Streptococcus, Staphylococcus
 Gram negatives  E. coli, Salmonella, Campylobacter
3. What is the in vitro susceptibility of the pathogens to antimicrobials?
 Susceptibility testing helps you to guide your treatment
 Microbes have inherent natural resistance to antimicrobials – so we cannot completely get rid of AMR
4. Where is the infection located? Can the antimicrobial get to the infection?
 What route of administration will you use to get the drug to the intended site?
 A lot of antimicrobials cannot cross the BBB, some do
5. Will the antimicrobial be effective in the pathogen’s environment?
 Early in infection: abscess does not have lots of fibrin, less neutrophils, less macrophages
 Late in infection: abscesses are firm chunky masses, with a fibrous capsule and lots of neutrophils.
o Once an abscess solidifies antimicrobials do not penetrate abscess very well
o Depends on PK/PD
o Site on infection ALTERS antimicrobial therapy
6. What is the appropriate drug formulation and dosage regimen?
 Oral administration = #1 route
 Injectable = IV, SQ, IM
 Specialized = intraarticular joint, IV regional perfusion (tourniquette on limb and inject into veins, high
concentrations local), interosseous (delivers drug into marrow cavity), intraperitoneal (into abdomen).
 Topical, ophthalmic, intrauterine administration
7. What adverse drug reactions or toxicities may occur?
 Not many ADR, generally very safe
8. For food animals, can you stay “on label”?
 Follow label recommendations!
Successful Antimicrobial Therapy

a) Administering sufficient doses so that bacteria at the site of infection are killed
 Doesn’t happen in reality – no drug is this amazing
b) Sufficiently suppress pathogen burden so that they can be eliminated by the host’s immune system
High Plasma Drug Concentrations are Assumed to be Advantageous:

 Large concentration of drug to diffuse into ECF (at the site of action)
 Soft tissue infections most of the bacteria are in the ECF
 Exceptions: new macrolide drugs have low [plasma] but high [tissue] – the macrolide drug binds leukocytes
and are carried to the site of infection.
Minimum Inhibitory Concentration (MIC)

 Lowest drug concentration that inhibits bacterial growth
 We want drug concentrations that are at least 2x the MIC
Minimum Bactericidal Concentration (MBC)

 Lowest drug concentration that kills 99.9% of the bacteria
 This will be a lot higher compared to MIC.
Mutant Prevention Concentration (MPC)

Antimicrobials
 The MIC of the least-susceptible single-step mutant bacterial population
 Normally with antimicrobials you kill the wimpy pathogens, and leave behind the resistant organisms.
 The MPC is VERY HIGH compared to the MBC – not practical to reach these concentrations
Antimicrobial Susceptibility Testing

 Kirby-Bauer disk testing = defines R, I, S
 S, I, R based on achievable plasma levels of the drug
 If we get a high concentration of antimicrobial compared to the MIC = then the microbe is susceptible
 If we get a low concentration of antimicrobial compared to the MIC = then the microbe is resistance
 C and S results are only a prediction of treatment success
Microdilution
 Each well has different antimicrobials at different concentrations
 Bacteria inoculated into each well
 First place you get no growth = MIC
 Labour intensive, costly
Disk Diffusion
 Antimicrobial impregnated disk, set on growth plate, measure zone of inhibition to determine if
bug is susceptible or resistant.
E-test
 Semi-quantitative
 Gradient of drug within the strip, put on agar plate
 See where zone of inhibition ends = MIC
 Expensive
MIC of Bacterial Populations

 Not talking about 1 specific bug – will have a wide variety of isolates
 MIC50 and MIC90
o MIC50 = contains the 50th percentile
Predictions from susceptibility testing CAN BE WRONG

 We do tests in a petri dish, but try to extrapolate these results to living animals
 Does not account for:
o Host immune system (humoral immunity, T cells, B cells, inflammation)
o Drug distribution in the body
 Concentration at the site of infection different from other sites of the body
o Bacterial growth rates and inoculum size
o Mixed infections
o Infection environment (debris, pus, etc).
o In vivo antimicrobial synergism
 Susceptibility testing does not account for topical drug applications
Categorization of Antimicrobials
Bactericidal = kills bacteria

 Ratio of MBC to MIC is less then 4-6x
 It is possible to obtain concentrations in patient that kills 99.9% of bacteria
Bacteriostatic = slows growth

 Ratio of MBC to MIC is large
 Not safe to administer enough antimicrobials to kill 99.9% of the bacteria
One drug can be either bactericidal and bacteriostatic – depends on PK/PD, location of action, etc.
Post-Antibiotic Effect (PAE)

 Bacterial growth suppressed even though antimicrobials dropped to concentrations below the MIC.
Antimicrobials
 May be the reason that many dosage regimens are effective despite not maintaining concentrations greter then
the MIC.
 Dependent on the specific combo of antimicrobial and bacteria
PKPD Integration for Antimicrobials (most important part of this lecture)

 PK = what body does to drug (ADME)
o Parameters:
o AUC = measure of drug exposure
o Cmax , T½, CIs
 PD = what drug does to bacteria (Kill, inhibit growth)
o Parameters: MIC, MPC (mutant prevention concentration)
Studies show that antimicrobials can be

1. Concentration Dependent Antimicrobials
 How high can we get the concentrations? (Cmax:MIC)
o Want the highest possible ratio
o We want Cmax to MIC ratio higher then 10
 How much exposure can we get? (AUC:MIC)
o Want AUC:MIC >125
2. Time Dependent Antimicrobials
 T > MIC
 Not worried about peak concentrations
 How long can we keep drug concentrations about MIC
Increase peak on graph = increases AUC (exposure)
 Antimicrobial Spectrum:
 PKPD:
 ADR:
 DI:
 Clinical Uses:
Beta-lactams
1. Penicillins, Aminopenicillins, B-lactamase inhibitors
2. Cephalosporins
Antimicrobials
Difference in SIDE CHAIN determines penicillin family
ALL SHARE a common B-lactam ring
Resistance Mechanisms:
 Penicillinase (-lactamase) enzymes
 Gram negatives: not susceptible to penicillin  Inability of  -lactam to penetrate bacterial cell wall
 Staph aureus: not susceptible to penicillin  exogenous –lactamase producer
 Gram negatives: if –lactam gets through cell wall, endogenous –lactamase will prevent it from having its effect
 Gram positives: exogenous –lactamase producer, but susceptible to cephalosporin
 Gram negative: susceptible to penicillin, transport through cell wall
Just cause it has –lactamase doesn’t mean it is resistance to all -lactams.


-lactamase enzymes:
 Inherent: constitutive chromosomal expression
 Transferable: plasmid mediated  the ones we really worry about, usually associated with multi drug
resistance, can be shared among bacteria
Antimicrobial Mechanism of Action Notes

Penicillin G Disrupts cell wall by  Antimicrobial Spectrum:
binding and inhibiting  Many gram positives have lots of peptidoglycan + high affinity
the Penicillin Binding of PBPs for -lactams,
Proteins found on  Most anaerobes
outside of bacterial  Few gram negatives: Histophilus, Pasteurella
cell membrane   Resistance:
Antimicrobials
interferes with  Most gram negatives: produce  lactamases, can’t penetrate cell
enzymes necessary wall, low affinity PBP
for peptidoglycan  Most staph spp: produces  lactamases
synthesis  cell wall  Formulations:
dysfunction  lysis of 1. Crystalline Pen G (Na/K) – sterile for injection, TID/QID dosing
bacterial cell 2. Procaine Pen G – short acting, salt, for IM/SC injection, classic
white penicillin on shelf, oral feed premixes, some intramammary
Bactericidal: KILLS products, lower but sustained plasma concentrations, injections
in neck absorbed more rapidly than in hindquarters (less carcass
damage), NEVER IV injection (CNS depression  death)
3. Procaine Pen G in oil – long acting, IM/SC injection, once daily
dosing
4. Benzathine Pen G – long acting, IM/SC injection, only one VM
formulation (Duplocillin®), very slowly absorbed, likely not high
enough to reach MIC, produces sustained by subtherapeutic
penG plasma concentrations, multiple days between doses, only
useful if plasma concentrations can reach MIC to begin with
 PKPD:
 Poor oral absorption, rapid hydrolysis in stomach acid.
Exception: phenoxymethyl penicillin V is acid stable  better
absorption from GIT
 Weak acid highly ionized in the plasma so sticks around in
plasma and ECF and not distributing to the tissues (low Vd)
 Increased distribution to tissues with inflammation
 Metabolism: very little
 Excretion: renal (GFR or secretion into renal tubules by OATs),
quick elimination
 Reduce dose in renal failure patients, in practice don’t worry
about reducing dose because penicillin is VERY safe
 Very short half-life (except procain/benzathine forms)
 Time dependent: we want to reach concentrations beyond
the MIC
 ADR:
 Hypersensitivity reactions
 Type I – anaphylaxis, local inflammation (more common)
– must be differentiated from injection site irritation
 Type II – autoimmune hemolytic anemia
 Type III – vasculitis
 GI flora changes (diarrhea)
 Drug residues in food animals (cheap and used a lot, persists in
tissues for a long period of time)
 Synergistic Drug Interactions: -lactam disruption of bacterial cell wall
may increase amount of aminoglycoside entry into the bacterial cell.
Not necessarily true for all types of infections. The spectrum of activity
of both of these drugs are great. Aminoglycosides good for gram
negatives, penicillins good for gram positives and anerobes  is a good
combination, not necessarily synergistic
 Clinical Uses:
 Inject the neck! Doesn’t ruin expensive cuts of meat around
rump
Isoxazolyl penicillins
 Antimicrobials spectrum: antistaphylococci
 None of these are necessary to know:
o Oxacillin, CloxacillinVM, Dicloxacillin, Methicillin, Nafcillin
 Active against same bacteria as Pen G but not quite as potent
 Resistant to S. aureus penicillinase
 Clinical use: treatment or prevention of bovine staph mastitis
Antimicrobials
MRSA/MRSP
 mecA gene – codes for PBP2a – low affinity for  lactam
 Once it changes, no matter what -lactam you have, it is not going to work
 Methicillin resistant because mecA is on a plasmid with a bunch of other resistance genes  multidrug
resistance!
Aminopenicillins: Ampicillin and Amoxicilin

 Active against same gram positive bacteria as Pen G
 Amino group has better penetration through the cell wall of gram negatives than pen G
o Amoxicillin better then ampicillin
 Anaerobes
 Still susceptible to microbial b-lactamase enzymes
 PKPD
o Acid stable – good oral F
o Distribution, metabolism, excretion = comparable to Pen G
o Short T½: BID dosing for oral form
o SID for ampicillin trihydrate after IM injection
 Drug Interactions
o Similar to Pen G
o Synergy with aminoglycosides
 ADR
o Similar to pen G  hypersensitivity
o If hypersensitive to classic pen g – there is cross reactivity and will be sensitive to ampicillin etc
o Oral adverse effects (V/D) especially ampicillin – not well absorbed, lots stays in GIT – BAD for hind
gut fermenters
 Ampicillin
o Trihydrate salt IV/SC injectable suspension for food animals, also dogs and cats
o Sterile human IV forms and oral forms
o Ampicillin trihydrate (Polyflex) – slow absorption (SC/IM)
o Ampicillin sodium – rapid, IV
 Amoxicillin
o Many veterinary oral tablets/suspensions
o With or without clavulanic acid (beta lactamase inhibitor)
o Indications: wide variety of infections in dogs/cats
o Soluble powder for medicated water
o Fed or fasting state okay – doesn’t effect oral F
Carboxypenicilins (Antipseudomonal penicillins)

 NONE are vet formulations, very expensive, human use only, IV administration
 Not resistant to beta lactamase enzymes
 Usually administered with beta lactamase inhibitor
 Resistant to a lot of antimicrobials
 Active against gram –
 Decreased activity to gram +
Beta lactamase inhibitors

 NEED TO KNOW:
o Clavulanic acid
 Little antimicrobial activity of their own
 MOA: irreversibly binds to and inactivates -lactamase enzymes
o Allows -lactam antimicrobial to exert full effects on PBP
 Often combined with amoxicillin:
o Good for G+ (including –lactamase producing staph), G-, anaerobes
 PKPD
o Quick and extensive oral absorption
Antimicrobials
o Renal excretion, T1/2 similar to amoxicillin
o Minimal ADR
Carbapenems (extended spectrum penicillins)

- NEED TO KNOW:
o Imipenem (should only rarely be used in vet med because it’s a LAST RESORT drug in humans)
 Extremely broad spectrum: G+, G-, anaerobes, resistant to  –lactamase enzymes
 Given IV, painful other ways
 Hydrolyzed In kidney to toxic metabolites by dihydropeptidase enzymes
Cephalosporins
 Has a beta lactam ring
 Two sidechains so there is a wide variety of cephalosporins .
 Cephamycins: derived from other microbes or synthetic derivation
Antimicrobials
Cephalosporins
 Mechanism of Action
o Disrupts synthesis of bacterial cell wall
o Inhibits penicillin-binding-proteins
o Interferes with cell wall peptidoglycan synthesis
 Advantages
o Stable against some -lactamase enzymes
o Good affinity for target proteins (PBPs)
o Good ability to penetrate bacterial cell wall (including gram -): bit better then penicillins
 Emergence of Resistance
o Different -lactamase enzymes (most common)
 Induction of expression of new -lactamase expression
 Extended spectrum -lactamase (ESBL) enzymes: can attach and degrade basically
all the - lactams
o Modify PBPs (mecA gene, others)
 If cephalosporins cannot bind PBPs they cannot have an effect
o Reduce cellular concentrations: decrease bacterial cell wall permeability, induc tion of efflux pumps
 Spectrum of Activity
o Gram (+): streptococcus, staph aureus, staph pseudintermedius
o Gram (-): many enterobacteriaciae (Ecoli, salmonella, histophilus, mannheimia, pasteurella)
o Most anaerobes
 Spectrum of Resistance
o Gram (+): MRSA, enterococcus (inherently resistant to cephalosporins)
o Gram (-): many enteric pathogens with ESBL activity, Rhodococcus equi, pseudomonas, mycobacteria
o Anaerobes: bacteroides (except cefoxitin)
 Pharmacokinetics
o Oral absorption is good
 Cefpodoxime proxetil = prodrug = deesterfied in GIT, Cefpodoxime absorbed
o Parenteral absorption: depends on the formulation used
 Cefazolin – extremely rapid
 Ceftiofur sodium (Excenel) – very rapid
 Ceftiofur HCl (Excenel RTU) – slower
 Ceftiofur crystalline free acid (Excede) – very slow, long acting formulation
o Distribution: low Vd
 Get high concentrations in plasma/ECF and not in tissues
o Metabolism occurs in some cephalosporins: not a limiting factor
 Ceftiofur  desfuroylceftiofur: still active against microbes, binds to acute phase proteins
which are sent to site of infection.
 Cephapirin – given intramammary/uterine so not systemic and no metabolic effects in liver
o Renal elimination: glomerular filtration & tubular secretion
 Do not need to change to dose if an animal has renal disease. You should change the dose if
the margin of safety is small!
o Short half-life (1-2 hours)
 Cefpodoxime & Cefovecin = highly protein bound, won’t be filtered at the glomerulus and not
secreted into tubule. Only free unbound drug is eliminated.
 Cefpodoxime T½ for dogs is 5-6 hours in dogs
 Cefovecine T½ 5.5-6.9 days after SC administration in dogs/cats
 Decreased clearance in kidney due to high protein binding
 Result = one dose biweekly
 AMR develops to this drug!!
 Ceftiofur (sodium = 2-3 h in cattle, HCl = 20 hrs in pigs, crystalline free = 40-50 h in pigs/cow)
 Adverse Effects
o Hypersensitivity: If your allergic to penicillin, stay away from cephalosporins (even though only ~15%
cross-react).
o GI upset
 Vomiting, diarrhea
 Loss of normal GI flora lead to bacterial overgrowth
o Coagulopathies/blood dyscrasias (rare)
Antimicrobials
 Extralabel use of Cephalosporins
o FDA banned use of cephalosporin class of antimicrobials in food animals.
o Veterinarians CANNOT alter the dose, route, frequency or duration or use it for prevention.
o Can use in minor species or for different indications
o NO in ovo injections into chicken eggs, also NO use of biobullets
NEED TO KNOW: all licenced for veterinary use in Canada

 Cephalexin: very common for small animal practice
o Vetolexin paste, Cefaseptin tablets
 Ceftiofur: very common in large animal practice
o Excenel (sodium salt)
o Excenel RTU (HCl)
o Excede (crystalline free acid)
o Spectramast (intramammary)
 Cefovecin (Convenia injectable): big drug in small animal practice, 3 rd generation cephalosporin
 Cefpodoxime (Simplicef tablets): $$$, not used much
 Cephapirin
o Cefa-Lak (sodium): for lactating cows
o Cefa-Dry, Metricure (benzathine): for dry cows
 Cefazolin (human sterile injectable): LOTS in small animal surgery
Cephalexin
 Formulations: oral tablets or paste
 Indications: canine superficial pyoderma caused by susceptible strains of Staphylococcus pseudintermedius
Ceftiofur
 Formulations
o Excenel (sodium salt): approved for cattle, horses, pigs, sheep, dogs
o Excenel RTU (HCl): approved for cattle/pigs (IM injection), viscous solution
o Excede (crystalline free acid): for cattle, horses, pigs out on the farm
o Spectramast (intramammary)
Cefovecin (Convenia)
 Indications: skin infections, urinary tract infections caused by Staph intermedius, Strep canis, E.coli, Proteus
mirabilis
 Problems: do you use this is 1st line drug, or should you save it for later
 Given every 2 weeks – in the system for 2 weeks (cannot take it out)
 3rd generation cephalosporin
Cefazolin
 Indications: often used perioperatively
 Evidence for perioperative use: no difference in cephazolin compared to crystalline penicillin, significantly
reduce incidence of infection compared to controls that did not get any antibiotics
Enterococcus are intrinsically resistant to cephalosporins. Do not use cephalosporins – is a risk factor for developing
VRE colonization.
Aminoglycosides
 3x 6 membered rings and lots of amino groups (NH2)
 pH = BASIC – would be ionized at physiological pH – amino groups suck up positive charges
NEED TO KNOW
 Gentamicin
o GentocinVM – sterile injectable product (IM, SC, IntraUterine infusions) IV offlabel
o Gentocin DurafilmVM – topical ophthalmic solution
Antimicrobials
o Otomax & Mometamaxx VM – topical ointments for otitis externa (also contains steroid and antifungals)
o TopagenVM - topical spray for dermal lesions
 Amikacin
o Amiglyde-VVM – sterile injectable product (off label), IntraUterine infusion use in mares , IV for sepsis
 Neomycin
o Calf scour boluses
o PanalogVM– topical ointment for otitis externa
NICE TO KNOW
 Apramycin (Aminocyclitol) – ApralanVM oral solution for swine scours
 Streptomycin – found in calf/pig/poultry vitamin/antibiotic soluble powder mixes – treats scours
 Dihydrostreptomycin – found in Special Formula 17900 – IMM product, hard time getting approved today
FYI ONLY
 Kanamycin
 Tobramycin: formerly found in human ophthalmic preparations
Mechanism of Action
 Binds bacterial ribosomal 30S sub-unit
o Incorrect tRNA translation, disrupts bacterial protein synthesis and  membrane permeability
 Needs to penetrate bacterial cell to reach binding site
o O2 dependent interaction b/w aminoglycoside (AG) cations with –ve charges on bacterial membrane
 AG has poor efficacy in anaerobic environment – cant get inside the cell, not good for
anaerobic bacteria.
o Effect of local pH
 Basic: more efficacy (AG non-ionized, easier transport)
 Acidic: less efficacy (AG ionized, less transport)
o Abscesses: purulent material may inactivate AG
Spectrum of Activity
 Effective for:
o Gram negative aerobic bacteria (including pseudomonas)
 Especially against gram negative enteric bacteria
o Staphylococcus spp (including MRSA, MRSP)
o Some activity against enterococcus, mycobacteria, mycoplasma
 NOT Effective for:
o Streptococcus, intracellular bacteria (salmonella), anaerobes
Resistance to Aminoglycosides
 Induction of plasmid mediated bacterial enzymes that degrade aminoglycosides and prevent binding to
ribosome 30S subunit
o Most relevant mechanism for determining clinical susceptibility
o Amikacin is most resistant to enzyme degradation
 Chromosomal resistance
o Changes to the 30S binding sites
o Many binding sites are available, so mutations unlikely to produce clinical resistance
o I.e., Streptomycin or Dihydrostreptomycin
 First exposure adaptive resistance ( uptake/permeability) – minimizes AG entry into bacterial cytoplasm
o Occurs within 1-2 hours of dose
o Lasts up to 16 h post exposure – then partial return of susceptibility
o The more bacteria are exposed to AG (increased # of doses) the adaptive resistance tends to increase
o Implication: once daily dosing to decrease adaptive resistance – DO NOT want bacteria constantly
exposed to AG. We want infrequent exposure
 We want to give a high dose for a short duration of time = minimizes adaptive resistance
Potency, Spectrum, Resistance

 Amikacin = most potent, best spectrum of activity (less strep activity)
 Amikacin > Gentamicin > Neomycin > Streptomycin
Antimicrobials
Pharmacokinetics of AG
 Bioavailability by route
o Very POOR oral F – DO NOT administer this way
 Calf scour boluses – no evidence that these work
 Exception: high doses or calves with enteritis absorb more of the drug then normal!!!
o Good absorption after IM/SC injection
 But due to toxicity concerns, often given IV (extralabel)
o Systemic absorption w/ IU (label) or IMM (ELDU) doses
o Topically – very poor F
o Local delivery: hopefully minimal absorption (intraarticular)
 Low Vd – high concentration in the plasma, low concentration in the tissues
 Rapid elimination (T½ = 1-2 hours)
 Elimination route = RENAL (Glomerular filtration)
o Renal disease =  GFR =  clearance of AG  DOSE MODIFICATION (lower dose or elongate
dosage interval)
o AG binds to proximal tubule cells  nephrotoxic!!!
 Concentration dependent: the higher the peak concentration (dose) relative to the MIC the more
effective they are clinically in terms of killing off bacteria
o Want the CMax to be 10x the MIC – want a high dose compared to the MIC of the pathogen
o High (trough) plasma concentration correlates with adverse events
o Long post-antibiotic effect (administer drug, it depletes rapidly, but still have bacterial imbibition even
after plasma concentrations have dropped)
o Clinical Implication: high dose, but only SID (or less) is most rational
 POTENTIAL EXAM QUESTION – why do we use a high dose of AG, but at a low dose
frequency
Adverse Events of Aminoglycosides
1. Nephrotoxicity (acute tubular necrosis)

o Most common ADR
o Mechanism: uptake and accumulation of AG into renal proximal tubule cells
o In tubular lumen, cationic AG binds to –ve charged phosphatidylinositol on tubular cells  AG
enters tubular cell via carrier mediated pinocytosis  AG sequestered in lysosomes  lysosomes
eventually ruptures  necrosis & cell death
o Protective Conditions: anything that decreases AG contact with the proximal tubule cell
o Increased GFR
 Fluid therapy (hydration): maintaining normal blood pressure and volumes, you have a
normal GFR, maintains transport through tubules minimizing contact time
 High protein diet (see below)
o SID, high dosing (vs. multiple smaller doses)
 Rapid elimination, so decreased contact
o High calcium/protein in diet
 Cations compete with +ve charges on AG
Study: High Protein Diet to Increase GFR and Decrease Nephrotoxicity

 3 dogs on 3 different protein diets
 On day 2 dogs on high protein diet had a LOW trough gentamycin concentration – this is what we want to
see to minimize nephrotoxicity
 Dogs on low protein diet had a much higher trough gentamycin concentration
 It worsened over time
 On day 0 there was not much difference in GFR (creatinine clearance) b/w groups
 At end of the study, for high protein dogs GFR stayed relatively consistent, but for low protein dogs the
GFR (creatinine clearance) dropped considerably
Why would a high protein diet lead to a higher GFR?

 Increased capillary pressure in glomerulus pushing the fluid out
Antimicrobials
 Capillary leakiness (gaps)
o Filtration Fraction: % of plasma that was filtered out was much higher compared to a low protein diet
o High protein diet = increased GFR = protective against AG toxicity
2. Ototoxicity: same mechanism as nephrotoxicity

 Nephrotoxicity and ototoxicity potentiated by diuretics (KEY POINT)
o Why?
 Decreased plasma volume (dehydrated)  more contact of AG with tubular cells
 Ototoxicity – effects cochlear duct
 Neomycin is bad for nephron and ototoxicity
 Amikacin is not as bad
3. Neuromuscular Blockade
 AG appears to block Ach at motor end plate (a problem with animals are under general anesthesia)
 Treat with IV calcium soln
4. Drug Interactions
 pH incompatibilities (mixing in syringe)
 Synergistic with -lactams (AG need to get into cell, -lactams destroy cell wall making it easier for AG to
get inside – studies on this show that it doesn’t work that well)
 Avoid use with other nephrotoxic drugs
5. Drug Residues
 Neomycin and Gentamicin
 Can be found for years after the drug has been administered – do not use AG in food producing animals
 Residues show up in kidneys
Therapeutic Drug Monitoring (Also done for phenobarbital and KBr)

 Commonly monitored in the plasma in the PAST (not really done anymore)
 Dose once a day of less frequently – diminishes the need for TDM
 Use to determine T which can be used to change dosing interval
How to Monitor Nephrotoxicity?

 GOLD STANDARD: Looking at urine GGT (gamma glutamyl transferase) to creatinine ratio in urine
o GGT:Cr may go up 2-3x baseline within 3 days of a nephrotoxic dose
o Cr in urine is baseline for comparing other compounds, it reflects GFR
 Look for proteinuria
o Non-specific – doesnt tell you what is happening, doesn’t tell you this is AG nephrotoxicity
o Use dipstick, easy, cheap, fast
 Increase in serum urea nitrogen and serum creatinine – not seen for 7 days
What can you do to prevent AG toxicity, increase effectiveness, or both?

 Add calcium to fluid line – reduces toxicity by preventing binding to proximal tubule cells
 Administer AG’s as 1 bolus, not a CRI
 Crank up the fluid rate, tries to increase GFR to flush out the kidneys, minimize contact time of drug with
proximal tubular cell
 Ensure adequate protein in the animal’s diet
 Local drug therapy: putting drug in specific area of the body (NOT systemic absorption)
o Intravenous regional perfusion: use tourniquet and put drug distal to it
o Intra-osseous: insert catheter into medullary cavity of bone and injec t drug
o Intra-articular: injecting drug into joint capsule, aseptic technique
o Antimicrobial-Impregnated Beads: no licenced products, drug slowly releases from sterile beads that
were plated at the local site of infection
Antimicrobials
Phenicols
 Relatively lipid soluble
NEED TO KNOW
 Florfenicol
o Nuflor: IM/SC solution in cattle and IM in swine
 Different withdrawel periods when given IM vs SC
 For cattle with respiratory disease (BRD pathogens), foot rot, pinkeye
 Broad spectrum – totally inappropriate to use Nuflor for foot rot/pinkeye
 For swine with respiratory disease
o Resflor: florfenicol + flunixin (NSAID) injectable solution (SC)
 Indicated for cattle with respiratory disease + pyrexia
 Doesn’t cause lesions like Banamine (different carrier component in the drug)
o Aquaflor: medicated feed premix for salmon
 Indicated for Aeromonas & Vibrio infections
o Osurnia: ear medication with terbinafine (antifungal) and betamethasone (steroid)
 Chloramphenicol  for small animal practice exclusively!!
Antimicrobials
o ChlorseptinVM – chewable tablet
 Variety of infectious conditions in dogs – non-specific label
 Scored to break pill into smaller doses
o Chlor®Palm250VM – oral suspension
 Variety of infectious conditions in dogs/cats – non-specific label
FYI ONLY: Thiamphenicol
Mechanism of Action
 Binds to bacterial ribosomal 50S sub-unit
o Causes incorrect tRNA translation  disrupts bacterial protein synthesis
 Inhibits mitochondrial protein synthesis in mammalian bone marrow (dose dependent)
o Have problems with RBC and WBC production
 Effective for:
o Many gram + species (some MRSA, MRSP)
o Many gram – species
o Many anaerobes (not as good as -lactams – not 1st choice)
o Some mycoplasma (In vitro)
 Clinical significance: might not work INSIDE the animal
o Some Rick ettsia & Chlamydia
 NOT effective for:
o Gram – enterics (often resistant to chloramphenicol, less resistant to florfenicol)
 Salmonella, E.coli, Klebsiella
o Pseudomonas, Enterococcus (usually), Rhodococcus, Mycobacterium, Nocardia
o Resistance emerges rapidly in many bacterial species
 Do susceptibility testing!!
Resistance
 Enzymes adding acetyl group
o Chloramphenicol acetyltransferases add acetyle group to chloramphenicol, prevents binding to
ribosome 50S subunit
o Florfenical is less susceptible to the enzymes
 Due to chemistry of drug
 Enzyme can add acetyl groups to 2 sites of chloramphenicol, but only 1 site on florfenicol
 Other
o Decreased phenicol permeability
o Increased efflux pumps (floR gene in G- enterics)
o Mutations to 50S binding sites – does occur, typically not the 1st emergence of resistance
 Resistance genes are mobile
o Plasmids, transposons, etc
Pharmacokinetics of Phenicols
 Bioavailability
o Chloramphenicol: good oral F
 Decreased absorption of palmitate formulation in fasting cats
 Inactivated in the rumen – not a real issue, not important
o Florfenicol
 Prolonged and variable absorption after IM/SC injection due to different carriers
 Flip flop kinetics: when the drug is eliminated slowly (but not due to problems with
elimination) due to being absorbed at the same time it is being eliminated
 Distribution
o Moderate/high Vd (~1L/kg)
o Specific tissues in dogs
 Highest [ ] in liver/kidney
 Lungs, spleen, heart, muscles similar to plasma [ ]
 Good penetrations in aqueous & vitreous humors of the eye
 Can diffuse into CSF, milk (don’t use in dairy cattle), pleural, peritoneal fluid, placenta
(careful during pregnancy)
Antimicrobials
 Little penetration into prostate unless it is inflamed
 Elimination
o Hepatic metabolism (glucuronide conjugation)
 Poor elimination in cats – so longer T ½ and dosing intervals
 Much longer T ½ in young animals… WHY?  Less liver activity when young
o Primarily renal excretion of inactive metabolites
 Bacteriostatic: inhibiting bacterial growth, ratio of MBC to MIC is large, so not safe to administer high enough
concentrations of the drug to kill 99.9% of the bacteria
o Considered time dependent  no good evidence to prove this, we assume they are time-dependent
o Recommended T> MIC for >50% of dosing interval
Drug Interactions (other antimicrobials) – may be antagonistic with other antibiotics

 DO NOT ADMINISTER PHENICOLS WITH THESE 4 DRUGS: FYI – just know using phenicols with other
drugs doesn’t have much of a benefit
Antimicrobial Why?
-lactams Phenicol-mediated bacterial protein
inhibition decreases -lactam effect
on cell wall synthesis
Macrolides Both act on bacterial ribosomal 50s
subunit
Aminoglycosides Bactericidal AG effect is decreased
with phenicol-mediated bacterial
inhibition
Fluroquinolones Interferes with lysis of bacteria after
FQ interfere with DNA synthesis
o Chloramphenicol
 Hepatic metabolism interactions
 Microsomal enzyme inhibitor (CYP)
o Can prolong pentobarbital anesthesia
o Can inhibit phenobarbital metabolism – could see signs of sedation, lethargy, and
liver damage from phenobarb toxicity
 Phenobarb is an inducer of CYP enzymes, may increase metabolism of
phenobarb
o Florfenicol not know to cause hepatic drug interactions…. WHY?  you won’t use a lot of medications in
COMBINATION in food animals, thus you wouldn’t see drug interactions
Adverse Events and Warnings

 Blood dyscrasias: anything that messes with RBCs (aplastic anemia, pancytopenia)
o Dose dependent blood dyscrasias: both CPHC and FLOR
 In humans and animals – cats more likely to develop toxicity (due to increased exposure)
 The magnitude of blood dyscrasias will be correlated to the total exposure (area under curve)
of the drug (dose and duration)
 Reversible
o Dose independent blood dyscrasias (idiosyncratic)
 In humans (can be fatal), very few reported cases in VetMed
 1 in 30,000 are susceptible
 Possibly via CHPCL drug residues in tissues or dermal exposure
o Residues in food producing animals can cause this!!
o Warn clients of dermal exposure
 Related to para-nitro group on CHPCL (not with FLOR) – due to difference in chemistry –
florfenicol residues not a big deal, residues of chlorphenicol are BAD
o END RESULT: chloramphenicol banned for use in food animals
 GI adverse effect
o Chloramphenicol: Vomiting, diarrhea, inappetance – not specific to phenicols
o Florfenicol: changes GI normal flora, leads to diarrhea in sick scouring calves
Dosing of Phenicols
 Use label dose
 Higher doses more appropriate (especially in cats, due to poor F)
Antimicrobials
 Prolonged administration not recommended
o Due to blood dyscrasias and other adverse effects
o The longer animal is on this drug, the more likely the ADR could occur and the faster antimicroabial
resistance is acquired
o Limit to 10 days of therapy, or if no response to treatment after 3-5 days
Uses of Chloramphenicol?
 First Case
o MDR pathogens (enterococcus)
o Enterococcus – inherently resistant to cephalosporin drugs
o Chloramphenicol only rational choice for this dog
 Second Case
o Staph pseudintermedius (skin infections)
o Resistant to many drugs, not chloramphenicol
Cattle Label Claims

- Bovine pink eye and foot rot
- Florfenicol (Nuflor) – not the best drug for these conditions, is OVERKILL
- Easily treated with other drugs
Sulfonamides
NEED TO KNOW: understand general sulfa drug properties, plus key characteristics of a few specific sulfa drugs
POTENTIATED SULFA DRUGS: Sulfonamide + other molecules (interact with different step of folate synthesis)
- Sulfadiazine (with trimethoprim)
o Indicated in horses for respiratory/soft tissue infections
- Sulfadimethoxine
o Medicated feed for furunculosis in salmon
- Sulfadoxine (with TMS)
o Injectable solutions – IM or SLOW IV administration
o Numerous pathogens in cattle and swine
- Human generic TMS – oral tablet formulations
OTHER SULFA DRUGS: not found in potentiated form with TMS

- Sulfaguanidine: in some calf scour boluses
- Sulfamethazine: found in oral triple sulfa boluses, medicated feeds, oral powders for medicated water
o Used lots in large animal practices
o Common source of drug residues (sticks to feed mixing equipment)
- Sulfanilamide: found in oral sulfa boluses, uterine sulfa boluses for retained placenta/metritis, topical
creams for pyoderma
Formulations (TMS, injectable)

- Trivetrin
Antimicrobials
- Tribressin
- Borgal
Human Generic Products
- Used in small animal practice
Mechanism of Action
- Sulfas: kicking them in the balls
o Blocks folate synthesis
o Structure of sulfa drugs very similar to the structure of PABA
o Competitive inhibitors of PABA incorporation into folate
o Considered bacteriostatic by themselves
- Diaminopyrimidines: slitting their throat
o Trimethoprim, ormetoprim, pyrimethamine
o Inhibits dihydrofolate reductase
o Sulfas + TMS = bacteriocidal (truly synergistic drugs)
- END RESULT
o No folate = no bacterial DNA synthesis
Why aren’t sulfa drugs toxic to us?

- Mammals get folate from diet and utilise it, we don’t need to synthesize it like bacteria do
Competitive inhibitor of PABA – implications?

- If you have lots of PABA in bacterias environment, it doesn’t matte r if you have sulfas or TMS around
- If you have lots of precursor molecules – competitive inhibition, being overwhelmed and cannot be
inhibited
- Clinical implications: bacteria with lots of PABA around are not effective for abscesses
Spectrum of Activity: highly variable for individual isolates & VERY broad
spectrum
 Generally susceptible:
o Some gram + isolates
o Some gram – isolates
o Many anaerobes
o Some protozoa & coccidia
 Generally, NOT/LESS effective:
o Resistance emerges rapidly in many bacterial spe cies (Strep
equi, E. coli, Salmonella)
o Pseudomonas
o Enterococcus
Mechanism of Resistance
 Chromosomal or plasmid-mediated – transferable resistance
 Hyper-production of PABA – if there is tons of PABA the bacteria don’t care that their enzymes are being
inhibited by sulfa drugs, they will still make folate.
 Altered DPS (sulfa) or DHFR (trimethoprim) enzymes
 Increased production of DHFR enzymes
 Reduced drug penetration into bacteria
 Cross resistance b/w sulfas is typical
o Resistance emerges more slowly with potentiated sulfas (TMS) than with sulfas alone
Pharmacokinetics
 Good oral bioavailablilty
 Distributes into many tissues (Vd slightly lower then phenicols, but more then -lactams or aminoglycosides)
 Differences in protein binding b/w sulfas & species
Antimicrobials
 Elimination
o Hepatic metabolism
o Renal excretion
 High concentrations in the urine may help for some types of UTI’s
 Sulfonamindes are filtered, but some tubular reabsorption can occur (depends on pH of the
urine  decreased tubular reabsorption with alkaline urine)
 Significant difference in PK b/w sulfas and potentiated sulfas
o TMP ratios challenging – ratio at 1-2 hours is not the same ratio at 24-48 hours
o Makes C & S results more difficult to interpret
o Differences b/w vet and human formulations (commonly used in small animal practice)
Uniprim (TMS) says give SID, but most reference sources recommend BID instead….. why?
 PK-PD not established for sulfas, but probably a time dependent antimicrobial
 Sulfas are really old drugs, and the label dose is based on historic dosing regimens
Sulfonamide Adverse Effects

1. Hypersensitivity reactions
 N1 nitro group associated with type I hypersensitivity reactions
 N4 nitro group forms reactive metabolites that causes cytotoxicity or an immune response
 Blood dyscrasias (IMHA – horses, thrombocytopenia & epistaxis)
 Arthritis – transient and non-septic
 Skin eruptions – especially Dobermans
 Hepatic necrosis
2. Keratoconjunctivitis sicca (KCS)
 Dry eye due to decreased tear production (sulfa toxic to lacrimal acinar cells)
 Occurs in ~15% of dogs (especially smaller dogs), typically resolves when sulfas discontinued
3. Renal damage
 Sulfas poorly soluble & precipitate in urine & form crystals
o Esp with decreased tubular flow (dehydration) or acidic urine (decreased sulfa solubility)
o Can lead to crystalluria, hematuria, and tubule blockage
o Not a big problem with TMS any more
 Lower doses of sulfa needed if used with trimethoprim
 Make sure patients are hydrated
4. Hypothyroidism
 Inhibition of thyroid enzyme activity
 Generally reversible
5. GI – diarrhea, vomiting, salivation
6. Anemia from chronic sulfa use (rare)
 Decreased folate production from intestinal bacteria
 Supplement folic acid (Vitamin B)
7. Injection reactions
 Lesions after IM injection
 Rapid IV injection may cause thrombophlebitis or anaphylaxis in horses
8. Drug interactions
 Procaine = PABA analogue
Antimicrobials
Tetracyclines
NEED TO KNOW:
 Tetracycline
o Licensed for food animals & horses
o Water soluble powders & oral boluses TC and OTC oral
 Oxytetracyclines capsules (humans)
o Multiple products (licensed in food animals only) used in small animals.
o Feed premix or water-soluble powder
o Injectable products
 Short acting (“LP”) for IM/IV use
 Long acting (“LA”) for IM/SC use – contains irritating carriers
 Chlortetracycline
o Oral premixes and boluses for food animals
 Doxycycline
o Primarily for small animals and horses
o Formulations: human tablets
 May need compounded forms to get appropriate sizes
 Vet formulations no longer available
Mechanism of Action
 Binds to bacterial ribosomal 30S subunit  incorrect tRNA translation  disrupts bacterial protein
synthesis
 Energy dependent transport into bacterial cell to reach binding sites
o Animals lack tetracycline transporters so it doesn’t get into their cells
 TCs have multiple charges on functional groups
o Overall neutral charge  increases uptake into bacterial cell
 Bacteriostatic but bactericidal at high concentrations
 Time-dependent: want prolonged exposure not high peak concentration
 TC, OTC, CTC have similar pharmacodynamics
o Differences in efficacy due to PK differences
Antimicrobials
Potentially Effective Probably NOT Effective
 Some G+ and G-  Staphylococci
 Many anaerobes  G- enterics often resistant
 Some Mycoplasma, Rickettsia,  Pseudomonas
Chlamydia, protozoa, and  Enterococcus
spirochetes  Resistance emerges rapidly in
many bacterial species
Mechanisms of Resistance
 Plasmid mediated
 Failure of active transport of drug into bacterial cell
 Increased efflux from cell
 Production of protein that protects bacterial ribosomes
Tetracycline Pharmacokinetics
 Absorption
o CTC/OTC: poor oral bioavailability
o Doxycycline: high oral F
o Oral F varies w/ feed status & formulation
 Better F when fasted  thus TC are typically given in the feed in food animal production –
greatly reducing the bioavailability of the drug
o Injectable OTC: high bioavailability
 LA formulations = flip-flop kinetics
 Distribution
o Good distribution to most tissues/fluids
o Doesn’t penetrate CSF well  Pgp substrates
o Low/moderate protein binding (except doxycycline)
o TCs bind to Ca/Mg  effects the teeth and bones
 Elimination:
o Little metabolism
o Excretion
 Via bile, into intestine (P-gp), enterohepatic recirculation
 Unchanged drug excreted mainly by kidneys
 High concentrations in urine  good for UTIs
 Longer T½ with renal failure  likely don’t need to modify dose
 T½ = 6-8 h (except LA injectable products ~ 24 h)
 Doxycycline excreted in feces
ADR and Interactions

 Generally, very safe….
 Chelation by calcium and heavy metals
o Don’t administer w/ dairy products/antacids  decreases the F
o Administration in young animals = teeth staining
 Nephrotoxocity @ high doses
o Dehydration
 Cardiovascular collapse with rapid IV injection
 GI signs: V/D, enterocolitis in horses
 Injection site reactions (long acting OTC) – depends on drug carrier
Antimicrobials
 Musculoskeletal effects
o OTC can relax flexor tendons
o Administerd to neonatal foals with contracted tendons (IV high dose)
o Mechanism: inhibition of matrix metalloproteinase enzymes
Macrolides
 Broad category of antimicrobials
 Similar chemical structure to macrocyclic lactones (mectins & mycins)
 Old macrolides have HIGH MICs for BRD pathogens
 New macrolides have low MIC for BRD pathogens - a much better choice
NEED TO KNOW:
 Tylosin (Tylan®) – feed premix or medicated water
o Lots of label claims in pigs & broiler chickens
o Reduction of liver abscesses in feedlot cattle
 Respiratory Disease Macrolides
o 4 Injectable Formulations Used in Cattle
 Tilmicosin (Micotil®)
 SQ injection ONLY in cattle/sheep
 Significant adverse events
 Oral and liquid formulations for swine, feedlot cattle & rabbits
o Just approved in rabbits for respiratory disease!
 Tulathromycin (Draxxin®) – SQ in cattle, IM in swine
Why do we have so many
 Slightly better then Tilmicosin
drugs for respiratory disease
 Gamithromycin (Zactran®)– SQ in cattle
in Cattle? – big market,
 Tildipirosin (Zuprevo®)– SQ in cattle
o Human Formulation benefits seen quickly,
 Azithromycin – NOT licenced for veterinary use economic benefits
 Formulations: oral tablet & suspensions
 Extralabel in small animal practice
NICE TO KNOW:
 Tylvalosin (Aivlosin®) – oral premix or medicated water for pigs
o Tx of porcine proliferative enteropathy (Lawsonia intracellularis) in pigs
 Erythromycin (Gallimycin®) – feed premix licenced for poultry with non-specific label claims
o Not many veterinary formulations left – not being produced anymore
o Still recommended (as 2nd/3rd line therapy) for certain conditions in dogs/cats/horses
FYI:
 Clarithromycin – often used in diagnostic susceptibility panels
Antimicrobials
o Not many reasons to use this over azithromycin
Others: Lincosamides, pleuromutilins, streptogramins
NEED TO KNOW:
 Lincosamides:
o Lincomycin – oral premix/solution, injectable solution
 Licenced for swine, poultry, dogs/cats
o Clindamycin - antirobe oral capsules or solution (tastes very bad)
 Used all the time in small animal practice
 Good oral F and high Vd – indications for a variety of body systems
 Used for skin, dental, bone or anaerobic infections
 Rapidly emerging resistance w/ chronic use
o Pirlimycin (Pirsue®) – IMM formulation
NICE TO KNOW:
 Pleuromutilins (Tiamulin) – Denagard® liquid solution or feed premix
o Tx & prevention of swine dysentery (Brachyspira hyodysenteriae)
 Streptogramins (Virginiamycin) – Stafac® feed premix
o Tx of swine dysentery and prevention of necrotic enteritis (broilers)
o Related to a bunch of antimicrobials in human medicine very important for treating vancomycin
o Use could lead to cross resistance
Solution – drug is dissolved into the aqueous solution, absorbed immediately into the GIT
Suspension – drug is suspended in the aqueous solution, not absorbed immediately into GIT, needs to be dissolved
first
Mechanism of Action (of Macrolides/Lincosamides)

 Binds to bacterial ribosomal 50S sub-units (same effect as phenicols)
o Incorrect tRNA translation  disrupts bacterial protein synthesis
o Activity is pH dependent – basic amine groups are ionized in acidic pH  decreased entry into
bacterial cell OR it could mean that the drug is ION trapped and reaches high concentration @ site of
infection.
 Often still effective due to use of high drug concentration.
o Bacteriostatic – depends on macrolide/pathogen combo
o Time-dependent
 Azithromycin shows some concentration dependent effects
 Generally effective for:
o Mostly G+ and some G- (Bovine/Swine respiratory disease pathogens)
o Some anaerobes (clindamycin)
o Helicobacter (azithromycin)
o Mycoplasma – clinically probably doesn’t work too well for this
o Intracellular pathogens – Lawsonia & Rhodococcus
o Spirochetes, Chlamydia, Toxoplasma (clindamycin)
 Not/Less effective for:
o Most G- enterics
o Pseudomonas
o Enterococcus
o Resistance emerges rapidly (cross resistance common)
 Inability to bind ribosome
o rRNA methylation (erm gene)
o mutations to ribosomal binding sites
 Efflux pumps  decreased drug entry to cell
o often plasmid mediated
 Enzymatic inactivation of drugs
Antimicrobials
 Plasmid-Mediated Resistance Genes
o Allows cross resistance to form rapidly
o See an MIC creep – until the drug is no longer clinically useful
o When we see resistance to one of the macrolides, we will probably see resistance to other macrolides
later on if you keep on using macrolides
Overuse of Macrolides for BRD?

 Yes, used as metaphylaxis on arrival to feedlot when respiratory infections tend to occur
 Leads to cross resistance to the whole family of macrolide antimicrobials
Pharmacokinetics: very interesting properties

 Absorption
o Lots of variation in F b/w individual drugs
 Special coatings, food may alter absorption
o All have good injectable F
 Distribution
o Highly lipophilic (KNOW THIS)
 Low plasma [ ] but very high Vd
 Penetrates tissues very well
o Specific tissues
 High concentrations in “lung” (good for BRD infections)
 CSF: lincomycin & clindamycin have increased distribution
o Drug concentrates in leukocytes and carried to site of infection
 Effective against intracellular pathogens
 Elimination: varies depending on drug
o Some hepatic metabolism, excretion via bile/urine
o Some macrolides have very long T½
 Drug (especially respiratory macrolides) sit in tissues and are “protected” and slowly eliminate
from the body = long half lives
 Tend to get graphs where the drug is eliminated quickly from the plasma, but slowly from the
tissues
 Long withdrawal periods – but concentrations are not that high in EDIBLE tissues
 Not a big problem from a food safety point of view
 Long acting respiratory disease macrolides
o Plasma [ ] persists pretty well, then starts dropping around 10 days
o Stays around longer in lungs – long acting
Adverse Events
 Tilmicosin: CARDIOVASCULAR TOXICITY (KNOW THIS)
o No toxicity with label SC dose in cattle/sheep
o Fatal when injected IV or when used in the wrong species (due to rapid absorption)
 Blocks Ca+ channels   Ca+ in blood stream
 Tachycardia (negative inotrope – stroke volume drops, CO drops, blood pressure drops 
reflex tachycardia)
 IV Ca+ administration may be protective
 Epinephrine contraindicated in these cases
o NOT for human use – causes fatalities
 GI toxicity after oral administration
o V/D common
 Especially with oral erythromycin – poor oral F and not stable in GI fluid
 Erythromycin increases gut activity
o GI flora changes
 Fatal colitis in horses after erythromycin use
 Caution in rodents/bunnies
 Injection site reactions
o Most cause some irritation  Tilmicosin (SQ) and Erythromycin (IM) are very irritating
 Hyperthermia: after erythromycin injections in foals
 Drug Interactions – minimal
Antimicrobials
o Some are CYP inhibitors (Erythromycin) – so if you administer with other CYP substrates you inhibit
their metabolism and increase their concentrations
o Antagonism when used with phenicols  both bind to ribosomal 50S subunit
 Macrolides don’t cause bone marrow toxicity
o Erythromycin + Rifampin = treats Rhodococcus equi
Non-Antimicrobial Properties of Macrolides

 Erythromycin: GI prokinetic
o Motilin receptor agonist, may stimulate cholinergic neurons
 Anti-inflammatory & immunomodulation
o  production of pro-inflammatory cytokines   neutrophil migration
o Tylosin: used as GI anti-inflamm
o Enhances efficacy for respiratory disease
 Due to anti-inflamm + anti-microbial activity
Fluoroquinolones
NEED TO KNOW: licenced for vet use
 Enrofloxacin (Baytril®)
o Oral tablets for dogs/cats, IM soln for dogs
o Otic solution – for ear infections (antifungal + antimicrobial + steroid)
o Broad label indications for small animal formulation (for bacteria susceptible to xxxfloxacin)
 Baytril 100 – food animals
o Injectable SC soln for cattle/swine respiratory disease (P. multocida, Mannheimia)
o NOT used as a mass medication for cattle/swine
o Label say it should only be used for single animals with resp disease after 1 st choice treatment failed
 Baytril less effective when scarring/tissue remodelling has set in
 Shouldn’t be used as a 1st line antibiotic, also not good as a 2nd line therapy
o Not used extra label in cattle/swine (illegal in USA)
 Danofloxacin (A180)
o Injectable SC soln for cattle respiratory disease
 Marbofloxacin (Zeniquin)
o Oral tablets for dogs/cats
o Otic soln
 Orbifloxacin (Orbax)
o Oral tablets for dogs/cats
 Pradofloxacin (Varaflox)
o Oral tablet & suspension for dogs/cats
o Indicated for skin infections only
o More potent than others, so has lower MICs, not sure if it translates into clinical efficacy
NICE TO KNOW: human formulation

 Ciprofloxacin – oral tablets & soln for IV use
o Enrofloxacin is metabolized to ciprofloxacin in the patient
FYI:
 Naladixic acid (fluoroquinolone precursor)
 Difloxacin (no longer in Canada)
Mechanism of Action
 Bacterial DNA is a double stranded-helix that is supercoiled into loops by the topoisomerase II enzyme (AKA
DNA gyrase)
 Bacterial DNA inhibition:
o FQs bind to DNA-DNA gyrase complex
 Inhibits sealing of cut DNA  damaged DNA then destroyed by exonucleases
o Inhibits topoisomerase IV (responsible for relaxing DNA supercoils  DNA replication cannot occur)
Antimicrobials
 Long post-antibiotic effect: plasma [] can dro below MIC yet bacterial growth still inhibited for some time (eg.
Aminoglycosides)
 Bactericidal: can reach high [ ] in order to kill 99.9% of bacteria
 Concentration (dose) dependent – want a high PEAK (KNOW)
o If you keep upping the concentration you get steeper kill curves and increased efficacy
o Want Cmax at 10x the MIC, and an AUC 125x the MIC
o High drug dose minimizes emergence of antimicrobial resistance
Generally Effective NOT Effective
 Some G+ (staph) and G- (BRD, SRD  Less effective for Strep and
& enteric pathogens  Mannheimia, Enterococcus
Histophius, A. suis Salmonella, E.  Anaerobes
coli, Clostridium)  Resistance emerged for
 Some anaerobes (Pradofloxacin) many isolates
 Pseudomonas (Ciprofloxacin)
 Some Mycoplasma, Chlamydia,
Rickettsia (intracellular pathogens)
 not sure if it transfers to clinical
efficacy
 Chromosomal mediated resistance – chromosome mutates & resistance emerges
o Topoisomerase genes mutate & FQ binding sites don’t work
 Need MULTIPLE subsequent mutations to get significant resistance
o  permeability /  efflux
 Plasmid-mediated resistance
o Qnr gene: protects DNA-gyrase complex from FQ binding
o Transmissible resistance element
 Cross-resi stance b/w FQs is common (KNOW)
o Selective pressure (prolonged exposure to low dose of FQ) leads to chromosomal mutations
o High dose, short course therapy is recommended (similar to aminoglycosides)
 Increases efficacy (dose-dependent effect)
 Minimizes AMR
 MIC slowly creeping up = indicative of resistance
Pharmacokinetics
 Absorption
o Good oral F
o Chelation w/ divalent cations (Fe2+) =  F
 Distribution = good
o Lipophilic & low protein binding = high Vd to tissues
o [Tissues] is similar or greater then [plasma]
 including CSF (good for septicemia/meningitis) and prostate
 good for sequestered infections (provide there is not much pathology, sequestration)
o Uptake into phagocytic cells (similar to macrolides)  good for intracellular pathogens
 Elimination
o Hepatic metabolism
 Enrofloxacin metabolized to ciprofloxacin in dogs/cats/horses
 Doesn’t matter because efficacy are comparable
o Excretion
 Renal (GFR & tubular secretion)  good for UTI’s if 1st choice doesn’t work
Antimicrobials
 Some biliary
 T½ = 4-10 h  SID dosing (high dose) works (post-antibiotic effect)
Adverse Events - these are pretty safe antimicrobials

 Strep Shock and Necrotizing Fasciitis – RARE
o Strep canis infected by bacteriophage & genetic transfer occurs
o Enrofloxacin mediated bacterial DNA damage  increased expression of proteins to fix damaged DNA
(SOS response).
 Phage genes encode toxin  also upregulated  toxic shock response occurs
 Exacerbated by concurrent NSAID/steroid use
o BEWARE: don’t use Enrofloxacin in a patient w/ S. canis infection
 Arthropathies
o Common in young dogs (large breed) and foals
o Likely because FQ binds and chelates Mg+
o Chronic, high dose FQ can cause articular cartilage lesions
 We should be using a short-term high dose FQ
o Don’t use FQs during rapid growth phase in dogs
 Retinopathy in Cats
o Feline ABCG2 transporter genes differs from other species by about 10 aa sites  this is consistent in
all cats   transporter function
o This transporter is present in retinal capillaries and pumps drugs away from the retina
o Cats accumulate Enro/Cipro at the retina  retinal degeneration/atrophy  blindness
o Seen in cats with a VERY HIGH DOSE OF ENRO (8x the label dose)
o NOT with PRADO, likely not with MARBO/ORBI
 Bone Marrow Suppression
o Prado not used in dogs in USA, allowed in Canada
o Risk of bone marrow suppression is low because suppression occurs at 9x the label dose
 GI – mild irritation
 Neuro: seizures in dogs/cats/horses
o SLOW IV injection in horses
o “Baythrill” – hallucinations in people
Drug Interactions
 Enro/Cipro are CYP enzyme inhibitors
o Other drugs that use CYP enzymes would reach higher [plasma]
 P-gp substrates
Antimicrobials
Miscellaneous Antimicrobials
Metronidazole Intracellular anaerobic Spectrum of Activity:
- All human products metabolism produces - Anaerobes (Clostridium, Bacteroides, Brachyspira)
- No veterinary reactive metabolites - Protozoa
formulations leading to DNA Resistance:
damage and cell death - Does occur, not common
- Cross resistance w/ other nitroimidazoles
Doesn’t work in PK:
aerobic conditions - Good oral F
- Vd high – good distribution (CSF, bone)
- Elimination: hepatic, bile, urine
ADR:
- Banned for use in food animals (carcinogenic)
- Avoid in pregnant animals (teratogenic)
- Minimal GI upset – salivation, inappetance
- Neurotoxicity: ataxia, seizures, lethargy (stop
therapy and administer diazepam)
DI:
- Caution when using w/ microsomal enzyme
inducers/inhibitors
- If used with inhibitor metronidazole [ ] goes up
Often combined with AG, lactams for broad spectrum
coverage
Nitrofurans Blocks bacterial Spectrum of Activity:

- Nitrofurazone – topical pyruvate metabolism - Broad spectrum (especially G- enterics)
vet product (energy production) - Problem: reaching MIC plasma levels requires
- Nitrofurantoin – oral doses that cause systemic toxicity (no high doses
human formulations used systemically)
Resistance:
- Does occur, no cross resistance
PK:
- Good oral absorption
- Topical absorption unknown
- High Vd – wide distribution in body
- Excretion: RENAL – can use low doses and
reaches high concentrations in the urine (used to
treat UTIs)
ADR: don’t see because we don’t use at high doses
- Cardiomyopathy (ventricular dilation)
- Reproductive toxicity
- Banned in food animals (carcinogen)
- Proud flesh formation in horses
Uses:
Antimicrobials
- Nitrofurantoin for E. coli UTIs (especially if they
have multi drug resistance – NOT a 1st choice!)
Rifampin Inhibits bacterial RNA Uses:
polymerase  inhibits - Tuberculosis in humans
protein synthesis - No vet formulations
Penetrates leukocytes, - Gram positive
kills intracellular - Mycobacterium (TB), Staph, Rhodococcus equi
pathogens for pneumonia in foals
PK
- Good oral F, good Vd
- Bacteriostatic
- Time-dependent antimicrobial activity: maintain
concentrations for a prolonged period of time
- Hepatic metabolism
- Bile and renal excretion
Resistance:
- Gram negative
- Single AA change in RNA polymerase reduces
rifampin binding
- Often combined with erythromycin – greatly
reduces the resistance to rifampin
ADR:
- Red tinged fluids (stains everything)
- INDUCER of CYP enzymes (increases clearance of
other drugs metabolised by CYP enzymes – Also
seen w/ Phenobarb) – not a big deal b/c you don’t
really use rifampin chronically
- Teratogenic – don’t use in pregnant animals
- Blood dyscrasias (rare)
Glycopeptides Inhibits peptidoglycan Spectrum of Activity:
- Vancomycin synthesis needed for - Nasty gram + rods/cocci (MRSA, Enterococcus)
(human formulation) bacterial cell wall Resistance:
- Gram negatives
- Major human health concern – VRE & MRSA w/
decreased susceptibility to vancomycin
- Plasmid-mediated vanA gene changes target
binding site
PK:
- Poor oral F, low Vd
- Excretion: Glomerular filtration (adjust dose for
renal failure patients)
ADR:
- Irritation on injection, slow IV injection
- Maybe nephrotoxic, ototoxic, allergenic
Polymyxin B Cationic detergent – Use:
binds cell membrane - Endotoxemia in horses
and disrupts structure Spectrum:
- Gram negatives only (due to cell wall type)
Endotoxin binding ADR:
effect - Very toxic systemically (use topically – otic,
ophthalmic)
Bacitracin Similar to -lactams Spectrum:
- Gram positives
- BNPH = bacitracin, Use:
neomycin, - Not systemically, maybe in some pre-mixes
polymixin B, (promotes growth, prevents enteritis)
hydrocortisone - Topically
Mupirocin Blocks bacterial Formulations: humans only
protein synthesis - Muricin for pyoderma in dogs
Antimicrobials
Uses:
- Topically for staph infections
- Intranasal for MRSA carriers
PK
- Good Vd into infected tissues
- Inactivated when absorbed systemically
Don’t use in Vet Med
- Linazolid Protein synthesis Uses:

inhibitor - Gram positives
- Anaerobes
- In humans for MRSA, VRE, C. difficile
- Colistin Related to polymyxin B Uses:

- Gram negative enterics
- Oral use in swine in China
- API use in Canada leads to pan-resistant enteric
pathogens
Skipping anti-virals and disinfectants – because there are very few and boring
Generic Drugs
Generic Drugs: Big Picture

Difference b/w pioneer and generic drug?
- New pioneer drugs have to go through all clinical trials, testing, development, safety trials, etc
- Generic drug doesn’t quite have the same burden of proof
What is the point of a generic drugs?

- More drug product availability
- Competition = drives down prices
o Caveat: generic drugs only come out once pioneer drug patent has expired
Why are generic drugs cheaper?

- Proven safety & efficacy of pioneer drug = no need to reproduce the same studies for the generic product
- Allows them to come to market faster and a lot cheaper
What does a generic drug need to prove?

- Clinical efficacy and safety
o Must be demonstrated to be bioequivalent with the original (pioneer) product
 What is the assumption here?
 Bioequivalent drug is going to have equal efficacy and safety as the pioneer drug
 Going to be looking at blood concentrations of the drug
 Assume blood concentrations are correlated to safety and efficacy
 If blood concentration of drug for generic and pioneer drug are similar the safety and
efficacy should also be similar
- Manufacturing & Chemistry (know this)
o For a generic drug the requirements are JUST AS RIGOROUS for a pioneer drug
 Purity: drug is what it says it is and not something else and it also cannot have a bunch of
other impurities
 Potency: the amount of the drug, if it says it’s a 100 mg tablet it better be a 100 mg tablet
 Stability: if expiry date is 24 months, then after 23 months it still better be stable
 Sterility: if injectable better not be filled with endotoxins
For vet: if it has a DIN you have assurance of quality control

- If something goes wrong you can go back to the manufacturer and they will support you
- NO DIN = VETS FAULT (if something goes wrong)
Bioequivalence: when the rate and extent of absorption of two pharmaceutically equivalent (same strength)
formulations of drugs (pioneer and generic) are sufficiently similar, within allowable limits, when administered under
similar experimental conditions
Pharmaceutically equivalent:
- Two drugs that contain identical amounts of the identical medicinal ingredient, in comparable dosage
forms
- Does not necessarily contain the same non-medicinal ingredients – provided they are not known to influence
absorption characteristics, safety and efficacy of the active ingredient.
Blood Level Study – cross over trial (each animal gets same drug and same dose – less variance = more power)
- Preferred study
- Target species (healthy)
- Half animals get pioneer drug, half get generic drug
- Wash out period of 10 days
Study Design for Oral Products

- Fasted vs fed: depends on pioneer drug label
o Fasted – less variability, preferred
o Fed – if required/recommended to dose with food
o If pioneer drug says administer in fasting state then the study should be done in the fasting state
- Collect blood samples over time (min 12)
o Early: capture absorption / Cmax
Generic Drugs
o Late: at least 3x half-life beyond Tmax
- Measure drug plasma concentrations – requires validated analytical method
So what do you compare in this bioequivalence study?

- Cmax = maximum drug concentration
- AUC = overall drug exposure
- Compare ratios of pioneer/generic AUG:Cmax – ideally ratios are 100% (no difference)
- Generic drugs need to be in passive zone. b/w 80% and 125% to be bioequivalent
- If confidence interval goes into fail zone = fail!
Reasons for failure to demonstrate bioequivalence:

- Products are truly not bioequivalent
- Products are bioequivalent but not proven
- Generic product might be better – cannot claim to be better, cant be approved as a generic
o Can come to market as a new drug
Veterinary Pharmacy Regulations & Dispensing Procedures

1. Who is responsible for regulating veterinary drug approvals in Canada?
Generic Drugs
- Health Canada
How to identify drugs? DIN #
Canada Food and Drugs Act = sets the legal framework
Food and Drugs Regulations

- What should be on product label
- How to establish new/generic drugs
- Defines what is a controlled product, prescription, narcotic etc
Health Canada enforces things when companies claim “natural health” produces are curative/treats serious
ailments
2. Who is responsible for regulating veterinary drug residues and biologics (Vx, Ab, diagnostic test kit)
approval in Canada?
- CFIA – under Health of Animals Act & Health of Animals Regulations
- Drug residue monitoring – multiple labs (eg. Centre for Veterinary Drug Residues – Saskatoon)
3. Who is responsible for regulating pesticide products in Canada?

- Health Canada – Pest Management Regulator Agency
- How to identify pesticides  PCP #
- Cannot legally use extra label or dispense partial packages (without entire label on dispensed package)
4. Who is responsible for regulating the USE of veterinary drugs in Canada? *know for exam
- The Province
o Provincial Veterinary Acts – legal framework
o Pharmacy Act – no one else can act like a pharmacist, except veterinarians (under Vet Act)
 Vets can prepare a compound, dispense and prescribe drugs
o VMA bylaws – the regulatory document that we should know
 Who makes them?
 The members of the veterinary profession
 Why does this matter?
 Only the members that show up are taken into consideration
 If you don’t give a shit, your still bound by these bylaws
- Provincial laws can be more stringent than federal laws, but cannot diminish them
The Veterinarians Act (SK)

- Have a hard time defining what procedures are a “vet practice”
o Castrating calves – good luck trying to get ranchers to believe only vets should do this
o Equine dentistry
- What vets do is BROADLY defined under this act
Issue w/ SCMA Bylaws – KNOW THIS

- Veterinarian Client Patient Relationship  Section 31
o Vet should not perform procedures or prescribe drugs to an animal without a valid VCPR
 VCPR – depend on the type of practice
 Small animal practice – must see the animal
 Food animal production – cannot reasonably be expected to see every sick animal or
be at every production unit every time
 Cannot establish a VCPR via telephone or electronic means
 VCPR includes follow up and emergency care
Narcotics (N)
- Look for N right beside the name
- Most narcotics have valid therapeutic uses but due to high risk of abuse, there are stringent restrictions on their
availability
o Eg. Morphine, heroin, hydro, buprenorphine, fentanyl, cocaine, ketamine, oxycodone, etorphine
o Cannabis: Right now it is NOT LEGAL for veterinarians to prescribe marijuana to patients
o Not included: reversal agents
Generic Drugs
Controlled Drugs ©
- Drugs with potential abuse, less significant than the narcotics products
o Most of these drugs are not dispensed to the clients to take home, some are
- Level 1 (amphetamine, pentobarbital)
- Level 2 (phenobarbital, butorphanol)
- Level 3 (anabolic steroids)
o Key point: growth promotion ear implants are not considered controlled drugs
Record Keeping Essential for Narcotics & Controlled Drugs

- Written documentation required for receiving/dispensing/disposal of narcotics and controlled drugs
- Must retain for 2 years & permits an audit
Information recorded for receipt of narcotics/controlled drugs

- Date of drug received
- Name of drug received – strength, dosage form
- Quantity received, size of container
- Supplier name
- Invoice # and PO #
Sales and Dispensing

- The actual prescription (keep separately in the medical folder)
- Keep records for a minimum of 2 years
- Information recorded:
o Name and quantity of the narcotic
o Quantity discarded from single use ampules
 Need a witness that saw you throw it out
o Name and address of whom it was furnished
o Date on which it was furnished
Destruction and Disposal

- Allowed to discard unused partial doses in a non-resealable container as long as you record what is discarded
- If you spill/break a vial of narcotics, document the name of drug, amount and date of spill
o Need your signature plus a witness signature
- Steps needed:
1. Contact OCS for written permission
2. Prepare inventory of drugs to be destroyed
3. Another vet must witness/sign form for destruction of drugs
4. Must destroy drug by putting in a container and mixing w/ kitty litter plaster, cement or chlorine bleach
Targeted/Control Drugs (TC)

- Slightly less stringent compared to narcotics and controlled drugs
All controlled/narcotic/TC medications need to be unavailable for people trying to steal them. They need to be
in a IMMOBILE SAFE.
- Gets difficult for ambulatory veterinarians that keep this stuff inside their vehicle
When do you need to have a prescription?

- If it is human labelled, we are using it extra label
o If we use it extra label, we need a prescription for it even though some of the drugs are OTC
- Veterinary products OTC don’t need prescriptions
- Veterinary products Rx need prescriptions
- ALL compounded drug products need a prescription label
Random Rules:
Generic Drugs
- Vets are not allowed to transfer prescriptions from one vet to another, they need to have a VCPR in order to fill
(dispense) the prescription.
- Refills only last 1 year from the date the prescription was written
- Only the vet can phone in the prescription.
- Vet tech can prepare medication and dispense it, but cannot diagnosis or determine the course of treatment.
- Veterinarians can prescribe and dispense drugs (w/ valid VCPR)
Legal Requirements for a Prescription (KNOW FOR EXAM)

1. Date
2. Name and address of client
3. Name or ID of patient and species
4. Drug (brand name or generic)
o Strength/concentration
o Dosage form – suspension, tablet, ointment
5. Directions (sig)
o Route (PO, IM, SC)
o Dose (two tablets, ¼ inch)
o Frequency (TID, q8h)
Duration
o Withdrawal times
6. Quantity (40 tablets, 60 mL)
7. Refills if requested (interval required for controlled drugs, NO refills for narcotics)
8. Veterinarians signature (printed name & phone #)
o Name of the facility, contact info
Prescription for In-feed Drugs

1. Animal production type (post weaning piglets, backgrounder cattle, etc)
2. Weight or age
3. Type of feed
4. Total amount of feed or feeding period
5. Amount of drug used per tonne
6. Manufacturing instructions
7. Cautions
8. CgFARAD # if applicable (for withdrawal period)
DO NOT assume that your clients understood/remembers your directions!

Do NOT cover important stuff on the box of drugs with the dispensing label
Dispensing Labels (what goes on drug for client to take home)

1. Name of Clinic
- Address
- Ph #
2. Name of client
3. Name of patient
4. Drug
5. Strength/concentration
6. Dosage form
7. Directions (must be specific, DO NOT abbreviate, us lay terms)
Generic Drugs
- Route (by mouth, under skin, into eye)
- Dose (one tablet, 3 drops, two mL)
- Frequency (twice daily, every 8 hours)
- Duration (until recheck, for 7 days)
8. Quantity
9. Refills (0-3 refills good for maximum of 1 year)
10. Clinician
11. Date
12. Extra labels if not already on package (“for vet use only” // “keep out of reach of children”)
Could also add the drugs expiration date – not a legal requirement
Dispensing Drugs
- “As is” = send home drug in manufacturer packaging
- Repackaged/labelled by vet tech
- Vet responsible no matter who dispenses the drug
Repackaging Bulk Drugs

- Label should contain name/strength of drug, manufacturer’s name, lot #, expiry date
Returned Drugs
- If it leaves your possession, you legally CANNOT take it back!!
- Cannot re-dispense to another animal
- We don’t know how the drug was handled or if it had the proper storage requirements
CANNOT DISPENSE:
- Ketamine
- Euthanasia Solutions (including T-61)
- Sodium pentobarbital (Euthansyl)
- General Anesthetics
o Propofol, halothane, isoflurance
- Injectable alpha-2 agonists

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Drugs Acting on the Autonomic Nervous System – Weber

Effector Tissues Sympathetic Response – fight/flight Parasympathetic Response – rest/digest

Muscarinic receptors (on effector organs in the

Norepinephrine and Epinephrine

Atropine Muscarinic selective  Inhibits muscarinic receptors.

 Can be used to treat hypertension.

Epinephrine    Equally activates all  and  receptors.

 Used in emergencies to support cardiac function, causes some

 High doses will also stimulate 1 receptors causing an increase in

Dobutamine   Good for cardiac support in crashing animal.

Phenylephrine   Selective agonist for 1.

Propranolol, Timolol   Not selective.

Two Types of Heart Failure

Reduced Stroke Volume & Cardiac Output secondary to:

Chronic Heart Failure

Failure on one side eventually leads to failure on the other side

Heart Failure Drugs

Drug Use Mechanism of Effect Notes

Class II 1 adrenergic  Negative chronotrope,  Supraventricular tachycardia,

Class I Anti-arrhythmic Drugs

Class Drug Na+ K+ Autonomic Hemodynamic Clinical Use

Class II, III, IV Anti-arrhythmic Drugs

Sotalol  Oral – ventricular

III Verapamil + Oral, IV – supraventricular (pacemaker

Class and Drug Mechanism of Use Notes

Lecture 1 – Sedation and Anticholinergic Drugs

 Induction: moving from a state of consciousness to unconsciousness

 Local Anesthesia: AKA analgesia

 Balanced Anesthesia: AKA multimodal, hits all the possible pathways.

3 Components of the Anesthetic State:

1. Analgesia – pain relief

2. Muscle Relaxation – needed before surgery

3. Narcosis/Amnesia – don’t want animal to remember what they went through

Stages and Planes of Anesthesia

Stage 1 •Voluntary Excitement

Stage 2 •Involuntary Excitement

Stage 4 •Cardiopulmonary arrest

Sedatives 2 agonists 2 receptors found Sedation and reduces  Very popular in

Benzodiazepines GABA agonist Anticonvulsant, spinal  First use for seizure

Trazadone SSRI – atypical antidepressant

Anesthetic maintenance using injectable drugs:

Continuous Rate Infusion – not changing rate

Lecture 3 – Inhalational Anesthesia

How the Body Affects Uptake

2. Lung Perfusion (cardiac output)

Elimination and Metabolism

Waste Gas Scavenging

Pregnancy and ORs

Lecture 4 – Support Drugs

Hypotension During Anesthesia

Treatment for Reduced CO

Treatment of Excessive Vasodilation

H1 blocking pharmacodynamics - used to reduce inflammation and itchiness.

1st Generation H1-blockers (anti-histamines)  DROWSY anti-histamines

2nd Generation H1-blockers

3rd Generation H1-blockers

Clinical Uses of H1-blockers for Allergic Reactions

Other Inflammatory Mediators