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3 Rdediton
3 Rdediton
Pharmacodynamics
Pharmacodynamic terms;
1
(4) Efficacy (intrinsic activity) refers to the maximal effect a drug can
produce.
(5) Potency refers to the dose that must be administered to produce a
particular effect of given intensity & is influenced by; i- affinity; ii-
pharmacokinetic processes that determine the drug concentration
in the vicinity of its site of action. Potency varies inversely with
dose, the lower the dose required to produce a stated response,
the more potent the drug.
(6) Antagonist is a drug that blocks the response produced by an
agonist by interaction with the receptor or other component of
the effector mechanism, competitive antagonism is reversible &
surmountable eg. atropine or propranolol. A non-competitive
antagonist conceptually removes the receptor, or response
mechanism, from the system eg. the platelet inhibiting action of
aspirin.
(7) Selectivity of a drug depends on its capacity to preferentially
produce a particular effect. The characteristic action of a drug is
produced at lower doses than those required to produce other
actions. A truly selective drug produces only one single effect,
e.g. heparin.
(8) Specificity when all the effects produced by a drug are due to a
single mechanism of action the drug is said to be specific. A
specific drug acts at only one type of receptors but may produce
multiple pharmacologic effects because of location of receptors
in various organs, e.g. acepromazine, with actions that include
sedation (increased dopamine turnover rate in the brain) ;
antiemetic (depress CTZ); hypotension (alpha-adrenergic
blockade) ;antispasmodic (anticholinergic action in the smooth
muscles of the GIT) ; & hypothermia (interference with the
hypothalamic control of temperature regulation). In the other
hand atropine is a specific drug wherein all its varied effects can
be attributed to its antimuscarinic action.
(9) Desensitization, tachyphylaxis, tolerance & resistance are synonymous
terms used to describe the gradual diminishing of drug effects
when it is given continuously or repeatedly. Mechanisms that
give rise to the phenomena include ;
1- Change in receptors.
2- Loss of receptors.
2
3-Exhaustion of mediators.
4-Increased metabolic degradation.
5-Physiological adaptation.
6-Active extrusion of the drug from cells (mainly
chemotherapeutics).
Tolerance ensues when the condition gets aggravated while resistance is a
term conserved for microorganisms.
Drugs
The word is derived from the Old French drogue which meant herb.
Drugs have been defined as articles intended to be used in the diagnosis, mitigation,
treatment or diagnosis of diseases in humans or other animals; & articles other than
food intended to affect the structure or function of the body.
Nutraceuticals
Are nutritional products which allegedly have some therapeutic value in
addition to their scientifically recognized nutritional contents.
Sources of drugs;
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5- Synthetic compounds.
The classification of drugs
1- Posology is the study of medicine dosage, the effect of the drug &
individual tolerance or susceptibility. Metrology is the study of
weights & measures as applied to preparation & administration of
drugs.
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2- A dose is the quantity of medication to be administered at one time.
Dosage refers to determination & regulation of multiple doses. An
effective dose is that amount of a drug necessary to elicit the desired
therapeutic response in the patient.
Targets for drug action
Protein targets for drug action on mammalian cells can be divided into
4 categories;
1- Receptors.
2- Ion channels.
3- Enzymes.
4- Carrier-molecules.
Other types of protein targets for specific classes of drugs are also
known & include;
5
Receptor, inactivated by binding with antagonist, becomes
unavailable to endogenous mediators & their characteristic
effects are inhibited.
-Dimenhydranate
-Diphenhydramine
- Chlorpheniramine
maleate
H2 Impromidine Ranitidine
Cimetidine
Famotidine
D2 Dopamine Chlorpromazine
Insulin Insulin ?
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2- Ion-channels;
Some ion channels, known as ligand-gated ion channels, are directly linked
to a receptor & opens only when the receptor is occupied by an agonist. Many
other types of ion channels also serve as targets for drug action.
The same type of K-channels occurs in smooth muscle cells, & is targeted
by the new vasodilator cromokalim that selectively opens such channels &
hyperpolarizes the cells.
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Ion channel modulation by drugs is one of the most important
mechanisms by which pharmacologic effects are produced at the cellular level.
3- Enzymes;
III- Pro-drugs; Drugs may require enzymatic degradation to convert them the
inactive pro-drug form to the active drug.
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Inactive Active
Cortisone Hydrocortisone
Predinsone Predinsolone
Active Active
- Heroin Morphine
- Codeine
Propranolol 4 hydroxypropranolol
Active Toxic
Paracetamol N-acetyl-p-benzo-quinone-imine
Halothane Tri-fluoroacetate
Methoxyflurane Fluoride
4- Carrier-molecules;
The transport of ions & small organic molecules across cell membrane
generally requires a carrier protein since the permeating molecules are
often too polar (ie. Insufficiently lipid-soluble) to penetrate lipid
membranes on their own.
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E.g.s include glucose & amino acids transport into cells, ions & organic
molecules by the renal tubules, Na & Ca ions out of cells & the uptake
of neurotransmitter precursors (eg. choline) or the NTs themselves (e.g.
noradrenaline, 5HT, glutamate & peptides) by nerve terminals.
Receptor families;
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A single polypeptide chain of 400-500 residues & 7 trans-
membrane α-helices, extra-cellular amino terminus, intra-
cellular carboxy terminus & a 3rd cytoplasmic loop that couples
to the G-protein.
Usually a particular R subtype couples selectively to a particular
G-protein.
G-proteins has enzymatic activity catalyzing the conversion of
GTP to GDP, the so activated G-protein by the activation of R
then dissociates releasing its active forms (α-GTP & βγ-
subunits) which diffuse in the membrane & can associate with
different enzymes & ion channels causing activation or
inactivation.
A single agonist-R complex can activate several G-protein
molecules.
These associate with effector enzymes & produce many
molecules of 2nd messenger.
Further amplification occurs before the final cellular response
is produced.
2nd messenger targets for G-proteins include;
1- Adenylate cyclase / cAMP system which regulates protein
kinases & enzymes of metabolism, cell division &
differentiation. Many drugs function
by increasing or decreasing the catalytic activity of
adenylate cyclase thereby lowering or raising cAMP within
the cell. M2 receptors of myocardium, α2-
adrenoceptors in smooth muscles & opioid receptors
inhibit ACase.
Forskolin & floride ions directly activate the enzyme.
Phosphodiesterases hydrolyse cAMP within the cells, the
hydrolysis is inhibited by drugs such as methylxanthines
(e.g. theophylline & caffeine). Selective inhibitors of
phosphodiesterases has use in cardiovascular, respiratory
& other conditions e.g. Sildenafil (Viagra).
2- The phospholipase C/ inositol phosphate system; lithium
an agent used in psychiatry blocks the recycling pathway of
PI. Inositol tri-phosphate acts on
specific R coupled to Ca-selective channel in the ER
membrane by releasing a flood of intra-cellular Ca. This
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occur in response to a variety of agonists e.g. in smooth m.
contraction, increased myocardial contraction, secretion
from exocrine glands & NT from neurons.
3- DAG is produced whenever R-induced PI hydorolyses
occurs activating the membrane bound protein kinase C
(13 types) which phosphorelates serine & threonine
residues of various intra-cellular proteins.
4- Regulation of ion channels directly without 2nd messenger
e.g. mAch. R in cardiac muscles enhances K permeability
causing hyper polarization inhibiting electric activity,
opioid analgesics reduce excitability by opening K
channels.
3- Tyrosine kinase & guanylate cyclase linked Rs; membrane Rs that
have intracellular protein kinase domain. Are Rs for hormones e.g.
insulin, when Rs are activated cytosolic kinases are activated
allowing control of many cellular functions e.g. cell growth &
differentiation, gene transcription, & release of inflammatory
mediators. Few hormone Rs e.g. ANF are linked to guanylate
cyclase.
4- Rs that regulate gene transcription; are intracellular proteins.
Ligands include thyroid hrn., vit. D & retinoic acid.
Rs have a conserved DNA-binding site attached to variable ligand-
binding & transcription control domains. DNA-binding domain
recognizes specific base sequences thus promotes or represses
particular genes. Depending on cell type & ligand nature effects are
diverse & are produced by altered protein synthesis i.e. slow.
Receptor malfunction associated with disease
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Inherited mutations of genes encoding G-protein coupled
receptors: e.g. mutated vasopressin & ACTH receptors leading
to resistance to these hormones; mutations in genes encoding
growth factors can result in malignant transformations.
1- (A) The relationship is depicted between the drug dose & the response.
The slope of the log dose-response indicates the range of doses over which the
drug acts, from minimally detectable to maximally effective. The variability in
response can be related to physiologic, pathologic or drug-indused variations
in a patient or to individual variations in a population of patients.
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point at the lowest dose of the drug & with the most-resistant members of the
population requiring the highest doses. At any given dose concentration an
individual patient has either responded to treatment or not. The sensitivity of
a drug is distributed normally with respect to the logarithm of the dose. In
this population, the dose required to produce the end point effect in 50% of
the individuals is known as the median effective dose (ED50). The quantal dose
response relationship can be depicted in on of 2 ways; a cumulative normal
distribution relationship, sigmoid, or a normal probability density function
relationship, bell-shaped.
The slope indicates the range over which the population is affected, the
steeper the slope the narrower the dose range which encompasses the majority
of the population.
Under the ideal & unlikely case that a drug has no undesirable toxic effects
the ED100 (the dose adequate to be effective in all individuals of the
population) can be used effectively in all patients, but for most drugs as the
dose is increased undesirable or toxic effects become increasingly common &
at hi dose may cause death, therefore the greater the gap between the dose
that effective dose & the toxic or lethal dose the safer the drug. The ratio
between the drug dose that produces toxic or lethal effect & that dose which
generates the desired therapeutic response is the therapeutic index & indicates
the selectivity of the drug & its usability.
Considering the low of mass action & assuming that a drug is reversibly binding
its receptors, & that the maximum response is produced when all the
receptors are occupied, then
Drug (c) + free receptors (100-Y) ← k1/k2 →Drug receptor complex (Y) ↔
response.
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At any given drug concentration
k1 + C (100-Y) = k 2 + Y.
Rearranging;
Y/ {C (100-Y)} = k1/ k 2.
The dose that will occupy half of the receptors in the drug-receptor complex
gives a 50% response. This corresponds to a situation wherein Y/ (100-Y) = 1.
& 1/ED50= k. so that the median effective dose is the reciprocal of the affinity
constant of the tissue receptor for the particular drug.
Pharmacokinetics
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Transfer of drugs across membranes;
Most drugs are weak acids or bases present in solution as both ionized
& non-ionized species. The non-ionized species are usually lipid-soluble &
readily diffuse across the membrane to achieve equilibrium on both sides. The
ionized moiety is often virtually excluded from trans-membrane diffusion
because of its low lipid solubility.
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The degree of ionization of an organic electrolyte is dependant on;
B- Carrier-mediated transport;
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1st pass effect; defines the effect of passage of drugs thro the
liver before reaching the systemic circulation.
Factors that modify absorption;
A- Enteral administration;
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drug is protected from 1st pass metabolism by the liver (completely
destroyed).
3. Rectal; useful in patients that are unconscious or vomiting. 50% of the
medication is approximately bio-available. Absorption is incomplete,
irregular & irritation to rectal mucosa is not uncommon.
B- Parenteral injection; is either vascular including i/v & intera-arteriorly, or
extra-vascular including I/m & S/c . Absorption is determined by the area of
the capillary membrane in I/m & S/c thro large aqueous channels in the
endothelial membrane by indiscriminate diffusion of molecules regardless of
lipid-solubility. Larger molecules e.g. proteins, slowly gain access to circulation
by way of lymphatics, parenterally-given drugs are subjected to 1st pass in the
lungs.
1- I/v;
Advantages;
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intentionally e.g. the soluble & insoluble forms of
insulin.
Solid pellets (e.g. hormones) are implanted under the
skin to produce effects over weeks & months.
Disadvantages in certain irritating drugs that may cause
severe pain & necrosis.
3- I/m administration;
6- Intra-peritonial;
Large surface.
Drug absorbed via portal circulation, 1st pass thro the liver.
Lab. procedure.
Infections & adhesions.
C- Pulmonary absorption;
Advantages;
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Poor ability to regulate dose.
Cumbersomeness of methods of administration.
Many drugs & gases irritate pulmonary epithelium.
D- Topical application;
T1/2A;
The time it takes for half of the administered drug to reach the systemic
circulation.
Drugs are conveyed thro-out the body in the circulating blood & reach the
tissues of every organ in an amount determined by blood flow & conc. to the
organ. The conc. attained in the tissues depends on the capacity of the drug
to;
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1. Penetrate capillary endothelium (influenced mainly by plasma-protein
binding).
2. Diffuse across cell membrane.
CNS & CSF;
C- Organic ions are extruded from CSF into blood at choroids plexus by
transport processes similar to those of renal tubules.
Sulfadimethoxine 81 % Thiopentone 75 %
Sulfisoxazole 68 % Sulfadiazine 17 %
Clorpromazine 94 % Chloramphinicol 39 %
Propranolol 97 % Amphetamine 27 %
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Morphine 12 %
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4- The GIT is the major trans-cellular reservoir in the case of
slowly-absorbed oral drugs & particularly those agents
undergoing entero-hepatic circulation.
III- Re-distribution;
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Volume of Distribution;
Vd = Q / Cp
Can be described as the time it takes 50% of the drug in the plasma to
distribute outside the bloodstream.
1st order kinetics i.e. the rate at which the drug is removed from the
compartment is proportional to its conc. in that compartment ,
wherein in zero-order kinetic a constant amount of the drug is
cleared from the compartment regardless of its conc. i.e. saturation
kinetics.
Partitioning depends on blood flow, lipid solubility & protein
binding.
Elimination takes place exclusively from the central compartment.
Absorption takes place exclusively to the central compartment.
3 Compartmental open models;
Drugs that has high affinity for certain tissues by selective binding e.g.
digoxin, pentazocin & diazepam.
Drugs that undergo re-distribution e.g. thiopentone.
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Drug Elimination
Drugs undergo metabolic changes in the body that are directed primarily
towards formation of metabolites that have physico-chemical properties
favorable to their excretion, metabolites are generally less lipid soluble &
more polar in nature rendering them suitable for carrier-mediated excretion
processes & more likely to be partitioned into fluids of the body such as the
blood stream.
PhaseI reactions;
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3. The interaction between this complex & a lipid soluble drug or steroid
substrate yields a hydroxylated substrate, oxidized P-450 & an
equivalent molar fraction of water;
“active oxygen complex” + Drug Oxidized Drug + A + H2O.
27
A drug or, phase I metabolite, containing a suitable functional group is
combined to endogenous substances that include glucouronic acid, glutathione,
glycine, cysteine, methionine, sulfate & acetate.
- Morphine Glucourinidation
- Salicylates
- Acetaminophen
- Chloramphinicol
- Steroid hormones*
- Thyroxin
- Bilirubin
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- Phenol Sulfate conjugation
- Acetaminophen
- Morphine
- Isoproterenol (CA)
- Ascorbic acid
Sulfonamides Acetylation
II- Physiologic;
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2. Inhibition ; competition between 2 or more drugs for the active site of
the same enzyme e.g. cimetidine & the antifungal ketoconazole inhibit
oxidative drug metabolism by forming tight complexes with CP450 , a
metabolite of erythromycin has the same effect.
Drug excretion
I- Glomerular filteration;
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Competition occurs between drugs sharing the transporter e.g.
penicillin & probenecid (ceftiofur)R
III- Diffusion across the renal tubule
pH- determined simple- diffusion of non- ionized spp. into saliva, sweat
& tears, attaining levels parallel to plasma.
The better part of alkaline drugs is partitioned to milk being more
acidic relative to plasma. Non-electrolytes such as ethanol & urea
equiliberate.
Sensitive methods for detection of toxic metals in hair & skin have
forensic significance.
Iatrogenesis
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Side effect
Classification of ADR
1. Lack of efficacy; provided that the drug is given at the proper dose,
route, interval & duration to treat a condition for which efficacy had,
previously, been instituted.
2. Allergy ;
Cannot be anticipated.
Are not dose dependant.
Clinical presentation ranges from mild rash to anaphylaxis.
Mechanism, usually, involves a drug or its metabolite(s)
forming covalent bonds with an endogenous substance
resulting in an antigen.
Cross-reactivity may develop i.e. a subject allergic to a drug
develops similar reactions to drugs belonging to the same
formulation. 100% of humans allergic to penicillin are equally
allergic to other penicillins, 20% react to cephalosporins.
3. Semi-allergy ;
Similar clinical presentation.
Underlying mechanism is not immunologic.
Haematologic reactions similar to autoimmune haemolytic
anaemia e.g. following I/v dimethyl sulfoxide (conc.> 20%).
Cardio-pulmonary reactions e.g. following I/v drugs dissolved
in polyethylene glycol vehicle.
Hyperpyrexia (drug fever) e.g. aspirin (due to uncoupling of
oxidative -phosphorylation).
4. Organ damage ;
Complex mechanisms.
Not related to drug pharmacodynamics.
Aminoglycoside & tetracycline nephro-toxicity is not
explained by the binding of these antibiotics to bacterial
ribosomal subunits & inhibition of protein synthesis.
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Acetaminophen reactive metabolites causing hepatotoxicity
not related to the analgesic antipyretic actions of the drug.
5. Idiosyncratic (individual);
Not described by 1— 4.
Not dose dependant.
Often genetically determined.
Characteristics of ADR;
Adrenaline + Na-bicarbonate.
Gentamycin + Carpenecillin.
Ketamine + Barbiturates.
Methylpredinsolone Na-succinate + Ca-gluconate.
In-vivo; I- Pharmacodynamic interactions;
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II- Pharmacokinetic interactions;
Definitions
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significant if alters therapeutic response or compromises nutritional status
thereby influences health outcomes particularly in vulnerable populations.
1. Multiple medications.
2. Extremes of age.
3. Genetic variants in drug transporters, enzymes or receptors.
4. Impaired organ function.
5. Poor nutritional status defined as altered body composition or function
due to any imbalance between an individual`s nutrient requirements
and intake, where due to poor dietary intake or altered nutrient
disposition.
Historic perspectives
Effect of On
Vitamin C deficiency Barbiturates action
Iron Tetracycline absorption
Isonaizid Vitamin B6 metabolism
Malnutrition Drug disposition
Drugs Nutrient disposition
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Site of interaction Consequence Mechanism
Delivery device or GI- Reduced bioavailability Physicochemical
lumen reaction and
inactivation
GI- mucosa Altered bioavailability Altered transporter
and/ or enzyme
function
Systemic circulation or Altered distribution/ Altered transporter,
tissues effect enzyme function or
other physiologic
function
Organs of excretion Altered clearance Antagonism,
impairment or
modulation of
elemination
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2. Drug effects in PCM
Definitions
Term BMI ≥
2
Overweight 25 kg/ m
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Obesity 30 kg/ m2
Morbid obesity 40 kg/ m2
BMI in combination with waist circumference are closely linked to
health risks of overweight.
BMI- for- age growth curves in children 5- 19 yr defines overweight
between the 85th - 95th percentiles, and obesity as ≥ the 95th percentile.
Non- obese middle aged adults have a fat mass of about 20 kg
corresponding to about 25% of TBW in men and 33% in women.
Obese individuals have a larger lean body mass accounting for 20-
40% of the excess weight, the rest 60- 80% is adipose tissue.
Obese individuals have higher absolute body water.
The term dosing weight refers an actual TBW or an alternative body weight
considered for dosing in volume- overloaded, or obese patient, it is affected by
the following factors:
38
(0.01281)(BMI)(kg)
39
adipose tissue compartments (i.e. omental, S/c) thereby affected by
obesity phenotype.
Hepatic 1st pass extraction is not affected, drugs that undergo
oxidation and conjugation (glucuronide and sulfate) may have
increased clearance in obesity (e.g. lorazepam, oxazepam).
Renal clearance can be increased due to increased GFR (e.g.
aminoglycosides, cefamandole, cefotaxime, ciprofloxacin, lithium,
procainamide), or tubular secretion (e.g. cimitidine, ciprofloxacin,
procainamide), or decreased reabsorption (e.g. lithium).
Taking pharmacokinetic alterations into account, even if a drug is
delivered to loci of action in appropriate concentration the
therapeutic response is other than expected. This occurs due to
alterations in tissue sensitivity at target organ or downstream.
There is increased sensitivity to e.g. (glipizide, glyburide,(atracurium,
verapamil). Receptor expression or affinity may be altered, the drug
effect may be more pronounced including toxicity.
40
4. Caloric load of the meal: as they increase feed-back signals from
intestine delay stomach emptying rate.
5. Meal type.
6. Meal viscosity.
7. Meal effect on GI pH.
8. Meal calcium content as the stomach regulates the rate of Ca delivery
to intestine, and the intestine regulates the stomach delivery of Ca-
chelators through feed-back mechanisms.
9. Drug binding to meal and biliary components.
10. Meal effects on first-pass elimination.
11. Permeability limitations due to intestinal efflux
12. Meal effects on region-dependant absorption.
13. Meal effects on splanchnic blood flow.
Azithromycin ↓absorption
Bisphosphonates ↓absorption specially dairy product
Dextroamphetamine ↓absorption specially acidic food
Digoxin Delayed absorption and peak levels
Diltiazem absorption↑ with fasting
Furosemide absorption↑ with fasting
Glipizide ↑ effect 30 minutes before meal
Levothyroxine absorption↑ with fasting
Metroindazole Food ↓ peak
Phenytoin ↓absorption
Proton pump inhibitors Before meals↑ effect
Quinolones Cations (Ca, Fe, Zn), antacids and
dairy products ↓absorption
Tetracyclines ↓absorption Fe/milk/food
Theophylline ↓absorption
Warfarin ↓absorption
Zafirlukast Food ↓absorption by 40%
Zolpidem Food delay onset of action
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Drugs to be taken with food
42
Anorexic drugs include antihistamines, bethionol, dacarbazine,
epirubicin, etoposide, fluvoxamine, perhhixiline, pimozide,
sibutramine, temozolamide, trazodone, and zonisamide.
Caffeine causes greater thermogensis, lipolysis, fat oxidation and
insulin secretion in obese individuals.
Alcohol and nicotine intake are associated with weight loss.
3. Drug- associated alteration of GI function
Altered taste perception.
Drug- induced emesis.
Drug- induced motility changes↕
4. Drug- induced metabolic effects
Hyo- or hyperglycaemia.
Lipid changes.
Protein changes.
5. Drug- induced nutrient depletion
Mineral/ electrolyte disturbances.
Vitamin deficiencies.
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5- Progesterone-mediated liver Elimination
induction
1. Dose.
2. Frequency of dosing.
3. Vd.
4. PPb.
5. Clearance.
6. Placental blood flow.
7. Rate of diffusion across the plancenta ; determined by
the following ;
Conc. differences between maternal & foetal
circulation.
Surface area for diffusion.
Lipid solubility.
pH ; maternal fluids are relatively slightly more
alkaline than foetal fluids , basic drugs e.g.
atropine, adrenaline, propranolol, quinidine,
erythromycin & trimethoprim tend to
concentrate in fetal plasma & acidic drugs e.g.
penicillin, aspirin, furosemide & phenobarbitone
diffuse slowly across the placenta.
Potential effects due to foetal exposure to drugs
1. Teratogenic effects.
2. Failure of implantation & early termination of pregnancy.
3. Mutagenesis & growth retardation.
4. Later in pregnancy the foetus may show manifestations of the
pharmacodynamics of the drug.
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1- Immature percutaneous barrier ↑ Percutaneous absorption
-irregular peristalsis
45
1) Increased gastric pH Alteration of ionization
46
1. Diminished clearance.
2. Diminished hepatic biotransformation & plasma protein binding due
to uremia.
3. Drugs requiring renal elimination & nephro-toxic drugs are contra-
indicated e.g. aminoglycosides.
Prescription order writing
47
should keep a copy for the files, this protects the physician & serves to
complete the record of treatment.
1. Date.
Address of patient.
3. Rx
7. Do not refill.
8. Signature.
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Rx is abbreviation for recipe the Latin for “Take thou”.
(4) drug, strength & inert additives, (5) directions to the pharmacist, (6)
directions to the patient, (7) refill informations.
1. The physician, & or pharmacist, should demonstrate how the drug is
used.
2. Expressions such as “Take as desired” or “Take as
necessary” or “Take every 8hrs” should be avoided (i.e.
specify).
3. To avoid possible error, the 1st word of the directions to the pt. should
serve as a reminder of the correct route of administration; Take for
internal use; Apply for ointment or lotion; Insert for
suppositories; & Place for drops of the conjunctival sac, external
auditory canal or nostril.
4. The directions to the pt should also include a reminder of the
intended purpose of the prescription e.g. “for relief of pain”,
“for relief of headache” or “to relief itching”.
5. If it is desirable to administer a drug in a larger amount than is
customarily employed, underline the dose or write ”Correct
amount” or “Correct dose” with your initials at the side.
6. Indicate the No. of refills on each original prescription order,
irrespective of whether the substance is controlled or not.
7. Dosage should include the no. of days for which medication is
contemplated, no. of doses per day & size of each dose.
8. The max. limit is indicated for most prescriptions depending on
stability & cost of the drug & the possible necessity for alternation of
the ttt.
9. If the pt is depressed or potentially suicidal do not prescribe total
amounts of drug that would prove lethal if taken all at one time.
10. Storage of unused portions of a prescription & sharing of prescriptions
with others should be discussed with any pt who receives an important
medication.
11. Usual dose is intended to serve only as a guide to the physician who
very frequently must give more or less than what is usual in order to
optimize therapy.
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Abbreviations commonly used in prescribing
aa ana Of each
A ante Before
C cum With
H hora Hour
M. misce Mix
50
q.i.d.(QID) quarter in die 4 times a day
Chapter 2
51
2) Inactivation in the liver & kidney by histaminase &
imidazole-N-methyl transferase.
3) Acetylation of histamine occurs in the GIT lumen & tissues
after absorption.
Release;
52
1- Salivation.
2- Vomiting.
3- Colic.
4- Diarrhea.
5- Rapid weak pulse.
Clinical use;
Clinical use
53
Metiamide, H2 antagonist, agranulocytosis.
Cimetidine, ranitidine, famotidine & nizatidine, H2 antagonists in
common use.
Clinical use
Side effects
De-activation
54
3) Fluoxetine blocks reuptake of released serotinine; antidepressant,
anxiolytic, psychomotor stimulant & appetite depressant.
4) Buspirone; anxiolytic.
Antagonists
Kinins
55
Actions
Its actions are similar to bradykinins but more rapid onset. It maintains
peristalsis. Has a neurotransmitter action in CNS.
Prostaglandins
56
4- Inhibit gastric acid secretion due to histamine.
5- Reproduction; PGF2α stimulates sperm transport in female genital
tract; regulates cycle by producing leutolysin; diffuses from uterus to
uterine artery, vein, ovarian artery, ovary & corpus leutium causing
leutolysis; increases uterine contractility at term wherein relaxin causes
relaxations; contracts the amblical vein & causes vasoconstriction
postpartum.
Clinical use
1) The leutolytic action of PGs e.g. the synthetic PGF2α, cleprestenol, can
be used to induce abortion & institute a new cycle.
2) Treatment of pyometra.
Contra-indications
Adenosine
Belong to the group of fatty acids produced in the lungs during anaphylaxis
associated with leukotrienes.
Vassopressin (ADH)
57
A hypothalamic polypeptide transported & stored in the posterior pituitary
bound to the neurophysins. It is released due to electrical discharge, Ach,
dehydration, haemorrhage, emotional or physical stress & alcohol.
Actions
58
(methysergide) - Rapid onset.
(methylergomethrine) - Effective
orally.
2) Oxytocin
Actions;
59
Chapter 3
Drugs affecting the cardiovascular system
Treatment of hypertesnsion
Decreases the risk of stroke, coronary events, heart failure and renal
impairment.
Aetiology of hypertension, risk factors and the presence of
complications such as left ventricular hypertrophy should be
established.
Advice on lifestyle changes should be given.
Drug strategy
Since
o BP = CO X TPR
o CO (cardiac output) = HR x SV
o R (resistance) α VL /r4. Wherein V is the blood viscosity, L is the
length and r is the radius of the vessel.
o ↓ TPR
o ↓ CO
o ↓ Body fluid volume
o Reflex tachycardia (with the risk of precipitating angina or MI) not seen
with sympatholytic drugs which would rather cause orthostatic
hypotension.
o Oedema due to renin release.
60
STAGE 140/ 90 135/ 85 o Treat pt under 80 who have target
1 organ damage, cardiovascular
disease or 10 year risk > 20% of
CV disease, renal disease, or DM.
o In the absence of these conditions
advise lifestyle changes.
o In the absence of these conditions,
in pt under 40, specialist advice for
2ndary causes of HTN is needed.
STAGE 160/ 100 150/ 95 Treat all pts regardless of age.
2
SEVERE Systolic ≥ Treat promptly as HTN crises.
180 or
Diastolic ≥
110
TARGETS
SPECIAL PATIENTS
61
HTN.
DM o Clinic 140/ 80 o HTN more common with
o 130/ 80 in renal, type 2.
eye, or o In type 1 HTN indicates
cerebrovascular co- presence of DM
morbidity nephropathy
o Require combination
therapy
o ACE-inhibitors or
receptor blockers are
useful in diabetic
nephropathy and delay
micro –albuminuria in
type 2 DM .
RENAL o Clinic 140/ 90 o ACE-inhibitors or
DISEASE o 130/ 80 in chronic receptor blockers.
renal disease, DM, o ACE-inhibitors caution
or proteinuria ≥ 1 with renal impairment.
gm/ 24 hrs. o Thiazides are ineffective.
o High dose loop diuretics
is required.
PREGNANCY o Uncomplicated o Labetalol, methyldopa, or
chronic HTN 150/ modified- release
100. nifedipine are commonly
o Chronic with target used.
organ damage o Aspirin 75 mg OD is
multiparas 140/ 90. advised in risk of pre-
o Pre-eclampsia, or eclampsia.
BP ≥ 160/ 110, or o Hi risk of developing
who require special pre-eclampsia is
care 150/ 80~ 100. associated with chronic
kidney disease, DM,
autoimmune disease and
chronic HTN.
o MgSO4 is used in pre-
eclampsia and eclampsia.
o 2 days postpartum
previous therapy is re-
62
instituted.
HTN CRISES o Too rapid o A HYPERTENSIVE
reduction of BP EMERGENCY is severe
precipitates the risk HTN with damage to the
of reduced organ target organs with signs of
perfusion leading to papilloedma or retinal
cerebral infarction, haemorrhage, or acute
blindness, coronary syndrome, acute
deterioration of aortic dissection, acute
renal function, or pulmonary oedema,
myocardial encephalopathy, cerebral
ischaemia. infarction or
o Few minutes~ 2 hrs haemorrhage, eclampsia
BP should be or renal failure.
reduced 20~ 25%. o I/V therapy of Na
o In HTN urgency BP nitroprusside, labetalol,
is reduced gradually glyceryl trinitrate,
over 24~ 48 hrs. phentolamine,
hydralazine, or esmolol as
need be.
o HYPERTENSIVE
URGENCY is severe
HTN BP ≥ 180/ 110
without acute target
organ damage.
o Oral labetalol, Ca-
channel blockers,
amlodipine, felodipine,
or isradipine.
o Sublingual nefidipine is
not recommended.
VASODILATORS
63
3. Drugs acting to open K channels
4. Calcium channel blockers
5. Nitrates
DIURETICS
SYMPATHOLYTICS
1. α- adrenoceptor antagonists
2. β- adrenoceptor antagonists
3. Combined α and β adrenoceptor antagonists
4. Ganglionic blockers
5. Adrenergic neuron blockers
64
Drugs interfering with storage vesicles
Guanethidine
β blockers:
65
Fatigue when they cross BBB.
Sexual dysfunction and ↓ libido by eliminating the role of
catecholamines in arousal.
Increased LDL and TG by inhibiting lipolysis, does not
cause overt clinical disease but in a patient with
dyslipidaemia α blockers is a better choice.
o Cautions include:
Asthma
Vasospastic disorders
DM (mask hypoglycaemic events such as palpitations)
Hydralazine
Nitroprusside
66
o Opening K channels they cause hyperpolarization of smooth muscles
resulting in arteriolar dilation.
o Diazoxide is used in hypertensive emergencies.
o Minoxidil is used in severe hypertension and as topical application in
baldness.
o Side effects:
Minoxidil causes hypertrichosis.
Diazoxide causes hyperglycaemia by interfering with insulin
release by hyperpolarizing the beta pancreatic cells, it has been
tried for ttt of insulinomas.
Both drugs cause oedema and reflex tachycardia.
[ACE-inhibitors]: Captopril
67
o Prevent degradation of bradykinin
Contraindication: pregnancy.
Bosentan
68
o Endothelin ET-1 is a vasoconstrictor more potent than angiotensin- II,
it is targeted by bosentan which is an endothelin ETA receptor
antagonist.
o Administered orally.
Epoprostenol
Sildenafil
Quinidine
69
o Muscarinic receptor blockade
o Alpha block ( possible reflex tachycardia)
o Wide clinical use in many arrhythmias; in atrial fibrillation, need initial
digitalization (to slow AV conduction)
o Side effects include Cinchonism (tinnitus, ocular dysfunction, CNS
excitation, GI), hypotension, prolongation of QRS and QT interval
(torsades)
o Drug interactions includes: hyperkalaemia inhances effects and vice
versa, displaces digoxin from tissue binding sites.
Procainamide
Disopyramide
Lidocaine
o Post MI
o Open cardiac surgery
o Digitalis toxicity
o Side effects include seizures due to CNS excitation, but less cardiotoxic
effects relative to conventional anti-arrhythmics.
o I.V. use only (due to first pass metabolism).
70
o Same as lidocaine
o Oral formulations.
Flecainide
o ↓ I K slowing phase 3.
o ↑ APD and ERP
Amiodarone
71
Side effects (are due to iodination of tissues)
o Pulmonary fibrosis.
o Blue pigmentation of the skin.
o Phototoxicity.
o Corneal deposits.
o Hepatic necrosis (rare).
o Thyroid dysfunction (5% of patients↑or ↓).
Sotalol
o ↓ I K slowing phase 3.
o β1 blockade leading to ↓ HR and AV conduction.
o Used in life- threatening ventricular arrhythmias.
Unclassified
Adonesine
72
o The drug of choice in supraventricular tachycardias and AV nodal
arrhythmias.
o Side effects include flushing, sedation and profound dyspnea `elephant
sitting on chest`.
o Antagonized by methylxanthines theophylline and caffeine which are
used in COPD but cause ventricular tachycardia.
Magnesium
Heart Failure
Pathophysiology:
o ↓ Preload
73
o ↓ Afterload
o ↑ Contractility
o ↓ Heart remodeling
ACEIs, ARBs, carvedilol, and spironolactone are used in CHF.
Inotropes are more beneficial in acute CHF.
Dobutamine
I/ C phosphodiesterase inhibitors.
Generate effects similar to dubtamine without using the β1 system
enabling their use beyond acute management of CHF.
Digoxin
74
Digoxin competes with K for the binding site and sits in the K influx
site blocking the ATPase pump and thereby the 2ndary active transport
pump.
↑ cellular Na → depolarization → muscle contraction.
↑ ↑ cellular Ca →↑ muscle contractility → + ve inotropy.
2. Indirect effect: Inhibition of neuronal ATPase → neuronal
depolarization + ↑ Ca level → the following
PANS ↑ vagal tone → ↓ HR + ↑ dystolic filling time i.e. –ve
chronotropic + +ve inotropic effects.
↑ sympathetic activity → ↑ contractility i.e. +ve inotropic effect.
Pharmacokinetics:
Uses:
CHF.
Supraventricular tachycardia.
Side effects:
Management of toxicity:
Interactions:
75
Quinidine and verapamil [displacement from tissues].
Proarrhythmics such as sympathomimetics.
Other drugs:
Diuretics:
Nesiritide
Pharmacology
Nitrates
76
o Nitroglycerine is broken down to NO with the requirement of cysteine
[a critical GSH amino acid] which limits the use of nitroglycerine on a
chronic basis. I.V., sublingual or transdermal patches.
o Nitroprusside is used as an I.V. drug of choice in hypertensive
emergencies, the potential of cyanide poisoning limits its use for 24
~36 hrs and decreased by the prior administration of nitrites and the
co-administration of thiosulfate.
o Isosorbide is prescribed for oral chronic use [extended release
formulations].
Side effects:
Contraindications:
Ca Channel Blockers
77
Beta Blockers
Carvedilol
o Unstable angina
o Non- ST- segment elevation myocardial infarction [NSTEMI].
o ST- segment elevation myocardial infarction [STEMI].
78
Rupture of atheromatous plaque characterized by:
Initial Management:
79
6. Clopidogril for 12 months.
STEMI
1. Aspirin 75 mg OD.
2. Clopidogril for 12 months.
3. Warfarin for those at low risk of beeding or intolerant to
Clopidogril.
4. β blockers: should be continued forever if not otherwise
contraindicated.
5. Diltiazem or verapamil if β blockers are inappropriate.
6. ACEIs.
7. Nitrates.
8. Eplerenone.
9. Statins.
80
Indications for ICD placement
Secondary prophylaxis
Primary prophylaxis
Pacemaker indications
81
Symptomatic sinus bradycardia
Tachycardia-bradycardia syndrome
Atrial fibrillation with sinus node dysfunction
Complete atrioventricular block (third-degree block)
Chronotropic incompetence (inability to increase the heart rate
to match a level of exercise)
Prolonged QT syndrome
Cardiac resynchronization therapy with biventricular pacing
2. Relative indications:
Magnet Inhibition
82
ICD complications and malfunctions
Pain
Bleeding
Pneumothorax
Hemothorax
Cardiac perforation with or without pericardial effusion
and tamponade.
Pulseless electrical activity following intraoperative
defibrillation threshold testing
Pain
Infection
Pocket hematoma
Wound dehiscence
Lead dislodgment
Deep venous thrombosis
Upper extremity edema
Degradation of lead function
Device-related pain
Lead fracture
Inappropriate shocks
Erosion of device through skin
Immunologic rejection – Rare
Pneumothorax
Pericarditis
Infection
Skin erosion
Hematoma
83
Lead dislodgment
Venous thrombosis
Failure to output
Failure to capture
Failure to sense
Pacemaker-mediated tachycardia
Runaway pacemaker
Pacemaker syndrome
Twiddler's syndrome
Cardiac monitor pseudomalfunction
Pacemaker pseudomalfunction
Inpatient Care
84
Chapter 4
Erectile disorders
Priapism
Erectile dysfunction
85
Is failure to produce satisfactory erection possibly due to psychogenic,
vascular, neurogenic or endocrine abnormality. Drug induced impotence is
not uncommon.
Alprostadil (PGE1)
1. Intracavernosal injection.
2. Urethral application wherein a barrier contraceptive should be used if
the partner is pregnant.
Contraindications
Side effects
Indications
1. Erectile dysfunction.
2. Sildenafil and Tadalafil are also indicated in pulmonary hypertension.
86
Cautions
Contraindications
Side effects
87
osmotic diuretics) inhibit specific enzymes ,transporter proteins
,hormone receptors or ion channels that function (directly or
indirectly) in renal Na re- absorption.
3. Diuretics also alter elimination of other ions to varying degrees
eg.K,H,Ca,Mg,Cl,HCo3 and phosphates.
4. The most common indication for diuretic use is mobilization of tissue
oedema.
1-Inhibitors of carbonic-anhydrase
Mechanism of action
88
3) 2% ophthalmic solution of dorozolamide is used in the treatment of
glaucoma-associated increased intraocular pressure without
cardiovascular or pulmonary side effects (bitter metal-like taste).
4) Adjunctive therapy for epilepsy and mountain sickness.
5) Limited diuretic use due to rapid development of tolerance.
2- Osmotic diuretics
89
3) Rapid expansion of plasma volume that may precipitate CHF or
pulmonary oedema.
4) Dehydration and electrolyte disturbances (hypertonic dehydration
developing although plasma volume is restored, body wt and
urinary output are monitored).
Contraindications
Therapeutic use
Mechanism of action
90
1) Hyponatremia, reduced blood pressure and organ perfusion (risk
to patients with renal, cardiac or hepatic disease).
2) Hypokalaemia.
3) Mg and Ca deficiency.
4) Ototoxicity (1arely ethacrynic acid).
5) Bone marrow depression.
6) Hyperglycaemia related to impairment of conversion of pro-
insulin to insulin due to decreased K level.
7) Sulfonamide toxicity (1arely hypersensitivity).
Contra-indications:
Drug interactions
Mechanism of action;
91
4) Peak diuresis is moderate compared to loop-diuretics, however,
they likewise enhance K excretion by increasing Na delivery to the
distal tubule.
Pharmacokinetics
1) K-wasting.
2) Fluid and electrolyte disturbances.
3) Hyperglycaemia.
4) Hypercalcaemia.
5) Hyponatraemia and hypochloraemia.
6) Sulfonamide hypersensitivity.
7) Patients with severe renal disease, hypovolaemia and impaired
hepatic function are at risk.
8) Diabetic patients are at risk (derangements of glucose).
Drug interactions;
92
1) A mild increase of NaCl excretion and K retention, slightly augment
diuresis.
2) Used with loop or thiazide diuretics to decrease K excretion.
3) Triamterene exert effects that prolong cardiac action potential
duration.
Adverse effects
1) Hyperkalaemia.
2) Renal dysfunction and stones.
3) Rash and photosensitivity.
4) Use in patients with hepatic or renal disease is contra-indicated.
Therapeutic use
Mechanism of action
93
5) Peak diuresis 2~ 3 days after initiation of therapy.
Adverse effects
1)
Hyperkalaemia.
2)
Hyponatraemia and dehydration.
3)
Hyperchloraemic acidosis.
4)
Sexual impotence related to binding to progesterone and
dihydrotestosterone receptors.
Therapeutic indications
1) Hyperaldosteronism.
2) Oedema.
3) K wasting.
Chapter 5
Antianaemic drugs
1- Iron
94
Treatment, or prevention, of iron deficiency anaemia in premature
infants, children, pregnant & lactating women, gastrectomy, severe
small bowl disease (mal-absorption), adults with blood loss,
menstruating women & GIT bleeding.
Although oral administration predominates, parenteral iron therapy is
used in patients unable to tolerate or absorb, or cannot be maintained
on oral iron.
Adverse effects;
Pharmacokinetics
95
Use
Pharmacokinetics
1) Pregnancy.
2) Haemolytic anaemia.
3) Mal-absorption syndrome.
4) Renal dialysis.
5) Use of certain drugs that interfere with folate absorption e.g.
phenytoin, oral contraceptives & trimethoprim.
4-Erythropoietin
96
1) Is produced in the kidney in response to tissue hypoxia.
2) Stimulates erythroid proliferation & differentiation by interaction
with specific erythropoietin receptors on red cell progenitors.
3) Induce the release of reticulocytes from BM.
Use
I Fibrinogen
II Prothrombin
III Thromboplastin
IV Ca
V Proaccelerin
VI ------------------
VII Proconvertin
IIX Antihaemophelic factor
IX Thromboplastin (Christmas )
X Stuart Prower
XI antecedent
XII Hageman factor
XIII Fibrin-stabilizing factor.
Anti-coagulent agents
1-Heparin
97
Pharmacodynamics
Use
1- Hypersensitivity.
2- Active bleeding.
3- Haemophilia.
4- Thrombocytopenia.
5- Purpura haemorragica.
6- Severe hypertension.
7- Brain haemorrage & surgery.
98
8- Endocarditis.
9- Active TB.
10- Ulcers.
11- Potential abortion.
12- Visceral carcinoma.
13- Advanced hepatic or renal disease.
Antidotal therapy
Pharmacodynamics
99
Anti-platelets agents
ASA (AspirinR)
Alters the balance between prostanoids which promote and those inhibit
platelets aggregation. It irreversibly inhibits COX by acetylating its active
enzymic site → ↓ platelets thromboxane A2 synthesis and ↓ endothelial
prostacyclin synthesis. Endothelium can synthesize new enzyme, platelets
cannot. Replacement of affected cohort of platelets takes 7~ 10 days.
Inhibition of endothelial COX requires higher doses of aspirin. Low dose
aspirin ↓ thromboxane A2 without drastically ↓ prostacyclin synthesis.
Aspirin ↓incidence of postoperative venous thrombosis in men and ↓fatal
pulmonary embolism in both sexes.
Clopidogrel
Dipyridamole
100
Side effects include GI effects, headache, myalgia, hypotension and
worsening symptoms of coronary disease.
Abciximab
Epoprostenol (prostacyclin)
FIBRINOLYTIC DRUGS
Streptokinase
101
Acts indirectly by forming stable complex with plasminogen which
gains enzymic activity due to a conformation change.
Antigenic, actions may be reduced by anti-streptococcal Abs if already
present.
Urokinase
Alteplase
Indications
Side effects
102
Nausea, vomiting and bleeding usually limited to the site of injection
but cerebral or other site bleeding is not uncommon.
In MI reperfusion arrhythmia and recurrent ischaemia and angina may
occur. Reperfusion may cause cerebral and pulmonary oedema.
Hypotension.
Convulsions.
Further embolism due to detached micro-emboli.
Contra-indications
Potential Haemorrhage.
Hx of CVI.
Use of streptokinase within 4 days of streptokinase or alteplase due to
prolonged persistence of Abs.
Cinical aspects
Venous thrombo-embolism
103
o Heparin is used for short- term effect followed by oral anticoagulants for
prolonged therapy.
o S/C 6- hourly heparin is effective in the prevention of DVT. Larger
doses for a week are required if the DVT has already occurred, followed
by oral therapy for 3 months in a localized thrombus, extended to 6
months if there has been embolism to the lungs.
o Fibrinolytic therapy sometimes may be used followed by
anticoagulation to prevent recurrence.
Arterial thrombo-embolism
DIC
ANTIFIBRINOLYTIC DRUGS
Analogue of lysine.
Inhibits streptokinase & urokinase and also prevents the formation of
plasmin by plasminogen activator.
Well absorbed orally and by injection.
Use for bleeding not associated with fibrinolytic therapy is not
uncommon.
Aprotinin (TransylolR)
104
A biologic kallikrein or protease enzyme inhibitor.
Tranexamic acid
Desmopressin
Etamsylate
Pharmacokinetics
105
o Neutral sterols are lost in faeces as cholesterol is
removed from tissues.
Uses
1- Hypercholesterolaemia (LDL).
2- Nephrosis.
3- Lipaemia (triglycerides).
4- Hyperlipoprotienaemia.
Adverse effects;
1- Cutaneous vasodilatation.
2- Warmth.
3- A mild allergic reaction.
Pharmacokinetics
o Potentiate lipoprotein-lipase;
o Lipolysis of lipoproteins & triglycerides;
o Decrease intracellular lipolysis of lipoproteins;
o Decrease plasma VLDL;
o Moderately increase HDL-cholesterol 2ndary to
decreasing plasma triglycerides.
Use
o Skin reactions.
106
o GIT symptoms & myopathy.
o Hypokalaemia & high level of GOT, GPT, & ALP.
3- Resins
1- Treatment of hypercholesterolaemia.
2- Relief of pruritis in cholestasis & bile salt accumulation (ecterus).
3- Removal of digitalis from GIT by binding the glycoside in overdose
toxicities.
Adverse effects
Pharmacokinetics
107
o Induce LDL receptors & increase hepatic catabolism of
LDL & VLDL.
o Decrease de novo cholesterologenesis.
Adverse effects
Antimalarial Drugs
1. Falciparum malaria
Quinine
108
o Children tolerate quinine ttt well. Oral dose is 10mg/kg TID for 7
days, I.V. infusion dose is calculated as for adults.
o Falciparum malaria is particularly dangerous during pregnancy
especially in the 3rd trimester. Quinine adult doses including the
loading dose can be given safely during pregnancy.
Malarone
Riamet
Artesunate
109
2. Benign malarias are caused by P. vivax and less commonly P. ovale and P.
malariae.
Chloroquine
o DOC.
o Primaquine is given after chloroquine course in P.vivax and P. ovale to
destroy parasites in liver and prevent relapse. This radical cure should
be postponed in pregnant ladies until pregnancy is over.
Contra-indications
Side effects
Chapter 6
ENDOCRINE PHARMACOLOGY
110
Insulin
Therapeutic indications
Therapeutic goals
1. To alleviate symptoms.
2. To avoid complications of therapy mainly hypoglycemia.
3. To maintain a normoglycemic status of 4- 9 mmol/l for most of the
time (4- 7 mmol/l before meals and less than 9 mmol/l postprandially)
or glycosylated hemoglobin (HbA1C) concentration of 6.5- 7.5%
(reference range 4- 6%).
4. To prevent complications of the disease.
Pharmacokinetics
111
4. Although S/C absorption is slow and fairly regular, absorption from a
limb site may be increased if the limb is used in strenuous exercise after
the injection.
5. I/V infusion peri-operational, and during diabetic emergencies via a
syringe pump. If a syringe pump is not available soluble insulin 16
units/l is added to the I/V infusion of glucose 5 or 10% containing K.
The infusion is run at a rate appropriate to the patient fluid
requirements, depending on the volume of depletion, cardiac function,
age and other factors.
6. The duration of action of I/V insulin is only a few minutes. The
infusion should be stopped for 30 minutes is the patient becomes
overtly hypoglycemic (≤ 3mmol/l).
7. K levels should be regularly monitored with other plasma electrolytes.
8. NaCl 9% should replace 5% glucose if high blood glucose level persists
(≥ 15mmol/l).
Side effects
1. Hypoglycemia.
2. All insulin preparations including porcine, bovine and recombinant
insulin are immunogenic, immunological resistance to insulin actions
is not uncommon. Preparations of human sequence insulin, by
enzymatic modification of porcine insulin, should theoretically be less
immunogenic, but no evidence supports this in the clinical trials.
3. Fat hypertrophy at recurrent site of injection. Can be minimized by
using different injection sites in rotation.
4. Local allergic reactions (rare).
5. Weight gain.
6. Large babies that might develop postpartum hypoglycemia.
Insulin preparations
112
e.g. Hypurin® purified DKA (30- 60min). adminstration.
porcine or Surgery Peak 2-
bovine 4hrs.
Duration
8hrs.
Soluble(Neutral) Human- DM Rapid onset Not indicated
e.g. Humulin® sequence DKA (30- 60min). for use in S/C
®
Insuman modified Surgery Peak 2- infusion.
porcine 4hrs.
Duration
8hrs
Aspart Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration. events.
analogue
Glulisine Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration events.
analogue
Lispro Recombinant DM Faster onset. Less
human Shorter hypoglycemic
insulin duration events.
analogue
113
e.g. Lantus® human Delayed be mixed
insulin onset 1- 2 with soluble
analogue hrs. insulin in
Peak 4- the same
12hrs. syringe.
Duration 16- OD or BID
35hrs. with soluble
insulin.
Insulin zinc Human- DM Long- acting.
suspension sequence or Delayed
(Mixed) porcine onset 1- 2
e.g. and/or hrs.
Hypurin® bovine Peak 4-
Bovine Lente insulin 12hrs.
complexed Duration 16-
with a 35hrs.
suitable zinc
salt
Isophane Porcine or DM Intermediate-
insulin bovine acting
(Isophane insulin or
protamine Human-
insulin sequence
injection) suspension
complexed
with a
suitable
protamine
Protamine Soluble DM Long- acting. Blunts the
Zinc Insulin insulin initial effect
complexed of soluble
with insulins.
protamine
and zinc
chloride
3. Biphasic insulins
114
Insulin Preparation Use Duration
Biphasic 25% insulin DM Intermediate-
insulin Lispro Lispro , 75% acting
e.g. insulin
Humalog®Mix Lispro
protamine
Biphasic 30% Insulin DM Intermediate-
insulin Aspart Aspart, 70% acting
e.g. Novomix® Insulin
Aspart
protamine
Biphasic Porcine or DM Intermediate-
Isophane human acting
insulin insulin
®
e.g. Mixtard complexed
with
protamine
sulphate in a
solution of
insulin of the
same species.
Sulphonylureas
Mechanism of action
Therapeutic indications
115
1. Type 2 DM after the patient fails to respond to a 3 month restriction of
carbohydrate and energy intake and increased exercise.
2. Type 2 DM in patients who are not overweight and did not respond to
or tolerate Metformin.
Contra- indications
Side effects
1. Hypoglycemia.
2. GIT disturbances.
3. Chlorpropamide due to prolonged duration causes hypoglycemia more
frequently and face flushing so no longer recommended.
4. Occasional alteration of liver function and cholestatic jaundice.
5. Initial allergic reactions which may proceed to erythema multiform and
exfoliative dermatitis or photosensitivity.
6. Blood disorders including pancytopenia.
Biguanides
Metformin (GlucophageR)
Mechanism of action
Therapeutic indications
1. Type 2 DM, the drug of choice in obese patients not controlled by diet
restriction alone.
116
2. Combined with sulphonylureas in patients not controlled by
sulphonylureas alone.
3. Increased insulin sensitivity aids in weight reduction.
4. Symptomatic management in polycystic ovary syndrome.
5. Normalization of menstrual cycle by increasing the rate of spontaneous
ovulation.
6. Improves hirsutism.
Contra- indications
Side effects
Acarbose (GlucobayR)
Mechanism of action
Therapeutic indications
1. Type 2 DM, reserved for use in patients when other oral hypoglycemic
drugs are contraindicated or are not tolerated.
2. Postprandial hyperglycemia in type 1 DM.
Contra- indications
117
1. IBD, predisposition to partial intestinal obstruction, hernia, previous
abdominal surgery.
2. Hepatic or renal impairment.
3. Pregnancy and breast- feeding.
Side effects
Mechanism of action
Therapeutic indications
Contra- indications
1. DKA.
2. Hepatic impairment.
3. Pregnancy and breast- feeding.
Side effects
1. Hypoglycemia.
2. GIT disturbances associated with flatulence and diarrhoea.
3. Allergy.
Thiazolidinediones
118
Pioglitazone and Rosiglitazone
Mechanism of action
Therapeutic indications
Contra- indications
1. Cardiovascular disease.
2. Hepatic impairment.
3. Pregnancy and breast- feeding.
Side effects
1. GIT disturbances.
2. Weight gain and oedema.
3. Headache dizziness, vertigo and visual disturbances.
4. Arthralgia and hypoaesthesia.
5. Insomnia and sweating.
Thyroid hormones
119
goiter. o IV injection is the TFC
3. Hashimoto`s in hypothyroid coma.
thyroiditis. o Adjunct. T. include
4. Thyroid carcinoma. fluids, hydrocortisone,
5. Neonatal congenital anti- infection and
hypothyroidism. assisted ventilation.
6. Juvenile myxoedema.
Potency 1 4
(25 microgms are equivalent
to 100 microgms of
levothyroxine).
Onset of Slow but sustained suitable Rapid in a few hrs and
action & for maintenance therapy. disappear within 24- 48 hrs.
T1/2E
Pregnanc o Crosses placenta. o Does not cross
y& o Hi- doses detrimental placenta.
lactation to foetus. o Too small amounts to
o Too small amounts to affect tests for neonatal
affect tests for neonatal hypothyroidism.
hypothyroidism.
Side Mimic symptoms of Mimic symptoms of
effects hyperthyroidism hyperthyroidism
Antithyroid drugs
Carbimazole
Mechanism of action
Indications
1. Hyperthyroidism.
2. Preparation of thyroidectomy patients for surgery.
Contra- indications
120
2. Pregnancy, risk of afflicting neonatal goiter and hypothyroidism and
congenital defects including aplasia cutis.
3. Breast- feeding, may affect neonatal thyroid function.
Side effects
Propylthiouracil
Mechanism of action
Indications
1. Hyperthyroidism.
2. Reserved for patients who are intolerant of carbimazole or who
experience sensitivity reaction and other treatments are not
appropriate.
Iodine
Indications
121
2. Radioactive Na- iodide (131I) is indicated for thyrotoxicosis in all ages, in
patients with heart disease and in those who relapse after
thyroidectomy.
Contra- indication
Indications
1. Thyrotoxic symptoms.
2. Adjunct to antithyroid drugs and iodine.
3. Neonatal thyrotoxicosis.
4. Supraventricular arrhythmias due to hyperthyroidism.
1. Emergency IV fluids.
2. Propranolol.
3. Hydrocortisone Na- succinate.
4. Oral iodine solution with carbimazole or propylthiouracil by NG- tube.
Corticosteroids
122
forms of steroids, with a hydroxylgroup at position-3 and a skeleton
derived from cholestane
ž Beclomethasone
ž Betamethasone
ž Cortisone
ž Hydrocortisone
ž Prednisone
ž Prednisolone
123
ž Methylprednisolone
ž Dexamethasone
Prednisolone:
124
release of inflammatory lysozyme and decreases capillary permeability
which prevents loss of plasma proteins to tissues, it also interferes with
complement pathway activation and formation of chemical mediators
derived from arachidonic acid such as leukotrienes.
5- Steroids in hyper reactive airway: their anti-inflammatory action leads
to decreased mucosal edema and prevents release of broncho-
constricter substances. They have permissive role for bronchodilator
medication, that is, they enhance the efficacy of bronchodilators so
used in asthma.
6- In post- operative nausea and vomiting )PONV): The antiemetic
mechanism of corticosteroids is unknown. Dexamethasone a
corticosteroid with strong anti-inflammatory effects provides
postoperative analgesia & prevents nausea and vomiting in patients
undergoing chemotherapy and reduces postoperative nausea and
vomiting.
7- Post intubation laryngeal oedema: Prevent post-operative laryngeal
oedema by their anti-inflammatory action e.g. dexamethasone.
8- Sepsis: Patients having severe sepsis or in septic shock were found to
have unrecognised adrenal insufficiency.
9- Anaphylaxis: Corticosteroids can decrease the swelling & prevent the
recurrence of symptoms. Hydrocortisone is the preferred steroid
because of its fast onset of action.
10- In cerebral oedema: Steroids are of value in reduction or prevention of
cerebral oedema associated with parasitic infection or neoplasms.
11- In ampulatory surgery: Post- operative and post- discharge nausea and
vomiting are the most common complication of ampulatory surgery,
steroids decrease the incidence of post operative nausea and vomiting,
post-operative pain & stimulate appetite and induce a sense of well-
being (due to the release of endorphins) e.g. dexamethasone.
12- Epidural steroid injection (ESI) has been used to treat back pain (due
to nerve root irritation) in patients with a wide variety of spine
pathologies including spinal stenosis, disk-space narrowing, and
vertebral fractures. The purpose of an ESI is to deliver medication
125
directly to the affected nerve root limiting the effects of systemically
administered steroids.
13- Analgesic effect: Analgesic effect of steroids is suspected to be mediated
by anti-inflammatory and immunsuppressive mechanisms. The anti-
inflammatory action results in decreased production of various
inflammatory mediators that play a major role in amplifying and
maintaining of pain perception e.g. methylpredinsolone.
14- Pre-operative replacement therapy: Corticostroid supplementation
should be provided for patients being treated with steroid either for
hypocortisolism or for other diseases. Increase in plasma level of
cortisol due to severe surgical stress is one of the important
components of stress response. In the preoperative period due to
adrenal suppression, there can be increased vascular permeability,
inadequate vasomotor response, decreased cardiac output, decreased
systemic vascular resistance and left ventricular stroke volume index
which can lead to severe hypotension and cardiovascular collapse,
respiratory depression, hyponatremia, hypoglycaemia, hypercalcemia
and hemoconcentration.
Side effects
Inhaled corticosteroids
Injected corticosteroids
Corticosteroids that are injected into muscles and joints may cause
some pain and swelling at the site of the injection. However, this
126
should pass within a few days. Over time, repeated steroid injections
into a muscle can weaken it.
Corticosteroids are usually only injected directly into the blood
when there is an urgent need for treatment. Corticosteroids injected
into the blood can cause side effects including:
stomach irritation, such as indigestion, tachycardia, nausea,
insomnia, a metallic taste in the mouth, mood changes, from feeling
very happy one minute to being irritable, depressed or restless the
next.
Topical corticosteroids can lead to thin skin, red skin lesions and
acne.
Oral corticosteroids
Side effects of oral corticosteroids that are used for short periods
include:
Mood changes.
Side effects of oral corticosteroids used for longer than three months
include:
127
Most side effects improve to reduced dosage. Osteoporosis can be a
persistent problem, particularly at over 65. With more vulnerablity to
breaking a bone.
Regular checks and tests for conditions such as diabetes, high blood
pressure and glaucoma are needed.
128
The onset of diabetes, or worsening of existing diabetes
Glaucoma
Cataracts
Mental heath
129
Depressed and suicidal intentions.
Vulnerability to infection
CHRONOBIOLOGY
130
Chronbiological mechanisms regulate sleep time, feeling hungry,
change in the level of hormones and in the body temperature.
The biological rhythms affect the time in which disease may occur
when or intensify e.g. onset of asthma crises at the time of sleep, and
most epileptic seizures occuring in the morning or evening.
CHRONOPHARMACOLOGY
131
The once daily administration of medications at specified time selected
so as to minimize inhibition of the endogenous cortical secretion of &
to preserve the temporal organization of biological functioning.
Prednisone & methylprednisolone satisfy these requirements when
given in the morning on alternate days to patients adhering to diurnal
activity & nocturnal rest.
Adrenal inhibition it is well documented with the administration of
corticosteroids at a time coinciding with the circadian crest of
endogenous adrenocortical secretion.
Pluricorticoid therapy is the combined therapy of 2 or more
corticosteroids administered twice daily at specific times.
132
Chapter 7
Indication
Action
133
Cachexia, anorexia & weight-loss associated with cancer.
Agents
Emesis
Afferent pathways
(4) Emetics
Indications
134
1- Central emetics S/c apomorphine stimulates CTZ.
2- Peripheral emetics act by local irritation of gastric mucosa
Rapidly acting as salts of heavy metals, hypertonic solutions or
mustard in warm water.
Slowly acting which are used as nauseating expectorants e.g.
tincture ipecacuanha, tincture senega & ammonium chloride
& carbonate.
135
Adverse effects;
136
Saline purgatives as Mg-sulphate (Epsom salt), Na-sulphate (Glauber`s
salt), K-Na-tartrate (Rochelle salt), Mg-oxide (Milk of magnesia) & Mg-
citrate. They are poorly absorbed from gut so retain water increasing
bulk. Act after 1-2 hours. Given before breakfast on empty stomach in
isotonic solution. Contraindicated in pregnancy & chronic
constipation.
Non-digestible sugar-alcohols lactulose, sorbitol & manitol are
hydrolyzed in the intestine to organic acids which acidify luminal
contents & draw water stimulating colonic motility. By saccharolytic
microflora acetic acid, lactic acid, etc. are formed lowering pH.
Lactulose used for treatment of hepatic encephalopathy by
acidification of large intestine favors the formation of the non-
absorbable ammonium ion than the readily-absorbable ammonia
molecule, which requires detoxification in the liver by the urea cycle,
hyperammonemia is thus prevented, other toxic amines absorption
also is reduced.
3- Emollients & wetting agents (lubricant purgatives)
Liquid paraffin; mineral oil; produce softening of the stools & easier
evacuation, act in 10 hours so given overnight, used in chronic habitual
constipation wherein saline agents are contraindicated.
Side effects
1- Mild irritant
137
Castor oil which when taken orally is transformed by pancreatic lipase
into glycerol & the hi-irritant ricinoleic acid which increases intestinal
motility yielding complete evacuation of the gut. Act in 2~6 hours at
dose range of 15~ 60 & is inactive in obstructive jaundice &
contraindicated during pregnancy.
Linseed oil & olive oil are less irritant & act by the respective
formation of linoleates & oliveates (the Na & K salts of the released
fatty acids) which are irritant soaps.
2- Moderate irritant
Indications of purgatives
1- Constipation.
2- Drug & food poisoning.
3- Before operation or radiography.
4- In treatment of helminthes.
5- To prevent straining as in heart failure or hernia.
(7) Enemata
138
Retention enema; nutrition, basal narcotic, MgSO4 & in
treatment of some parasitic diseases. Small volume slowly given
at low head pressure.
(8) Treatment of constipation
1. Steroids.
2. Sulphasalazine, sulphapyridine & 5-amino-salicylic acid which act to
inhibit leukotriene synthesis.
3. Azathioprine.
(12) Uses of Magnesium sulphate
139
1. Cholagogue, small oral dose.
2. Bulk purgative, large oral dose.
3. A dehydrating agent, rectally.
4. Anticonvulsant (in eclampsia); hypotensive & calcium antagonist,
parenterally.
(13) Drugs used in hepatic encephalopathy
(15) Cholagogues
(16) Choleretics
(17) Hydrocholeretics
140
(18) Spasmolytics
(20) Octreotide
141
a) Acute Ulceration and Erosions:
1. Related to acute gastritis due to predisposition to aspirin, excess
alcohol & bile reflux.
2. Related to shock: severe pain, major trauma, cerebrovascular
accident, septicemia, ACTH or corticosteroid therapy.
3. Ulceration is usually multiple and asymptomatic.
b) Chronic Peptic Ulcers; usually single and penetrate muscularis
mucosa.
c) Pathophysiology: ↑ aggressive forces or factors including HCL,
pepsin & Helicobacter pylori &/or ↓ protective or defense
mechanisms including prostaglandins, mucus & bicarbonates.
d) In gastric ulcer the acid secretion is normal or reduced suggesting an
impaired mucosal resistance. The pain is less regular (½-1hr) after
meal.
e) In duodenal ulcer there are excess acid and pepsin secretions with
tendency to nocturnal hyper-secretion. Typically pain relieved by
taking food.
f) Goals of therapy: 1- relief of pain. 2- promotion of healing . 3-
prevention of recurrence.
(22) Treatment of Peptic ulcer
a) Measures to relief pain
General measures.
Antacids.
Anticholinergics.
b) Measures to promote healing:
General measures.
Drugs:
1- Large doses of antacids.
2-Antisecretory (drugs which inhibit acid secretion): H2
blockers, proton pump inhibitors, anticholinergics, gastrin
antagonist (proglumide) and prostaglandins (misoprostol) .
142
3- Mucosal protective agents: sucralfate, colloidal bismuth
cpd, carbenoxolone, prostaglandins.
143
Neutralize gastric acidity → relief of pain.
Increase pH of the stomach → ↓ proteolytic activity of pepsin .
Some (in large doses) →↑PGs and eradicate H. pylori.
Classification :
Are classified as chemical or physical anti-acids .
1- chemical anti-acids :
a- Systemic antacids: soluble and absorbable; can produce systemic
alkalosis e.g. NaHCO3.
b- Non-systemic (insoluble and non-absorbable); like salts of Al+++,
Mg++ and Ca++ .
Uses:
1- Peptic ulcer→ relief of pain.
2- Gastro-esophageal reflux and heart burn.
3- Gastritis.
144
1. Ca, Mg and Al decrease tetracycline absorption
2. Al(OH)3 decreases absorption of digoxin, phenytoin, warfarin,
etc
3. Antacids decrease absorption of anticholinergics, phenothiazine
& iron preparations.
4. Systemic antacids increase excretion of acidic drugs and decreases
excretion of basic drugs.
Drug interactions:
a) affect bioavalability of other drugs e.g. Ca, Mg and
Al↓absorption of tetracyclines; Mg and Al ↓absorption of
warfarin,digoxin, iron, theophyline, ketoconazole and
quinolones
b) change pH of bowel contents
c) adsorption or chelation
d) change gastric emptying or transit time
Preparations:
NaHCO3: is the only useful water-soluble antacid. It acts rapidly but
has a transient action (short duration) and absorbed bicarbonate in
higher doses may cause
1. systemic alkalosis,
2. CO2 release→ abd.distention→ discomfort, dissolve
mucus,
3. alkalinization of urine: a- precipitates phosphate stones . b-
↓excretion of weak basic drugs e.g. ephedrine.
4. hypernatremia which is contraindicated in heart failure
and hypertension.
Al(OH)3: has a relatively slower action. Al+3 ions form complex with
certain drugs like tetracycline & constipation, a mixture of Al(OH)3
and Mg(OH)2 may be used to minimize the effect on motility.
Mg(OH)2: insoluble in water and has a fairly rapid action. Mg++ has a
laxative effect → diarrhea.
GavisonR: (alginic acid, Mg tri-silicate, Al(OH)3 gel, NaHCO3). The
alginic acid in presence of saliva reacts with NaHCO3 to produce a
high viscous foaming solution of Na alginate in which librated CO2
145
is trapped. This material swells and floats on gastric contents as a
chaff which usually prevents gastric reflux.
146
b) Anticholinergics:
Their unwanted effects (dry mouth, constipation, urinary retention,
tachycardia, excitement, glaucoma, etc) limit their uses.
They also decrease the lower esophageal sphincter (LES) pressure,
increase the gastro-esophageal and delay the gastric emptying.
Mechanism of action:
1. ↓ gastric acid secretion
2. ↓motility and spasm by blocking muscarinic receptors in gut.
3. Are less effective alone but may be useful when combined with H2-
blockers or antacids.
They are of two types:
1) Non selective: Oxyphenonium (5mg tds) and propantheline (15mg
qid) Dicyclomine.
2) Selective M1-blockers: Pirenzepine (50mg bid orally for 4~6 weeks)
and telenzepine which are selective blockers of peripheral muscarinic
receptors near gastric parietal cells. They selectively inhibit gastric acid
secretion with minimal side effects.
Measures to promote healing
Antacids in high doses (patient compliance is poor)
Anticholinergics with H2-blockers or antacids.
Mucosal protective agents:
1) Liquorice Derivatives (carbenoxoloneR):
These are derivatives of glycyrrhizinic acid and have steroid-like molecules.
Mechanism of Action:
I. ↑ mucosal resistance as they slow down gastric epithelial turnover.
II. ↑secretion.
III. Alter its chemical composition decrease back diffusion of H+ ions
into mucosa.
Preparations:
I. Bio-gastrone for gastric ulcer
147
II. Duo-gastrone for duodenal ulcer (enteric caps act topically)
Side Effects:
Mineralcorticoid actions (↑Na, hypertension, edema, ↓K).
2) Sucralfate:
It is an aluminum salt of sulfate sucrose.
It promotes healing of duodenal ulcer and may also be used in
gastric ulcer.
Mechanism of Action:
Acts topically by forming a complex with protein in ulcer to form a
protective barrier against the acid, pepsin and bile salts.
Stimulates the release of prostaglandins (PGs).
Requires an acidic pH to be activated and should be administrated
simultaneously with H2-blockers or antacids.
Dose:
1gm QID on an empty stomach or 1hour before meals.
Side Effects:
Not absorbed systemically, it has few side effects like constipation.
It decreases the bioavailability of tetracycline, digoxin and
phenytoin.
148
4) Colloidal Bismuth Compound (de-nolR):
It promotes healing of gastric and duodenal ulcers.
Mechanism of Action:
Acts locally combining with exudate and mucosa in the base of the
ulcer providing a protective coat.
Stimulates mucus secretion & inhibits Helicobacter pylori.
Dose:
As suspension 15mg or tablets 120mg QID before meals.
Side Effects:
Unpleasant ammoniacal odor, black stools and teeth discoloration.
In cases of chronic treatment, there may be encephalopathy especially
in renal failure.
4) Prostaglandin synthetic analogs (misoprostolR200mg tablets):
a. Provide mucosal cytoprotection.
b. Increase mucus and HCO3 secretion.
c. Maintain gastric blood flow.
d. Stimulate mucosal cellular renewal and regeneration.
e. A mild inhibitory effect on gastric acid secretion.
149
5) Histamine (H2 receptor) Antagonists:
Reduce both daytime and nocturnal gastric acid secretion.
Block acid secretion induced by histamine, gastrin, cholinergic drugs
and vagal stimulation.
Mechanism of Action:
Competitively inhibit histamine at H2-receptor of parietal cells.
1) Cimetidine (tagametR):
Rapidly absorbed from upper small intestine.
Excreted by kidney.
Adverse effects:
1) Diarrhea, nausea, vomiting, fatigue and skin rash.
2) CNS: headache, dizziness, elderly mental confusion and delirium.
3) Endocrine: hyperprolactinemia, galactorrhea and infertility in females
and gynecomastia in males.
4) Anti-androgenic action: loss of libido, impotence and decreased sperm
count.
5) ↑ serum transaminases, hepatitis, cardiac arrhythmias, bone marrow
depression & blood dyscrasias.
6) Slow metabolism of some drugs due to inhibition of cytochrome P-450
leading to ↑level & effect of warfarin, β-blockers, phenytoin,
diazepam & theophylline.
150
2) Ranitidine (zantacR):
Differs from Cimetidine in the following:
1) Chemically it is not an imidazole but a substituted furan.
2) 5~10 times more potent and more selective H2-blocker.
3) A slightly longer duration of action.
4) Less side effects and drug interactions.
5) Doesn’t inhibit CP-450 or block androgen receptors.
6) No evidence of CNS effect.
Dose: 300mg BID.
3) Famotidine (pepcidR): Is 8~10 times more potent.
4) Nizatidine (AxidR): Stronger than ranitidine, 100% bioavilable.
6) Proton Pump Inhibitors (omeprazole):
They are activated at acidic pH to sulfonamide derivatives that binds
irreversibly to H+-K+ATPase (an enzyme found at the secretory surface
of the parietal cells).
So, they inhibit the final transport of H+ via exchange with K+ ion in
gastric lumen.
They inhibit both basal and stimulated acid secretion.
Use & dose:
Peptic ulcer and Zollinger-Ellison’s syndrome.
20~40mg /day, orally.
Side Effects:
1) GIT: diarrhea & colic.
2) CNS: headache & dizziness.
3) Skin rash, leucopenia & transient ↑ in liver enzymes.
4) ↑ gastric pH leads to ↓ absorption of ampicillin, iron preparation,
ketoconazole, etc
5) Pronounced acid inhibition at extremely high doses leads to feedback
elevation of gastrin and subsequent enterochromaffin-like-cells change
of the stomach.
151
Preparations:
1. Omeprazole (losecR)20~40mg od .orally and I.V.
2. Lansopprazole (lanzorR):15~30mg od. Orally for 4 weeks(duodenal
ulcer)
3. Pantoprazole (controlocR) : 20-40mg od. Po and 8 weeks(gastric ulcer)
4. Rabeprazole (parietR): 20mg p.o.
Metoclopramide:
It is a pro-kinetic drug.
The main action is to prevent enterogastric reflux.
More effective in gastric than duodenal ulcer.
Prevents gastroesophageal reflux- in reflux esophagitis.
152
(24) Gastroesophageal reflux disease (GERD):
– Backflow of stomach acid into the esophagus
– Esophagus is not equipped to handle stomach acid => scaring.
– Usual symptoms are heartburn, an uncomfortable burning
sensation behind the sternum (MI often mistaken for GERD).
– More severe symptoms: difficulty swallowing, chest pain.
– Reflux into the throat can cause sore throat.
– Complications include esophageal erosions, esophageal ulcer and
narrowing of the esophagus (esophageal stricture).
– In some patients, the normal esophageal lining or epithelium
may be replaced with abnormal (Barrett's) epithelium. This
condition
(Barrett's esophagus) has been linked to cancer of
the esophagus.
– Primary treatment option are proton pump inhibitors.
153
Chapter 8
154
Types of Asthma
A. Extrinsic or Allergic (early onset) Asthma: caused by extrinsic factor or
external stimuli. It is more common in children and precipitated by
known allergens resulting in antigen-antibody reaction. The antibodies
are of IgE type and attach to mast cells in bronchial mucosa. The
reaction leads to release of allergo-toxin mediators as histamine,
leukotrienes, Ach, PGs and kinins resulting in bronchoconstriction.
B. Intrinsic or Late-onset Asthma: is common in adulthood. The
symptoms being triggered by non-allergic factors like:
o viral infection (bronchitis)
o epithelial damage or mucosal inflammation
o emotional upset (thought to be mediated by excess
parasympathetic input; psychological troubles)
o exercise (thought to be due to water and heat loss from the
airways that triggers mediator release from mast cells)
Mechanism:
155
An asthmatic attack may be precipitated by inhalation of allergens such as
dust, pollen, animal dander,
industrial chemicals such as hair
spray, industrial trigger such as wood,
graven dust. These allergens interact
with mast cells coated with IgE
Allergen cross-links IgE
Production of antibodies (generated in response to
a previous exposure to the same
Specific IgE
allergen). Mast cells release mediators
such as histamine, leukotrienes and
chemotactic factors. These promote
(1) bronchial spasm & (2) mucosal
thickening from oedema and cellular
infiltration.
Mast cell
Activation and
Degranulation
Mediators
Asthma
a
Time hrs
bronchitis): a 2nd delayed FEV reduction following a return to the
normal. Responds to glucocorticoids.
Both phases respond to sodium cromoglycate.
Pathophysiology:
Bronchi and bronchioles are supplied by sympathetic autonomic fibers and
not parasympathetic but contain muscarinic receptors.
Sympathetic stimulation of β2
Bronchodilation
receptors
Stimulation of muscarinic receptors Bronchoconstriction
The bronchial muscle tone depends on the level of cAMP and cGMP:
• ↑ cAMP → bronchodilation
• ↑ cGMP → bronchoconstriction
ATP + Adenyl cyclase → cAMP + Phosphodiesterase → 5’AMP
Adenyl cyclase is a surface enzyme associated with β receptors & can be
activated through:
I. Stimulation of β2 receptor by β2 agonists.
II. Inhibition of phosphodiesterase enzyme by theophylline.
GTP + Guanylate cyclase → cGMP
This is less important since cGMP level is less than cAMP. Guanylate
cyclase enzyme is associated with muscarinic receptors. Its effect can be
brought about by parasympathomimetics and can be inhibited by
atropine (parasympatholytic). Elevation of cGMP leads to activation of
certain protein kinases ending in muscle contraction by enhancing the
activity of free Ca2+.
There is evidence that the bronchial muscle contains α-adrenoceptors
in addition to β2 receptors. So, stimulation of α receptors leads to ↑
cGMP levels → bronchoconstriction. Accordingly, the use of α blockers
157
e.g. phentolamine as aerosol leads to bronchodilation and
improvement of the asthmatic attack in some cases.
Precipitating Factors in Asthma:
1) Hypersensitivity mechanism in many patients with allergic asthma.
2) Exercise-induced asthma; many patients with asthma especially
children become wheezing with severe exercise.
3) Respiratory infection precipitates asthmatic attack in all ages.
4) Non-specific irritants; cigarette smoke, dust, temperature change, etc.
5) Emotional factors; psychological stimuli e.g. stress and anxiety can
provoke or worsen bronchoconstriction and may affect the
effectiveness of bronchodilators used to treat asthma.
6) Drug-induced bronchial asthma:
o Cholinomimetic drugs.
o Histamine and histamine-releasing drugs e.g. morphine and
curare.
o Non-selective β adrenergic blockers. Also cardio-selective in
large doses.
o Prostaglandins especially PGE2.
o As part of allergic reaction to a drug e.g. penicillin.
o Salicylate and other NSAIDs e.g. aspirin, ibuprofen and other
prostaglandin synthesis inhibitors that lead to synthesis of
leukotrienes. These can induce asthma in patients with late
onset asthma through non-allergic mechanism.
o Inhalation of sodium cromoglycate is irritative and may induce
reflex airway obstruction. That is why it is contraindicated
during acute asthma.
o Morphine which is contraindicated in bronchial asthma (1)
releases histamine, (2) stimulates the vagal center and (3)
inhibits the respiratory and cough centers.
2. Lines of treatment of bronchial asthma:
1) Avoidance of the precipitating cause
158
1. Desensitization or avoidance of the Ag if known.
2. Treatment of respiratory infection.
3. Psychotic adjustment.
4. Avoidance or withdrawal of drugs precipitate asthmatic attacks.
2) Relief of bronchoconstriction; relaxation of bronchial musculature
1. Sympathomimetics (β adrenergic stimulant).
2. Theophylline derivatives (aminophylline).
3. Anticholinergic (ipratropium & deptotropine).
3) Relief of edema and congestion of bronchial mucosa; non- specific
reduction of the response to Ag-Ab reaction
1. Disodium cromoglycate.
2. Glucocorticoids.
3. Antihistaminics has been used but are ineffective.
4) Maintenance of good oxygenation
5) Expulsion of bronchial secretions
Expectorants & mucolytics render the mucous less viscid.
A. Bronchodilators:
I. β 2 agonists.
II. Xanthines derivatives.
III. Anticholinergics.
1. Sympathetic Bronchodilators:
β2 agonists are the first choice in the treatment of the immediate phase, they
act directly on β2 receptors and produce:
1) Relaxation of bronchial smooth muscles.
2) Inhibition of the release of mediators (bronchoconstrictor substances)
from mast cells.
3) Increase ciliary activity or affect the composition of mucous secretion
facilitating its transport.
159
Non-selective β agonists as epinephrine, ephedrine, and isoprenaline
when used and cause cardiac stimulation via β1 receptors. In addition,
epinephrine is contraindicated in hypertensive patients.
These have been replaced by selective β2 agonists with the advantages
of:
1. Long duration of action.
2. Less toxic effect on the heart. Effectiveness after oral
administration or inhalation.
Examples of Selective β2- agonist classified into:
Side Effects:
160
2. Methylxanthine derivatives:
These are Phosphodiesterase inhibitors; direct smooth muscle relaxants.
I. Naturally- occurring e.g. caffeine, theophylline and theobromine.
II. Synthetic derivatives e.g. aminophylline –a potent bronchodilator
which is a combination of theophylline, ethylene diamine and
Enprofylline.
Pharmacological actions:
They have antihistamine-action.
They reduce the immediate phase by direct bronchodilation.
Reduce the delayed phase by an unknown mechanism.
Other actions:
Positive inotropic, positive chronotropic,↑ COP ,↓ venous
pressure.
CVS Dilate blood vessels EXCEPT cranial blood vessels which are
constricted.
enprofylline doesn’t constrict cranial vessels
Stimulate brain → ↑ alertness.
CNS May cause tremor, nervousness.
Interfer with sleep.
Renal ↑ Diuretic activity,↑ GFR.
GIT ↑ Acid & pepsin secretion.
They have narrow therapeutic window due to the untoward effects
that include these wide range actions
Theophylline has a narrow therapeutic window. The optimal
therapeutic effects are obtained with serum level of 10~20 μg/ml
(100~200 μmol/l). Adverse effects may appear with levels in excess
of 200 μmol/l. Careful monitoring of serum levels is therefore
essential to ensure efficacy and avoid toxicity.
Pharmacokinetic:
161
Xanthine drugs are usually given orally as sustained release
preparations which have lower incidence of side effects and longer
duration of action.
Aminophylline can be administered by slow intravenous or by
infusion.
Theophylline and enprofylline are well absorbed from the GIT.
Theophylline is metabolized in the liver while enprofylline is
excreted unchanged in the urine.
Half-life of theophylline is 8-12 hrs in adult and less than 4 hrs in
the children, while t1/2 of enprofylline is 2 hours.
The t½ is prolonged in liver disease, heart failure, viral infection
and with erythromycin, contraceptives, ciprofloxacin and
cimetidine.
The t½ is shortened by cigarette smoking, rifampicin, phenytoin,
phenobarbiton, carbamazepine & in patients with
hypothyroidism.
Mechanism of action:
1. They are thought to cause bronchodilation by blocking or
competing with adenosine receptor at A1 and P1 (Adenosine can
cause bronchoconstriction in asthmatics). Enprofylline is not an
adenosine antagonist but a powerful bronchodilator that lowers
cGMP.
2. Inhibition of phosphodiesterase enzyme -which catalyzes formation
of AMP from cAMP- leads to an increase of cAMP and broncho-
dilation is produced.
162
3. Increased strength of the skeletal muscle, diaphragm or improved
diaphragmatic contraction probably via mobilization of intracellular
calcium.
4. They may inhibit antigen-induced release of mediators as histamine.
Therapeutic iundications:
Systemic relief of bronchial asthma. They are useful with other
drugs to treat prolonged attacks and in status asthmaticus.
Treatment of reversible bronchospasm associated with chronic
bronchitis or emphysema.
Side Effects:
Nausea, vomiting, epigastric pain and ulcerations that lead
GIT
to bleeding.
Arrhythmia, palpitation, rapid i.v. may lead to cardiac
arrest.
CVS
Dilation of blood vessels except cranial (constriction) and
hypotension.
Psychological function disturbance (↓ blood flow to cranial
vessels), irritability, insomnia, nervousness and muscle
CNS
twitching (leads to generalized convulsions except
enprofylline)
Respiratory Tachypnea, hyperventilation and respiratory arrest.
Weak diuretic effect involves both ↑GFR and ↓
Renal
reabsorption in tubules except enprofylline.
Seizures (antidote diazepam or phenytoin i.v.),
Toxic symptoms
Severe emesis and agitation.
Contraindications:
Cardiac arrhythmia; myocardial infraction; hyperthyroidism; peptic ulcer;
hepatic and renal dysfunction .
3. Parasympathetic depressants (muscarinic antagonists):
Ipratropium bromide (AtroventR)
163
o Is isopropyl-atropine; better bronchodilator with less drying effect on
sputum. Actions are surmountable because acts by competitive
antagonism i.e. block muscarinic receptors.
o Prevents accumulation of cGMP and produce bronchodilation.
Indications:
o Used in asthmatic patients in whom sympathomimetics are
contraindicated; heart disease and thyrotoxicosis.
o Should not be given in glaucoma or prostatic hypertrophy.
o Safe, well tolerated and can be used in combination with β2-agonists.
Routes of administration:
o The drug is given by inhalation to limit systemic side effects.
o It has slower onset (peak effect 30 min) and more prolonged effects
(3~8 hrs) than β agonists.
Dose:
o Ipratropium as aerosol (20μg /puff/6hrs) or (1~2 puffs QID).
o Oxitropium 200μg BID.
B. Anti-inflammatory Agents or Prophylactic Agents:
I. Glucocorticoids.
II. Mast cell stabilizers.
Regular anti-inflammatory treatment (including corticosteroids and sodium
cromoglycate, etc.) must be given to patients who:
1. Require an inhaled bronchodilator more than once a day.
2. Have nocturnal symptoms.
I. Glucocorticoids:
These include corticosteroids and ACTH. The present inhaled
corticosteroids are the drugs of choice in adults.
Beclomethasone and budesonide are used at doses of 100~400 μg
BID. Higher doses are used if symptoms persist & inhaled
corticosteroid should be reduced -if possible- once symptoms and peak
164
expiatory flow have improved. It is an indicator in cases which does not
respond to bronchodilator in severe asthma and in status asthmatic.
ACTH dose is 20-40 unit I/V.
In case of status asthmatic, a dose of 200μg hydrocortisone is given
initially then repeated every four hours or according to the response.
Mechanism of Action:
1. ↑ Membrane stability of many cells e.g. endothelial cells, smooth
muscle cells and lysosomes membrane including mast cell granules.
This reduces the release of broncho-constrictor substance and inhibits
the response of smooth muscle to them. They may also inhibit synthesis
of mediators.
2. ↓ Capillary permeability and hence edema.
3. Suppress immune response and antibody synthesis.
4. Potentiate the endogenous catecholamines and sympathomimetic
bronchodilators by blocking non-neuronal uptake of catecholamines.
5. Direct relaxant effect on smooth muscles.
Preparations and routes of administration:
165
adults and 20~30 mg/ day for children in four-divided-doses. Then it is
reduced to 5-10 mg/ day and then alternate day therapy followed by an
aerosol preparation to avoid adrenal suppression.
Intravenous: Hydrocortisone is given in cases of status asthmaticus,
followed by prednisolone. Methylprednisolone is a very effective
alternative.
Indications:
Indicated as prophylaxis against asthma that doesn’t respond well to non-
steroidal drugs.
Notes:
Side effects:
166
Supression of endogenous glucocorticoids synthesis → Iatrogenic
Cushing's syndrome.
↑ appetite.
Metabolic actions; tendency to hyperglycemia and hypertension (due to
Na & water retention).
167
Metabolism Non
Absorption <10%
Excretion 50% in bile and feces and 50%
urine
Side Effects:
Direct irritation by the powder that leads to bronchospasm, wheeze,
cough, nasal congestion and pharyngeal irritation.
Rarely, there could be laryngeal edema, urticaria, and eosinophilic
pneumonia.
Contraindications:
Patients who show hypersensitivity.
During acute attacks because it may aggravate the case due to irritation
by the powder.
B. Ketotifen:
Used for prophylaxis of bronchial asthma, given orally.
Similar to DSCG it inhibits the mast cells release of mediators but has
an additional anti-histaminic action.
It may be used in allergic rhinitis and allergic skin disease.
Used in the treatment of mild childhood bronchial asthma.
Dose:
1mg tablets or capsules BID, effects appear after 3~4 weeks.
Side Effects:
Sedation, dry mouth, and dizziness at the begining of ttt.
C. Histamine antagonists (H1-receptor antagonists):
Azelastine
168
Inhibits the synthesis of LTc4 and blocks the effect of Ach,
serotonin, LTc4 and histamine.
Decreases the response to allergic agents.
Inhibits moderately exercise-induced asthma & ↓ daily asthmatic
attacks & the concomitant therapy needed.
Terfenadine & Astemazole
Both groups are beneficial when used alone in mild and moderate asthma or
in combination with β2 agonists for exercise or aspirin-induced asthma or in
patients with poor compliance with inhaled drugs because of poor inhalation
techniques.
3. Severe acute asthma; or status asthmaticus:
The term is used to describe a very severe and sustained attack of asthma
which fails to respond to treatment with the usual measures. Early and
extensiventreatment is required:
169
1. Humidified oxygen or oxygen/helium mixture to relief hypoxia
and to reduce respiratory distress and dyspnea.
2. Treatment of dehydration orally or by IV fluid.
3. Systemic steroid: IV hydrocortisone 200 mg repeated every 4~6 hrs
until the acute attack is controled, then continue with 5 mg
prednisolone 6 hourly, the dose then gradually reduced.
4. Inhalation salbutamol in oxygen given by nebulizer or IV
(salbutamol may be given with intermittent positive pressure
breathing).
5. Or I/V infusion of aminophylline.
6. Expectorant and bronchial aspiration.
170
171
172
4. Cough
Cough is a protective reflex mechanism which serves the purpose of expelling
sputum and other irritant material from the upper part of the respiratory
airways.
• Irritant, & perhaps chemo- & stretch receptors initiate the cough reflex
• Bronchoconstriction is the most frequent & important cough
stimulus.
There are essential 2 types of cough:
1. Dry cough (unproductive) e.g. smoker`s cough, due to local irritation.
2. Productive cough that effectively expels secretion and exudates from
the respiratory passages.
Treatment of dry cough
I- Peripheral antitussives
Suppress the irritated sensory nerve ending
1. Demulcents: to relieve cough due to sore throat & pharyngitis e.g.
Liquorices lozenges.
2. Steam inhalation in tracheo-bronchitis: half a litre of boiling water +
tea spoonful tincture of benzoin or menthol.
3. Drugs with local anaesthetic activity e.g. benzonatate.
II- Central antitussives suppress the medullary cough centre
1- Non-addicting narcotics
a- Codeine
• It is natural opium alkaloid.
• It has less liability to cause dependence.
• It has mild analgesic effect.
• It causes constipation.
• It decreases bronchial secretions which thickens sputum.
173
• It inhibits ciliary activity which reduces clearance of thickened sputum.
b- Hydrocodone
• More potent than codiene.
• Less respiratory depressant effects.
c- Phlocodine
• Pholcodine mainly used as antitussive.
• It has no analgesic or euphoric action.
• Its addictive liability is less than that of codeine
2- Addicting drugs
• These are not commonly used as antitussive because of their addicting
properties e.g. morphine, heroin, methadone, dihydromorphine.
3- Non-narcotic antitussives
Dextromethorphan
• It is a synthetic morphine substitute.
• It has no analgesic or addictive properties.
• Its antitussive potency is equivalent to codeine
• With less constipation and inhibition of mucociliary clearance.
Narcotine:
• Natural opium alkaloid with an antitussive action mainly.
4- Non-opiate synthetic derivatives: Chlorphedianol, carbetapentane,
oxeladin, benzonatate, caramiphenethane disulphonate, diphenhydramine.
Treatment of productive cough
1- Expectorants
a- Sedative expectorants:
174
Stimulate the secretion of protective mucus & increase the fluidity of
sputum & help it expectoration by cough.
b- Alkaline expectorants e.g. Na & K citrate and acetate.
c- Nauseant expectorants e.g. tincture ipecacuanha & ammonium chloride.
d- Saline expectorants e.g. creosote, cuaiacol, & terpene hydrate.
2- Mucolytic agents:
They liquefy viscid bronchial secretions and enhance the therapeutic effect
of expectorants.
Acetylcystein:
It has free sulphydryl (SH) group that opens disulphide bonds in the
mucus & reduces its viscosity.
Administered by inhalation - as an aerosol- or by direct instillation into
the tracheal tree through bronchoscope.
Bromohexine:
• It reduces the viscosity of the bronchial secretion by depolymerization
(fragmentation) of the mucopolysaccharide which forms the ground
substance of the bronchial secretion.
Carboxymethylcysteine:
• In addition to its mucolytic property it reduces the mucus gland
hyperplasia which usually is associated with chronic bronchitis.
3- Decongestants
The indications include
• Sinusitis of allergic or viral etiologies & reverse sneezing or
• Other complications of postnasal drip.
Two drug categories are commonly used as decongestants
H1 receptor antagonists e.g. Dimenhydrinate Diphenhydramine &
Chlorpheniramine.
Sympathomimetic drugs i.e. α-agonists e.g. Ephedrine,
Pseudoephedrine & phenylepherine.
175
Chapter 9
The ANS, with the endocrine system, coordinates the regulation and
integration of the body functions. The endocrine system sends signals to
target tissues by varying the level of blood-borne hormones. By contrast, the
nervous system exerts its influence by the rapid transmission of electrical
impulses over the nerve fibers. Drugs that produce their primary therapeutic
effects by altering the function of the ANS are called autonomic drugs which
act either by stimulating portions of the ANS or by blocking the action of the
ANS.
Introduction to the Nervous System
An Overview of the
Nervous System:
Peripheral Nervous
Central Nervous
System
System
-Brain
-Spinal Cord
Sympathetic Division
--“fight or flight” Parasympathetic
--activated by stress Division:
--Routine
176
Sympathetic Parasympathetic
Short preganglionic fibers and long Long preganglionic fibers and short
postganglionic fibers postganglionic fibers
Tends to function as a unit & often Doesn’t have a function entity as such
discharge as a complete system e.g. and never discharge as complete
severe exercise & reaction to fear system. If it did, it would produce
massive, undesirable and unpleasant
177
symptoms. Instead parasympathetic
fibers are activated separately and
function to affect specific organs such
as the stomAch or eye
178
The Main Peripheral Effects of the ANS:
Sympathetic Parasympathetic
Organ
Receptor Response Response
SA node β1 ↑ rate Slow rate
Atrial β1 ↑ conduction ↑ conduction
muscle velocity velocity
β1
A.V. node ↑ conduction Slow conduction
Heart velocity velocity (AV
β1 block)
Ventricular
muscle ↑ contractility,
conduction velocity No effect
and automaticity
Arterioles
-Skeletal α Constriction No effect
muscle β2 Dilation No effect
Blood Constriction No effect
α
vessels -Skin &
mucous
α Constriction No effect
membranes
β2 Dilation
Veins
Smooth β2 Dilatation M-receptor
Bronchi
muscle Contraction
179
bladder Trigone and α1 Contraction Relaxation
sphincter
Iris
-Radial α1 Contraction -
muscle (mydriasis) Contraction
Eye -Circular - (miosis)
muscle - Contraction
Ciliary
muscle
Male sex organ Α Ejaculation Erection
α,β Thick viscous Profuse watery
Salivary glands
secretion secretion
Kidney β1 Renin secretion No effect
β2 Glycogenolysis No effect
Liver
Gluconeogenesis
180
Types of Nerve Fibers
These are based on the transmitter molecules released from their terminals
1) Cholinergic Fibers:
These fibers release Ach that acts on Ach receptors (cholinoceptors) on
effector cells; smooth muscles, cardiac muscles and glands.
Ach is the transmitter of:
All preganglionic fibers; sympathetic and parasympathetic.
All postganglionic parasympathetic fibers.
Some postganglionic sympathetic fibers such as those to the sweat glands
and sympathetic vasodilator fibers supplying blood vessels in skeletal
muscles.
181
Preganglionic fibers (greater splanchnic nerve) to the adrenal medulla
which can be considered as modified sympathetic ganglia.
Certain neurons within the CNS.
so
m
Motor Skeletal
fiber Ac
sy muscles
h
m
Smooth muscles
Preganglion Postganglion
ic Ac ic N Cardiac muscles
sy h E
m Gland cells
182
These fibers release dopamine. They are present in the extra-pyramidal &
the limbic system.
4) Histaminergic Fibers:
These release histamine from mixed somatic nerves (e.g. sciatic) and dorsal
nerve roots.
5) Serotoninergic Fibers (5-HT):
This fibers release serotonin in autonomic ganglia and mainly in the
hypothalamus.
6) Purinergic Fibers:
These fibers release ATP and/or adenosine. They mediate inhibitory
responses in the smooth muscles of the gut, lung and blood vessels. They are
excitatory in the urinary bladder.
transmitt
effector
Neuro-
Gangli
mitter
trans
onic
Preganglionic Postganglionic
er
CNS:
neuron neuron
Brain Synaptic connection = ganglion Effector organ:
183
They are present in:
o The heart
o Exocrine glands
o Smooth muscles (eye, bronchi, GIT, urinary bladder and blood
vessels).
Autonomic ganglia; sympathetic and Selective agonist:
parasympathetic neurons
oxotremorine
M1 CNS neurons
Selective antagonist:
Some presynaptic sites particularly in
pirenzepine, telenzepine
stomAch
Selective agonist:
Heart pilocarpine
M2 Presynaptic cholinergic fibers (inhibit Selective antagonist:
Ach release) gallamine, methodramine,
himbacine
Smooth muscles
M3
Secretary glands
b) Nicotinic Receptors:
o They are also known as Central Cholinergic receptors.
o They are called N-receptors or nicotinic receptors because nicotine –
in small doses– produces the same effect of Ach on these receptors.
They are found in:
Sympathetic and parasympathetic ganglia.
Neuromuscular junction (NMJ) of motor end plate.
The spinal cord.
They are classified according to the blocking agents into:
Neuronal NN: In autonomic ganglia
Etamon sensitive Supra-renal medulla
184
receptors
Muscular NM:
Neuromuscular junction (NMJ)
Curare sensitive receptors
Autonomic Drugs
Are classified into adrenergic & cholinergic drugs. Each drug is either an
agonist i.e. stimulant (mimetic), or antagonist i.e. blocker (-lytic).
Cholinergic Drugs
CAA Cholinergic Drugs
Direct
•Physostigm
oxime
Re-
•Parathion Ach receptor agonist
•Suramin
ineactivators
•Neostigmin
e
Ach receptor
Ach receptor antagonist
stimulant
185
Ach receptor blocker
Parasympathomimetic
Parasympatholytic
Cholinomimetic
Cholinergic Agonists
According to the mechanism of action cholinomimetic agents can be
classified into
(1) direct acting and
(2) indirect acting cholinomimetics.
According to the receptor type or spectrum of action cholinomimetics can be
classified into
(1) muscarinic and
(2) nicotinic.
They are also called Cholinergic Acting Agents CAA. They are classified into
(1) direct acting cholinomimetic,
(2) indirect acting cholinomimetic and
(3) cholinesterase re-activators or regenerators.
Neurotransmission
Synthesis and release of Ach from cholinergic neurons involve 6 steps:
1) Synthesis : transport of choline from extracellular into the neuron through
Na co- transporter system and reacts enzymatically (choline acetyl
transferase) with activated acetate (acetyl-CO A) to form Ach ( transport of
choline is inhibited by hemicholinium).
2) Uptake into storage vesicles: Ach is protected from degradation in storage
vesicle.
3) Release of neurotransmitter: entrance of Na creates an action potential that
leads to a depolarization which results in opening of Ca channels that
increase intracellular Ca which results in fusion of vesicular membrane
186
with the terminal membrane and release of Ach (release is blocked by
bottulinum toxin. Spider venom causes release of Ach
4) Binding to receptors: postsynaptic receptor is activated by binding of
neurotransmitter.
5) Degradation of : Ach is rapidly hydrolyzed by ChE in the synaptic cleft to
choline and acetate.
6) Recycling of choline: choline is taken up by neuron.
Choline Choline
Na Na AcCoA
Ach
Synaptic vesicle
Ca++ Presynaptic
receptor
choline
acetat
e
Intracellular
response
187
Acetylcholine (Ach)
Ach is a neurotransmitter of parasympathetic or cholinergic nerves. It is a
quaternary ammonium (polar) ester of choline with acetic acid. It is rapidly
188
hydrolyzed by both true and pseudo-cholinesterase. It has both muscarinic
and nicotinic action.
Ach is of little therapeutic importance because of:
Multiple actions (M & N actions).
Rapid inactivation by cholinesterase enzymes.
Irregular absorption.
Mechanism of Action:
Ach acts by activation of muscarinic and nicotinic receptors. The esteratic
site of the receptor receives the acetyl group of Ach. The cationic head of Ach
(tri-methylamine) which has strong positive charge combines with the negative
charge at the anionic site of the receptor by a weaker ionic bond.
CH3
Acetyl group
CH – C – CH2 – CH2 – N+ – CH3
Amine group CH3
O
189
2nd step Acetylated enzyme → acetate is released + enzyme is set free
Cholinesterase Enzymes
I, True ChE, II, Pseudo ChE,
AchE Butyryl-ChE,
Specific: responsible for hydrolysis of Non-specific: hydrolytic enzyme
Ach released in the cholinergic which hydrolyzes esters.
transmission.
Essential for life
Presents in : Presents in:
At the terminals of cholinergic fibers Plasma type
RBCs, type Skin
Nervous tissue Intestine
Some sites in the CNS.
Very slow turnover: Rapid turnover:
120 days to regenerate Synthesized in liver (2~3 wks)
Proper substrate: Proper substrate:
Ach Butyrylcholine
MethAcholine Succinylcholine
Benzyl-choline
Actions of Ach
Muscarinic Ach Actions:
1) CVS:
Heart: ↓HR (bradycardia) and ↓COP. It mimics the effect of vagal
stimulation reducing the rate of firing at SA node. The vagal activity is
regulated by release of Ach at SA node.
190
Blood vessels: causes vasodilation.
BP: ↓the BP due to ↓ COP and vasodilation, but large I/V dose will ↑
BP due to (1) stimulation of adrenal medulla that releases catecholamines
and (2) activation of sympathetic ganglia that release noradrenaline and
adrenaline from postganglionic neurons.
2) GIT:
↑Motor activity and peristaltic activity.
↑Motility (↑frequency and amplitude).
Relaxation of most sphincters.
↑Secretions (polyuria and diarrhea).
3) Respiratory:
Contraction of the bronchial muscle leading to bronchospasm.
↑bronchial secretions.
4) Urogenital:
Promotes micturition by stimulation of the bladder wall:
1) Contraction of the detrusor muscle.
2) Relaxation of the sphincter and/or trigone muscle.
Contraction of the ureter.
Contraction of smooth muscles of the uterus (humans are less sensitive).
5) Eye:
Stimulates ciliary muscle contraction for accommodation for near vision.
Constriction of the papillary sphincter muscle, which causes miosis.
These effects facilitate aqueous humor outflow (opening of Schlemm’s
canal).
Lowers intraocular pressure IOP.
↑Lacrimation.
6) Exocrine Glands:
↑Secretion of salivary, lacrimal and sweat glands.
It enhances salivation, lacrimation, urination and defecation (SLUD).
191
Nicotinic Ach Actions:
1) NMJ:
Stimulates the N-receptors in NMJ resulting in skeletal muscle contraction.
At high concentration, the membrane depolarization becomes sustained
and neuromuscular blockade may occur (flaccid paralysis of skeletal
muscle).
The muscle contraction induced by Ach could be blocked by
neuromuscular blocker e.g. d-tubocurarine or succinylcholine.
2) Autonomic Ganglia:
Stimulates both sympathetic and parasympathetic ganglia (preganglionic).
The initial response is a mixture of both sympathetic and parasympathetic
effects.
The N-receptor at the ganglia is blocked by ganglionic blockers e.g. Tea.
3) CNS:
Brain is a muscarinic site while the spinal cord is enriched with nicotinic
receptors.
Ach is excitatory transmitter in the basal ganglia:
1) Small amounts (tobacco smoke) → slight alteration.
2) High concentrations → convulsions that terminate in fatal coma.
Stimulates the release of ADH by hypothalamus.
4) Endocrine:
Stimulates adrenal medulla to release catecholamines.
Direct Acting Cholinomimetics
A cholinergic agonist mimics the effects of Ach by binding directly to
cholinoceptors. It could be:
A synthetic ester of choline (choline esters) e.g. Ach and methAcholine.
Carbamic ester of choline or carbamoyl choline: as carbachol and
bethanchol.
Naturally occurring alkaloids: such as pilocarpine, muscarine, nicotine,
lobeline.
192
Few synthetic agents: as oxotremorine and dimethylphenylpiperazinium
(DMPP). These are of interest in pharmacological researches.
Chemistry & Pharmacokinetics
They are permanently charged and relatively lipid insoluble because they
contain the quaternary ammonium group [N+-(CH3)3] therefore poorly
distributed to the CNS.
They are all hydrolyzed in the GIT so are less active by oral route.
They look like Ach but slightly differ in their susceptibility to hydrolysis by
ChE enzymes in the body. The carbamic esters of choline as carbachol and
bethanchol are extremely resistant to hydrolysis by ChE enzymes and have
a corresponding longer duration of action.
They also differ in their action in muscarinic and nicotinic receptors.
However, the presence of the β methyl group in methacholine and
bethanchol reduces the potency of the drug at the nicotinic receptors
(more muscarinic in action).
Advantages of synthetic choline esters (bethanchol, carbachol and
methacholine) over Ach:
1) They have longer duration of action.
2) They are effective orally as well as parentraly.
3) They are more selective in their action.
Properties of Choline Esters
Choline esters ChEs susceptibility M effects N effects
Ach ++++ +++
++++
Methacholine ++++ Trace
Carbachol +++ +
Negligible
Bethanchol +++ None
Properties of Alkaloids
The tertiary alkaloid cholinomimetics pilocarpine, nicotine and lobeline
are well absorbed from the site of administration.
193
Nicotine is lipid soluble & crosses the skin.
Muscarine is a quaternary amine less absorbed from the GIT. It is toxic
when ingested in certain mushrooms. Excretion is renal and accelerated by
acidification of urine.
Oxotremorine is a potent synthetic muscarinic agonist that is used in
research. It is well distributed to the CNS.
Lobeline is a plant derivative (Indian tobacco) with lower potency than
nicotine but has similar spectrum of action.
DMPP is a potent synthetic nicotinic stimulant with little access to CNS. It
is a research tool used for selective stimulation of ganglionic nicotinic
receptors.
Methacholine
Mecholyl, acetyl β- methyl choline: the drug is incompletely absorbed from
GIT therefore the oral dose is 20 times the parentral dose. It is hydrolyzed by
true ChE enzyme only (in slower rate). Therefore, it is more stable than Ach.
Chemically, it differs from Ach by addition of methyl group to β position of
choline that results in:
It becomes more muscarinic in action (insignificant in nicotinic).
It resists hydrolysis by cholinesterase but is hydrolyzed in slower rate by true
ChE enzyme. So, it has longer duration of action.
Actions
Its actions are similar to Ach but its muscarinic actions are more prominent
especially on the CVS (bradycardia and vasodilation) than GIT and urinary
tract.
Therapeutic Uses
It was formerly used in the following conditions:
Relief of attacks of paroxysmal atrial tAchycardia (15~25 S/C).
As a vasodilator in treatment of peripheral vascular disease e.g. Raynaud’s
disease.
194
Diagnosis of paroxysmal hypertension due to phechromocytoma (15~25
S/C). During the normotensive phase, it produces a rise in both systolic
and diastolic Bp instead of the usual depressor response in normal persons.
Carbachol
Doryl or carbamyl choline: the drug is completely absorbed from GIT and
the oral dose is thus nearly equal to the parentral one. It is not suitable to
hydrolysis by both true and pseudo cholinesterase .
Actions
Carbachol differs from Ach in the following:
It has longer duration of action.
Its muscarinic effects are more prominent on the eye, GIT, and urinary
bladder.
It has nicotinic effects similar to Ach.
Therapeutic Uses
It is rarely used therapeutically because of
1) Its high potency
2) Long duration of action (1hr).
3) Exception is the use in the eye as a miotic agent or in glaucoma
(0.75~5% eye drops).
Adverse Effects
It causes a generalized cholinergic stimulation including: sweating, salivation,
flushing, a decrease in blood pressure, nausea, abdominal pain, diarrhea,
bronchospasm, etc.
Bethanechol (Bethanecholine)
It is a carbamic ester.
Chemically it has structure features of both methacholine &
carbachol.
It has a long duration of action (about one hour).
195
It is mainly muscarinic in actions. Its major action is on the smooth
muscle of the bladder and GIT (with no significant action on CVS).
Actions
It directly stimulates the muscarinic receptors causing:
Increased intestinal motility and tone.
Stimulation of the Detrusor muscle of the bladder causing expulsion of
urine.
Therapeutic Uses
Urological treatment: often used to stimulate the atonic bladder
particularly postpartum or postoperative urinary retention.
Abdominal distension.
Esophageal reflux.
Adverse Effects
It causes a generalized cholinergic stimulation as mentioned above.
Pilocarpine
It is a tertiary amine alkaloid which is less potent than Ach and its
derivatives.
Its action is similar to methacholine.
It has mainly muscarinic activity and is unaffected by ChE enzyme.
Actions
Causes miosis and a decrease in the intraocular pressure (↓IOP).
By opening the trabecular meshwork around the Schlemm’s canal, it
leads to immediate drop in IOP as a result of the escape of aqueous
humor.
Therapeutic Uses
It is used in the treatment of glaucoma (the drug of choice in both
narrow (closed) angle glaucoma and wide (open) angle glaucoma).
The action lasts a few hours and can be repeated. It is used topically
as eye drops (0.5 % solution) to prevent the systemic effects.
196
Adverse Effects
Mechanism of Action
1) Edrophonium
It binds reversibly by weak electrostatic forces mainly to the anionic site of the
enzyme. The enzyme-inhibitor complex is thus short lived (2~10 min). Used
in the diagnosis and treatment of myasthenia gravis. Also used in the
differentiation between myasthenia gravis and cholinergic crisis.
197
2) Carbomic esters
They bind to both anionic and esteratic sites of the enzyme. They undergo a
two-step- hydrolysis by the enzyme similar to Ach. However, the covalent bond
of the carbamylated enzyme is more resistant to the second hydration process
which is prolonged (at least 2~4hrs).
Reversible Anti-cholinesterases ( Carbomates)
198
4.- Uses 1. Eye drops : (miosis, contraction 1. Eye: miotic in
of the cillary M. Accommodation glaucoma
for near object, ↓IOP,
2. GIT: paralytic ileus
lacrimation, twitches of the eye
lid (N. action)-uses : 3. Urinary: post operative
urine retention
a- glaucoma
4. Skeletal muscles:
b-counteract action of mydriatics
myasthenia gravis
c- alternatively with mydriatics to (diagnosis and treatment )
cut recent adhesion between iris
5. Others
and lens
Antidote to curare
2. treatment of:
toxicity
a) atropine- poisoning:
(antagonize central and peripheral
actions of atropine).
b) phenothiazine and tricyclic
antidepressants overdose
3 treatment of Alzheimer disease
"dementia" due to deficiency of
cholinergic neurons in CNS
5- Toxicity Anti Ch E
- Muscarinic: bradycardia, ↓BP, bronchospasm,
vomiting, diarrhea ,↑secretion and miosis
- Nicotinic: sk muscle twitches, eye lid, facial, trunk
CNS convulsions, collapse, Absent
Coma and death from depression
of Resp. Center
6- treatment StomAch wash ,Oxygen and artificial respiration
of toxicity
Atropine 1mg + anticonvulsant ( diazepam )
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Irreversible Anticholineserases
Organophosphorous (organo-phosphate) Compounds
These compounds are designed as high lipid soluble to be absorbed
through the insect and distribute to its CNS very rapidly.
They are:
Mainly used as insecticides.
Used as nerve gases
Few of them (as echothiophate) have limited effect in glaucoma.
They include:
diisopropyl fluorophosphates (DFP)
isofluorphate
ecothiophate
malathion (thiophsphate)
parathion
As well as sarin and somarin. They have been studied for use in war
as nerve gases.
All of them except ecothiophate are highly lipid soluble and well absorbed
from skin, lung, gut and conjunctiva, can cross BBB. Poisoning with these
agents, therefore, includes important effects in CNS.
Toxicity of Organophosphate
Causes of organophosphate poisoning are usually outside clinical practice e.g.
agriculture, industrial, transport accidents, etc.
Manifestations
Excessive muscarinic stimulation (salivation bronchial secretion,
bronchospasm, abdominal cramps, urination and defecation, sweating and
hypotension), nicotinic (respiratory muscles Paralysis) and CNS effects
(convulsion, etc.).
Paralysis of respiratory muscles due to :
1) Peripheral neuromuscular blockade
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2) Excessive bronchial secretions and bronchospasm causing respiratory
failure.
Death due to respiratory failure and CNS effects (convulsion, etc.)
Chronic exposure to certain organophosphates causes neuropathy
associated with de-mylination of the nerve axons.
Treatment
1) Decontamination:
This is to prevent further absorption by removal of the clothes, washing of the
skin (sodium bicarbonate) and gastric lavage if any of the substances has been
ingested.
2) Maintenance of the vital organs:
Aspiration of bronchial secretion, endotrAcheal intubation, oxygen or
artificial respiration may be needed.
Stimulation of the heart by adrenaline.
3) Atropine:
It is given in large doses to compensate the muscarinic and CNS effects.
1-2mg dose is given every 15 minutes until signs of adequate atropinization
occur (dry mouth, HR 70b/min, etc).
The patient should be kept fully atropinized for at least 24hrs.
4) Antidote:
Antidote as cholinesterase re-activator e.g. oxime is given.
5) Diazepam:
It may be needed for convulsions.
Mechanism of Oxime Agent Action
The oxime has very high affinity to the phosphorus atom.
It is attAched to the unoccupied anionic site of the enzyme and the free
oxime end attAches the phosphorus atom from the esteratic site of the
enzyme. Oxime displaces the enzyme and binds to the organophosphate
compound. Oxime agents are able to hydrolyze the enzyme if the complex has
NOT aged. Thus, it should be administrated within 12hrs of poisoning.
201
Examples of oximes include pralidoxime (PAM), diacetylmonoxime (DAM)
and obidoxime.
Pralidoxime can regenerate ChE associated with NMJ. DAM and obidoxime
have an advantage that they can cross BBB and regenerate some of CNS
ChEs.
Dose of DAM:
I/V infusion 1~2mg over 5~30min. additional dose may be given if muscle
weakness persists.
Myasthenia Gravis
Many theories are applicable to this condition:
Circulating curare-like substances.
Defective rate of Ach synthesis.
Excessive amount of acetyl-cholinesterase in the NMJ.
Autoimmune disease which is the main theory.
Drug-induced myasthenia.
It is an autoimmune process which causes production of antibodies that
decrease the number of functional nicotinic receptors on the post-junctional
end plate.
It is characterized by weakness extraocular muscles, bulbar, muscles of the
neck, followed by other muscles. It shows muscle weakness and fatigability
resulting from failure of neuromuscular transmission.
Diagnosis
Edrophonium test:
Give 2mg I/V. After 45 seconds, if no reactions occur, give additional 8mg
in one or two-divided dose.
A positive test is dramatic relief of muscle weakness.
Neostigmine:
Give 1.5mg neostigmine plus 0.6mg atropine (to abolish muscarinic
action).
If the muscle weakness is improved, the diagnosis of myasthenia is
confirmed.
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Treatment
a) Symptomatic treatment:
Pyridostigmine: 60mg orally given every 6hrs. The dose is increased if
necessary. Pyridostigmine is preferred because its action is smoother than
neostigmine.
Neostigmine: 15mg orally given every 6hrs. The dose is increased if
necessary. It has faster onset of action and is useful for morning weakness.
Atropine may be needed to control muscarinic side effects.
b) Immunosuppressive drugs:
They are used to eliminate Ach-receptor antibiotics.
Steroids: start with small dose of prednisolone (10mg/day) to avoid
worsening of muscle weakness as steroids render ChEIs more effective and
cholinergic crisis may be provoked. The dose should be increased slowly.
Steroids are indicated in:
1) Seriously ill patients prior to surgery.
2) Patients unsuitable or not benefited from thymectomy.
3) Those with poor response to anticholinesterase.
Other immunosuppressive drugs e.g. cyclosporine.
c) Other measures
Thymectomy for patients under 40yrs and those who have thymomas.
Plasmapheresis to remove antibodies.
Myasthenia crisis Cholinergic crisis
Muscle weakness due to Muscle weakness due to excessive
exacerbation of myasthenia: anticholinesterase treatment.
1. Inadequate treatment
2. Drug-induced myasthenia
3. Infection
Diagnosis: positive edrophonium Worsened by edrophonium.
test. Muscarinic symptoms are present
No Muscarinic symptoms
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Treatment: Treatment:
Ant cholinesterase Withdrawal of ant cholinesterase
Mechanical respiration is Mechanical respiration is required
required PAM 0.5mg I/V infusion may be
Early and effective antibiotic tried
therapy (for infection) Atropine to block excess
Plasmaphoresis has been tried muscarinic effects
Cholinergic Antagonists
They are also known as cholinergic blockers, anticholinergic drugs or
Ach receptor antagonists.
They are referred to as parasympathatolytic because they selectively
reduce or abolish the effect of parasympathetic stimulation.
All of them are competitive antagonists of Ach at muscarinic or
nicotinic receptors. They bind to choline receptors but do not trigger
the usual receptor mediated intracellular effect.
They selectively block the muscarinic and nicotinic synapses of the
parasympathetic nerves and the actions of sympathetic stimulation are
left unopposed.
Because of importance of Ach as neurotransmitter, the drug that blocks
Ach receptor has very important clinical applications. This includes
drugs acting at muscarinic and nicotinic sites.
Classification
They are classified according to their affinity to receptors into:
Anticholinergic
Antimuscarinic Antinicotinic
Synthetic
Natural Ganglionic blockers NMJ blockers
Semi-synthetic
Antimuscarinic Agents
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They are called muscarinic antagonists or atropine-like drugs.The
effectiveness of antimuscarinics varies with the
(1) source of antagonist and
(2) the tissue under the study.
They are subdivided on basis of their ability to distribute in the CNS into
(1) quaternary and
(2) tertiary amine groups.
They include:
Natural Agents (alkaloids):
1) Atropine: di-hydro-scyamine in Atropa belladonna and Datura
stramonium.
2) Scopolamine: hyoscine in Hyoscyamus niger.
Synthetic and semi-synthetic: They are atropine’s substitutes mainly three
groups:
1) Mydriatic and cycloplegic.
2) Anti-secretary and antispasmodic.
3) Anti-parkinsonism.
Pharmacokinetics
The tertiary drugs are well absorbed from the gut, conjunctiva and
skin. In contrast, (10~30%) of a dose of a quaternary agent is
absorbed after oral administration reflecting the decrease in lipid
solubility.
They rapidly disappear from the blood within (t½ = 2hrs) and (60%)
excreted unchanged in urine.
The effect of the drug declines rapidly from all organs (4hrs) except
the eye (72hrs~days).
Mechanism of Action
They cause competitive blockade of the action of Ach at muscarinic
receptors.
The antagonist could be overcome by increasing the concentration of
Ach at receptor sites of the effector organs e.g. by anticholinesterase.
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Atropine
Mechanism of Action
It competes reversibly with Ach at muscarinic receptor.
At very high concentrations, it blocks Ach at ganglionic synapses and
motor nerve endings.
It antagonizes the action of Ach in CNS.
Pharmacological Effects
1) CVS:
Heart: it produces divergent effects depending on the dose (initial
bradycardia followed by tachycardia).
1) Low dose (0.5 mg): decrease COP and bradycardia due to
activation of vagal afferent outflow.
2) High dose (1 mg): blocks cardiac muscarinic receptors M2 resulting
in tachycardia. This is more apparent in young athletes with high
vagal tone than in old patients or infants.
Bp: since blood vessels have no cholinergic innervation, blood pressure
is unaffected. Oral or I/M doses have little effect but I/V dose will
increase heart rate and that causes arterial blood pressure to increase.
Atropine has a direct vasodilating effect on small blood vessels due to
prevention of calcium passage through the blood vessel wall.
Toxic doses: lead to marked dilation of cutaneous blood vessels
(Atropine Flush).
2) CNS:
Atropine produces both stimulant and depressant actions in CNS:
Stimulant actions:
1) Therapeutic doses stimulate the cardio-vagal center leading to
bradycardia.
2) Very large doses stimulate the cerebral cortex leading to restlessness,
hallucinations and delirium.
This central excitation is followed by depression.
Depressant actions: manifested by
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1) Decreased tremors and rigidity in Parkinsonism.
2) Antiemetic action in some cases of motion sickness (hyoscine is
better).
3) Counteraction of the central excitatory action of eserine and
organophosphate compounds.
4) Reduction of electric activity of the brain.
3) GIT:
It decreases the amplitude and frequency of peristaltic contractions
and reduces the tone of the stomach, small intestine and colon
(antispasmodic action).
It reduces gastric acid secretion in both volume and total acid
content.
4) Other Involuntary Muscles:
Relaxation of biliary tract smooth muscles.
Relaxation of bronchial smooth muscles. It prevents reflex
bronchoconstriction during anesthesia by bronchodilation action and
reduction of bronchial secretion (reduces the risk of airway
obstruction and pneumonia).
Reduces contraction of the sphincter and trigone leading to retention
of urine.
In ureter, it is antispasmodic.
5) Secretions:
All secretions (salivary, lacrimal, bronchial and sweat secretion) EXCEPT
milk are diminished.
Dry mouth is common.
Bronchial secretion is reduced and becomes viscid.
Thermoregulatory sweating is suppressed causing atropine fever which
is not dangerous except in warm environment especially in infants and
children.
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In large doses (over 1 mg), gastric acid secretion is decreased. It
reduces pepsin and mucous and volume out put. The gastric pH is
little affected.
6) Eye:
Atropine locally or systemically blocks Ach response of the:
1) Ciliary muscle of the lens producing cycloplegia (inability to focus for
near vision).
2) Circular smooth muscle of the iris producing mydriasis (dilatation of
the pupil).
Both effects precipitate acute attack of glaucoma in patient with narrow
anterior champer.
Loss of normal pupillary reflexes which may last for two weeks.
Reduction of lacrimal secretions leading to dry eye or sandy eye.
May cause rise in IOP due to closure of Schlemm’s canal and obstruction
of space of Rontana. This is dangerous in patient with glaucoma.
Tolerance of Atropine:
Natural tolerance to atropine is present in certain species e.g. rabbits which
naturally have atropinestease enzyme in the blood and liver that destroys the
alkaloid! In man, however, tolerance to atropine occurs to a limited extent in
patients with Parkinsonism following prolonged use of the drug.
Therapeutic Uses
1) CNS disorders:
Pre-anesthetic medication: atropine is administrated half an hour before
general anesthesia in order to:
1) Decrease salivary and bronchial secretions which are usually increased
with certain irritant anesthesia as ether. It also causes bronchodilation.
2) Protect the heart from excessive vagal tone which may occur with
halothane anesthesia.
3) Counteract the inhibitory effect of morphine on respiratory center.
4) Antiemetic.
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Parkinsonism: to reduce rigidity, tremor and autonomic effect. Synthetic
substitutes are better.
Motion sickness: 0.3-0.6mg injection.
2) GIT & genitourinary tract disorders:
Dicyclomine is used in hypermotility induced by drugs such as
anticholinesterase (reduces gut motility).
Widely used to reduce gastric acid in patients with peptic ulcer
(synthetic substitutes are better). Histamine antagonists have
replaced them all.
As antispasmodic in cases of intestinal, biliary and renal colic.
In irritable bowel syndrome.
In traveler’s diarrhea.
In sensory urgency.
In nocturnal enuresis (tricyclic antidepressants are preferable).
3) Ophthalmic uses:
In fundus examination.
Accurate measurement of refractive errors especially in young children.
(Aids in ophthalmoscopic examination of the retina).
In cases of iritis and corneal ulcer to prevent adhesions formation
(synechia).
Used in alteration with mitotic to break down recent adhesions
between the iris and the lens.
Homatropine, cyclopentolate and tropicamide are drugs developed
specifically for ophthalmic uses.
4) CVS disorders:
Severe bradycardia and syncope associated with hyperactive carotid
sinus reflex.
Heart block due myocardial infraction or overdose of digitalis or
propranolol.
5) Respiratory:
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Ipratropium bromide is an effective bronchodilator in bronchial
asthma but the sputum become viscid and more difficult to expel.
6) Cholinergic poisoning:
As antidote to parasympathomimetic e.g. organophosphate poisoning.
In mushroom poisoning.
Tertiary members are preferable to reverse central and peripheral effects
7) Other:
In hyperhidrosis (excessive sweating).
In urolithiasis to relief the smooth muscle spasm caused by passage of
stone.
Adverse Effects
o Dry mouth.
o Blurred vision and photophobia.. sandy eye and Loss of normal
pupillary reflexes
o Acute glaucoma in patients with narrow anterior champer.
o Tachycardia.
o Flushing and hyperthermia especially in infants.
o Retention of urine in old patients with enlarged prostate and
constipation.
Contraindications
Patients with glaucoma.
Elderly men with history of prostate (urine retention).
Patients with peptic ulcer because it delays gastric emptying. So,
treatment of ulcer with antacid and H2 blocker is preferable.
Atropine Poisoning
The symptoms appear quickly and may proceed for some days.
(1) Parasympathetic Depressant Symptoms:
These include: dry mouth, mydriasis, blurred vision, hot and dry skin, flush
in addition to hyperthermia.
(2) CNS Symptoms:
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They include: restlessness, confusion, hallucination, delirium and mania
followed by depression.
The patient is described as:
“Dry as a bone” Dry mouth
“Hot as a hare” Inhibition of sweating
“Red as a beet” Tachycardia and coetaneous vasodilation
“Blind as a bat” Blurring of vision
“Mad as a hen” Hallucination and delirium
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o Bronchial muscles.
o Intestine.
3) CNS action:
o Atropine has longer duration of action and in therapeutic doses it does
not depress the CNS. Hyoscine is chiefly a CNS depressant and may
some times causes excitement.
o It produces amnesia.
o Hyoscine is preferable than atropine in pre-anesthetic medication
because of amnesia effect, depression of CNS, strong anti-secretary
action and strong antiemetic action. In addition, it counteracts
respiratory depressant of morphine.
Therapeutic Uses
They are similar to that of atropine but it is excellent for treatment
of motion sickness.
It is more useful as prophylactic than as treating the condition after
it occurs. It is mainly used as antiemetic and antispasmodic.
The dose is 0.5~1.0 mg orally or parenterally.
Atropine Substitutes
They are also known as synthetic or semi-synthetic antimuscarinic
drugs.
They include (1) tertiary and (2) quaternary ammonium compounds.
The tertiary antagonists are used often for their effect on the eye and
CNS.
The quaternary members are developed to reduce CNS effects. They
are mainly used for GIT and genitourinary disorders. They are poorly
lipid-soluble with lower CNS effects and their distribution is mainly
extra-cellular. In addition, they have ganglionic blocking activity.
Atropine Substitutes for Ophthalmic Use
They produce mydriasis and cycloplegia (for short duration) which are
easier to be antagonized.
Homatropine (1.2~0.5%drops). It has short duration of action than
atropine (1~3days) and is less likely to cause serious rise in IOP. It is
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unreliable in children in whom atropine is preferred. It is used to produce
cycloplegia and mydriasis for ophthalmic refraction.
Eucotropine is used as mydriatic in acute iridocyclitis.
Tropicamide (mydracil 0.5~1.0%). It has short duration of action (1hr). It
produces mydriasis but is inadequate cycloplegic.
Cyclopentolate (cyclogyl 0.5~2.0%). It has shorter duration of action than
homatropine. It is thought to be act by direct relaxation of muscle rather
than competitive antagonist of Ach at muscarinic receptor.
Atropine Substitutes for GIT & Genitourinary Use
They are mainly used against muscle spasm and hypermotility. Examples
include:
Propantheline (7.5~15mg orally)
Clidinium.
Hyoscine (N-butyl-bromide buscopan 10mg).
Oxyphenonium.
Isoprpamide (5mg orally).
Pirenzepine (gastrozepine) and telonzepine are M1 blockers that are
preferable in treatment of peptic ulcer than antimuscarinic blockers.
Emepronium (cetiprin 200mg orally). It is used to reduce the bladder
motility and capacity.
Ipratropium bromide (20mg). It is a synthetic quaternary analogue of
atropine, which is used by inhalation as bronchodilation. It has a little
effect on mucous viscosity.
Nicotinic receptor antagonists
NiThese drugs affect the neurotransmission at either the ganglia or the
effector organs
Nicotine
Nicotine is a toxic and addictive drug derived from tobacco leaves. It is the
active ingredient of tobacco.
It acts by depolarizing the ganglia resulting first in (1) stimulation followed by
(2) paralysis of ganglia i.e.:
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In low doses: causes ganglionic stimulation by depolarization.
In high doses: causes ganglionic blockade by persistent depolarization,
The effects are complex including:
↑ COP and Bp.
↑peristalsis and secretion.
Pharmacokinetics
Absorbed through oral mucosa, GIT and skin.
Cigarette contains 6~8 mg of nicotine and the lethal dose is 60 mg.
Nicotine substitution therapy as chewing gums (contains 2 mg) or
nicotine patch reduce withdrawal symptoms.
Mechanism of Action
It is highly lipid soluble, penetrate and stimulate CNS, then depresses
the vital medullary and respiratory centers.
Low doses: Relaxation; improved attention, learning, reaction time,
problem solving and some degree of euphoria.
High doses: Respiratory paralysis; severe hypotension caused by
medullary paralysis; & complex peripheral effects including a fall in
blood pressure, cessation of GIT and urinary activity.
Pharmacological Actions
↑Heart work due to increase in the rate and force of contraction.
↑FFA level in blood causes vasospasm.
↑Gastric acid secretion.
↑Incidence of pre-eclampsia due to constriction of blood vessels and
↑neonatal mortality.
Lowered ciliary reactivity of bronchi.
Induction of liver microsomal enzymes.
↑Incidence of cancer.
↑Incidence of CVDs.
214
It decreases the oxygen carrying capacity of blood and causes amblyopia
(rare) which is characterized by decreased visual activity due to spasm of
retinal blood vessels.
Adverse Effects
CNS: irritability and tremor.
Peripheral: intestinal cramps, diarrhea, increase heart rate and blood
pressure.
Accelerate drug metabolism: increases rate of metabolism of number of
drugs.
Withdrawal symptoms: physical dependence of nicotine develops
rapidly including: irritability, anxiety, restlessness, difficulty in
concentration, headache and insomnia, appetite often affected, and
GIT pain may occur.
Ganglionic Blockers
These drugs act on nicotinic receptors on autonomic ganglia.
They block both sympathetic and parasympathetic ganglia WITHOUT
selection i.e. block the entire output of ANS at nicotinic receptors.
The effects observed are complex and widely spread making it
impossible to achieve selective actions. So rarely used therapeutically
today. They are not effective as neuromuscular blockers.
Presynaptically:These drugs block synthesis and/or release of Ach.
Postsynaptically: block nicotinic receptors in both sympathetic and
parasympathetic ganglia.
1) Depolarizing Ganglionic Blockers
o These include large doses of ganglionic stimulants that block the
ganglia by persistent depolarization.
o They have no therapeutic application.
o Examples include nicotine, lobeline, DMPP and TMA.
2) Non-depolarizing Ganglionic Blockers
o These are competitive blockers
o Examples include trimethaphan, mecamylamine, etc.
215
Actions of ganglionic blockers
1) Blockade of sympathetic ganglia:
Drop in blood pressure due to (1) peripheral vasodilation & (2)
decreased venous return.
Postural and exercise hypotension due to blockade of cardiovascular
reflex.
Sexual function impairment (failure of erection and ejaculation).
2) Blockade of parasympathetic ganglia:
In the eye: mydriasis, cycloplegia and increased IOP.
Tachycardia.
Reduction of GIT secretion and motility with constipation.
Urinary retention.
Impotence.
Sweat gland thermoregulatory block leading to hyperthermia (a
problem except in hot environment) but cutaneous vasodilation
maintains normal body temperature.
Therapeutic Uses
Treatment of hypertension; trimethaphan is used to control blood
pressure.
In autonomic hyper-reflexia in patients with spinal cord injury
characterized by sweating, flushing and severe headache that may be
associated with a marked rise in arterial blood pressure, bradycardia
and confusion.
TEA is used for diagnosis of pheochromocytoma. 100ml is given I/V to
produce a lowering in blood pressure due to direct stimulant action on
the tumor as a result of ganglionic blockade.
In acute pulmonary edema. By causing peripheral vasodilation blood is
shifted from the pulmonary circulation to the peripheral.
Trimethophan (Arfonal)
This is a short acting, non-depolarizing (competitive), ganglionic blocker. It
lowers the blood pressure by:
216
Ganglionic blockade.
Direct vasodilation.
Histamine release.
Therapeutic Uses
A single administration lasts 1~2min, a continuous infusion (0.1%
solution in 5% dextrose in water) lowers blood pressure instantly.
Used to control blood pressure (1) during surgery, (2) in malignant
hypertension and (3) hypertension caused by pulmonary edema.
Mecamylamine hydrochloride (inversin)
It produces a competitive nicotinic block of ganglia.
Duration of action is 10hrs after a single administration.
Absorption is good in contrast to trimetaphan.
It reaches CNS producing tremor and mental confusion.
A dose of 25mg orally achieves the hypotensive effect.
Drugs Acting at the NMJ
Skeletal Muscle Relaxants
1- Neuromuscular blockers (NMB).
2- Spasmolytics.
1) Neuromuscular blockers NMB
Are drugs that interfere with NM transmission. They act pre-synaptically or
post-synaptically.
A) Pre-synaptic (pre-junctional) agents:
Are drugs that depress Ach output from motor nerve terminal (interfere
with synthesis and\or release of Ach) they may act by the following ways:
a) inhibition of Ach synthesis:
They block the uptake of choline by the nerve terminal, hence,
blocking Ach synthesis .e.g. Hemicholinium, triethylcholine.
b) Inhibition of Ach release: This may be activated by:
i. Lack of Ca++, or excess of Mg++ or phosphate ions.
ii. Local anesthetics e.g. procaine {as they depress the nerve action
potential}.
217
iii. Botulinium toxin.
B) Postsynaptic(post-junctional) agents:
They prevent action of released Ach on receptors, either by competition
or depolarization:
c) non-depolarizing (competitive reversibly) NMBs:
They compete with Ach for N-receptors preventing depolarization of
motor end plate {MEP} by Ach, leading to failure of transmission
and muscle paralysis .e.g tubocurarine, pancuronium,
gallamine…etc
d) depolarizing (non-competitive) NMBs:
They have same action of Ach, but instead of initiating
depolarization, they produce prolonged depolarization {fasciculation
followed by muscle paralysis} e.g. succinylchloine, decamethonium
A. Non-depolarizing NM blockers:
Mechanism of action:
1. At low doses: they combine with N-receptors preventing binding of
Ach, thus preventing depolarization of muscle cell membrane and
inhibit muscle contraction.They are called competitive because they
compete with Ach on N-receptors.Their action can be overcome by
increasing the concentration of Ach on synaptic cleft by administration
of anticholinesterases as neostigmine and edrophonium.
2. At high doses: they block channels of MEP (Na+ channels, not Ca++
channels) leading to further weakening of NM transmission and
reduced ability of anticholinesterases to reverse their action. Muscles
affected are:
i. Muscles innervated by the cranial nerves
ii. Muscles of the limbs and trunk
iii. Intercostal muscles and diaphragm. Death from toxic doses is
due to paralysis of respiratory muscles.
3. They have weak ganglionic action, i.e., large doses are required to block
autonomic ganglia than for blocking NM transmission.
4. They have histamine releasing action leading to bronchospasm,
hypotension, and excessive bronchial and salivary secretion.
Hypotension is due to:
i. Peripheral vasodilatation due to histamine release.
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ii. Sympathetic ganglionic blockade
iii. Diminished venous return due to loss of skeletal muscle tone.
Pharmacokinetics:
Since they are quaternary ammonium compounds (alkaloids) they do
not enter CNS, oral absorption, so they have to be given parentally.
Many of these drugs are not metabolized and are excreted unchanged
in urine.
Most of them have a relatively long duration of action ranging from
30min~1 to2 hrs
Therapeutic uses:
Used as adjuvant drugs in surgical anesthesia.
Adverse effects:
Only tubocurarine may cause bronchospasm, skin wheals due to release of
histamine.
Toxicity:
Profound and prolonged muscle relaxation with consequential respiratory
paralysis and hypoxia.
Treatment of toxicity of all members:
1. Artificial ventilation
2. Antidote neostigmine 1~8mg I.V preceded by 0.6mg atropine to
prevent excessive bradycardia, or edrophonium 10mg repeated as
required owing to its short duration of action.
3. Anti-histamine to counteract the signs caused due to histamine release.
Drugs interactions:
The action is potentiated by:
1. Halogenated hydrocarbon anesthetics as halothane and ether that
enhance NM blocking by exerting a stabilizing action at NMJ.
219
2. Antibiotics (streptomycin, polymixine) that inhibit Ach release
from cholinergic nerves by competing with Ca++, they synergize with
tubocurarine and other competitive blockers enhancing the block.
3. local anesthesia, anti-arrhythmic drugs , quinidine ,quinine , K+
depleter (diuretics) ,cholorpromazine, Ca++ channels blockers that
increase NM block of tubocurarine and other competitive blockers
as well as depolarizing blockers.
Their action is antagonized by anticholinesterases. K+…..etc
Tubocurarine:
Pharmacokinetics:
o Highly ionized, so, it does not cross membranes and have limited Vd.
o 50%-60% of it is excreted through bile.
Pharmacological action:
1. paralysis of skeletal m.:
IV dose cause muscle weakness more than muscle flaccidity and
inexcitibility to stimulation. Not all muscles are equally sensitive to
blockage by competitive blockers, that is, small rapid contractile
muscles of the face and the eye are more susceptible and paralyzed
first followed by finger muscles, neck and trunk muscles, and
intercostals muscles, and lastly the diaphragm.
Duration of action: 20min~1 to2 hrs after a single administration
(depending on the dose).
2. other effects:
a) A small degree of ganglionic blockade by block N-
receptors at autonomic ganglia.
b) The adrenal gland may be blocked.
c) A fall in BP by release of histamine.
Dose:
Initially 10~15mg IV, then supplement accord to response.
Adverse effects:
Hypotension, bronchospasm, and allergy, effect of diplopia may persist for
few days.
220
Toxicity:
Profound and prolonged muscle relaxation with consequential respiratory
paralysis and hypoxia.
Preparation and dosage:
1. D-tubocurarine chloride (tubarine) 15~20mg IV: a test dose of
5mg is given first to test the patient susceptibility.
2. Dimethyl tubocurarine iodide (metubine): a semi synthetic
derivative of D-tubcurarine which is 3 times more potent.
221
The depolarization persist because succinylcholine is not rapidly
hydrolyzed, the resulting muscle paralysis is flaccid.
2) Phase II block (desensitization):
With repeated or prolonged administration of succinylcholine,
phase I block changes to phase II block.
The end plate membrane becomes repolarized. It does not
respond to Ach, so the membrane is said to be desensitized to the
effects of Ach (desensitization block).
Succinylcholine (suxamethonium) Sch:
The only member of this group commonly used clinically.
It is a dicholine ester (2molecules of Ach linked end to end) which
attachs to N-receptors and acts like Ach to depolarize NMJ.
Pharmacokinetics:
Has a short duration of action (5~10 min) due to rapid hydrolysis by pseudo
cholinesterase (butyl cholinesterase), hydrolysis occurs in 2 steps:
1. initial rapid step: conversion of Sch to succinylmonocholine (a much
weaker NMB).
2. slow prolonged step: conversion of succinylmonocholine to succinic
acid and choline (inactive products).
Pharmacodynamic:
1. Skeletal muscles: IV administration causes transient fasciculation
followed by paralysis, this affect the arms, neck, leg, pharyngeal
muscles, and lastly respiratory muscles.
Post-operative muscle pain may follow paralysis.
2. Autonomic ganglia: Stimulation, leading to a transient bradycardia &
salivation (parasympathetic action) followed by tachycardia & increase
in BP (sympathetic action).
3. Histamine release (particularly in high doses).
4. A transient increase in intra-ocular pressure due to the transient
vasodilatation and contraction of extra-ocular muscles.
5. Occasionally, an increased intra-gastric pressure due to fasciculation of
abdominal muscles that may cause regurgitation of gastric contents.
Dose:
1. 0.5~1.0 mg/Kg IV for short duration (relaxes muscles for 5min).
222
2. IV infusion 0.1~ 0.2% solution in 5% dextrose (or 0.9% saline) at the
rate of 2~ 4ml/min (relaxes muscles as long as required).
Adverse effects and toxicity:
1. Post-operative muscle pain
2. Malignant hyperthermia
3. Bradycardia, cardio muscular collapse, and cardiac arrest.
4. Hyperkalemia
5. Increased intra-ocular pressure
6. Salivation.
Treatment of overdose:
1. Artificial respiration until the muscle power returns.
2. Fresh blood transfusion in case of lack of cholinesterase enzyme in
the plasma (when phaseI block is present).
3. No specific antidote is available.
4. When phaseII block is present, IV anti-cholinesterase may be used;
edrophonium 10 mg, neostigmine 2~5mg, atropine 1 mg.
Sch- apnea:
It is a prolonged apnea produced by Sch use, due to lack of
peudocholinesterase which may be:
1. Genetically abnormal: the enzyme is either totally unable to split
Sch or its activity is less than normal or totally absent.
2. Acquired: low plasma level of enzyme activity and/or amount as
in cases of liver diseases, malnutrition, organophosphate
poisoning…etc
3. During pregnancy its level decreases by 25%, pregnant women
are more susceptible to Sch- apnea.
Contraindications:
1. Patient with abnormal plasma pseudo cholinesterase.
2. Patient with history of malignant hyperthermia.
3. Patient with acute narrow angle glaucoma, or penetrating eye
injuries.
4. Patient with allergy to Sch.
5. During pregnancy.
Indications:
223
1. Adjustment in general anesthesia to prolong muscle relaxation
during operation and decrease the amount of anesthesia
required
2. Facilitation of endotracheal intubation, laryngeoscopy,
bronchoscopy, and oesophageoscopy.
3. Controlling convulsions (used in the symptomatic treatment of
all convulsions states as tetanus).
4. Prevent cough and laryngeospasm during operation.
2) Spasmolytics:
A. Centrally acting muscle relaxants
They act on spinal cord and brain inhibiting multi-synaptic reflexes
involved in producing and maintaining muscle spasm of varied
etiology.
They do not relax tense muscles directly.
Diazepam (valiumR):
Facilitates GABA-mediated pre-synaptic inhibition (by opening Cl-
channels producing hyper-polarization reducing neuronal excitability).
At high doses, it may suppress NM transmission.
Baclefen (LioresolR):
1. An orally active GABA-mimetic agent that acts on pre-synaptic
GABA receptors leading to inhibition of the release of excitatory
transmitter in the brain and the spinal cord.
2. It inhibits mono- and poly-synaptic reflexes
3. It can also inhibit release of substance P in the spinal cord
reducing pain in patients with spasticity.
4. Is less sedative than diazepam.
5. It does not reduce general muscle strength as does dantrolene.
6. It benefits some cases of trigeminal neuralgia. Dose:15 mg twice
a day.
B. Direct acting spasmolytics:
Dantrolene (DantriumR):
Does not act on central suppressor of NMJ
224
Mechanism of action:
1. Acts directly on muscle, preventing release of activator Ca++ from
sarcoplasmic reticulum interfering with excitation-contraction
coupling.
2. Main action on skeletal muscles, but cardiac and smooth muscles
may be affected.
Uses and dosage;
1. Spastic state e.g. tetanus 25~100 mg orally/day.
2. Malignant hyperthermia 1~2 mg/Kg IV.
Adverse effects:
1. Generalized weakness.
2. Sedation and hypotension.
3. Constipation.
225
also dopamine and ephedrin
4) According to selectivity on adrenergic receptors (type of receptors)
226
Vasoconstriction, increase in PVR. Increased Bp. Relaxation of GIT
α1 smooth muscle. Salivary secretion. Mydriasis. Hepatic glycogenolysis.
Closure of the internal sphincter of the urinary bladder
Inhibition of NE and Ach release from autonomic nervous system.
α2
Platelet aggregation.
Increase cardiac rate and force. Relaxation of GIT smooth muscle.
β1
Lipolysis.
Bronchodilation. Vasodilatation and slight decrease in PVR. Relaxation
β2 of visceral smooth muscle. Hepatic glycogenolysis. Muscle tremor.
Relaxation of uterine smooth muscles .
227
4) The activated GTP bound α-subunit then regulates the activity of its
effectors. These effectors of activated α-subunit include adenylyl cyclase/
cAMP system, cGMP, phospholipase C/ inositol phosphate system and ion
channels.
The inactivation of α-subunit occurs due to hydrolysis of the bound
GTP to GDP + PI and the consequent re-association of α-subunit
and β-γ dimer.
The α1 receptors differ greatly from α2 in their physiology.
1) The α1 receptors are mediated by second messenger phospholipase C,
which increases intracellular Ca++ and leads to activation of protein kinase
and hence the physiological response.
2) The α2 and β receptors act on another enzyme which is adenylyl cyclase
that leads to conversion of ATP to cAMP.
β-receptors are coupled to stimulating type of G-protein (Gs) whereas
the α2-receptors are coupled to inhibitory type of G-protein (Gi).
They cause stimulation and inhibition, respectively, of the target
enzyme adenylyl cyclase.
So, the effects of β-receptor stimulant are brought about by
activation of adenylyl cyclase via (Gs) with consequent increase in
intracellular cAMP that initiates a sequence of enzymatic β-effects. In
addition, Gs proteins directly enhance the activation of voltage
sensitive calcium channels in plasma membrane of skeletal and
cardiac muscles.
The α2-receptors produce their effects by inhibiting adenylyl cyclase
via (Gi) reducing intracellular cAMP. The Gi proteins also activate
potassium conductance and inhibit voltage sensitive calcium
channels.
Neurotransmission:
Uptake and Degradation (Fate) of Catecholamines:
Catecholamines differ markedly from Ach in the way by which their
action is terminated.
There is no sympathetic enzyme as AchE that rapidly degrades
catecholamines.
228
The main mechanisms by which the released transmitter is inactivated
are:
1) Reuptake of NE by adrenergic nerve terminals and by other cells.
2) Circulating NE and E are degraded enzymatically but much more slowly
than Ach. The two main enzymes MAO and COMT are located in the
intracellular so, uptake into cells necessarily precedes metabolic
degradation.
Reuptake:
It is a major mechanism by which the released NE is removed from the
vicinity of autonomic endings.
The sympathetic nerve uptakes amine from circulation and releases it
again as a transmitter by sympathetic stimulation.
1) Neuronal uptake; uptake Ι:
Amine pumps actively transport NE into the neuronal cytoplasm.
It is blocked by cocaine, tricyclic antidepressant as desipramine or
imipramine and chloropromazine.
It is a high-affinity system with a relatively low maximum rate of
uptake.
Substrates uptake is relatively selective for NE (specificity NE >E).
2) Extra-neuronal (non-neuronal) uptake; uptake II:
NE is taken to muscles and into gland cells prior to destruction.
It is blocked by steroid hormone or glucocorticoids,
phenoxybenzamine, normetanephrine and metanephrine.
It has low affinity for NE, but much higher maximum rate.
The substrate specificity accumulates epinephrine and isoprenaline
(E>NE).
3) Granular uptake:
It actively transports cytoplasmic NE into the storage resides.
It can be inhibited by reserpine.
(N.B. uptake I and II are the major mechanisms).
Enzymatic Catabolism (metabolic degradation:
229
Endogenous and exogenous catecholamines are metabolized mainly by two
enzymes;
a. monoamine oxidase (MAO) and
b. catechol ortho- methyl transferase (oxidant COMT).
Direct Acting Adrenergic Agonists
Epinephrine (Adrenaline)
It is one of the three natural catecholamines which is synthesized from
tyrosine in the adrenal medulla and released with small quantities of
NE in the blood stream.
It interacts with both α and β receptors.
At low doses → β-effects on the vascular system predominate.
At high doses → α-effects are stronger
Pharmacological Actions:
a) Local Actions: When applied to mucous membranes or surfaces, it leads to
vasoconstriction and accordingly it produces:
1. Local haemostatic action when applied to a bleeding surface.
2. Decongestive action.
3. Delay in the absorption of associated drugs when injected s/c.
230
CVS Actions:
Increased heart rate; positive chronotropic action (β1 effect).
Increased force of contraction; positive inotropic action (β1 effect).
Increased excitability leading to extra systolies.
Increased cardiac output so increased oxygen demand of the
myocardium.
Vasoconstriction of the arteriolar blood vessels of the skin and mucous
membranes (α1effect).
Vasodilatation of the skeletal muscles and coronary blood vessels (β2
effect).
N.B.
The cumulative effect is in systolic pressure due to increased COP and
there is a slight change in diastolic pressure.
The increase or decrease depends on the final effect on peripheral
resistance that depends on the ratio of α and β activity on vascular
beds. If α is blocked there would be a fall in Bp since there is only β
effects.
Respiratory system
Stimulation of respiratory system through a central mechanism.
Powerful bronchodilation (β2 effect). In bronchial asthma it acts
directly on smooth muscle and relives all known allergen- or histamine-
induced bronchoconstriction.
In acute asthmatic attack, it rabidly relieves the dyspnea (labored
breathing) and increases the tidal volume (volume of gas inspired and
expired).
Urinary bladder
It relaxes the detrusor muscle (β2-effect).
It contracts the sphincter and trigone (α1-effect)
Uterus
In experimental animal it has variable actions on the uterus depending
on the species and stage of the cycle.
231
It relaxes the pregnant human uterus.
Eye
It has limited effect on the size of the pupil (local application) for two
reasons:
1) It is partly destroyed by the alkalinity of tears.
2) It causes vasoconstriction of the conjunctiva blood vessels and thus
hinders its own absorption.
It lowers IOP in open angle glaucoma.
GIT
Stimulation of both α and β receptors, leads to inhibition of tone and
motility of GIT smooth muscles.
2) Metabolic actions:
Adrenaline increases blood glucose level (hyperglycemia) by two
mechanisms:
a) By β2 effect; enhancement of glycogenolysis in liver and increased
release of glucagon. It also decreases uptake of glucose by peripheral
tissues.
b) By α- effect; decreased release of insulin.
Initiates lipolysis through β1 activity.
Increases blood concentration of free fatty acids as a result of increased
breakdown of triglycerides in adipose tissue.
Increases metabolism (has a calorigenic action). This is evidenced by
increased oxygen consumption 20~30% after the usual doses.
Produces a transient rise in plasma potassium followed by a prolonged
fall.
3) Adrenocortical actions:
It stimulates anterior pituitary to secrete ACTH, which enhances the
secretion of hydrocortisone from the adrenal cortex.
4) Skeletal muscle action:
232
Adrenaline facilitates neurotransmission and hastens recovery from
fatigue.
5) Antihistamine and antiallergic action:
Adrenaline is the physiological antagonist of histamine.
6) Action on blood coagulation:
Adrenaline accelerates blood coagulation by increasing factor V
activity.
7) Action on the CNS:
Adrenaline has a weak stimulatory action on the CNS.
It may cause restlessness and tremors.
Clinical indications:
1. Bronchospasm; produces bronchodilation and reduction of congestion
and edema of bronchial mucosa.
2. Glaucoma; decreases IOP.
3. Anaphylactic shock (hypersensitivity reaction).
4. Shock; decreases hyperkalemia (promotes K+ uptake).
5. Anesthesia; to prolong duration of action of infiltration anesthesia;
localizes the action and decreases bleeding.
6. Cardiac arrest; restores cardiac activity.
7. Insulin hypoglycemia.
8. Epistaxis; as local haemostatic, the nose is packed with cotton or wool
soaked with adrenaline solution.
Adrenaline Reversal:
α effect β effect
It is the fall (instead of elevation) in
α-blockage
blood pressure produced by adrenaline
when given following blockade of α-
adrenergic receptor; the vasodilation reflects the ability of adrenaline to
activate β2 receptors which, in vascular smooth muscle, are inhibitory.
233
Pharmacokinetics:
It has a rapid onset and brief duration of action.
It is inactive orally because of:
poor absorption from GIT
rapid destruction by digestive juices
rapid metabolism by the liver
By subcutaneous injection, it has slow absorption due to local
vasoconstriction (α effect).
Absorption is more rapid after intramuscular injection, but can be
delayed by admission of the drug in oil.
Its strong solutions as nebulizer or inhalant are used locally in
respiratory tract.
Side Effects:
Minor side effects; Anxiety, restless, headache, tremors and palpitation.
Anginal pain in patients with angina pectoris due to increased cardiac
work.
Cardiac arrhythmias occur when adrenaline is employed during
anaesthesia with chloroform, trichloroethylene, cyclopropane, or
halothane. These lead to potentiation of adrenaline excitability
leading to ventricular fibrillation or extra systole, which could be
treated by β-blockers.
Large doses raise Bp leading to cerebral hemorrhage.
Severe vasoconstriction or even gangrene of fingers or toes may follow
infiltration anesthesia containing adrenaline.
Pulmonary edema which leads to pulmonary hypertension
Contraindications:
1. Coronary diseases because it may induce anginal attacks.
2. Hyperthyroidism
3. Hypertension
4. Chloroform and some other anesthesia
234
5. In patient receiving digitalis therapy (adrenaline and other
sympathomimetics as ephedrine).
Preparations:
1) Adrenaline HCL: solution 1/1000 in distilled water 0.5 ml.
2) Adrenaline HCL: 1% solute by oral inhalation from nebulizer.
Drug Interactions:
Hyperthyroidism: epinephrine shows enhanced cardiovascular actions
in patients with hyperthyroidism, so the dose must be reduced. The
mechanism is by increasing adrenergic receptors.
Cocaine: it produces exaggerated cardiovascular action in presence of
cocaine.
Norepinephrine (Noradrenaline)
NE is a neuromediator of adrenergic nerves that stimulates all types of
adrenergic receptors.
It has similar effect of that done by adrenaline but its α-effect is more
than β-effect (β2 is stimulated to a lesser degree).
Actions:
1) Produces intensive vasoconstriction so it increases peripheral resistance
(α-effect) and both systolic and diastolic Bp are increased
2) Baroreceptor reflex: In isolated cardiac tissue, NE stimulates cardiac
contractility but in vivo little effect is noted. This is due to NE-induced
increase in vagal activity by enhancing baroreceptor activity
3) Effect of atropine pretreatment: Atropine blocks the transmission of
vagal effects so NE stimulates the heart and produces tachycardia
Pharmacokinetics:
NE like adrenaline is ineffective orally. It is given by i.v. infusion ONLY. It is
not given s/c or i/m because of its strong vasoconstrictor effect that produces
necrosis and sloughing.
Therapeutic Uses:
It is used as a hypertensive agent. However, dopamine is better because it
does not reduce blood flow to the kidney (other uses are not considered
clinically significant).
235
Side Effects:
1) Anxiety, headache and bradycardia are common side effects.
2) NE may cause severe hypertension in excessively sensitive persons e.g.
hyperthyroidism patients.
3) Necrosis and sloughing.
Isoproterenol (Isoprenaline)
It is a direct acting synthetic catecholamine; isopropyl-noradrenaline.
It is a powerful direct stimulant of the β-adrenoceptor and very weak
stimulant to α-receptor.
Actions:
1. CVS:
It produces intensive stimulation in heart leading to increase in its rate and
force of contraction. These increase cardiac output. So, it is used in treatment
of atrioventricular block or cardiac arrest. Also, it dilates the arterioles of
skeletal muscle (β2-effect). Because of cardiac stimulation, it may increase
systolic Bp slightly but reduces mean arterial and diastolic Bps.
2. Respiratory system:
Its pulmonary effect is rapid bronchodilation.
3. Other effects:
It increases blood sugar and increases lipolysis (β-effect).
Clinical Uses:
It is used in (1) acute bronchial asthma and (2) heart block.
Side Effects:
Similar to epinephrine, it causes palpitation, arrhythmias, anginal pain,
flushing of skin, headache and tremors.
Administration:
Can be absorbed systemically by sublingual and more reliably absorbed
parentally as inhaled aerosol.
Dopamine
It is a naturally occurring catecholamine.
236
It is the immediate precursor of NE.
It has a transmitter role in the CNS (dopamine receptors D1 and D2).
Peripherally, it acts on α and β receptor as well as dopaminergic
receptors (not influenced by α and β blockers).
Stimulation of D1 leads to relaxation of muscles.
Stimulation of D2 leads to increased NE.
Also it stimulates β1 i.e. it has both positive inotropic and positive
chronotropic effects.
Low doses → decrease VPR
High doses → activate α-receptor leading to vasoconstriction.
Via dopaminergic receptor it dilates renal and splanchnic arterioles
leading to increase in blood flow to kidney and other viscera (this
action is not affected by α and β blockers).
The increased blood flow to the kidney enhances the GFR and causes
sodium dieresis, dopamine is superior to NE which diminishes blood
supply to kidney and may cause kidney shutdown.
Uses:
It is used in the treatment of shock due to many causes as myocardial
infarction or congestive heart failure, trauma and septicemia.
Adverse Effects:
Overdose produces sympathetic stimulation.
It is rapidly metabolized but adverse effects include nausea,
hypertension and arrhythmias. All are short lived.
Dobutamine
It is a synthetic, direct acting catecholamine.
a β-receptor agonist that increases cardiac contractility and output,
with few vascular effects and little effect on arterial Bp.
Chemically, it is related to isoprenaline. It differs from isoprenaline
by producing a lesser fall in peripheral vascular resistance and a lesser
rise in heart rate for a given increase in cardiac output.
Unlike dopamine, it has no renal vasodilator effect.
237
The drug also stimulates α-receptors to some extent (in high dose).
Therapeutic Uses:
In shock due to myocardial infarction; cardiogenic shock
Used to increase cardiac output in congestive heart failure (oxygen
demand, etc)
Kinetics:
It is not absorbed orally. The t½ is two minutes and is given I/V.
Adverse Effects:
It should be used with caution in arterial fibrillation since the drug increases
atrioventricular conduction. Other side effects are similar to those caused bys
epinephrine.
Metaproterenol
It is a more selective β2-agonist with longer duration of action.
It is used as bronchodilator and to reduce uterine contraction in
premature labor.
Ritodrine
It is a selective β2-agonist used to relax uterine contraction of premature
labor.
Salbutamol and Terbutaline
They are selective β2-agonists used in bronchial asthma.
Albuterol
Selective β2-agonist with properties similar to terbutaline.
It is used to relief bronchospasm
Phenylephrine
It acts directly on α-receptor, but α1- is favored over α2-receptor.
Actions in CVS include vasoconstriction that rises systolic and
diastolic Bp.
It has no effect on heart.
When taken orally, it produces reflex bradychardia.
Used topically as mydriatic agent.
238
Therapeutic Uses:
Nasal decongestion
Used to raise Bp and to terminate episode of supraventricular
tAchycardia.
Mydriatic
Adverse effects include hypertension and cardiac irregularities when used in
large doses.
Methoxamine
It is a direct acting sympathomimetic binds to α-receptor, but α1- is
favored over α2-receptor.
It stimulates α1 causing vasoconstriction that increases total
peripheral resistance.
Adverse effects include hypertension, headAche and vomiting.
Clonidine
It is an α2-agonist which is used to lower Bp & to minimize
symptoms of withdrawal of opiates. or benzodiazepines.
Acts centrally to produce inhibition of sympathetic vasoconstriction
centers.
239
Smooth muscle Bronchi: insignificant action
Relaxation of detrusor muscle
Urinary bladder
Contraction of sphincter
GIT Relaxation in spastic states
Eye Local application leads to mydriasis
2) Central Actions:
It stimulates the cerebral cortex, reticular activating system, vital medullary
centers and spinal cord. This stimulation is more potent than that of
ephedrine.
a) Psychic stimulation: This includes euphoria, wakefulness, alertness
and increased mental and physical activity. (Psychic stimulation is
followed by depression)
b) Anorexigenic Action: It depresses appetite and reduces food intake
through:
Central action on the hypothalamic feeding center
Reduction of acuity of smell and taste
Facilitation of mono- and poly-synaptic transmission in the spinal
cord
Uses:
Obesity, narcolepsy and Parkinsonism (to elevate the mood)
Narcotic and barbiturate poisoning
Mental and physical fatigue
Psychic depression
Nocturnal enuresis(the drug is given at night to lighten sleep )
Chronic alcoholism
Hyperkinetic syndrome in children (to calm)
It can be used as decongestive but because of its strong central activity it
becomes neglecting.
Tyramine
240
It is a natural non-catecholamine compound. It acts indirectly causing release
of endogenous transmitters (E, NE and DM) leading to hypertension followed
by little decrease in Bp due to the effects in β2-receptors. It does not bind to
receptors.
It can be found in cheese, fish, ferminted food as ripe, cheese, wine,
tears, beers, especially old substances.
It is metabolized by MAO.
If it is taken in food by persons using MAOI, it leads to hypertension
e.g. (cheese reaction → hypertension crisis).
So, tyramine is contraindicated in MAOI usage.
Mixed-action Adrenergic Agonists:
Ephedrine:
• It is an alkaloid obtained from Ephedra plants. It is also prepared
synthetically.
• It is not a catecholamine poor susceptibility for COMT and MAO.
• It has an excellent absorption orally and from parental sites and has
long duration of action. Greater part is excreted unchanged in urine. It
can penetrate CNS.
Actions: Having a wide variety of actions, it is similar to epinephrine but is
less potent.
Cardiac stimulation; raises both systolic and diastolic blood
CVS
pressure
bronchi: bronchodilation but less potent than epinephrine
Smooth
muscles Used as prophylactic to prevent attack rather than to treat
acute attack
GIT Inhibition of the smooth muscles of the gut
Relaxation of the bladder muscle and constriction of
Urinary tract
sphincter and trigone
Eye Mydriasis
Uterus Varied with species and cycle - It relaxes human uterus
Skeletal Facilitates neuromuscular transmission (used in myasthenia
241
muscles gravis)
Enhances contractility and improves motor function
Stimulates CNS like amphetamine but the action is lesser
Mild stimulation; increased alertness, decrease fatigue and
CNS
prevent sleep
Used to improved athletic performances
Uses:
As prophylactic to prevent asthmatic attack
Nasal decongestion (vasoconstriction)
Mydriasis
To prevent fall in Bp during spinal anesthesia or to raise Bp in GA
Myasthenia gravis
Heart block
Nocturnal enuresis and narcolepsy
Side Effects:
They are similar to adrenaline. In addition, it produces insomnia
(counteracted by barbiturate) and urine retention.
Metaraminol
It is a mixed-acting agonist having similar actions to norepinephrine.
It is used
(1) to treat shock (when infusion with NE or dopamine is not possible) and
(2) to treat acute hypotension (given parentally as single dose).
It enhances cardiac activity and produces vasoconstriction
Adrenergic Antagonists; Adrenoceptor Blocking Drugs
Adrenergic antagonists
The effect of sympathetic nerve stimulation can be blocked or inhibited
through one of the following mechanisms:
242
1- Adrenergic receptor blockers:
A. α adrenergic blockers
B. β adrenergic blockers
C. α and β adrenergic blockers
2- Adrenergic neuron blockers or anti-adrenergic drugs:
A. Peripherally acting drugs (interfering with release or storage)
1- Drugs interfering with release e.g. guanethedine and bretylium
2- Drugs interfering with storage e.g. reserpine (deplete of NA)
B. Centrally acting drugs (inhibition of VMC = α2 agonist)
Stimulation of presynaptic α2-receptor→ inhibit NA release e.g. α methyl
dopa , clonidine
3- Ganglionic blockers: block the transmission in the sympathetic ganglion
Note:
1. NE: inhibit tyrosine hydroxylase{rate-limiting step in NE synthesis}
2. α- methyl tyrosine: inhibit conversion of tyrosine into Dopa by inhibiting
tyrosine hydroxylase enzyme which is essential for biosynthesis of NE.
3. Chemical sympathectomy occurs by 6-hydroxy dopamine.
1- Adrenoceptor- blocking drugs:
α1 Prazosin, doxazosin, terazosin
α1- α2 Phenoxybenzamine, phentolamine
α2 Yohimbine, tolazoline, idazoxan
α– β Labetalol
β1 atenolol, alprenolol, acebutolol, metoprolol, esmolol
Β1- β2 Propranolol, timolol, andolol, pindolol
β2 Butoxamine
243
α- Blockers:
Classification of α- blockers:
244
Sexual function is adversely affected by α-blockade leading to inhibition of
ejaculation with the possibility of retrograde ejaculation (inability of
internal sphincter of the bladder to close during ejaculation).
Produce nasal stuffiness and decrease adrenergic sweating.
Dilate blood vessels in the skin, mucous membranes, and sex organs
{increasing sexual desire (aphrodisiac), increase ADH release, & a local
anesthetic action that may improve symptoms in painful diabetic
neuropathy.
Therapeutics uses:
1. Primary hypertension; selective α1 –blockers.
2. Hypertension due to excess Catecholamines; pheochromocytoma
and sudden clonidine withdrawal.
3. Peripheral vascular diseases (Ca++ channels blockers can also be
used).
4. Reverse severe vasoconstriction due to leakage of NE during IV
infusion.
5. Treatment of neurogenic vascular dysfunction in which internal
sphincter closes spontaneously during micturition and urine
stagnates in bladder because of incomplete voiding.
6. Treatment of patients with spinal cord injuries (paraplegia) who
may suffer from hyper-reflexia, which results in increased
sympathetic activity to the blood vessels and causes high blood
pressure. Thus, predisposes paraplegics to strokes. The drug blunts
this response and aids to normalize paraplegic Bp.
7. Treatment of patients with benign prostatic hypertrophy (reduces
the size of the prostate and antagonizes smooth muscles
contraction in enlarged prostate by selective α1 –blockers).
8. Phentolamine is injected with papavrine to induce erection in
male sexual dysfunction (PGE can also be used).
Note:
Sildenafil (ViagraR) inhibits phosphodiesterase-5, so increase cGMP, it is
given orally to increase erection.
245
Alhpa- blockers
Ergot Imidazoline Phenoxybenz prazocin Yohim
alkaloids amine e bine
tolazoline phentola
mine
Select α1– α2 α1– α2 α1– α2 α1– α2 α1 α2
ivity
Mech Partial Competiti Competiti Non- Competi Comp
anism agonist ve ve competitive tive etitive
antagonist antagonist irreversible antagoni antago
antagonist{slo st nist
w onset and
long duration
of action}
additi 1.smooth 1.histami 1. α – 1.close 3 phosphd 1-
onal muscle ….. ne-like blocker,5t other iesterase aphro
actio imes more receptors: inhibitor disiac
n vasoconstr 2.periphe histamine.5H {increase
potent
iction ral T,muscarinic cAMP 2-
sympatho2.much and ADHr
oxytocic mimetic 2.block elease
less in cGMP}
2.CNS:{++ 3.sympath other uptake 1 and
uptake2 of 3-local
CIC,CTZ,-- omimetic actions. anesth
R.C,VMC} NE
etic
Uses Acute Periphera 1.PVD 1.PVD hyperten 1.aphr
attack of l vascular sion odisiac
migraine diseases{P 2.diagnosi 2.diagnosis of
VD} s of pheochromoc 2.diab
pheochro ytoma etic
mocytoma neuro
3.shock pathy?
Side - -peptic Less than Hypotension -1st dose -
effect tingling,ga ulcer tolazoline phenom increas
e
246
s ngrene -angina enon ADH
-angina - -angina -edema
hypotensi
- on -edema
hypertensi
on -allergy
-abortion
-
nausea,vo
miting
CIC= cardio inhibitory centre CTZ=chemoreceptor trigger zone
RC=respiratory centre VMC=vasomotor centre
++ = stimulation -- = Inhibition
Note:
Phenoxybenzamine:
The only mechanism by which the body can overcome the block is the
ability to synthesize new α-adrenoceptors in one day.
Therefore, the action of this drug lasts 24 hours after a single
administration. When the drug is injected, the actions delay for few
hours before α-blockade develops because drug undergoes change to
the active form.
Clinical pharmacology of α-receptor blocking drugs:
Phaeochromocytoma (Phenoxybenzamine + β-receptor antagonist e.g.
atenolol)
Hypertensive emergency (labetalol)
Chronic hypertension (prazosin, doxazosin, terazosin)
Peripheral vascular disease as Raynaud's syndrome (phentolamine,
tolazoline)
Local vasoconstrictor excess (phentolamine)
Urinary obstruction (phenoxybenzamine).
247
Classes of β- blockers
Non- Solubility Metaboli Durati Local I. S. Uses
Selective sm on anesthet A.
ic
action
Propranolo Lipophilic Hepatic Short + No Angina, arrhythmia,
l (CNS (extensiv 4~6hr hypertension.
action) e) s
Nadolol Hydrophili Renal Long No No Angina, hypertension.
c 12~24
hrs
Oxprenolol Lipophilic Hepatic Short + ++ Angina, arrhythmia,
hypertension. Not used
with hypersensitive R
Pindolol Lipophilic Hepatic Short + + Not used with
hypersensitive R
Sotalol Hydrophili Renal Long No No Antiarrhythmic, addition
c class III action
Timolol Lipophilic Hepatic Short No + - WA-glaucoma, eye
drops.
- Absorbed systemically,
avoided in heart block.
- Does not affect
accommodation.
248
Metoprolol Lipophilic Hepatic Short + No Angina, arrhythmia,
hypertension.
Atenolol Hydrophili Renal Long No No Angina, hypertension given
c once a day.
Acebutolol Lipophilic Hepatic Short + ++ Angina, arrhythmia,
hypertension.
Bisprolol Angina, arrhythmia,
hypertension.
Esmolol Esterase Ultras No No Supraventricular
in RBCs hort arrhythmia & severe
(T1/2E hypertension, IV;
10min) 50~400μg/kg/min.
Pharmacokinetic:
Most of them are well absorbed.
Rapidly distributed and have large volume of distribution.
Half-lives between 2~5 hours.
Mechanism of action (Pharmacodynamic):
The effect is due to occupation and blockade of β-receptors, however some
effects may be due to other mechanisms.
Effect on C.V.S.:
Lower blood pressure.
Negative inotropic and chronotropic.
Slow atrioventricular conduction with increased PR interval on ECG
Effect on the respiratory tract:
Blockade of β2-receptor increases the airway resistance in patients with
asthma
Effects on the eye:
Reduce intraocular pressure
Metabolic and endocrine effects:
Inhibit lipolysis
Inhibit glycogenolysis
Therapeutic indications of β-blockers:
CNS:
249
1. anxiety
2. prophylaxis against migraine
Eye:
3- open angle glaucoma
CVS:
4. angina pectoris
5. acute phase of myocardial infarction
6. arrythmia
7. cardiomyopathy
8. essential hypertension
9. hypertension due to pheochromocytoma{in combination with alpha
blockers}
B.vessels:
10. vascular surgery
11. prevention and treatment GIT bleeding{oesophgeal varicies }
Endocrine:
12. hyperthyroidism
13. other: antiparkinsonism{reduce the tremors}
250
4- Hypotension and severe bradycardia
5- Bronchospasm
6- Augmentation of the hypoglycemic action of insulin and masking of
symptoms.
7- Allergic reactions (skin rash, fever & purpura).
8- Hallucinations & nightmares.
9- Cold hands due to vasodilatation in cutaneous vessels.
10- Abrupt discontinuation of propranolol or other β-blockers lead to a
withdrawal syndrome (sever exacerbation of angina attacks and myocardial
infarction), so it should be stopped gradually.
Contraindications:
1- Bronchial asthma.
2- Congestive heart failure.
3- Partial heart block.
4- Hypotension.
5- Angina due to vasospasm.
6- IDDM.
7- Pregnancy.
8- Peripheral vascular disease.
Side effects & Contraindications of β- blockers
System Side effects Contraindications
CNS Sedation, depression & nightmares.Severe depression
(only the lipophilic β- blockers (use hydrophilic β- blockers).
that cross the BBB).
Eye Oculumucu-cutaneous syndrome withNot used any more.
practolol
CVS- - Heart failure in cases of inadequate- Varient angina.
A) Heart myocardial function as MI. - CHF.
- Heart block ( atropine is - H block & severe bradycardia.
the antidote) - Not used with verapamil or
diazepam → contraction &
conduction → HF or H block.
B) BVs Cold extremities, Raynaud`s phenomenon &
Rynaud`s phenomenon, numbness, other Peripheral vascular
tingling & intermittent claudication. diseases.
C) BP Hypertension. Hypertension.
Respiration Precipitate acute attacks of BA inBronchial asthma
251
asthmatics. (β1 are used).
Metabolism - Hypoglycemia (severe in patientsHypoglycemia
receiving insulin or (with hypoglycemics).
Oral hypoglycemic).
- Atherosclerosis (↓HDL).
- Hyperkalemia especially in uremic
patients.
Others If given with supersensitive receptorsUse β- blockers without ISA
(sympatholytics, with supersensitive receptors.
MAOI…) → exaggerated
sympathomimetic action
(only in β- blockers with ISR).
- Sudden discontinue (withdrawal) →
sympathetic over-
activity & precipitation of anginal
attacks or even MI.
252
Methyldopa is a dopa decarboxylase inhibitor & prevents the conversion
of dopa to dopamine.
Pharmacological action:
1- Bradycardia
2- Hypotension
3- Sedation (due to depletion of 5HT)
Therapeutic uses:
Treatment of hypertension usually in combination with a diuretic, because
renal blood flow is not reduced with its use.
Side effects:
1- Central effect: sedation, vertigo, parkinsonism and psychic depression.
2- GIT: dry mouth, nausea, vomiting and diarrhea.
3- Hypersensitivity: fever, reversible liver damage, granulocytopenia,
thrompcytopenia and autoimmune haemolytic anaemia.
4- Postural hypotension
5- Salt and water retention and weight gain.
6- Hyperprolactinaemia, gynaecomastia, and galactorrhoea.
B. Drugs that affect noradrenaline storage:
Reserpine:
An alkaloid excreted from the root of Rawulfia serpentine.
Mechanism of action:
At low conc. reserpine blocks the transport of NA into synaptic vesicles.
Accordingly, NA may leak into the cytoplasm where it is rapidly
metabolized by MAO enzyme.
Reserpine impairs the uptake of dopamine by the granules and thus
inhibits the synthesis of NA therein.
Pharmacological action:
C.V.S: hypotension and bradycardia through:
Peripheral action: reserpine interferes with the uptake and retention of
noradrenaline by the tissue storage sites and with its intraneuronal storage
leading to depletion of catecholamine stores in sympathetic nerve ending
and in peripheral tissues. Consequently the symp. tone of the blood
vessels falls with a resultant drop in blood pressure.
Central action: reserpine causes vasomotor depression leading to a
decrease in the peripheral resistance. It also depletes catecholamine and 5-
HT stores in the CNS, leading to sedation and lowering of blood pressure.
253
Therapeutic uses:
1- Small dose for hypertension (0.25 mg).
2- Large dose for psychotic states (5~10 mg).
Side effects:
1- Parasympathetic effects: salivation, cutaneous vasodilatation, nasal
stuffiness, diarrhea, and bradycardia. Activation of peptic ulcer.
2- Centrally: psychic depression, Parkinsonism, suicidal tendencies,
nightmares.
3- Weight gain due to an increased appetite and sodium and water retention.
4- Endocrine disturbances: such as feminization, with loss of libido and
impotence.
5- Prolonged use may increase the incidence of carcinoma of the breast.
Contraindication:
Psychic depression.
Peptic ulcer.
Drug interactions:
1- MAO inhibitors reverse the hypotensive action of reserpine.
2- The use of general anaesthesia in patients taking reserpine may cause
hypotension.
C. Drugs that affect noradrenaline release:
1- Noradrenergic neuron blocking drugs e.g. guanethidine, bretylium,
bethanidine and deprisoquin.
2- Indirect acting sympathomimetic amines e.g. ephedrine, tyramine and
amphetamine.
3- Interaction with presynaptic receptors that enhance release e.g. dopamine
or inhibit release e.g. α2-agonist.
4- By increasing or decreasing available stores of NA e.g. reserpine and MAO
inhibitors.
Guanethidine:
It is incompletely absorbed from the GIT and excreted by the kidney.
It is too polar so not effective centrally.
The drug is cumulative since it is stored then slowly released from the
tissue.
Pharmacological actions:
Guanethidine inhibits the release of noradrenaline from adrenergic nerve
fibres.
254
It depletes NA from its tissue stores
Is taken up by adrenergic nerves by the same mechanism involved in NA
uptake. It then accumulates in the storage granules and displaces NA from
them.
It does not penetrate BBB & does not affect the level of NA in the brain.
It does not antagonize injected catecholamines.
Effect on C.V.S:
Rapid IV administration produces:
An initial rapid fall in B.P. associated with increase COP and decrease
peripheral resistance due to direct action on the arterioles.
This is followed by a rise in blood pressure due to the release of
catecholamines from their stores in the peripheral tissues.
Finally the drug causes hypotension associated with bradycardia, decrease
pulse pressure and decrease COP.
Oral administration produces:
A fall in systolic and diastolic B.P and bradycardia.
Hypotension is more marked in the ambulant patient than the supine
one.
Other effects:
Increased GITmotility, increased gastric acid secretion, failure of ejaculation,
miosis and lowering of intraocular pressure in case of glaucoma.
Therapeutic uses:
1- Treatment of severe hypertension (usually with diuretics or other
hypotensive agents).
2- Treatment of glaucoma by local application.
Side effects:
1- Postural hypotension and exertional hypotension
2- Nasal congestion & stuffiness.
3- Fluid retention with heart failure.
4- Failure of ejaculation without impotence.
5- Parotid gland pain and diarrhea.
255
Chapter 10
256
ii- Anionic channels allow mainly chloride ions to pass & are opened
by inhibitory NTs.
6. The other type of inophore component is a 2nd messenger activator
that generates prolonged neuronal responses (seconds to months).
ACh
257
1- Increases K conductance.
2- Inhibits pain pathways in the spinal cord.
3- Pons & upper brain stem & projects to many brain & spinal cord
areas.
4- Serotoninerigc neurons control sleep & wakefulness, mood &
emotion, temperature, appetite & neuroendocrine control.
5- Presynaptic autoreceptors.
6- Nerve terminals that release other NTs e.g. dopamine.
Histamine
258
Neuropeptides
A- Specific
259
2. Pre-synaptic transmission can be depressed by halting NT release or
synthesis; reserpine interferes with intracellular storage of
monoamines therein limiting their availability for immediate release.
3. Amphetamine increases the release of the NT.
4. Cocaine affects the uptake of the NT.
5. Physostigmine affects the degradation of the NT.
6. Post-synaptically drugs may mimic the action of the NT on receptors
e.g. opioids, or block the R.
B- Non-specific
260
(10) Thymoleptics drugs that alleviate the symptoms of depressive
illness i.e. maintain or stabilize an euthymic mood e.g. the
antidepressants TCA & MAO-inhibitors.
(11) Analgesics pain killers.
(12) Anticonvulsants prevent or suppress convulsions.
Hypnotic effect less than ethanol, toxic effects are due to the metabolic
formation of formaldehyde which can cause blindness.
Used in disinfection but not sterilization.
Alcohols are not clinically useful hypnotics because of their diuretic
effect & variation of sleep pattern, both interfere with normal sleep.
261
A crystalline chemical substance with sedative & hypnotic actions,
metabolized in the liver to trichloroethanol which is pharmacologically
active.
When absorbed it is distributed to most body tissues, also is oxidized in
the liver to trichloroacetic acid for 1~2 days, it also is conjugated to
glucouronic acid to form urochloraic acid which is excreted in urine.
Sedative effects in 1/2 hr, plasma T1/2E 6hrs. Does not depress reflexes
so is not anticonvulsive.
Clinically useful as a light sedative & a basal narcotic before
anaesthesia.
Contrindicated in CS as it crosses placenta & depresses fetal
respiration.
4. Barbiturates
Structure-activity relationship
262
The phenyl group at C5 confers a selective anti-convulsive effect e.g.
Phenobarbitone. A small change in the barbiturate molecule can
otherwise generate a convulsive state.
Pharmacology
1. All Bs depress the CNS, they differ only in degree, they possess no pain
killing effect.
2. Depress the utilization of O2 by the brain, cerebral O2 consumption is
decreased by 55%.
3. Prevent the synthesis of ACh in the brain by blocking the conversion of
pyruvate to acetate.
263
increased chloride conductance is maintained ( GABA-
mimetic sedative & hypnotic effect e.g. Pentobarbitone).
(b) GABA-independent direct activation of Cl-channels at hi
concentrations thereby depressing sensory areas of the brain (
anaesthesia e.g. Thiopentone).
(c) Depress motor areas in the brain & thereby used to control
seizures e.g. Phenobarbitone.
(d) The direct effect (increased membrane conductance) can be
suppressed by GABA antagonists such as picrotoxin &
penicillin.
(e) GABA, benzodiazepines & barbiturate receptors are associated
together in many ways.
4. Depressant effects on respiration.
Clinical uses
1. A local anaesthetic.
2. A counter irritant.
3. Certain centrally acting drugs.
4. The use of certain anti-pyretics.
264
Analgesics
Analgesics are drugs that relieve pain. They are usually divided into two
groups:
1- Opioid (narcotic) analgesics
2- Non-opioid (non-steroidal anti-inflammatory-NSAIDs) analgesics
Other drugs relief certain types of pain, but are not regarded as proper
analgesics include: Local anaesthetics, carbamezapine (for trigeminal
neuralgia), ergotamine (for migraine), colchicines (for gout), rubefacients and
counterirritant such as camphor & capsicum, obtundants e.g. clove oil,
physical protectives e.g. demulcents & emollients.
265
Pharmacological actions of morphine:
Sedation Nausea
266
2- Euphoria: euphoria is a strong feeling of contentment and well being,
codeine and pentazosine do not cause euphoria while nalophrine
causes dysphoria.
3- Respiratory depression: All types of opioids cause varying degrees of
respiratory depression. This effect is thought to be due to a decrease in
the sensitivity of medullary respiratory centre to Pco2, It causes death
from over dose. Bronchial secretions are stimulated then depressed.
4- The cardiovascular centre is the least affected, stimulate the vagal
centre slowing the pulse.
5- Depression of cough reflexes: opioids depress cough reflexes and use in
treatment of cough. Codeine suppresses cough in subanalgesic doses so
used in cough medicine.
6- Nausea and vomiting: which is common and transient.Apomorphine is
the prototype central emetic drug.
7- Papillary constriction: opioids constrict pupil. They produce pin-point
pupils, used as diagnostic feature of morphine addiction or coma
produced by morphine. This effect is centrally through stimulation of
the oculomotor centre.
8- GIT effects: opioids increase tone of GIT & decrease motility. They
cause constipation. They contract the muscles of the gall bladder and
constrict the sphincter so increase intra-biliary pressure, so morphine
not used in gall bladder colic. Other effects include contraction of the
uterus, urinary bladder sphincter & constriction of the urethra.
9- Histamine release: they release histamine which leads to local itching
and urticarial and systemic effects including bronchoconstriction and
hypotension. Cutaneus vasodilatation due to release of 5HT causes
267
hypothermia. Catalepsy & hypothermia can be prevented by
thyrotropin-RH.
10- Immunosupressant action: with chronic use.
11- All the actions on opioid receptors are antagonized by naloxone.
Pharmacokinetics:
Side effects:
1- Respiratory depression.
2- Sedation, physical and psychological dependence.
3- Constipation, nausea and vomiting.
4- Pupil constriction
5- Bronchoconstriction and hypotension. Local itch and
urticaria.
6- Acute overdose lead to coma, respiratory depression &
pupil constriction. This is treated by naloxone. In case of
addiction naloxone precipitates withdrawal syndrome.
Heroin
268
(2 hrs). Less emetic action synthesis of heroin is stop in many countries. It
causes more dependence.
Codeine
Pethidine
Derived from morphine but of less narcotic potency. Stimulates the vomiting
centre the CTZ action when injected I/v.
Fentanyl
It has the same analgesic effect like morphine. It used for anaesthesia to cause
neuroleptanalgesia.
Etrophine
269
It is a semi-synthetic drug 1000 times more potent than morphine. It is used
in arrow darts to immobilize the wild animals.
Methadone
As potent as morphine. Half life is more than 24 hours due to high binding
to extravascular tissues. It causes less sever abstinence withdrawal syndrome
thus uses to treat withdrawal syndrome of morphine.
Pentazocine
It is mixed agonist and antagonist. In low dose it has similar analgesic effect of
morphine. In high dose it cause dysphoria, night mares, hallucination and
increase blood pressure. It has less- tendency to cause dependence.
Opioid antagonist
Nalorphine
At high dose it causes morphine like action while in low dose it antagonizes
the effects of morphine. Used as antidote to morphine overdoses. It
precipitates the physical dependence of morphine and heroin addicts. It
causes respiratory depression.
Naloxone
270
It uses in treating respiratory depression cause by opioid overdoses. In
neonate after delivery to reverse the effect of opioid on their
respiration.
It administered I.V 2-3 times daily. In addict it precipitates withdrawal
effect.
Naltroxone
(NSAIDs)
271
Analgesic effect: (reduction of certain sorts of pain) PGE1 and E2
sensitize nociceptive receptors to the action of certain mediators such as
bradykinin, histamine and 5-HT. NSAIDs are effective mainly against
pain associated with inflammatory processes of mild to moderate
intensity e.g. pain associated with arthritis, headache, toothache or
dysmenorrhoea, in which conditions there is an increased production
of PGs.
Anti-inflammatory effects: (modification of the inflammatory reaction)
PGs are one of many factors playing a role in inflammation. NSAIDs
inhibit the synthesis of PGs but one NSAID may be more effective than
other against a certain inflammatory condition if it happens to affect
more the mediators involved in that particular condition.
Mechanism of action:
272
compounds with a selective action on COX-2 such as meloxicam show
potent anti-inflammatory activity with minimal gastric side-effects.
Aspirin binds covalently to both COX-1 and COX-2, thus resulting in
irreversible inhibition of cyclo-oxygenase activity.
Classification of NSAIDs
Salicylic acid is irritant and therefore only used locally. The derivatives e.g.
acetylsalicylic acid (Aspirin)R is less irritant and used systemically.
Pharmacokinetics:
273
Aspirin is absorbed and rapidly hydrolyzed in tissues and plasma to
salicylic acid. 50~ 90% bound to albumin.
Salicylate is partly excreted unchanged and partly undergo conjugation
with glycine or glucouronic acid before excretion. Excretion is relatively
slow and is mainly renal and increases in alkaline urine.
Pharmacological actions:
I- Local actions: salicylic acid and methyl salicylic acid have a local irritant
action on the skin and mucosa. Salicylic acid has keratolytic, antiseptic
and fungistatic properties.
II- General actions: sodium salicylate and aspirin are used systemically and
produce the following actions:
1- Analgesic action: they are effective in relieving dull aching pain e.g.
headache, myalgia, arthralgia and toothache. Chronic use does not
lead to tolerance or addiction.
2- Antipyretic action: salicylates lower the elevated temp to normal,
but does not affect normal body temp. Toxic dose raises body temp
especially in young children. Hyperthermia is due to uncoupling of
oxidative phosphorylation.
3- Anti-inflammatory and anti-rheumatic action: this action is due to
one or more mechanisms: inhibition of PGs synthesis, inhibition of
the kallikrein system, inhibition of fibrinolysin, inhibition of
chemotaxis and uncoupling of oxidative phosphorylation.
4- Aspirin in low doses inhibits platelet aggregation and prolongs the
bleeding time.
274
5- GIT: salicylates irritate gastric mucosa leading to epigastric distress,
nausea and vomiting. In high doses, gastric ulceration and bleeding
may occur.
6- Kidneys: small doses depress uric acid secretion resulting in uric acid
retention, while large doses inhibit the tubular reabsorption of uric
acid and increase its excretion.
7- Respiration: large doses cause stimulation of the respiratory centre
leading to hyperventilation and respiratory alkalosis due to excessive
CO2 loss.
8- Metabolism: although salicylates generally lower blood glucose level,
large doses can cause hyperglycaemia due to depression of aerobic
glycolysis & increased adrenal cortical activity wherein
hydrocortisone stimulates glycogenolysis & gluconeogenesis. Serum
cholesterol is reduced by hi dose taking at least 2 weeks. Cellular
enzymes are inhibited; i)
uncoupling oxidative phosphorylation decreasing the BMR &
arresting formation of ATP (the formation of a haemostatic plug
depends on the release of ATP from platelet);
ii) inhibition of the transaminases & the dehydrogenases.
9- Associated hypoprothrominaemia responds to vitamine K.
Therapeutic uses:
Local uses:
275
Systemic uses
1- Antipyretic
2- Analgesic for headache, myalgia, arthralgia and toothache.
3- Common cold
4- Gout: 5-6 g/day
5- Rheumatoid arthritis:
6- Acute rheumatic fever in patients not suffering from heart failure.
7- Reducing the risk of myocardial infarction, stroke and venous
thromboembolism.
Side effects:
276
CNS: Restlessness, vertigo, tremors, delirium, hallucination,
convulsion, and coma.
Skin eruption
GIT: Anorexia, nausea, vomiting
Metabolic acidosis in children and respiratory alkalosis in adults.
Haemorrhagic phenomena
Hyperpnoea, hyperpyrexia and dehydration.
Treatment:
277
Peptic ulcer, aspirin hypersensitivity, bleeding tendency (haemophilia,
hypoprothrombinaemia)
Patient taking oral anticoagulants & children with viral infections.
Paracetamol (Acetamenophen)
It is completely absorbed from the GIT. Peak achieved after 30-60 min.
it is conjugated in the liver to glucouronic acid or sulphate. Half life is
2-4 hours.
Therapeutic uses:
278
It is the aspirin-paracetamol ester. It has the same pharmacological
action of aspirin with less GIT disturbances and less hepatotoxicity, but
there is increased risk of kidney damage.
Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen, Tiaprofenic acid,
oxaprozin & Fenoprofen
279
Indomethacin
Not generally used for analgesia. Should not be used in children. Used
in acute gout, rheumatoid arthritis, ankylosing spondylitis and
osteoarthritis.
Used in the management of patent ductus arteriosus in premature
infants, being kept patent by continuous production of PGs, and
closure is accelerated by I.V infusion indomethacin.
Adverse effects
280
Contraindication:
It is well absorbed orally and has a long half life allowing once daily
dosing. It is metabolized by conjugation to glucouronic acid.
It has potent anti-inflammatory properties and is used in the treatment
of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.
The common side effects are GIT symptoms, headache, tinnitus,
dizziness and rash.
Mefenamic acid & Flufenamic acid
281
It is a pyrazolone derivative.
It produces agranulocytosis.
It can be given by oral, IM or IV routes.
Phenylbutazone
282
The drug increases the effects of sulfonamides, anti-coagulants and oral
hypoglycaemic drugs by displacing them from protein binding.
Selective COX-2 inhibitors (Meloxicam & Celecoxib)
283
If conc. of G.A. is increased other sites of brain are affected including
motor control and reflex activity, respiration and autonomic regulation
leading to respiratory and myocardial depression.
Stages of anaesthesia
If a slow acting G.A. is applied then four well-defined stages will be generated:
Stage I voluntary movement (Stage of analgesia):
Patient is conscious but drowsy, amnesia has not developed but there is
reduced responsiveness to painful stimulation.
This stage reflexes the inhibition of sensory interneurons of the dorsal
horn and spinothalamic pathways.
Analgesia occurs gradually and the sense of hearing is increased during
this stage.
In some cases of anaesthesia for obstetric purposes it stops in this stage.
Stage II involuntary movement (Stage of excitement and delirium)
Patient is unconscious and responds to painful stimuli
The subject may move, talk, choke or vomit. Signs may include irregular
respiration, rapid pulse, increased blood pressure, the pupils are dilated
but reactive. There also is increased muscle tone (involuntary movement)
This stage is due to inhibition of inhibitory pathways in brain (looks like
excitation).
This stage is dangerous and should be shortened or avoided (new
anaesthetics eliminate this stage)
Stage III (Stage of surgical anaesthesia)
In this stage muscle tone is reduced, the involuntary movements disappear
and respiration becomes regular.
284
The pupil is no longer dilated, roving movement of the eye ball may be
observed and there is loss of eyelid and conjunctival reflexes.
Respiration becomes progressively shallower as anaesthesia deepens, until
it finally ceases due to failure of the intercostals muscles followed by the
diaphragm
This stage is due to inhibition of ascending pathways of the reticular
formation.
Stage IV (Stage of medullary paralysis)
In this stage depression of respiratory and cardiovascular system takes
place, followed by death.
The pupils are fully dilated with no response to light, the eyes become
fixed, the blood pressure very low, skin becomes grey, cold and covered by
clammy sweat.
285
Analgesia is maintained by analgesic agents e.g. opiate.
To produce muscle relaxation use a neuromuscular blocking agent e.g.
tubocurarine.
Effects of G.A. on the cardiovascular and respiratory systems:
All G.A. depress the isolated heart, but in vivo their effects vary according
to the action on the sympathetic nervous system.
Some agents, e.g. nitrous oxide, increase plasma noradrenaline conc.
thereby increasing blood pressure, while halothane and other halogenated
G.A. oppose this effect and decrease blood pressure.
Halothane produces cardiac dysrhythmias, particularly ventricular
extrasystolies which may develop into ventricular fibrillation if plasma
level of NA is high.
The mechanism of dysrhythmia is not known but is thought to be due to
sensitization of heart to the action of NA, this effect is especially harmful
in the case of operations with excessive release of NA (e.g.
phaeochromocytoma) wherein the use of halothane becomes dangerous.
All anaesthetic except nitrous oxide and ketamine depress respiration.
Inhalational anaesthetics
Pharmacokinetic aspects:
The main factors that determine the speed of induction and recovery are:
1- Properties of the anaesthetic
- Blood: gas partition coefficient
- Oil: gas partition coefficient
2- Physiological factors
- Alveolar ventilation rate
- Cardiac output.
286
Solubility of G.A in the blood is expressed as blood: gas partition
coefficient which is defined as: "Fraction of gas dissolved in blood" so the
lower the blood: gas partition coefficient the faster is the induction and
recovery e.g. nitrous oxide.
Oil- gas partition coefficient: Anaesthetics have to pass from blood into
tissue and lipid. In the normal subject about 20% of weight is fat, also
anaesthetics have to pass through brain
Oil- gas partition coefficient reflexes the potency of anaesthetics. The high
the oil: gas partition coefficient the high the potency.
Oil- gas p.c. accounts for anaesthetic distribution in the body fat i.e.fat acts
as a reservoir from which it is slowly released. This prolongs the recovery
period and prolongs the hangover period: “the period of semi-
consciousness which follows anaesthesia due to slow release of the
anaesthetic from fat deposit".
The higher the pulmonary ventilation the faster the induction. This is of
little importance considering a drug with low blood solubility.
The greater the pulmonary blood flow (increase in cardiac output), the
slower the rise in arterial tension. In patients with circulatory shock, the
combined effects of decreased COP and increased ventilation may
accelerate the induction of anaesthesia with some anaesthetics (least likely
occurs with nitrous oxide).
Metabolism and elimination:
- Most inhalation anaesthetic are eliminated unchanged through the lungs
50% of methoxyflurane is metabolized to fluoride ions, and oxalate,
leading to renal impairment.
287
30% of halothane is metabolized, in the liver, to bromide ions and
fluoroacetic acid (immunogenic compound). The combination of
fluoroacetic acid and liver proteins lead to immunologic interactions
generating hepatic damage.
Minimum Alveolar concentration (MAC):
The MAC of inhalation anaesthetics is regarded as the least concentration of the
anaesthetic in the lungs that would permit a surgical incision to be performed
without pain or involuntary reflexes in 50% of patients.
The lower the MAC value, the more potent would be the anaesthetic agent.
1- Diethyl ether
- A colourless volatile liquid with irritant odour.
- Of little use now because it is very explosive in a mixture with oxygen.
- Diethyl ether is a relatively safe anaesthetic agent with a large therapeutic index.
The ratio between the dose that produces cardiac & respiratory depression and
the anaesthetic dose is large.
- It has analgesic effect but weak neuromuscular action.
Disadvantages:
Irritant to respiratory tract leading to copious secretion of mucous leading
to post-operative infections.
Induction & recovery are slow, with a prolonged hangover period during
which nausea and vomiting may take place.
2- Halothane
- Halothane is a colourless volatile liquid halogenated ether.
- Non-inflammable, non-explosive and non-irritant to respiratory tract.
- It has low solubility in blood so produces smooth, rapid induction and a
relatively rapid recovery.
288
- May produce bradycardia due to increased vagal activity and depression of the
sinoatrial node.
- Causes cardiac arrhythmias due to myocardial sensitization to adrenaline.
- Decreases blood pressure due to vasodilatation, cardiac depression and
vasomotor centre depression. It also potentiates the action of ganglion blockers.
- Relaxes uterus so is contraindicated during labour.
- Decreases motility of the GIT, produces bronchodilatation and respiratory
depression.
- About 30% of absorbed halothane is metabolized in the liver to trifluoroacetic
acid which reacts with proteins to form immunogenic compounds leading to
hepatotoxicity.
3- Nitrous oxide
The Laughing Gas
A colourless, odourless, non-inflammable and non-explosive gas
Rapid action due to low blood: gas partition coefficient
Pharmacological actions:
Induction is rapid, consciousness is lost in 20-30 seconds and recovery is
rapid.
Low potency, if administered for continuous 2 minutes it produces
cyanosis, a rise of blood pressure and slow pulse.
This is avoided by mixing 80% nitrous oxide in 20% oxygen.
However this conc. can not produce loss of consciousness, therefore, it is
usually used to induce anaesthesia in combination with other potent G.A.
e.g. thiopentone and halothane.
Nitrous oxide has analgesic effect in low conc. (35%) so useful for
producing analgesia during childbirth.
289
Toxic effects:
During recovery from nitrous oxide anaesthesia the gas diffuses rapidly
outwards lowering the oxygen conc. in the alveolar air, producing hypoxia
especially in patient with respiratory disease, wherein oxygen has to be
supplied during recovery.
Produces oxidation of cobalt in vitamin B12, which is required to co-factor
methionine synthetase. This enzyme serves as a methyl donor in the
synthesis of DNA & other proteins. Exposures to nitrous oxide lead to
inhibition of cell division, which results in anaemia and leucopenia.
Single administration of nitrous oxide does not produce these effects
because the bone marrow has sufficient reserve.
Prolonged exposure to nitrous oxide even in low conc. has been suspected
to be a cause of abortion and foetal abnormality among female theatre
staff.
4- Methoxyflurane
Non-explosive, does not produce respiratory irritation or postoperative
vomiting.
A very potent G.A. with high lipid solubility, i.e. high blood- gas part.
coefficient, therefore slow induction and recovery.
Comparable with halothane produceing similar effects on the
cardiovascular & respiratory system.
More analgesic effect & less uterine relaxant activity.
Metabolites produce nephrotoxicity so has been replaced by enflurane and
isoflurane.
5- Enflurane
290
A halogenated ether, non- inflammable and faster in action than
halothane.
Less liable to accumulate in body fat
Produces better muscle relaxation
Metabolized to a minor extent so does not cause kidney damage.
At high conc. it causes seizures during induction and following recovery,
therefore should be avoided in patients with EEG abnormalities or with
history of seizures.
6- Isoflurane
Non-inflammable and not metabolized with few signs of toxicity
Not convulsive.
Enhances the action of neuromuscular blockers
Very expensive.
Increases the incidence of coronary ischemic attacks so avoided in patients
with coronary heart diseases.
7- Desflurane:
Similar to isoflurane but faster in induction and recovery.
8- Sevoflurane:
Resembles desflurane in excellent control of anaesthetic depth and rapid
recovery.
Less irritant to the respiratory tract and does not increase cardiac rate.
Intravenous anaesthetics
These agents are not used to maintain anaesthesia, only used as induction
agents.
291
Rapid onset of action, ease of administration, no irritation of respiratory
passages.
They subclasses into:
1- Induction anaesthesia: rapid onset action (20 seconds) e.g. thiopentone
2- Basal anaesthesia: onset 2-3 minutes used to produce sedation e.g.
ketamine, diazepam.
1- Thiopentone
A barbiturate but instead of (O2) atom has (S) atom.
Pharmacokinetics:
Highly lipid soluble with a rapid transient action.
Onset 10 seconds, duration 10 minutes.
Once injected I.V. a rapid decline in plasma concentration takes place due
to redistribution of drug into high blood flow tissues (brain, liver, kidney),
followed by slow decline due to slow uptake of drug by fat tissues (physical
redistribution).
Adipose tissues act as a reservoir leading to a prolonged hangover so
thiopentone can not be used to maintain surgical anaesthesia.
Metabolized by oxidation followed by glucouronic conjugation.
Highly bound to plasma protein (70% binds to albumin), binding is
reduced in case of liver & kidney disease & malnutrition.
Pharmacodynamics and side effects:
Induce rapid hypnosis and loss of consciousness.
No analgesic or neuromuscular blocking action.
Depresses the respiratory centre and may cause bronchospasm.
Therapeutic doses may cause transient hypotension, laryngeal spasm,
cough & sneezing. Excessive doses associated with abrupt fall in blood
292
pressure due to depression of cardiac contractility and reduction of COP,
hypothermia & profound cerebral impairment.
Sodium salt used is highly soluble and very potent, alkaline, but not stable
so prepared immediately before I.V injection.
If injected outside a vein, causes tissue necrosis, procaine should
immediately be injected by the same needle as antidote.
Thiopentone may precipitate prophyria in susceptible subjects.
Indications
Induction of general anaesthesia.
Anaesthesia of short duration.
Reduction of raised intracranial pressure if ventilation controlled.
Status epilepticus.
Contraindications
Inadequate resuscitative facilities.
Inconfidence of ability to maintain a batent airway as in the presence of a
tumor in the pharynx or larynx.
Cardiovascular, pulmonary or hepatic impairments.
Acute porphyria.
Myotonic dystrophy.
Breast feeding.
Caution in pregnancy & surgery of the mouth, pharynx or larynx.
2- Etomidate (Hypnomidate) R
It has a large therapeutic index, a large margin between the anaesthetic
dose and the dose producing respiratory and cardiovascular depression.
More rapidly metabolized than thiopentone. No hangover effect.
293
Etomidate may cause involuntary movement during induction and
recovery, can be minimized by an opioid analgesic or a short acting BD
given before induction.
May cause postoperative nausea and vomiting.
Prolonged use leads to adrenal cortex suppression which may cause death
in very ill patients
Used mainly as induction agent in patients with risk of circulatory failure.
Indications
Induction of general anaesthesia.
Contraindications
As in other I/v anaesthetics.
Use for maintaince (adrenal suppression).
3- Propofol (DiprivanR)
Similar in action to thiopentone.
Rapidly metabolized, no hangover.
Convulsions, anaphylaxis & delayed recovery. Special caution after day
surgery is advised for delayed convultions.
I/v antimuscarinic prevent an occasionally profound bradycardia.
Can be used continuously by infusion to maintain anaesthesia.
No involuntary movement or adrenal cortex suppression.
5- Ketamine (KetalarR)
Structural analogue of phencyclidine a psychotomimetic drug.
Less liable to cause euphoria & sensory distortion compared to
phencyclidine.
294
Both drugs block NMDA receptor of glutamate (block activation of
excitatory receptor)
Administered I.V or I.M or infusion to produce dissociative anaesthesia
The eyes remain open but the patient does not respond to external stimuli
without loss of consciousness.
Analgesia, muscle paralysis and amnesia are marked.
Ketamine increases blood pressure and heart rate but respiratory system is
not affected.
Unwanted effects:
It causes hallucinations, delirium and irrational behavior during recovery.
Children are much less susceptible to these phenomena, so used in
combination with diazepam for minor operation in pediatric surgery.
6- Midazolam
A short acting benzodiazepine. Has slower onset and recovery.
Does not depress respiratory or cardiovascular system
Neuroleptanalgesia:
A combination of neuroleptic and analgesic drugs to produce a state of
deep sedation and analgesia. The patient responds to simple commands &
questions, but not to painful stimuli.
Further reading Conscious sedation in the provision of Dental care,
w.w.w.dh.gov.uk.
Neuroleptic agents
295
Mental disorders
Mechanism of action
296
2) α; orthostatic hypotension, & contributing to the sedative
action of the class.
3) H1; sedative & antiemetic property.
Pharmacokinetics
Clinical use
1) Treatment of SZP.
2) Antiemetic ttt of uraemia, iatrogenic nausea, & vomiting caused by
radiation.
3) Ttt of Huntington chorea (e.g. haloperidol).
4) Ttt of depression (e.g. sulpiride).
Side effects
297
4) Lithium.
5) SSRI e.g. flouxitine (Prozac).
Mechanism of action
Pharmacokinetics
MAO Inhibitors
Side effects
298
Hypotension, excessive central stimulation (tremor, excitement &
convultions), wt gain, atropinic effects, hepatotoxicity.
Interactions
Lithium
Mechanism of action
Pharmacology
Withdrawal
299
GI disturbances.
Headache, anxiety, dizziness, paraesthesia, sleep disturbances, fatigue,
influenza-like symptoms & sweating on abrupt withdrawal.
Side effects
Indications
Anxiolytics
1- The Benzodiazepines
Mechanism of action
300
CNS
Cardiopulmonary
Skeletal muscles
Drug interactions
Pharmacokinetics
Indications
301
1) Reduction of anxiety & aggression, maintenance of verbal contact
during certain diagnostic & outpatient procedures.
2) Sedation & induction of sleep. Decrease the time taken to get to sleep
& increase its total duration especially in subjects sleeping less than
6hrs. Improve the quality of sleep by not interfering with REM periods.
3) Reduction of muscle tone.
4) Anticonvulsant.
5) Tapering diazepam is used in ttt of dependence.
Acute toxicity
3- Buspirone
Contraindications
302
4- Meprobamate
Anticonvulsants
Are those drugs used to control motor disorders e.g. convulsive seizures,
epilepsy, Parkinsonism & spasticity.
A. Convulsive seizures
303
The gradual side effects include hyperplasia of the gums &
megaloblastic anaemia. Hypersensitivity reactions are not uncommon.
(C) Phenobarbitone, primidone, ethosuximide, trimethadione:
Phenobarbitone is well absorbed orally, 50% of the drug in the
plasma is bound to albumin, T1/2e 50~140 hrs, 25% is excreted
unchanged in urine, excretion increases if urine is made alkaline, 75%
is oxidated & conjugated. The drug is a particularly effective hepatic
enzyme inducer. Primidone pharmacological actions are due to the
formation of phenobarbitone as the active metabolite. Ethosuximide
has been developed by the modification of the barbituric acid
structure. It closely resembles trimethadione which was the first drug
effective in the control of absence seizures (often in children), causes
hypersensitivity reactions including aplastic anaemia & may produce
foetal abnormalities.
(D) Valproate: is a simple monocarboxylic acid, not a class relative, that
causes a significant increase in the GABA content of the brain by
inhibiting the 2 enzyme systems that inactivate GABA, the
transaminase & the dehydrogenase. Is well-absorbed orally & excreted
as the glucouronide, T1/2e 15hrs, relatively free of untoward effects
other than the thinning & curling of hair, in about 10% of the
patients, & an increase in SGOT. Has been a drug of choice in
infantile epilepsy due to the lack of toxicity & of sedative effects.
(E) Carbamazepine (Tegretol) R & oxacarbazepine: are the drugs of
choice in partial, primary & secondary generalized tonic- clonic
seizures, trigeminal neuralgia or other neuropathic pain states & the
prophylaxis of bipolar disorder unresponsive to lithium. Side effects
include vomiting, drowsiness, headache, confusion, agitation, visual
disturbances especially diplopia, leucopenia & other blood disorders,
& rash. Contraindicated in AV conduction abnormalities & history of
marrow depression.
(F) Gabapentin & pregabalin: are
indicated in partial seizures & peripheral neuropathic pain. Side
effects are GI symptoms, hypertension, cough & rhinitis, depression
304
confusion & hostility, diplopia, paraethesia, amnesia, impotence &
urine incontinence.
(G) Lamotrigine: indications similar to carbamazepine, side effects similar
to gabapentin.
B. Epilepsy
A neurological disease due to abnormal bioelectrical activity in the brain
which might be focal, localized or spread all over the brain thereby generating
focal seizures involving one finger or a facial muscle (according to
representation) or generalized grand-mal epilepsy characterized by:
Aura.
Loss of consciousness & falling down.
Tonic phase, clonic phase then plateau (all taking 3 min).
Patient regains consciousness or sleeps.
Retrograde amnesia.
Absence petit mal epilepsy:
Mainly in hyperactive children with brief absence of consciousness
without falling or tonic clonic phases.
Narcolepsy:
Patient suddenly falls asleep (in mid-sentence).
Temporal loop psychomotor epilepsy:
SZP symptoms, change of behavior during sleep; grinding of teeth;
yawning; walking with stereotypy, sleeps & awakes amnestic.
Status epilepticus:
Seizures continue in a series without regaining consciousness, can be fatal.
1. Emergency treatment is instituted IV using;
Phenytoin Na.
Diazepam.
General anaesthesia.
2. Long term therapy (for 3 uninterrupted yrs) includes:
Carbamazepine 200 mg BID.
Na valproate 200 mg BID which can be combined with clonazepam
(ClonitrilR).
3. Amphetamine
305
Is used in the treatment of hyperkinetic children (paradoxical) & in the
treatment of narcolepsy.
C. Parkinson`s diease
Is an acquired progressive motor disorder characterized by
(A) Levodopa:
Dopamine itself does not cross the BBB, so levodopa was introduced as
the 1st line treatment.
306
It has to be given in large & frequent doses amounting 3~8 gms/day in
3~4 doses. Well-absorbed from small intestine by active transport,
much inactivated (by MAO) in intestinal wall, T1/2e 2hrs, 95% is
converted to dopamine in peripheral tissues, ≤ 1% enters brain wherein
rapid decarboxylation occurs.
Pharmacologic effects:
Side effects:
Domperidone:
Carbidopa:
Selegiline:
307
Is a MAOI that acts to facilitate dopaminergic transmission & is used
in mild cases or as adjunct to levodopa.
(B) Bromocriptine:
CNS Stimulants
308
centres. effect.
- Convulsions.
2) Psychomotor stimulants
Pharmacologic effects
309
5) Peripheral sympathomimetic actions including a rise in blood pressure
& inhibition of GI motility.
6) Fenfluramine is a particular agonist that causes anorexia without
stimulation due to release of serotonin rather than noradrenalin or
dopamine.
Pharmacokinetics
Clinical uses
Side effects
1) Hypertension.
2) Insomnia.
3) Tremors.
4) Precipitation of schizophrenia.
5) Dependence.
Cocaine
310
Is a potent inhibitor of catecholamine uptake by noradrenergic nerve
terminals.
Strongly enhance sympathetic activity with similar effects in CNS to
amphetamine.
1) Euphoria, garrulousness & ↑ motor activity.
2) In excessive doses there is tremor, convulsions & respiratory & motor
depression.
3) Peripheral sympathetic effects include tachycardia, vasoconstriction & a
raised blood pressure.
4) Body temperature is increased by increased motor activity & reduced
heat loss.
5) T1/2e of an I/v dose is 15min.
6) No appreciable physical withdrawal syndrome, a psychological
dependence ensues characterized by depression & dysphoria.
Use
Mode of action
311
2) Antagonizes some of the effects of adenosine.
3) Dieresis results from vasodilatation of the afferent glomerular arterioles
↑ GFR.
Clinical use
Untoward effects
3) Pschotomimetic agents
312
Bad trips: Are more persistent mental disorders in which altered
perception & hallucinations have lasted for 3 weeks following a single
dose of LSD, the disorder may recur later after initial response to
antipsychotic therapy.
Phencyclidine
Cannabis
Pharmacodynamics
313
B) Vasodilatation (especially scleral & conjunctival vessels).
C) Reduced IOP.
D) Inhibition of nausea & vomiting.
E) Bronchodilation.
Mechanism of action
Tolerance
Non.
Adverse effects
314
- Ester linkage is essential for susceptibility to metabolic degradation by
pseudocholinesterase in plasma or liver. Therefore drugs with ester linkages
have shorter duration than those with amide bridges.
- L.A. are weak bases (Pka 8-9) so at acidic pH or physiological fluids they are
partially ionized.
- The uncharged form is important for penetration of biologic membranes;
however the cationic form is important for binding with channel receptor to
produce blockade.
- This explains the observation by dentists & surgeons that L.A. are less
effective in infected tissues (infection = low pH, so L.A. in ionized form).
Classification of L.A.:
1- Esters:
Ester of benzoic acid: cocaine
Ester of P.aminobenzoic acid: Procaine (Novocaine), Tetracaine
(Pontocaine), Benzocaine (Americaine), Chloroprocaine (Nesacaine).
2- Amides: Lidocaine (Xylocaine), Dibucaine, Mepivacaine (Carbocaine),
Prilocaine (Citanest), Bupivacaine (Marcaine), Etidocaine (Duranest),
Ropivacaine (Noropin).
Methods of administration of L.A.:
1- Surface anaesthesia:
- This refers to the local anaesthesia produced by direct application of the drug in
a suitable form to an accessible surface e.g. wounds, ulcers, burns, mucous
membrane of the eye, nose, pharynx, trachea, urinary tract. Surface anaesthesia
does not work well on the skin which is better anaesthesized by ethylchloride
aerosol which evaporates rapidly causing freezing of skin.
315
Example: lignocaine, tetracaine.
- If the drug is applied in high dose on a large area it may cause systemic toxicity
therefore a vasoconstrictor is added e.g. adrenaline or phenylephrine to prolong
the duration of action and limit delocalization.
2- Infiltration anaesthesia:
- The drug is injected in the subcutaneous tissues to reach a nerve terminal, used
in minor surgery.
- Adrenaline is added to prolong duration of action but it is contraindicated in
toes because it causes ischemic tissue damage.
3- Nerve block anaesthesia:
L. A. is injected close to a nerve trunk e.g. intercostals or dental nerves. Used for
surgery, dentistry, analgesia.
4- Spinal anaesthesia:
L.A. is injected in the subarachnoid space in the lumbar region. The drugs
diffuse in the C.S.F to act on spinal roots and spinal cord. Used for abdominal,
pelvis or leg surgery when general anaesthesia can not be used.
The level of spinal anaesthesia depends upon:
Posture of the patients
Specific gravity of the injection solution (relative to CSF) isobaric,
hyperbaric or hypobaric. Controlling specific gravity by controling the
conc. of glucose.
Side effects:
1- Hypotension due to blockade of preganglionic sympathetic nerves
2- Headache
3- If the drug reaches to the phrenic nerve supplying diaphragm, respiratory
arrest ensues.
316
4- Septic meningitis may occur due to bacterial contamination.
5- Epidural anaesthesia
The drug is injected into epidural space. Used as for spinal anaesthesia but the
side effects are less due to reduced longitudinal spread of L.A.
6- Paravertebral block:
L.A. is injected around spinal roots from the paravertebral formina. This used to
relief postoperative pain and to produce painless childbirth.
7- Intraarticular.
8- Regional intravenous block using a tourniquet.
Mechanism of action:
L.A. prevents both generation and conduction of nerve impulses. Their
site of action is the cell membrane. They block conduction by interference
with the permeability to Na+ by stabilization of the cell membrane and
blocking Na+ transport along Na channels.
Blocking of the channels has use-dependent property, i.e. the depth of
block increases with the level of activity of the channels and with the
number of open channels,
Na+ channels exist in 3 functional states: activated (open), resting (closed)
and inactivated. In the resting state the nerve is less sensitive to the local
anaesthetics (L.A. does not bind to receptor). It binds to the receptor
when the channel is active or inactive, but it has higher affinity to the
channel in the inactive state and it stabilizes it. The more inactivated the
channel the more is the degree of blockade.
L.A in the charged form can only gain access to receptor when the channel
in active (open) state.
317
Elevated extracellular Ca+2 partially antagonize the action of L.A. while
elevation of extracellular potassium enhances their effect.
L.A. has differential blockade: smaller diameter fibers are more susceptible
to the action of L.A. than larger ones. They block myelinated nerve before
unmyelinated nerves of the same diameter.
Pain Aδ fiber & C fiber which are unmyelinated and have small diameter
are more susceptible to L.A. Sensation of pain is blocked before sensation
of pressure & touch. Motor activity (autonomic or skeletal) transmitted by
motor neurons which have large diameter fibers are the last nerve blocked
by L.A. Recovery of conduction occurs spontaneously.
Pharmacological actions:
1) Local anaesthetic action.
2) In the central nervous system: restlessness, agitation, tremor and
convulsions. Central stimulation is followed by depression. Death may
occur from respiratory failure. They may cause euphoria e.g. cocaine.
3) In the cardiovascular system; myocardial depression due to blockade of
Na+ channel leading to decreased the intracellular Na+ which is
exchanged with Ca+2, thus Ca+2 is reduced.
4) On blood vessels L.A. cause dilatation (except cocaine) decreasing blood
pressure which if sudden may be detrimental.
Side effects:
1) Restlessness & convulsions followed by respiratory depression.
2) Hypotension, cardiac arrest.
3) Hypersensitivity reactions (rare).
Pharmacokinetics:
318
1) L.A. vary in their ability to penetrate membranes which affect the
onset of action and recovery and also affect the application sites, e.g.
procaine has poor penetration so it is not useful as a surface
anaesthetic. Rapidness of onset of action may be aided by the
addition of bicarbonate to the L.A. solution or the mucolytic
enzyme hyaluronidase.
2) Increased systemic absorption & higher peak level in blood is
correlated to overall dose injection into sites of hi vascularity. The
concurrent use a vasoconstrictor such as adrenaline ( e.g. at a conc.
ratio of 1:200 000) reduces the peak blood levels of the shorter
acting drugs (e.g.Lidocaine) but a lesser pronounced effect on the
more lipophilic & longer acting agents (e.g. Etidocaine).
3) Drugs with ester linkage have limitd distribution & short duration
of action (minutes) because they are rapidly metabolized by
cholinesterase e.g. procaine. Pregnancy reduces plasma
cholinesterase activity prolongs clearance & increases the potential
for toxicty. Subarachnoid administration effects will continue until
the the drug is systemically absorbed due to lack of
pseudocholinesterase activity in the CSF.
4) Products of hydrolysis undergo hepatic biotransformation or
otherwise can be directly excreted by the kidney (e.g.nearly 25% of
diethylaminoethanol from the hydrolysis of procaine). Para-
aminobenzoic acid (PABA) is a breakdown product of esters
responsible for allergic reactions in some patients.
5) Amide– type local anesthetics are widely distributed following I/v
absorption following a 2 or 3compartment model. Anatomic,
319
pathologic & physiologic factors influence their distribution. Lung
extraction limits the amount of drug reaching the systemic
circulation & downstream sensitive sites. Conversely hypercapnia &
resulting acidosis in the CNS will likely increase regional blood flow
& therefore increase local anesthetic conc in the brain & risk of
toxicity. Protein binding influences the free drug available for both
activity & clearance by the liver, toxic plasma level is inversely
proportional to degree of protein binding.
6) Drugs with amide linkage are metabolized in the liver by N-
dealkylation and their metabolites are pharmacologically active.
7) Changes in hepatic or renal function or blood flow influence
clearance of these drugs.
8) Cocaine is an atypical ester that undergoes significant hepatic
metabolism & renal excretion.
Esters
Procaine 1 Slow 60 8.9 3 6 0.6
Chloprocaine 3 Rapid 45 8.7 5 - -
Tetracaine 8 Slow 180 8.5 7 76 80
Amides
320
Lidocaine 2 Rapid 120 7.9 25 70 2.9
Mepivacaine 1.5 Intermed180 7.6 39 77 1
Bupivacaine 8 Intermed480 8.1 15 95 28
Etidocaine 8 Slow 280 7.7 33 94 141
Prilocaine 1.8 Slow 120 7.9 24 55 0.9
Ropivacaine 8 Intermedi480 8.1 15 94 28
Cocaine:
Cocaine is a naturally occurring alkaloid obtained from the leaves of Erythroxylon
coca a tree indigenous to Chile, Peru & Bolivia. It is an ester of benzoic acid.
Pharmacological actions:
I. It stimulates the central nervous system
II. It has sympathomimetic action because of blocking the neuronal
CA uptake so it produces tachycardia, vasoconstriction and
increases blood pressure.
III. It has anti-fatigue action thus coca leaves were chewed by mountain
people living in South America to allay hunger, fatigue and produce
psychic stimulation & euphoria.
IV. Used only for surface anaesthesia of eye and larynx.
V. Absorbed from all sites of application including mucous
membranes, metabolized by liver and partly excreted unchanged in
the urine.
VI. Causes psychic dependence. No tolerance develops to its action.
321
VII. Poisoning symptoms include excitement, hyperpyrexia, tachycardia,
convulsions and finally coma. Death may result from respiratory
failure.
Procaine
Procaine is a synthetic derivative of PABA.
Little is absorbed from mucous membranes so it is effective only by
injection for infiltration, nerve block and spinal anaesthesia.
It causes vasodilatation so is commonly combined with adrenaline to
limit its diffusion and prolong duration of action.
Is given as hydrochloride by I.V infusion to relieve pain in arthritis and
burns.
The amide derivative (procainamide) is used as an antiarrhythmic drug.
Procainamide is metabolized in liver to PABA and diethylaminoethanol.
PABA antagonizes the action of sulfonamides.
Lidocaine
Is effective as L.A. for surface, infiltration, nerve block and spinal
anaesthesia. Is also used as an antidysrhythmic.
Lignocaine
More potent as L.A. than procaine
Has a rapid onset of action
Useful for surface anaesthesia because it penetrates mucous
membranes.
It is most popular in dental anaesthesia
Duration of action is longer than procaine
It is class I antidysrhythmic.
322
It stimulates C.N.S and may cause convulsions.
Chloroprocaine:
Resembles procaine but less allergenic.
Tetracaine:
Is a potent L.A. suitable for surface and injection L.A.
Dibucaine:
Extremely potent L.A. but is very toxic. It is used as solution or ointment
for surface anaesthesia. It is well-absorbed from mucous membranes. It
must be used in very dilute solution when injected.
Bupivacaine:
Long acting L.A.
Prilocaine:
Resembles lidocaine pharmacologically, but with a longer duration of
action and a delayed onset. Its metabolites cause haemoglbinaemia after-
effect toxicity.
Chapter 11
ANTI-RHEUMATIC DRUGS
Actions
323
corticosteroids which mask the symptoms of the disease by their
analgesic and anti-inflammatory actions.
o DMARDs can improve not only the symptoms of inflammatory joint
disease but also extra- articular manifestations such as vasculitis.
o DMARDs reduce the ESR, C- reactive protein, titre of RF and may
retard erosive damage as judged radiologically.
Indications
Contra- indications
Side effects
o Anaphylactic reactions.
o Stomatitis, mouth ulcers and taste disturbances.
o Colitis, hepatotoxicity with cholestatic jaundice.
o Pulmonary fibrosis.
o Peripheral neuropathy.
o Nephrotic syndrome and proteinuria.
o Blood disorders.
o Gold deposits in eye, skin reactions and alopecia.
Penicillamine:
Indications
324
o Wilson`s disease.
o Autoimmune hepatitis.
o Cystinuria.
Contra- indications
o SLE.
o Caution with concomitant nephrotoxic drugs and gold.
o Caution with renal impairment and pregnancy.
Side effects
o Nausea and anorexia. Rashes and fever are also initial side effects.
o A 6 weeks loss of taste after 6 weeks of initiation of therapy.
o Blood disorders including thrombocytopenia, leukopenia,
agranulocytosis and aplastic anaemia.
o Proteinuria, nephrotic syndrome, rarely haematuria, and haemolytic
anaemia.
o Stomatitis, mouth ulcers, skin reactions and alopecia.
o SLE- like syndrome, myasthenia gravis- likesyndrome, polymyositis
which may involve cardiac muscles, Goodpasure`ssyndrome, and
Stevens- Johnson`s syndrome.
o Bronchiolitis and pneumonitis.
o Male and female breast enlargement.
Indications
Contra- indications
325
Side effects
Indications
Contra- indications
Side effects
o GIT disturbances.
o Transient acute toxic psychosis and CNS stimulation.
o Yellow discoloration of skin and urine and chronic dermatosis.
Glucosamine
Indications
Contra- indications
o Allergy.
o Pregnancy.
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o Breast feeding.
Side effects
Indications
Contra- indications
Side effects
327
o Raised BP, leucopenia, anemia, hyperlipidemia, hypokalemia and
hypophosphatemia.
o Headache, dizziness, asthenia and paraesthesia.
o Rash, pruritus, rare hepatitis or jaundice, alopecia and dry skin.
o Tenosynovitis, tendon rupture or interstitial lung disease.
1. Discontinue therapy.
2. Wash- out procedures including administration of colestyramine and
activated charcoal before starting other DMARD.
Methotrexate
Azathioprine
Leflunomide
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Ciclosporin
Cyclophosphamide
Colchicine
Mechanism of action
Indications
Contra- indications
329
Side effects
Indications
Allopurinol
Mechanism of action
Indications
o Prophylaxis of gout.
o Prophylaxis of uric acid and of calcium oxalate renal stones.
o Prophylaxis of hyperuricaemia associated with cancer chemotherapy.
Contra- indications
Side effects
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o Seizures, headache, vertigo, drowsiness, visual and taste disturbances
(all rare), paraesthesia and neuropathy.
o GIT disorders.
o Alopecia and gynaecomastia.
o Blood disorders including thrombocytopenia, leukopenia,
agranulocytosis and aplastic anaemia.
Sulfinpyrazone
Mechanism of action
Indications
o Prophylaxis of gout.
o Hyperuricaemia.
o Indicated instead of Allopurinol or in conjunction with it in cases that
are resistant to treatment.
Contra- indications
Side effects
Mechanism of action
Indications
331
o Probencid is used to prevent nephrotoxicity associated with Cidofovir
therapy.
o Rasburicase is indicated in the prophylaxis and treatment of
hyperuricaemia associated with initial chemotherapy of haematological
malignancy.
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Chapter 12
Chemotherapy
Is the treatment of disease by use of pure chemicals which have a specific
antagonistic effect on the organism causing the disease.
Paul Erlich is the father of chemotherapy, in 1900 he stated that “A
chemotherapeutic agent should be maximally parasitotropic & minimally organotropic”,
thereby establishing the modern concept of assessment of the therapeutic value
using the therapeutic index represented by the ratio: Median LD/ Median curative
dose. The greater the TI, the more valuable is the drug. The aim of the modern
chemotherapeutic index is to a special mechanism of an organism metabolism
which is not common to that of the host, having found that, a compound is
found which utilizes that peculiarity in attacking the organism without affecting
the metabolism of the host.
Chemotherapeutic agents are chemical substances that elicit a selective toxicity
against the parasitic cells e.g. bacteria, fungi, protozoa, helminthes & cancer cells.
Antibiotics are substances produced by certain microorganisms that kill or
inhibit the growth of other microorganisms.
Classification of antibiotics:
1- According to spectrum
a- Broad spectrum: e.g. tetracycline & chloramphenicol
b- Narrow spectrum: e.g. penicillin & streptomycin.
2- According to whether they kill or inhibit microbial growth:
a- Bactericidal: causes death of the microorganism e.g. penicillin, cephalosporin,
streptomycin, aminoglycosides & polymixin
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b- Bacteriostatic: inhibits growth of microorganisms e.g. tetracyclines,
chloramphenicol & sulfonamides.
3- According to the mechanism of action:
a- Antibiotics acting on the microbial cell wall:
- Inhibitors of the D-alanine linkage e.g. cycloserine
- Inhibitors of peptidoglycan biosynthesis e.g. bacitracin & vancomycin
- Blockers of transpeptidation e.g. penicillins & cephalosporins
b- Antibiotics increasing the permeability of the cytoplasmic membrane e.g.
polymyxin, nystatin & amphotericin
c- Antibiotics interfering with protein synthesis
- aminoglycosides, streptomycin, gentamycin, kanamycin & tetracyclines bind
to the 30S subunit of the microbial ribosomes.
- chloramphenicol, erythromycin & clindamycin bind to the 50S subunit of
microbial ribosomes.
d-Inhibitors of nucleic acid synthesis e.g. rifampicin, pyrimethamine,
trimethoprim, sulfonamides, quinolones & griseofulvin.
4-Antibiotics limited by toxicity
The drugs discussed under this heading are considered to be suitable for treating
generalized infection only in desperate situations, nevertheless, they share the
following advantages:
a) Highly bactericidal.
b) Slow development of resistance.
c) Not absorbed from the gut.
I. Neomycin.
II. Polymixin A~ E, except B.
III. Bacitracin.
334
IV. Erythromycin.
V. Tylosin, bactriostatic, especially active against mycoplasma. Particularly
distributed to lungs in RI due to hi lipid solubility.
VI. Lincomycin.
VII. Griseofulvin used for ttt of wring worm, ineffective as local application,
passes from blood to newly formed keratin enabling skin & hair to resist
fungal attack. Contraindicated 6 month before, & during, pregnancy.
VIII. Nystatin effective against yeast & Candida albicans infections &
superinfection following use of broad spectrum antibiotics such as
tetracycline.
Choice of a suitable antibacterial drug:
The clinician must consider 2 factors:
(1) The patient: history of allergy, renal & hepatic function, age, sex, severity of
illness & resistance to infection.
(2) The known or likely causative organism and its antibiotic sensitivity
Empiric antimicrobial therapy:
In many cases wherein the causative pathogen or its specific antibiotic
susceptibility is unknown the use of antibiotic is known as empiric therapy
(presumptive therapy) i.e. initiated based on the experience.
Bacteriological identification and sensitivity tests:
Properly obtained and processed specimens for culture frequently yield reliable
information about the causative microorganism.
Principles of Antiobiotic Therapy
1) Do not use antibiotics for trivial self-limiting conditions which are better
left to natural defense mechanism & development of immunity.
335
2) Use a specific narrow spectrum antibiotic, where possible, to avoid
disruption of normal resident bacteria.
3) In general continue treatment for 24~ 48hrs after disappearance of
symptoms because if the infection is not completely eliminated there may
be a relapse or the infection may become chronic particularly in ttt of
pyogenic infections.
4) Use early in disease, in adequate dosage & by a route insuring effective
affected-tissue concentration.
5) Antibiotic combination may be used either in mixed or unknown
infection, or to attempt to achieve synergism.
6) Consider relative cost.
β-Lactam antibiotics
β-Lactam antibiotics share a mechanism of action & a β-Lactam ring in their
molecules. They include penicillins, cephalosporins, monobactams &
carbapenem.
Mechanism of action:
They are bactericidal & affect the microorganisms during their growth. After
binding to the receptor (penicillin-binding protein) on the bacterium they
inhibit cell wall synthesis by blocking the transpeptidation of peptidoglycan.
They also activate the autolytic enzymes in the cell wall leading to lysis of the
bacterium.
Penicillins
A large group of substances that share the basic structure 6-amino- penicillanic
acid. Some penicillins are obtained naturally from moulds of Penicillium spp.,
while others are semi-synthetic.
336
Resistance:
Certain bacteria e.g. staph., H. influenzae, & other G-ve species produce β-
Lactamase enzymes that inactivate the penicillin by breaking the β-Lactam ring
responsible for its antibiotic activity.
Spectrum:
G+ve: Streptococci, pneumococci, staph., Bacillus anthracis, C. diphtheria &
clostridia.
G-ve: Gonococci, meningococci
Spirochaetes: Treponema pallidum, actinomyces
Ampicillin also is effective against the G-ve bacilli shigella & salmonella.
Pharmacokinetics:
1- Benzylpenicillin (penicillin G)
Destroyed by gastric juice so is administered parenterally, is completely
absorbed from I.V or I.M. administration, certain acid-resistant penicillins
are taken orally.
Penetrates C.S.F with difficulty unless the meninges are inflamed, widely
distributed in body fluids, passing into the joints, pleural and pericardial
cavities, into bile, saliva, milk & across placenta.
Protein binding is low with the exception of cloxacillin & dicloxacillin.
Most are excreted rapidly by tubular renal mechanism. This excretion can
be blocked by probencid. Ampicillin excreted more slowly.
Penicillin G T1/2e is 30~ 60 mints.
Unwanted effects:
Penicillins are relatively free from toxic side effects.
337
Hypersensitivity reactions are common with parenteral, but less marked
with oral penicillins. Symptoms include: skin rash, fever, urticaria,
asthma & in severe cases generalized oedema.
Acute anaphylactic shock is rare but is dangerous.
Broad spectrum penicillins particularly the oral forms cause GIT
disturbances & diarrhea.
Clinical use
Is used in a water soluble salt form given only I.M or I.V because of
destruction by gastric acidity, must be freshly prepared.
Has a short duration of action, T1/2 30 minutes, so is administered 4~
6 hourly.
Destroyed by β–lactamases. It covers G+ve and some G-ve bacteria.
Used in: meningococcal meningitis, respiratory tract infections,
tonsillitis, pharyngitis, pneumonia, gonorrhea & syphilis.
Long acting penicillin-G preparations:
Are relatively insoluble & hence slowly absorbed from the injection
site, producing low but sustained plasma concentrations.
Are usually given I.M only & never I.V.
A. Procaine penicillin: is given once or twice daily.
B. Benzathine penicillin: given 1~ 4 weekly, not used in acute
infections because of low blood level, used in chemoprophylaxis.
2- Phenoxymethyl penicillin (penicillin V):
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3- β-lactamase-resistant penicillins:
339
A. Carbenicillin: given I.M or I.V. spectrum as ampicillin plus
pseudomonas and proteus, T1/2e 80 min., excreted in urine.
B. Ticarcillin: more active against pseudomonas, available in combination
with clavulanic acid.
C. Azlocillin, mezlocillin, piperacillin: more active against pseudomonas
& some klebsiella strains than carbenicillin & ticarcillin, , given I.V.,
T1/2e 60 min., excreted in bile & urine, indicated in serious G-ve
infections, used in combination with gentamycin to prevent the
emergence of resistant strains.
6- Reversed-spectrum penicillins:
A. Mecillinam: less potent against G+ve, but highly active against G-ve
bacteria including E. coli, klebsiella, salmonella & shigella,
pseudomonas are resistant. Given parenterally.
B. Pivmecillinam: a pro-drug of mecillinam, given orally, excreted in
urine & bile, used in typhoid fever.
β-lactamase inhibitors:
340
Cephamycins are derived from Streptomyces spp.
Both have β-lactam ring structures.
Are bactericidal, inhibit cell wall synthesis by inhibiting transpeptidase
resulting in failure of cross-linking of peptidoglycan.
According to their resistance to β-lactamase, spectrum of activity,
administration & distribution, they can be classified into generations:
1) First generation cephalosporins:
341
Cefamandole, cefoxitin, cefotetan, cefonicid, cefuroxime, cefprozil,
ceforanide: parenterally.
Wider spectrum of activity than first generation especially against G-ve
bacilli: enterobacter, klebsiella, indole +ve proteus.
Cefamandol, cefuroxime, cefonicid, ceforanide & cefaclor are active
against H. influenza.
Cefoxitin, cefmetazole & cefotetan are active against B. fragilis &
serratia.
All are less active against G+ve than the first generation.
More stable to β-lactamases than first generation.
CSF penetration is unreliable except cefuroxime.
In renal failure, dosage adjustments are required.
Clinical uses:
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Ceftizoxime & moxalactam have good activity against B. fragilis.
Highly resistant to β-lactamases.
All are parenteral antibiotics except cefixime which is oral.
All, except cefoperazone & cefixime penetrate BBB and attain high
CSF conc.
Clinical uses:
Meningitis, sepsis
Neutropenic & febrile immunocompromised patients (combined
with gentamycin).
Gonorrhea due to penicillin-resistant gonococci.
Mixed infections, involving chest, abdomen or pelvis.
4) Fourth generation cephalosporins:
343
Renal toxicity (interstitial nephritis, tubular necrosis) has been
reported following administration of the withdrawn cephaloridine.
Bleeding due to hypoprothrombinaemia, thrombocytopenia and/or
platelet dysfunction occur with cephalosporins containing a
methylthiotetrazole group (cefamandole, moxalactam, cefoperazone,
cefotetan). They also can cause severe disulfiram-like reactions, so
alcohol must be avoided.
Many second and particularly third generation agents are ineffective
against G+ve organisms especially staph. & enterococci. These
organisms plus fungi often grow and may induce super-infection.
Monobactams
Are drugs with monocyclic β-lactam ring.
Are resistant to β-lactamase and are active against G-ve bacteria including
pseudomonas and serratia, but have no activity against G+ve species or
anaerobes.
Aztreonam is the most widely used and can be given I.V or I.M.
Carbapenems
Imipenem has a wide spectrum against G-ve, G+ve species & anaerobes.
Highly resistant to β-lactamase, but inactivated by dihydropeptidase in the
renal tubules.
Administered, I.V or I.M., in combination with an inhibitor of renal
dihydropeptidase (Cilastatin).
The most common side effects are nausea, vomiting, diarrhea & rash at
the infusion sites. High dose or high conc. in the plasma may cause
seizures.
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Aminoglycosides
Streptomycin, Neomycin, Kanamycin, Amikacin, Tobramycin, Sisomicin,
Netilmicin, Parmomycin etc. are produced by species of Streptomyces,
gentamycin is produced by the mould micromonospora pupurea.
They are bactericidal drugs. They bind to the 30S subunit of the bacterial
ribosomes inhibiting protein synthesis.
Water-soluble and more active at alkaline than at acid pH, poorly
absorbed from the intestine, when given orally their effects are restricted
to the GIT.
Systemic effects are produced parenterally.
Wide extracellular distribution, minimum plasma protein binding except
streptomycin, & a very limited penetration into CSF.
Excreted mainly unchanged by the kidney.
Side effects:
Ototoxicity: hearing loss, start with high-frequency tones or as vestibular
damage (vertigo), ataxia & loss of balance.
Nephrotoxicity: aminoglycosides accumulate in the kidney in high conc.
especially neomycin (not used systemically) and gentamycin.
In high doses, they produce a curare-like effect with neuromuscular
blockade leading to respiratory paralysis. (Treated by calcium gluconate
or neostigmine as antidote).
Streptomycin
It is not absorbed orally, when given its actions are limited to infections
of GIT. It is rapidly absorbed after I.M. injection.
Is excreted by glomerular filtration in the kidney, some may be excreted
in bile, milk, sweat & tears.
345
Crosses the placenta, & into the CSF only if the meninges are inflamed.
Narrow spectrum bactericidal activity against Mycobacterium
tuberculosis, G-ve bacilli such as E. coli, H. influenza & some staph
strains.
Maximum activity is achieved in a slightly alkaline medium & reduced at
pH of 6 or less.
Therapeutic uses:
1- Tuberculosis, usually in combination with antimycobacterials.
2- Tularemia, plague & brucellosis.
3- Bacterial endocarditis due to Streptococcus viridans or Strep. faecalis & G-
ve bacteremia e.g. Pseudomonas sp.
Adverse reactions:
1- Allergy: rash, fever & eosinophilia.
2- Pain at the site of injection.
3- Reversible disturbance of vestibular function (vertigo, nausea,
dizziness & loss of balance).
4- Pregnancy administration → newborn deafness.
5- Hi dose → respiratory paralysis due to NM blockade
Gentamicin
Bactericidal effects against G-ve bacilli Pseudomonas aeruginosa, Proteus
spp., E. coli, Klebsiella pneumonia, Enterobacter spp. & the G+ve
staph., Strep. viridans & faecalis.
Gentamicin + some penicillins → synergistic effect, but cannot be mixed
in one syringe or intravenous solution.
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Most strep. are resistant to gentamicin. G-ve organisms aquire plasmid
governed gentamicin-inactivating enzymes. These organisms are often
resistant also to kanamycin, tobramycin, but infrequently to amikacin.
Therapeutic uses:
1- Severe infections caused by G-ve organisms resistant to other
less toxic drugs e.g. UTI, pneumonia, infected burns,
osteomyelitis & septicaemia.
2- Infective endocarditis combined with penicillin G.
3- Topically: in the treatment of septic wounds & burns.
4- Intrathecally in meningitis.
Side effects
Like streptomycin, it is highly nephrotoxic and ototoxic with irreversible loss of
hearing by prolonged hi drug levels.
Tobramycin
Similar antibacterial spectrum to gentamicin but more active.
There is cross-resistance between gentamicin & tobramycin.
(80%) excreted by glomerular filtration.
Slightly less nephrotoxic than gentamicin.
Amikacin
Is a semisynthetic less toxic kanamycin derivative.
Broader in spectrum than other aminoglycosides.
Resists enzymes that inactivate gentamycin & tobramycin, used against
infections resistant to these drugs.
Nephrotoxic & ototoxic.
Netilmicin
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Similar to gentamicin, not inactivated by many resistant bacteria.
Less nephrotoxic and less ototoxic than other aminoglycosides.
The neomycin group
Kanamycin
Active against G+ve & G-ve bacteria and some mycobacteria.
Pseudomonas & streptococcui are resistant.
May be used orally for GIT infection, but usually parenterally for serious
infections.
Dose reduced in elderly patients & in renal impairment.
Ototoxic & nephrotoxic.
Neomycin
Similar to kanamycin in spectrum & activity.
Limited by nephro- & ototoxicity to topical or oral use.
Topically effective against staph. & G-ve bacilli skin infections.
Other agents e.g. bacitracin & polymyxin are usually combined in the
ointment to minimize the development of resistance.
Prolonged local application may cause skin sensitization.
Oral use for acute intestinal infections, preparation of the bowel for
surgery & in hepatic coma.
Parmomycin
Effective oral use in enteritis.
Effective against E. histolytica intestinal amoebiasis.
Spectinomycin
Is an aminocyclitol antibiotic (related to aminoglycosides)
I.M. effective against many G-ve & G+ve species.
Alternative treatment for gonorrhea.
348
Causes pain at the injection site, fever, nausea, nephrotoxicity & rarely
anaemia.
Polypeptide antibiotics
Polymyxins
The group is active against G-ve bacteria including pseudomonas.
The high nephrotoxicity limits use to polymyxin B & E.
Bactericidal, disrupt the osmotic properties and transport mechanisms of
the bacterial cell membrane.
Not absorbed orally, poor tissue distribution, urinary excretion.
Polymyxin B may be used orally for intestinal infections, or in ointment
mixture with bacitracin & neomycin in skin, eye or ear infections. It
Causes paresthesia, dizziness & in-coordination, nephrotoxicity &
respiratory paralysis at hi blood levels.
Bacitracins
Not absorbed orally, nephrotoxic parenterally, limited to topical use.
Highly active against G+ve & neisseria. Combined with other
antibiotics in creams & ointments for wound & skin infections.
Chloramphenicol & Tetracyclines
Chloramphenicol
Isolated from Streptomyces venzuelae, is now produced synthetically.
Pharmacokinetics:
Parenteral chloramphenicol succinate is highly water soluble & is
hydrolyzed in tissues to liberate free chloramphenicol.
Oral chloramphenicol palmitate (a tasteless salt) absorption is rapid &
complete, GI hydrolysis liberates the free drug.
349
Exists in different crystal shapes, a phenomenon known as
polymorphism, the particle size & shape of crystals play an important
role in absorption.
Wide tissue distribution including CNS & CSF. (Cp = conc. in brain
tissue).
30% is bound to plasma proteins.
Reduced or conjugated to glucuronic acid in the liver.
Metabolites, plus 10% in the active form, are excreted by the kidney.
Mechanism of action:
1) Bacteriostatic, attachment to the 50S subunit ribosomes inhibits protein
synthesis.
2) Inhibits mitochondrial protein synthesis in mammalian bone marrow
cells.
3) Broad spectrum antibiotic activity against a wide array of G+ve & G-ve
species, rickettsia & Chlamydia, some salmonella & bacteroids.
4) Gradual resistance due to the emergence of mutants, no cross resistance,
but plasmids may transmit multiple drug resistance (chloramph.,
tetracycline, streptomycin) from one bacterium to another by
conjugation, resulting from the production of chloramphenicol
acetyltransferase, which inactivates the drug.
Therapeutic uses:
1- Acute stage typhoid & paratyphoid fever, for 14~21 days, severe rickettsial
diseases.
2- Meningitis & other H. influenza infections including pneumonia or
laryngiotracheitis.
3- Life threatening sepsis, brain abscess and bacteroids infections.
350
4- Eye infections, topically.
Adverse reactions:
1- GI disturbances: nausea, vomiting and diarrhea.
2- Candidiasis.
3- An irreversible, fatal but rare marrow depression.
4- Grey baby syndrome with vomiting, flaccidity, hypothermia, grey color,
shock & collapse due to high blood level of the active drug in newborn
infants due to undeveloped hepatorenal elimination pathways.
Drug interaction:
1. Enzyme inhibitor that prolongs the T1/2e of tolbutamide, phenytoin &
warfarin.
2. Antagonizes the bactericidal action of penicillins or aminoglycosides.
Tetracyclines
Tetracycline was isolated from Streptomyces spp.
Chlortetracycline, oxytetracycline, tetracycline, demeclocycline,
methacycline, doxycycline & minocycline were recently developed new
tetracyclines for good absorption & prolong duration of action.
Broad spectrum bacteriostatic against many G+ve and G-ve bacteria
including some anaerobes, rickettsia, Chlamydia, mycoplasma, & some
protozoa e.g. amoeba.
Bind 30S ribosomal subunit interfering with protein synthesis.
Resistance:
Some bacteria lack an active transport mechanism or passive
permeability to tetracyclines.
Plasmid-transmitted by transduction or conjugation.
351
Usually transmitted to multiple drugs e.g. aminoglycosides,
sulfonamides & chloramphenicol.
Pharmacokinetics:
Incomplete oral absorption (30% of chlortetracycline, more
tetracycline, oxytetracycline & demeclocycline, & 100% of doxycycline
& minocycline).
The pyrrolidino-methyl derivative of tetracycline is water soluble and can
be given intravenously.
Absorption orally occurs in the upper small intestine and is best in the
absence of food.
Combine with metal ions, e.g. Ca++, Mg++, Fe++ and Al+++ to form
insoluble chelates. The presence of these ions (e.g. in milk or antacid
preparations) tends to prevent absorption.
Distributed throughout body tissues, including fetal circulation and are
excreted in milk. Low conc. reaches the CSF. High conc. of minocycline
reaches to tears & saliva useful in eradicating the meningococcal carrier
state.
Variable protein binding, excreted mainly in bile & urine, bile
concentrations are high. Entero-hepatic recycling contributes to the
steady blood levels observed with these drugs.
Deposited in growing bones & teeth, causing yellow discoloration of
teeth & dental enamel hypoplasia.
Doxycycline & minocycline are almost completely absorbed from the
gut and excreted slowly, leading to prolonged duration of action.
Doxycycline is mainly excreted in bile therefore a good risk in renal
failure.
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Clinical use:
1- Chlamydia, rickettsia & mycoplasma infections
2- Mixed RT infections.
3- STD e.g. syphilis (tetracycline).
4- Brucellosis, tularemia & plague, in combination with
rifampicin (doxycycline).
5- Prophylaxis & treatment of Vibrio cholerae infections
(tetracycline).
6- Amoebic dysentery & Plasmodium falciparum
(oxytetracycline).
7- Inhibition of the action of ADH in the renal tubule in
chronic hyponatraemia due to inappropriate ADH secretion
(Demeclocycline).
Adverse reactions:
1- GI disturbances, nausea, vomiting and diarrhea.
2- Super infection with Candida albicans
3- Vitamin B complex deficiency.
4- Discoloration & increased susceptibility of teeth to caries, growth
inhibition of growing bones.
5- Impair hepatic function, especially during pregnancy or when given I.V.
6- Expired preparations cause acidosis and renal injury.
7- Administration with diuretics may produce polyurea, proteinurea or
nitrogen retention.
8- I.V. injection produces thrombosis, I.M. produces local irritation.
9- Photosensitization especially demeclocycline.
10- Dizziness, vertigo, nausea & vomiting may occur with minocycline.
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Macrolides
Erythromycin, clarithromycin & azithromycin inhibit bacterial protein
synthesis by binding to 50S ribosomal subunit, elicit bactericidal or
bacteriostatic actions depending on the conc. & the microorganism.
Erythromycin, similar to penicillin in spectrum, is effective against G+ve
& spirochaetes, the G-ve N. gonorrhoea & to a lesser extent H.
influenza, mycoplasma, legionella & Chlamydia.
Azithromycin is more effective against G-ve H. influenza & legionella. It
has excellent action against toxoplasma.
Clarithromycin is as effective, and its metabolite is twice as active,
against H. influenza as erythromycin. Effective against Mycobacterium
avium cellular and Helicobacter pylori.
Pharmacokinetics:
Azithromycin, clarithromycin, erythromycin stearate & ester are acid-
resistant, administered orally. Erythromycin gluconate is administered
parenterally.
All diffuse into most tissues including prostatic fluid & placenta, but do
not cross BBB. T1/2e of erythromycin is 90 min, clarythromycin is 5~ 7
hrs & azithromycin is 40~ 60 hrs prolonged by concentration in tissues
& in phagocytes.
Inactivated in the liver, erythromycin more than azithromycin,
clarithromycin metabolites are active. Excreted mainly in bile.
Resistance:
A plasmid-controlled alteration of the binding site on the bacterial
ribosome (rRNA- methylation).
354
Staph. rapidly develop resistance if treatment is prolonged more than 10
days.
Therapeutic use:
1- Corynebacterial diphtheria & sepsis.
2- Penicillin-sensitive patients with pneumococcal or
streptococcal infections.
3- Pneumonia caused by mycoplasma & legionella.
4- Chlamydia infections in pregnancy.
5- Clarithromycin & azithromycin are effective in suppressing
disseminated Mycobacterium avium intracellulare infections
in patients with AIDS.
6- Clarithromycin is used in peptic ulcer.
Adverse reactions:
1- GIT: anorexia, nausea, vomiting & diarrhea.
2- Hepatotoxicity: erythromycin estolate produces a reversible acute
cholestatic hepatitis (fever, jaundice, impaired liver function).
3- Allergic reactions.
4- Erythromycin inhibit cytP450 & increases the effects of warfarin, digoxin
& conc. of cyclosporine & antihistamines e.g. terfenadine & astemizole.
Lincomycin & Clindamycin
Clindamycin is the chlorinated derivative of lincomycin the natural
isolate from Streptomyces lincolnensis.
Lincomycin resembles erythromycin in activity, Clindamycin is more
potent. Both inhibit protein synthesis by binding to 50S ribosomal
subunits of bacteria.
355
Clindamycin is active against G+ve cocci including penicillin-resistant
staph. & anaerobes such as Bacteroid spp.
Orally or parenterally widely distributed in tissues & body fluids but not
CSF. T1/2e 21 hrs. Some is metabolized in liver, metabolites are active,
excreted in bile & urine.
Uses:
1. Bacteroides & staph. joint & bone infections.
2. Topical use for staphylococcal conjunctivitis.
Side effects:
GI disturbances, diarrhea & pseudomembranous colitis due to a
necrotizing toxin produced by the drug-resistant Clostridium difficile.
Treatment is by oral vancomycin & metronidazole.
Glycopeptide antibiotics
Vancomycin is bactericidal inhibiting cell wall synthesis, effective against
G+ve spp. including methicillin-resistant staph. & enterococci. It
synergises with aminoglycosides.
Not absorbed orally, given I.V., widely distributed, eliminated via the
kidney, T1/2e 8 hours.
Use limited to pseudomembranous colitis, multi-resistant staph.
infections & endocarditis.
Side effects include fever, rashes and local phlebitis.
Ototoxicity, nephrotoxicity & hypersensitivity reactions are not
uncommon.
Quinolones
356
Synthetic antibiotics, Nalidixic acid is the prototype agent, achieves
low systemic levels & narrow spectrum, useful only as a urinary
antiseptic.
Fluroquinolones
357
- Eradication of meningococci from carriers or prophylaxis in
neutropenic patients.
Adverse effects:
358
4. Plasmid-mediated synthesis a mutant enzyme of lowered affinity for the
drugs generates resistance.
5. Effective against a wide array of G+ve & G-ve bacteria, Chlamydia &
Trichomonas.
Pharmacokinetics:
Readily absorbed from GIT, usually not given topically (except silver
sulphadiazine) because of sensitization & allergic reactions.
Distribution depends partly on plasma protein binding, cross placenta
& BBB.
Acetylated in the liver to inactive form, excreted in urine.
Clinical uses: now are seldom
1- UTI.
2- Respiratory tract infections
3- STD.
4- Sulphasalazine in inflammatory bowel disease.
5- Silver sulphadiazine in infected burns.
6- Na-sulphacetamide locally in the eye for conjunctivitis.
7- Combined with pyrimethamine in the treatment of
toxoplasmosis and drug-resistant malaria.
8- Combined with trimethoprime in the treatment of
Pneumocystis carinii.
Side effects:
359
3- Crystalluria due to precipitation of the drug or its metabolites in the
urine, prevented by giving large volume of fluids & urine alkalinization.
4- Hypersensitivity including rash, fever & photosensitivity.
5- Hepatic injury.
6- Bone marrow depression.
Trimethoprim
360
Carcinogenesis
Epipodophyllotoxins Leukemia
etoposide & teniposide
361
Oxazaphosphorines Urinary bladder,
cyclophosphamide & ifosfamide. leukemia
• Uncontrolled Proliferation
• Invasiveness (Spreading)
• Metastasis (spread of cancer from its primary site to other places in the
body )
Management of Cancer
• Surgical
• Radiation
• Chemotherapy
• The neoplastic cell burden is initially reduced either by surgery and /or
radiation followed by chemotherapy or combination therapy.
• Surgery and radiation are local treatments. These modalities are likely
to produce a cure in patients with a truly localized disease but because
most patients with cancer have metastatic disease at diagnosis, localized
therapies often fail to completely eliminate the cancer. In addition,
systemic diseases such as leukemia cannot be treated with a localized
modality.
Chemotherapy
362
• Adjuvant: Additional treatment after the primary treatment to lower
the risk that the cancer will come back.
Cell Cycle
• G2: Gap between DNA synthesis and mitosis, the cell will continue
to grow.
1. Goal of treatment:
• The ultimate goal of chemotherapy is cure. i.e. long term disease free
survival.
363
2. Indications for treatment:
• Rapidly dividing cells are generally more sensitive to anti cancer drugs,
therefore the fraction of tumor cells that are in replicative stage of their
cycle are most susceptible.
• Non proliferating cells usually survive the toxic effects of many of these
agents
• The normal and tumor cells differ in the number of cells that are in
various stages of the cycle.
• The non specific drugs have more toxicity in cycling cells and are
useful against tumors that have low percentage of replicating cells.
• The growth rate of most solid tumors in vivo is initially rapid, but
growth rate decreases as tumor size increases. Because of unavailability
of nutrients and oxygen.
364
6. Treatment regimens and scheduling:
• Resistance:
a) Inherent
b) Acquired
Side Effects
• Anemia
• Neutropenia
• Thrombocytopenia
Effects on GIT
• Vomiting
• Stomatitis
• Dysphagia
• Constipation
365
• Diarrhea
Effects on skin:
• Skin dryness
• Sunburn
• Decrease menstruation
• Antimetabolites
• Vinca alkaloids
366
Cell Cycle non-Specific Drugs:
Effective for both low-growth (solid tumors) and high growth fraction
malignancies.
• Alkylating agents
• Antibiotics (Dactinomycin)
• Cisplatin
1. Alkylating agents:
367
• These drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and
phosphate groups of cellular constituents.
2. Antimetabolites:
Their maximal cytotoxic effects are in S-phase and therefore are cell-
cycle specific.
Methotrexate
Pyrimidine Analogs
Purine analogs
368
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used
occasionally. 6-MP is a sulfhydryl-substituted analog of hypoxanthine
that must be converted to an active form by hypoxanthine-guanine
phosphoribosyltransferase (HGPRT). The active drug inhibits synthesis
and metabolism of purine nucleotides and thus disrupts synthesis and
function of DNA and RNA. This is an S phase-specific drug.
3. Microtubule Inhibitors:
4. Antineoplastic Antibiotics:
• Cell-cycle nonspecific.
5. Hormonal Agents:
369
Direct antitumor effects are related to their lympholytic properties.
6. Monoclonal Antibodies:
Antibodies that are made in the lab rather than by a person's own
immune system.
Chapter 13
Addendum notes
Addendum notes 1:
370
Disinfectants & Antiseptics
371
Boric acid 5% in water or as powder is used as antimicrobial on skin
lesions, highly toxic if absorbed, not advised.
Benzoic acid 0.1% is a food preservative. Its esters are used as
antimicrobial preservatives of certain drugs.
Acetic acid 1% is used in surgical dressing as antimicrobial. Acetic
acid 0.25~ 2% is antimicrobial in external ear and for irrigation of
the lower urinary tract, active against G-ve bacteria including
pseudomonas.
Salicylic acid & other fatty acids act as fungicides on skin.
Mandelic acid is excreted unchanged in urine if taken orally, lower
pH to 5 which is antibacterial.
Halogens and halogenated compounds
Iodine
372
Chlorine 0.25 ppm is effectively bactericidal.
Organic matter reduces it antimicrobial effect.
Used for disinfection of inanimate objects & purification of water.
Halazone USP is chloramines available in tablet form for the
sterilization of drinking water.
Sodium hypochlorite 0.5% solution is an irrigating disinfectant fluid
for contaminated wounds & as household bleaches containing
chlorine used as disinfectants for inanimate objects.
Oxidizing agents
Mercury
373
bacteriostatic antiseptics & used also as preservatives in biologic
products.
Silver
374
Soap or detergents containing 3% hexachlorophene are effective in
preventing colonization of newborn's skin with staph. in hospitals,
not used due to its CNS toxicity if absorbed systemically.
Carbanilides or Salicylanilides are also added to soaps as antiseptics.
Chlorhexidine is antiseptic agent for G+ve bacteria, used as skin
cleanser in soap and as a mouth-wash.
0.2% chlorhexidine gluconate can reduce plaque accumulation on
teeth and may be of some value in gingivitis. It is used for vaginal
flushing in prophylaxis against neonatal infections.
Cationic surface-active agents
375
1- To achieve a synergistic effect e.g. penicillin + gentamycin in
bacterial endocarditis. Sulfamethoxazole + trimethoprim (co-
trimoxazole)R are often combined to obtain a bactericidal effect.
2- To delay development of bacterial resistance, especially in chronic
infections e.g. tuberculosis.
3- To treat mixed bacterial infections e.g. peritonitis, UTI.
4- To broaden the spectrum of antibacterial activity.
5- To treat urgent infections before bacteriological diagnosis has been
made.
6- To reduce the toxic effects of antibiotics by giving small doses of
each.
Rules in combination of antibacterial:
1- Bacteriostatic + Bacteriostatic drugs combinations → additive effect
(arithmetic sum of the effects of the individual drugs)
2- Bacteriostatic + Bactericidal drugs combinations → antagonistic effect (the
addition of a second drug actually diminishes the antibacterial
effectiveness of the first drug) e.g. tetracycline + penicillin. Bactericidal
agents kill mainly multiplying bacteria, but if the bacterial growth is
prevented by a bacteriostatic agent, the bactericide will no longer be able
to act efficiently.
3- Bactericidal + Bactericidal drug combinations → a synergistic effect (the
results is far greater than that of each drug alone & greater than could be
expected from simple addition effects) e.g. penicillin + gentamycin.
Addendum notes 3:
376
a- Non-genetic resistance: active replication of bacteria is required for
most antibacterial drug action. Consequently microorganisms that
are metabolically inactive (non-multiplying) may be resistant to
drugs e.g. mycobacteria.
b- Genetically inherited resistance: The majority of resistant microbes
have emerged as a result of genetic changes & subsequent selection
that may be either chromosomal or extra-chromosomal.
Chromosomal resistance develops as a result of spontaneous
mutation, with selective multiplication of the resistant strains till
they eventually dominate. Extra-chromosomal resistance involves
extra-chromosomal genetic elements known as "plasmids" which
are small circular bodies consisting of 2 helical DNA strands and
carrying up to 100 genes regulating the various metabolic processes
of bacteria. The R-plasmids are especially encoded to confer
antibiotic resistance upon the organisms which acquired them.
Genetic material and plasmids can be transferred from one
bacterial cell to another by one of the following mechanisms:
i. Transduction: the passage of DNA from one cell to another of the
same species by means of a bacterial virus "bacteriophage". Thus the
plasmid carrying the gene for β–lactamase production can be
transferred from a penicillin-resistant to a penicillin-susceptible
staphylococcus.
ii. Transformation: DNA released from one cell of a species to another
cell, thereby altering its genotype. This type is common to Gram-
positive bacteria.
377
iii. Conjugation: Through physical contact a unilateral transfer of
genetic material between two bacteria of the same or of different
species. This is important for the spread of plasmid-mediated
resistance.
iv. Translocation "transposition": An exchange of short DNA
sequences occurs between one plasmid and another or between a
plasmid and a portion of the bacterial chromosome within a
bacterial cell.
Biochemical mechanisms of resistance to antimicrobial drugs:
1- Microorganisms produce enzymes that inactivate the drug e.g.
staphylococci resistant to penicillin G produce a β–lactamase that
destroys the antibiotic, other G-ve bacteria produce β–lactamases.
2- Microorganisms become less permeable to the drug and can no longer
accumulate it e.g. tetracyclines which are normally transported actively
across cell membranes of susceptible bacteria & are accumulated within
the cell. Resistant strains do not accumulate tetracyclines. Resistance to
polymyxins also is associated with a change in permeability to the drugs.
3- Development of an altered structural target for the drug. Chromosomal
resistance of aminoglycosides is associated with loss of the specific
protein on the 30S subunit of the bacterial ribosome that serves as a
receptor in susceptible organisms. Erythromycin-resistant organisms also
have an altered receptor site on the 50S subunit.
4- Microorganisms induce changes in target enzymes rendering them less
susceptible to the antibiotic, while retaining their normal metabolic
function e.g. when the enzyme dihydropteroic acid synthetase of some
378
bacteria loses its affinity for sulfonamides while retaining its affinity for
PABA.
5- Development of an altered metabolic pathway that bypasses the reaction
inhibited by the drug e.g. some sulfonamide-resistant bacteria, which
develop certain enzymes that can utilize preformed folic acid and do not
required extracellular PABA.
Cross resistance: Microorganisms resistant to a certain drug may also be
resistant to other drugs that posses the same chemical nucleus e.g.
tetracyclines or the same mechanism of action e.g. neomycin ~ kanamycin.
Addendum notes 4:
Contrast Materials
Contrast materials, also called contrast agents or contrast media. Are used to
improve pictures of x-rays, computed tomography (CT), magnetic resonance
(MR) imaging and ultrasound. They temporarily change the way x-rays or
other imaging tools interact with the body making certain structures or tissues
in the body appear different on the images than they would if no contrast
material had been administered. Contrast materials help distinguish or
“contrast” selected areas of the body from surrounding tissue. By improving
the visibility of specific organs, blood vessels or tissues, contrast materials help
physicians diagnose medical conditions.
Routes of administration
Orally
Rectally
Intravenously or intra-arterially
379
CLASSIFICATION:
When taken by a specific tissue, they block or limit the ability of x-rays to pass
through. As a result, blood vessels, organs and other body tissue that
temporarily contain iodine-based or barium compounds change their
appearance on x-ray or CT images.
a. Iodine-based compounds
b. Barium-sulfate
Is the most common contrast material taken orally. It is also used rectally
and is available in several forms, including: powder, which is mixed with
water before administration, liquid, paste, and tablet.
Are used to enhance x-ray and CT images of the gastrointestinal (GI) tract,
including: pharynx, esophagus, stomach, the small intestine, and the large
intestine.
380
Intravenous Contrast Materials
Hepatocyte agents
381
Use of contrast media in suspected perforation
Air
100 ml of air can be injected down an NG- tube and the film is taken after the
patient lies for 10 mints in lateral decubitus position. This allows passage of
air to the peritoneal cavity.
Intestinal obstruction
Paediatric
In neonates water soluble contrasts are used instead of barium. Low osmolar
water soluble contrasts include iohexol and iopamidol. They have no adverse
effect if extravasated into peritoneum or mediastinum or aspirated into the
respiratory tract.
Administration of contrast media can be via a cup- and- straw, feeding bottle,
or syringed into the mouth if necessary. NG- tube allows better control of
contrast volume and bolus passage into the duodenal loop.
382
Water- soluble contrast enema is indicated in neonatal low GI obstruction
and post necrotizing enterocolitis strictures. Also in older children in
suspected Hirschsprung`s disease or after colonic surgery. In IBD
colonoscopy is better avoiding ionizing radiation and allowing taking biopsy.
Stomach cramps
Diarrhea
Nausea
Vomiting
Constipation
Symptoms:
Hives
Itching
Red skin
Swelling of the throat
Difficulty breathing or swallowing
Hoarseness
Agitation
Confusion
Fast heartbeat
Bluish skin color
383
Iodine-based Contrast Materials
Difficulty breathing
Cardiac arrest
Swelling of the throat or other parts of the body
Convulsions
Profound low blood pressure
Contrast-Induced Nephropathy
384
History of allergy
Heart disease
Dehydration
Sickle cell anemia, polycythemia and myeloma
Renal disease
The use of medications such as Beta blockers, NSAIDs, interleukin 2
Having received a large amount of contrast material within the past 24
hours.
MR-Gadolinium
385
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