Professional Documents
Culture Documents
Neral
Neral
GENERAL PHARMACOLOGY
(Introduction to
Pharmacology)
Index
Introduction 2
pharmacokinetics 5
a)absorption 5
b)Distribution 13
c)Metabolism 17
d)Excretion 21
Questions 23
Routs of administration 24
Fundamental principles of pharmacokinetics 27
Pharmacodynamics 29
Types of receptors 34
Factors modifying dose & action of the drug 37
Adverse drug effects 43
Pharmacology:
It is the science which deals with drugs.
Drugs:
These are chemical agents used for:
1) Treatment (cure) of diseases.
2) Prophylaxis (prevention) of diseases as rifampicin in prophylaxis against meningitis,
aspirin in prophylaxis against thrombo-embolism, and nitrates in prophylaxis
against angina pectoris.
3) Diagnosis of diseases as radioactive iodine (I132) in diagnosis of thyroid function.
4) Prevention of pregnancy (contraception).
Most drugs are purchased only according to a "prescription" and are known as
"Prescription-only medication = POM" whereas few drugs are purchased without a
prescription as antipyretics (aspirin and paracetamol), drugs for common cold, and
laxatives used in treatment of constipation. These drugs are known as "Over The
Counter" drugs (OTC).
I- Sources of Drugs:
1) Plant sources: e.g. Atropine is obtained from Atropa belladonna and other plants,
Morphine is obtained from Papaver somniferum, Ephedrine is obtained from Ephedra
plant, etc…
2) Animal sources: e.g. animal Insulin was prepared from pigs (known as porcine insulin)
and from cattle (known as bovine insulin), Heparin (unfractionated heparin = UFH) is
obtained from the lungs and intestines of cattle and pigs. These drugs are highly
antigenic and are replaced now by human insulin and low molecular weight heparins
(LMWHs); respectively.
3) Microorganisms: Antibiotics (as penicillin G) are prepared from microorganisms as fungi
and bacteria.
4) Mineral sources: e.g. iodine and magnesium sulphate, and also radioactive isotopes as
I131 (therapeutic) and I132 (diagnostic).
5) Synthetic drugs: most drugs are chemically synthesized, e.g. Aspirin, Propranolol,
Sulphonamides, Benzodiazepines, Paracetamol, etc…
6) Biotechnology (genetic engineering): some drugs are prepared using "recombinant
DNA technology" as Human insulin, Growth hormone, recombinant tissue Plasminogen
Activator (r- tPA = Alteplase).
The main disadvantage of these drugs is their high cost (expensive).
II- Chemistry:
Some drugs as Aspirin (Acetyl Salicylic Acid) and Barbiturates- are weak acids, whereas
others- as Ephedrine and Amphetamine- are weak bases.
Most drugs are organic compounds but few drugs are inorganic elements as Lithium
and Iron.
Some drugs contain a specific chemical ring, e.g. Steroid hormones as Cortisone contain
a steroid ring, and catecholamines as Adrenaline contain a catechol ring.
III- Pharmacokinetics:
The term "pharmacokinetics" describes the movement of drugs inside the body, and is
usually referred to as "what the body does to the drug".
Pharmacokinetics includes:
1) Absorption
2) Distribution
3) Metabolism = Biotransformation
4) Excretion
(N.B.: Pharmacokinetics is sometimes referred to as "absorption and fate", and
metabolism and excretion are called together "elimination" or "clearance").
IV- Pharmacodynamics:
The term pharmacodynamics is referred to as "what the drug does to the body" and it
includes:
1) Mechanism of Action:
The most important mechanism of action is on specific "receptors", but some drugs
may act on enzymes, cell membrane, DNA, chemically, physically, etc. (see later).
2) Pharmacological Actions:
The actions of the drug may be:
1) Local actions (also known as topical actions) where the drug acts at the site of
application, e.g. skin ointments and eye drops.
2) Systemic actions: the drug reaches the systemic circulation and is distributed to
different systems as CNS, CVS, respiratory system, etc.
3) Reflex actions (also called remote actions): e.g. drugs that elevate arterial blood
pressure as Noradrenaline lead to "reflex bradycardia" through vagal stimulation.
VII- Contraindications:
The diseases in which the drug should be avoided, e.g. Aspirin is contraindicated in peptic
ulcer.
Pharmacokinetics
As previously mentioned; the term "pharmacokinetics" describes the movement of drugs
inside the body, and is usually referred to as
"What the body does to the drug". Pharmacokinetics includes:
1) Absorption
2) Distribution
3) Metabolism = Biotransformation
4) Excretion
1-Absorption:
Definition: it is the passage (transfer) of the drug from the site of administration to the
systemic circulation.
It is obvious that absorption from any site (GIT, lung, skeletal muscles, skin, and mucous
membranes) occurs by passage of the drug across the cell membrane (which is made of
phospholipid bi-layer and contains minute water-filled channels and ion channels).
Passage of drugs across cell membranes "transmembrane movement of drugs":
occurs by one of the following methods:
a) Passive transfer:
1) Simple diffusion (the most important method for drug absorption).
2) Filtration (important for drug excretion by the kidney).
b) Special transfer (Specialized transport):
1) Active transport.
2) Facilitated diffusion.
N.B. Active transport and facilitated diffusion are known as "carrier-mediated
transport".
3) Pinocytosis (Endocytosis or Cell drinking): it is an active process (energy-
dependent) in which the drug is "engulfed" inside the cell, e.g. absorption of
vitamin B12/ intrinsic factor complex by the ileum.
4-Facilitated 1) The drug passes through the lipid The drug is lipid insoluble
diffusion: bi-layer. (cannot pass by simple diffusion)
2) The drug moves from the higher and too large (cannot pass by
to the lower concentration = filtration).
along (with) concentration Example: glucose absorption.
gradient.
3) No energy is needed.
4) Carrier is needed.
5) Saturation occurs.
6) Competition with other drugs or
endogenous substances may
occur.
Ionized form
2) pKa = pH + log (For basic drugs)
Unionized form
8) The same rules are applied to renal excretion of drugs: alkalinization of urine by
NaHCO3 enhances (increases) renal excretion of acidic drugs as aspirin because aspirin
will be mostly ionized so it will be hydrophilic and excreted not reabsorbed (ion
trapping), but if urine is made more acidic by vitamin C (ascorbic acid) or NH4Cl, most of
aspirin will be unionized and lipid soluble so it will be "reabsorbed" by renal tubules.
On the other hand, basic drugs as amphetamine and ephedrine will be more excreted
by acidification of urine.
Oral absorption is usually variable due to the effect of GIT and the liver on the
drug before reaching the systemic circulation; this is known as
"1st pass effect" (see later).
(I.V. > Inhalation > I.M. > S.C. > Intact skin).
2) Surface area of the absorbing surface: the more the surface area exposed to the
drug, the better the absorption; e.g. small intestine (about 1000 times the surface
area of the stomach due to the presence of microvilli) and lung alveoli.
3) Vascularity (blood supply) of the absorbing surface: the richer the blood supply of
the absorbing surface, the better the absorption; e.g. the small intestine and the
lung alveoli.
4) State of health of the absorbing surface: oral absorption is greatly decreased in the
presence of diseases of GIT as malabsorption.
5) State of general circulation: in cases of shock; blood flow to the subcutaneous (S.C.)
tissues is markedly reduced due to diminished tissue perfusion and sympathetic
stimulation causing vasoconstriction of subcutaneous blood vessels. That is why
drugs as morphine should be given I.V. in case of shock.
6) Specific factors: oral vitamin B12 is absorbed only in the presence of intrinsic factor
synthesized by the gastric parietal cells.
Factors affecting (modifying) oral drug absorption:
a) Factors related to the drug: see before.
b) Factors related to the patient:
1) Surface area of the absorbing surface: see before.
2) Vascularity (blood supply) of the absorbing surface: see before.
3) State of health of the absorbing surface: see before.
4) Specific factors: see before.
5) Gut motility: drugs that stimulate gut motility and accelerate gastric emptying-
known as "prokinetic drugs" as (metoclopramide) will increase oral absorption of
rapidly disintegrated drugs as paracetamol but they will decrease absorption of
slowly disintegrated drugs as digoxin. Drugs that inhibit gut motility and slow gastric
emptying as (atropine) have opposite effects.
6) Gut pH: acidic drugs as aspirin are better absorbed in acidic medium as the stomach,
whereas basic drugs as ephedrine and amphetamine are better absorbed in alkaline
medium as the intestine (why?).
7) Gut contents (food and other drugs):
As a general rule; drugs should be given on empty stomach (before meals or 2
hours after meals) to avoid:
a) Dilution of the drug by food.
b) Competition between amino acids (from digested dietary proteins) and some
drugs as L-DOPA on the same carrier (transporter).
Exceptionally; irritant drugs-as aspirin and other NSAIDs, and iron preparations-
should be given after meals.
Food containing Ca2+ (as milk and dairy products), and antacids containing Al3+
and Mg2+ decrease absorption of tetracyclines due to chelation.
Tetracyclines and tannic acid (in tea and coffee) decrease absorption of iron.
Cholestyramine and activated charcoal decrease absorption of most drugs
(activated charcoal adsorbs drugs).
Tannic acid in tea and coffee decreases absorption of iron.
Grape fruit inhibits P-glycoprotein-which is responsible for reversed transport of
drugs from gut mucosa into gut lumen-and so grape fruit increases drug
absorption.
P-glycoprotein also causes efflux of anticancer drugs as Methotrexate out of the
cancer cells. It was found that Verapamil-a calcium channel blocker-inhibits P-
glycoprotein and so it increases uptake of methotrexate
8) First pass effect (first pass metabolism or pre-systemic metabolism): orally-
administered drugs may be partially or completely metabolized while passing in GIT
(gut first pass) or the liver (hepatic first pass) before reaching the systemic
circulation.
a) Gut first pass effect:
Some penicillins are destroyed by gastric acidity and are known as "acid-
sensitive penicillins", e.g. benzyl penicillin (penicillin G).
Polypeptide hormones as insulin are destroyed by the digestive enzymes.
Some drugs are metabolized by the gut mucosa as chlorpromazine and α-
methyl dopa.
b) Hepatic first pass effect (much more important than gut first pass):
Lipophilic drugs are metabolized by the liver (see later).
Some of these drugs are largely metabolized by first pass hepatic effect, e.g.
propranolol. Other drugs are extensively metabolized, as nitroglycerin, or
almost completely metabolized as lidocaine and natural sex hormones.
Hydrophilic drugs as Atenolol and Nadolol are minimally metabolized by the
liver.
Bioavailability:
Definition: it is the fraction (proportion or percentage) of the chemically unchanged
drug reaching the systemic circulation following administration by any route.
Bioavailability after I.V. injection = 100%.
Bioavailability is very high following administration by inhalation (inhalation general
anaesthetics).
Bioavailability after I.M. injection is higher than after S.C. injection.
Bioavailability after S.L. administration is higher than after oral administration
Oral bioavailability is variable because of first pass effect, and is calculated as
follows:
AUCoral
▬▬▬▬▬ x 100
AUCIV
AUC: Area Under plasma concentration-time Curve.
The factors affecting bioavailability are the same factors affecting absorption of
drugs (see before).
Bioequivalence: two drugs or two forms of the same drug show bioequivalence if
they have the same bioavailability and the same rate of absorption (they reach the
peak plasma concentration at the same time).
Therapeutic equivalence: two drugs have the same efficacy and safety.
2- Distribution:
Once the drug is absorbed from any site, i.e. it reaches the systemic circulation; it may be
distributed to the body fluids and tissues as follows:
A) Compartment Model:
The body fluids = 42 L. representing 60% of the total body weight (TBW) of an average 70
Kg. person and include: plasma (4 L.), interstitial fluid (10 L.), and intracellular fluid (28 L.).
The plasma is referred to as "intravascular compartment", whereas the plasma and the
interstitial fluid together (14 L.) are referred to as "extracellular compartment".
28 Liters
10 Liters
4 Liters
Drugs are bound reversibly mainly to albumin and to a lesser extent to globulin and α-
acid glycoprotein.
Some drugs as aspirin and sulphonamides have a highly affinity (are highly bound) to
plasma proteins and they displace other drugs with lower affinity as digoxin,
sulphonylureas (oral hypoglycemics), and warfarin (oral anticoagulant) if administered
together, which results in increase in the free "active" form of the latter drugs and this
may lead to severe adverse (toxic) effects:
Aspirin and sulphonamides displace digoxin leading to digitalis toxicity.
Aspirin and sulphonamides displace sulphonylureas (as Tolbutamide) leading to
hypoglycemia.
Aspirin and sulphonamides displace warfarin leading to bleeding.
Sulphonamides displace bilirubin from plasma proteins, which increases free bilirubin
causing hyperbilirubinemia and may be kernicterus in neonates.
The more the bound form of the drug, the longer its duration. This is shown with some
sulphonamides.
A (in mg.)
Vd = ▬▬▬▬▬▬ (A →Amount or dose of the administered drug, C →Concentration of the drug in plasma)
C (in mg. /ml)
Significance of Vd:
1) The term "apparent" indicates that it is a hypothetical - not always a true value -as in
the case of digoxin which has a Vd of 500 liters which is much higher that the total fluid
volume (42 L. in an average 70 Kg. person).
2) High Vd indicates that the drug is distributed as a multicompartment model or has high
tissue concentration (highly bound to tissue proteins). Drugs with very high Vd have
slow rate of elimination and long T1/2.
3) Low Vd indicates that the drug is retained in plasma (intravascular, one compartment
model) mostly due to high binding to plasma proteins.
4) Knowing the Vd allows the estimation of the "loading dose" which is the initial dose
required to reach a specific drug concentration, and also allows measurement of the
total amount of the drug in the body: A = Vd X C
5) Drugs with low Vd as aspirin are highly bound to plasma proteins meaning that they a
have high plasma concentration, that is why hemodialysis is useful in treatment of
acute toxicity by these drugs.
It is clear that hemodialysis is not beneficial in treatment of acute toxicity by drugs with
high Vd because they have low plasma concentration being highly distributed or highly
concentrated in tissues.
3-Metabolism=Biotransformation:
These are chemical reactions that occur mainly in the liver.
The aim of biotransformation reactions is to "convert lipophilic (lipid soluble) drugs into
water-soluble (hydrophilic, ionized,or polar) metabolites to be easily excreted in urine.
It is clear that water-soluble drugs do not undergo metabolism and are excreted
"unchanged" in urine.
On the other hand; lipophilic drugs-after filtration through the renal glomeruli-will
undergo "reabsorption" by the renal tubular cells, making renal excretion of these
drugs very slow. So, they are metabolized to be converted into water soluble form to
promote their renal excretion.
reduction
Chloral hydrate (active) ▬▬▬▬▬▬►trichloroethanol (active).
3) Conversion of an "inactive" drug into an "active" metabolite and in this case the
parent drug is known as a "prodrug", e.g. cortisone (inactive) is changed into
cortisol=hydrocortisone (active), and enalapril(inactive) is metabolized into
enalaprilate (active).
Oxidation
Imipramine ▬▬▬▬▬► desipramine.
4) Very rarely; a toxic metabolite is formed, e.g. methyl alcohol (methanol) is
metabolized by oxidation into formaldehyde which causes permanent blindness,
being retinotoxic. ( اﺻﺎﺑﺔ ﻋدة اﺷﺧﺎص ﺑﺎﻟﻌﻣﻰ ﻟﺗﻧﺎول اﻟﺧﻣور اﻟﻣﻐﺷوﺷﺔ: )إﻗرأ ﻓﻰ ﺻﻔﺣﺔ اﻟﺣوادث
In addition, insecticides as Parathion and Malathion are oxidized into toxic
Para oxon and Mala-oxon; respectively.
b) Phase II Reactions:
These are "Synthetic" or "Conjugation" reactions.
The drug or a metabolite resulting from phase I reaction is "conjugated" with an
endogenous polar compound as glucuronic acid, sulphate, glycine, acetate, glutathione
or methyl group.
Phase II reactions mostly result in drug inactivation, with some exceptions as morphine
(active) which is partially converted into morphine 6-glucuronide (active metabolite),
and minoxidil (inactive) is conjugated into minoxidil sulphate (active).
N.B. most drugs are metabolized by phase I reactions followed by phase II reactions,
undergo phase I reaction only, or phase II reactions only. Few drugs as isoniazid is
metabolized by conjugation (phase II) followed by hydrolysis (phase I), i.e. there is
"reversal of order of the phases".
Sites of biotransformation reactions:
1) The liver: it is the main site of drug metabolism.
2) The plasma: e.g. plasma cholinesterase (pseudo cholinesterase) is responsible for
metabolism of some drugs as Succinylcholine.
3) Other sites: the lung, the kidney, the skin, and GIT.
Types of Enzymes Responsible for Biotransformation Reactions:
Microsomal Enzymes Non-Microsomal Enzymes
1) Found in smooth endoplasmic reticulum of 1) Found in the cytoplasm and
liver cells, that is why they are referred to as mitochondria of liver cells, skin, GIT,
"Hepatic" microsomal enzymes (HME). lungs, and in plasma.
3) Their activity varies with age, sex of the 3) ☻Their activity varies with age and
patients, starvation, liver diseases, and by sex, but is not affected by drugs
drugs: their activity is increased or decreased
by drugs known as HME inducers and HME
inhibitors; respectively (see later).
4) Act on lipophilic drugs. 4) Act on lipophilic and hydrophilic
drugs metabolites.
2) Age:
The activity of HME is lower in extremities of age; i.e. neonates (especially if premature)
and old age, so they should be treated with lower doses than adults.
3) Sex (Gender):
Male sex hormones (androgens) act as HME inducers whereas female sex hormones
(estrogen and progesterone) act as HME inhibitors. This is an important cause why females
receive lower doses than males (of the same age and weight).
4) Pathological conditions:
Liver diseases as cirrhosis markedly reduce the activity of HME and the dose of drugs
metabolized by these enzymes should be adjusted according to liver function tests.
Cancer and starvation have the same effect on HME activity.
4- Excretion:
Drugs and their metabolites are excreted by the following routes:
1-Kidney (Renal excretion):
The most important route of drug excretion is excretion in urine.
The drug undergoes one –or more-of the following processes in the nephrons:
1) Glomerular Filtration (passive process): the free (unbound) form of the drug is
filtered, depending on the glomerular filtration rate.
2) Tubular Reabsorption (passive process): the unionized (lipophilic) form of the drug
undergoes tubular reabsorption.
3) Tubular Secretion (active process): some drugs- as well as endogenous substances
as uric acid-are actively transported into the lumen of the proximal convoluted
tubules (PCT) of nephrons.
There are 2 active transport systems (carriers); one for secretion of organic acidic drugs
as penicillin, thiazides, loop diuretics (frusemide), and probenecid, and the other for
secretion of organic basic drugs as digoxin, quinidine, ephedrine and amphetamine.
Penicillin and probenecid compete for the same carrier are secreted by the same
transport system (carrier); that is why probenecid increases the duration of action of
penicillin, as probenecid will decrease tubular secretion of penicillin leading to increase
in its plasma concentration.
The pH of urine changes the rate of urinary excretion of drugs; i.e. alkalinization of
urine by NaHCO3 increases urinary excretion of acidic drugs as aspirin and
phenobarbitone, because most of the drug will be in the ionized hydrophilic form,
which is easily excreted and not reabsorbed (ion trapping).
On the other hand; acidification of urine by ammonium chloride (NH4Cl) or vitamin C
(ascorbic acid) promotes excretion of basic drugs as amphetamine and ephedrine.
These facts are clinically useful in treatment of acute drug toxicity by increasing their
excretion in urine through changing the pH of urine.
2-GIT:
Some drugs may be excreted by:
a) Bile:
Some drugs are excreted in bile; either as free drugs (active), as ampicillin and
rifampicin, or conjugated drugs, as morphine and phenolphthalein (a chemical
laxative).
Ampicillin and Rifampicin are effective in treatment of GIT infections and gall
bladder infections (cholecystitis) being excreted in an active form in bile.
Some drugs excreted by bile (as phenolphthalein and rifampicin) may be reabsorbed
from GIT undergo, i.e. undergo "entero-hepatic recycle" which prolongs the
duration of action of such drugs.
The unabsorbed drugs are excreted in feces.
b) Saliva: e.g. morphine, iodine (which may cause a metallic taste and inflammation of the
salivary glands), aspirin, and rifampicin.
c) Stomach: morphine is partially excreted in the stomach; that is why stomach wash is
performed in case of acute morphine poisoning despite the fact that morphine is
administered intravenously.
d) Large Intestine (Stools): drugs that are poorly absorbed orally as aminoglycosides (e.g.
streptomycin) and some tetracyclines are excreted in stools.
4-Sweat: very few drugs are excreted in sweat as rifampicin and B12.
5-Breast milk: many drugs can be excreted in breast milk and can affect suckling infants,
e.g. laxatives (as phenolphthalein), antihistaminics (in common cold medications), oral
anticoagulants (as warfarin), antibiotics (as chloramphenicol, tetracyclines and
fluroquinolones), morphine, antithyroid drugs, etc.
It is well known that basic drugs as amphetamine and morphine are "trapped" and
excreted in breast milk (see before).
N.B.
1) Rifampicin is excreted in urine, sweat, saliva, and even in tears causing orange-
red discoloration of all the fluids.
2) Sweat glands and mammary glands are called "skin glands".
Enumerate:
1) Factors affecting drug absorption.
2) Factors affecting oral absorption.
3) Factors affecting bioavailability.
4) Factors affecting drug distribution.
5) Factors affecting hepatic microsomal enzyme activity.
Define:
1) Absorption
2) Pka
3) Bioavailability
4) Vd
c)S.C.: As IM. Use only non- Slower and lower Not suitable in:
irritant drugs. bioavailability than 1)Shock.
IM (less vascular). 2)irritant drugs.
3)large volumes.
Pharmacodynamics
Receptors regulation: Under normal conditions; the number of receptors is fixed. This may
vary in the following conditions:
1) Long use of an agonist leads to decrease in the number (and sensitivity) of
receptors, this is known as "down-regulation".
2) Long use of an antagonist or deficiency of an endogenous agonist as
neurotransmitters leads to increase in the number (and sensitivity) of receptors.
This is known as "up-regulation".
2-ANTAGONISTS = BLOCKERS:
Antagonists are drugs that block the receptors thus preventing the action of the agonist,
and are characterized by the following:
1) Affinity.
2) No efficacy (zero efficacy): no change in the activity of the cell in the absence of an
agonist, but they prevent the action of the agonist.
3) Slow rate of association and dissociation.
B-Pharmacological Actions:
The actions of the drug may be:
1) Local actions (also known as topical actions) where the drug acts at the site of
application, e.g. skin ointments and eye drops.
2) Systemic actions: the drug reaches the systemic circulation and is distributed to
different systems as CNS, CVS, respiratory system, etc.
3) Reflex actions (also called remote actions): e.g. drugs that elevate arterial blood
pressure as Noradrenaline lead to "reflex bradycardia" through vagal stimulation.
Maintenance Dose: It is dose given regularly to maintain Css and is equivalent to the
amount of drug eliminated.
Maintenance dose = clearance of the drug (Cl) X Css X Dose interval (Tm)
Maintenance dose (MD) = Cl X Css X Tm
N.B.:
1) The smaller the dose interval (Tm), the smaller the maintenance dose.
2) In case of IV infusion there is no dose interval and the maintenance dose = Infusion rate
= Cl X Css
3) Clearance (Cl): it is the volume of the body fluids cleared from the drug in a unit time,
measured in ml/ minute (the volume of body fluids from which the drug is removed by
metabolism and /or excretion in a unit time).
Clearance = constant of elimination X Vd
Cl = Kel X Vd
Cl = 0.693 X Vd
T½
Minimal effective dose: the lowest dose required to produce a therapeutic effect.
Maximal Tolerated Dose: It the maximum dose that can be safely administered without
inducing toxic effects.
Median Effective Dose (ED50): It is the dose that induces a specific therapeutic effect in
50% of experimental animals.
Median Toxic Dose (TD50): It is the dose that induces a particular toxic effect in 50% of
experimental animals.
Median Lethal Dose (LD50): It is the dose that induces death in 50% of experimental
animals.
Therapeutic Index: = LD50/ED50 .It is a measure of drug safety; the higher the index the
safer the drug.
Elderly between 60 and 70 years require 2/3 of the adult dose and those over 70 years
require 1/2 of the adult dose due to:
1) Weakness of hepatic microsomal enzymes.
2) Reduced renal excretory functions.
2) Body Weight:
The more the body weights the higher the dose except in cases of edema or fat which
are not taken into consideration.
In obese patients due to excessive body fat increase the dose of lipophilic drugs and
reduce that of hydrophilic drugs.
6) Tolerance:
Definition: failure to obtain the usual response by the usual dose.
Types:
a) Congenital which is either:
1) Racial: Negros are tolerant to the mydriatic action of ephedrine.
2) Species: rabbits are tolerant to the systemic actions of atropine due to the
presence of atropine esterase (atropinase) in their plasma.
3) Individual: this is due to genetic variations.
b) Acquired: long use of drugs as morphine, barbiturates, nicotine, ethyl alcohol, and
amphetamine leads to acquired tolerance which is usually reversible, and may occur
to some –not all- actions of the drug (see morphine).
Causes of acquired tolerance:
a) Pharmacokinetic causes: HME inducers as nicotine and barbiturates increase their
own metabolism.
b) Pharmacodynamic causes: long use of drugs leads to "down-regulation" of receptors
or depletion of endogenous transmitters. Animal insulin induces antibody formation
Special types of acquired tolerance:
Tachyphylaxis: acute acquired tolerance (see effect of ephedrine on ABP).
Cross tolerance: occurs between drugs having similar effects as morhine, barbiturates,
or ethyl alcohol with general anaesthesia (all are CNS depressants).
7) Dependence:
It is either:
a) Psychic dependence = Habituation: sudden cessation of the drug does not cause
withdrawal symptoms but may cause emotional distress for a short time, e.g.
methylxanthine beverages as tea and coffee.
b) Psychic and Physical dependence = Addiction:
Sudden cessation of the drug leads to severe –and may be fatal- withdrawal symptoms
"Abstinence syndrome" which are the reverse of the drug actions, e.g. opiates
(morphine, heroin, and codeine), ethyl alcohol, barbiturates, and nicotine.
8) Supersensitivity =Intolerance:
It is an exaggerated normal drug response. It is due to upregulation of receptors, due to
inhibition of metabolizing enzymes, or due to diseases as thyrotoxicosis (see adrenaline). It
requires reduction of the dose.
9) Hypersensitivity = Allergy:
It is an abnormal unpredictable drug response due to antigen-antibody reaction (the
drug or a metabolite acts as an antigen or binds to a hapten).
It does not occur on the first exposure to the drug which sensitizes the patient but
occurs on subsequent exposures, and is not dose-dependent.
Manifestations: skin rash, urticaria, photosensitivity (skin rash on exposure to sun-
light), asthma, angioneurotic edema, anaphylactic shock, bone marrow depression
(blood dyscrasias) by chloramphenicol, sulphonamides, dipyrone and thioamide
antithyroids-cholestatic hepatitis and jaundice by chlorpropamide, testosterone,
chlorpromazine, and alpha methyldopa.
Cross allergy occurs between drugs having the same chemical structure as
sulphonamides and thiazide diuretics, or between drugs having the same mechanism of
action as aspirin and other NSAIDs in asthmatics.
10) Idiosyncracy:
It is an abnormal unpredictable drug response due to genetic defects.
13) Cumulation:
It occurs when the rate of drug administration exceeds the rate of elimination (by
metabolism and excretion), e.g. cardiac glycosides especially digitoxin, and guanethidine. It
is more liable with drugs following zero order kinetics (see later).