GENERAL PHARMACOLOGY 2011/2012

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

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GENERAL PHARMACOLOGY 2011/2012

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).

 Drugs "modify" an existing cell function either by stimulation (activation) or inhibition

(depression) but they do not create a new function. However; gene therapy may be
beneficial in "creating" a function as ability to secrete insulin in type I diabetes mellitus.

 Names (Nomenclature) of drugs:

1) Chemical name
2) Non-proprietary = Generic name (may be referred to as scientific name).
3) Proprietary = Commercial name (may be referred to as trade name).

 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).

Points to discuss about drugs (Scheme):

1) Source
2) Chemistry
3) Pharmacokinetics (and Routes of Administration)
4) Pharmacodynamics
5) Pharmacotherapeutics: Indications (Therapeutic uses) and dosage
6) Adverse effects
7) Contraindications
8) Drug Interactions

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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").

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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.

V- Indications = Therapeutic uses:

The diseases for which the drug is prescribed to treat or prevent, e.g. Aspirin is indicated in
treatment of headache and fever, and to prevent thromboembolism.
N.B.: "Pharmacotherapeutics" includes therapeutic uses and dosage of drugs.

VI- Adverse effects:

This term describes the unwanted drug effects and is sometimes referred to as "side
effects" or "toxic effects" (see later).

VII- Contraindications:
The diseases in which the drug should be avoided, e.g. Aspirin is contraindicated in peptic
ulcer.

VIII- Drug Interactions:

1) Drug-Drug interactions: when 2 or more drugs are prescribed to the patient, these
interactions may be beneficial (favorable) or harmful (unfavorable).
2) Drug-Food interactions, e.g. MAO inhibitors (used in treatment of depression) interact
with food containing tyramine as cheese and yoghurt and lead to serious and may be
fatal elevation of arterial blood pressure.

IX- Routes of Administration (see later).

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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.

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Method Characteristics Factors and forces affecting

1-Simple 1) The drug passes through the lipid 1) Lipid solubility (lipid/water or
diffusion: bi-layer of the cell membrane. oil/ water partition
2) The drug moves from the higher to coefficient): the more the
the lower concentration = along lipophilicity of the drug, the
(with) concentration gradient. more the absorption.
3) No energy is needed. 2) Degree of ionization: the
4) No carrier is needed. more the unionized (non-
5) No saturation occurs. ionized) form of the drug, the
6) No competition with other drugs more its lipid solubility and
or endogenous substances. accordingly the more its
absorption.
3) Molecular size: the smaller
the molecular size, the better
the absorption.
4) Concentration gradient: the
higher the gradient, the
higher the rate of passage of
the drug.
5) Water solubility is a must.
2-Filtration: 1) The drug passes through the 1) Water solubility.
aqueous pores (channels) in the 2) Molecular weight: the pores
cell membrane. have minute size and allow
2) The drug moves from the higher to only the passage of drugs of
the lower osmotic pressure = low molecular weight (< 500).
along (with) osmotic pressure 3) The drug must be free
gradient. (unbound to plasma
3) No energy is needed. proteins).
4) No carrier is needed. 4) Blood flow.
5) No saturation occurs. 5) Hydrostatic and osmotic
6) No competition with other drugs gradient.
or endogenous substances.
(Glomerular filtration is essential for
renal excretion of most drugs).

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3-Active 1) The drug passes through the lipid

transport: bi-layer.
2) The drug moves from the lower to
the higher concentration = against
concentration gradient.
3) Energy is needed.
4) Carrier is needed.
5) Saturation occurs.
6) Competition with other drugs or
endogenous substances may
occur.
(Active transport is also required for
the renal excretion of some drugs as
penicillin and is known as "active
tubular secretion").

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.

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Drug Ionization (Effect of pH on oral absorption and renal excretion):

How much of the drug is ionized (lipid insoluble-hydrophilic-polar) and how much is
unionized (nonionized-lipid soluble-lipophilic) is determined according to the following
rules:
1) Most drugs are either weak acids as aspirin (salicylates) and phenobarbitone
(barbiturates), or weak bases as ephedrine and amphetamine.
2) Drugs are present either in an acidic medium (as the stomach which is highly acidic, or
urine which is slightly acidic), or in an alkaline medium (as the intestine).
3) The presence of an acidic drug-as aspirin- in an acidic medium-as the stomach- makes
most of the drug unionized and lipid soluble, so it will be easily absorbed by simple
diffusion.
4) The presence of an acidic drug- as aspirin- in an alkaline medium as the small intestine -
makes most of the drug ionized and lipid insoluble, and accordingly it will be poorly
absorbed (ion trapping).
5) The presence of a basic drug in an acidic medium renders most of the drug ionized and
poorly absorbed (ion trapping); whereas the presence of a basic drug in an alkaline
medium allows most of the drug to be in the unionized form and almost complete
absorption occurs.
6) Ionization Constant = Dissociation Constant=pKa: it is the pH of the medium in which
50% of the drug is ionized and 50% is unionized.
It is clear that pKa is "constant" for every drug, e.g. pKa of aspirin = 3.5. This means
that at pH 3.5, 50% of aspirin is ionized and 50% is unionized.
7) Henderson-Hasselbalch Equation: this equation clarifies the relation between pKa, pH,
and degree of drug ionization. It states that:
Un ionized form
1) pKa = pH + log (For acidic drugs)
Ionized form

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.

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Factors affecting (modifying) drug absorption:

The factors that influence drug absorption can be classified into factors related to the drug
and factors related to the patient.

a) Factors related to the drug:

1) Lipid solubility and lipid-water partition coefficient: the more the lipid solubility (i.e.
the higher the lipid-water partition coefficient), the better the absorption.
2) Degree of ionization: the more the unionized form of the drug, the more the lipid
solubility and hence the better the absorption.
3) Valency: ferrous salts (Fe2+) are better absorbed than ferric salts (Fe3+).
4) Chemical nature: inorganic drugs are better absorbed than organic drugs (due to
smaller molecules).
5) Pharmaceutical formulation:
 Aqueous solutions are better absorbed than suspensions.
 Drugs that are rapidly disintegrated (dissolved) in the stomach –as paracetamol-
are better absorbed than slowly disintegrated drugs as digoxin.
Important notes:
1) Quaternary ammonium drugs as Neostigmine are ionized and so poorly absorbed orally.
2) Tertiary amine drugs as Physostigmine are unionized and lipid soluble, and accordingly
are well absorbed orally.
3) Aminoglycosides-as Streptomycin-have high pKa, so they are always ionized in any
medium in the body including the alkaline medium of the intestine, and accordingly are
almost not absorbed orally.
4) Some drugs are not absorbed orally although they are unionized, e.g. Sulfaguanidine.
b) Factors related to the patient:
1) Route of administration:
 Intravenous injection (I.V.): 100% of the drug reaches the systemic circulation
almost immediately.
 Intramuscular injection (I.M.): most of the drug is rapidly absorbed due to the
high vascularity of skeletal muscles.
 Subcutaneous injection (S.C.): absorption is less than after I.M. injection because
the S.C. tissue is much less vascular than the skeletal muscles.
 Inhalation: lipid soluble drugs as inhalation general anaesthesia are rapidly and
almost completely absorbed because the alveoli have a very wide surface area
and very rich blood supply.
 Sublingual: drugs given as sublingual pellets –as nitroglycerin in treatment of
acute anginal attacks-are better and more rapidly absorbed than orally
administered drugs because they reach the systemic circulation directly and
avoid passage through GIT and the liver.

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 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).

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 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.

How to avoid first pass effect ?:

1) Increase the dose of orally- administered drugs as propranolol and nitroglycerin.
2) Change the route of administration: the drug may be given I.V. as benzyl penicillin and
lidocaine, S.C. as insulin, or sublingual (S.L.) as nitroglycerin.

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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.

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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

PLASMA INTERSTITIAL INTRACELLULAR

Drugs are distributed according to one of the following patterns of distribution:
1) One Compartment Model:
Drugs that are extensively bound to plasma proteins and drugs that have a very high
molecular weight as high molecular weight heparin (HMWH) and dextran (plasma
expander) can not pass through the capillary endothelium and are distributed in plasma
only = intravascular compartment = 4 L.
2) Two Compartment Model:
Drugs that are hydrophilic and with low molecular weight can pass through the
capillary endothelium but can not pass the cell membranes being lipid insoluble and
ionized-as quaternary ammonium compounds (neostigmine)-and accordingly are
distributed in 2 compartments: plasma and interstitial fluid =extracellular compartment
= 14 L.
3) Multicompartment Model:
Drugs that are of low molecular weight, non-ionized, and lipophilic are distributed in all
compartments-both extracellular and intracellular-and accordingly are distributed in
42L.
4) Special Distribution=Tissue reservoir:
Some drugs are concentrated in certain tissues, e.g. tetracyclines are concentrated in
bone and teeth (Ca2+-containing)-iodine is concentrated in thyroid tissue-thiopentone
in fatty tissues-heavy metals as lead and arsenic in hair and skin-digitalis in cardiac
muscles-thiopentone in fat-Vitamin B12 and chloroquine in the liver.

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B) Binding of Drugs to Plasma Proteins:

 After reaching the systemic circulation, any drug will be found in 2 forms; the free
(unbound) form and the bound form.

Free Form Bound Form

 Diffusible.  Non-diffusible (confined to plasma).
 Active.  Inactive.
 Liable to liver metabolism.  Not liable to liver metabolism.
 Liable to renal excretion (mostly by  Not liable to renal excretion.
glomerular filtration).  Acts as a "reservoir".

 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.

 In conditions causing "hypoalbuminemia" as in old age, liver diseases, malnutrition or

starvation; the free form of drugs as phenytoin (antiepileptic) is higher than in normal
individuals and toxic effects may occur with therapeutic doses.

 The more the bound form of the drug, the longer its duration. This is shown with some
sulphonamides.

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C) Passage across Barriers:

1) Passage across blood brain barrier (B.B.B.):
 Lipid soluble unionized drugs can penetrate B.B.B. and exert C.N.S. actions, whereas
hydrophilic ionized drugs cannot pass across B.B.B. and have almost no C.N.S.
actions in normal conditions.
 Penicillins cannot penetrate normal meninges but can pass across inflamed
meninges to C.S.F. in case of meningitis (due to increased permeability), and so are
useful in treatment of meningitis.

2) Passage across placental barrier to fetus:

 Most drugs can pass across the placental barrier from the maternal circulation to
the fetus.
 Lipid soluble unionized drugs pass more easily than hydrophilic ionized drugs.
 Some drugs –as aspirin, cortisone, ACE inhibitors, benzodiazepines, phenytoin,
etc…cause fetal malformations known as "teratogenicity" or "fetotoxicity" especially
if given in early pregnancy (1st trimester).
N.B. Thalidomide (which was used as axiolytic and hypnotic) caused amelia or
phocomelia on a large number of newborn infants which was known as "Thalidomide
disaster". Recently; drugs are classified into categories: A, B, C, D, and X according to
their possible teratogenic effect.
3) Passage through breast milk:
 Most drugs can pass through breast milk to the suckling babies; some of which may
cause serious adverse effects as morphine, fluroquinolones, radioactive iodine, etc...
 Basic drugs are ionized and "trapped" in breast milk because its pH is relatively more
acidic (= 7) compared to plasma pH (= 7.4).
 Lipophilic drugs are retained in breast milk because of its rich fat content.

D) Apparent volume of distribution (Vd):

 The apparent volume of distribution (Vd) is a rough measure of drug distribution; the
larger the Vd, the more the drug distribution.
 The apparent volume of distribution is calculated in liters (or in liters /Kg.) according to
the following equation:
Amount of drug
Vd = ▬▬▬▬▬▬▬▬▬▬▬▬
Concentration in plasma

A (in mg.)
Vd = ▬▬▬▬▬▬ (A →Amount or dose of the administered drug, C →Concentration of the drug in plasma)
C (in mg. /ml)

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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.

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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.

Phases of Biotransformation Reactions:

a) Phase I Reactions:
 These are "Non-Synthetic" reactions.
 The drug undergoes either: oxidation, reduction, or hydrolysis.
 Phase I reactions will result in one of the following:
1) Conversion of an active drug into an "inactive" metabolite.This is the most
common result, e.g.:
Hydrolysis
Acetylcholine ▬▬▬▬▬▬▬► choline + acetic acid
2) Conversion of an active drug into an "active" metabolite, e.g.:
oxidation
Phenacetin (active) ▬▬▬▬▬► paracetamol = acetaminophen (active).

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.

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GENERAL PHARMACOLOGY 2011/2012

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.

2) They catalyze the following biotransformation 2) They catalyze the following

reactions: biotransformation reactions:
 Oxidation (by cytochrome P 450 =CYP450  Oxidation.
enzymes).  Reduction.
 Reduction.  Hydrolysis.
 Hydrolysis.  Conjugation except with
 Conjugation with glucuronic acid only. glucuronic acid.

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.

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GENERAL PHARMACOLOGY 2011/2012

Factors Affecting Hepatic Microsomal Enzyme activity:

1) The Effect of Drugs:

 Some drugs increase the activity of hepatic microsomal enzymes (HME) and are known
as HME inducers or activators, whereas other drugs reduce or inhibit the activity of
HME and are thus called HME inhibitors.
 Examples of HME inducers: phenytoin, phenobarbitone, rifampicin, nicotine (tobacco
smoking), testosterone (androgens), carbamazepine, griseofulvin, chronic alcohol
ingestion, coffee and tea.
 Examples of HME inhibitors:
1) Direct HME inhibitors: cimetidine, chloramphenicol, contraceptive pills (containing
estrogen and/or progesterone), ketoconazole, erythromycin, fluroquinolones,
allopurinol, grape fruit, omeprazole, sulphonamides, sodium valproate, MAO
Inhibitors, isoniazid, and acute alcoholism.
2) Indirect HME inhibitors, which are either:
a) Drugs causing hepatic toxicity as carbon tetrachloride.
b) Drugs reducing hepatic blood flow as Propranolol and Cimetidine.

Importance of HME induction:

1) HME inducers increase their own metabolism (auto-induction), which may lead to
tolerance and dependence, e.g. phenobarbitone, nicotine and chronic alcoholism.
2) HME inducers increase the metabolism of other drugs given at the same time leading to
decreased activity of the other drugs. This requires increasing the dose of the other
drugs.
3) Some HME inducers as phenytoin increase the metabolism of vitamins as folic acid,
vitamin K, and vitamin D; leading to megaloblastic anemia, hemorrhage, and
osteomalacia; respectively.
4) HME inducers as phenobarbitone are used in treatment of mild hyperbilirubinemia in
neonates as they induce conjugation of bilirubin.

Importance of HME inhibitors:

Administration of HME inhibitors with some drugs – as warfarin, digitalis, oral
hypoglycemics and theophylline- may lead to increased plasma levels of such drugs even
with therapeutic doses, which may lead to "toxicity". That is why we should reduce the
dose of warfarin, digitalis, oral hypoglycemics and theophylline if given with HME
inhibitors.

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GENERAL PHARMACOLOGY 2011/2012

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.

5) Genetic factors (Pharmacogenetics):

There is marked variation (polymorphism) in the enzyme activity among the population
which influences drug action and toxicity.
In addition, genetic abnormalities may result in defective or abnormal enzymes; e.g.
genetic defect in pseudocholinesterase enzyme greatly reduces metabolism –and
increases the action- of succinylcholine (skeletal muscle relaxant) and may lead to
"apnea". This abnormal drug response due to genetic defect is known as "idiosyncrasy".

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GENERAL PHARMACOLOGY 2011/2012

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.

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GENERAL PHARMACOLOGY 2011/2012

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.

3-Respiratory System: inhaled general anaesthetics, whether gases as nitrous oxide, or

volatile liquids as halothane, are excreted by lungs.

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".

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GENERAL PHARMACOLOGY 2011/2012

Give Reason (Explain):

1. Aspirin is partially absorbed from the stomach.
2. NaHCO3 is essential in treatment of acute salicylate toxicity.
3. Acidification of urine by NH4Cl or ascorbic acid is helpful in treatment of acute
amphetamine toxicity.
4. Salicylates are better absorbed from the upper part of the small intestine than from its
terminal part.
5. In case of shock; morphine should be given I.V. and not S.C.
6. Drugs are absorbed mainly from the small intestine not from the stomach.
7. The dose of orally- administered nitroglycerin is much higher than the S.L. dose.
8. It is not advisable to prescribe aspirin to patients treated with warfarin.
9. Sulphonamides are contraindicated in late pregnancy and neonates.
10.Hemodialysis is beneficial in acute salicylate toxicity.
11.The dose of drugs metabolized by HMEs is higher in smokers than in non-smokers.
12.The dose of warfarin should be reduced in patients treated with allopurinol.
13.The dose of theophylline should be increased in patients treated with phenobarbitone.
14.Hypoglycemic coma may occur if oral hypoglycemic drugs are given with cimetidine.
15.Severe hemorrhage may occur in patients treated with warfarin and consuming grape
fruit.

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

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Routes of Drug Administration:

There are 4 main routes of drug administration:

1) Enteral route: drugs are given through GIT. It is either:
a)Oral (P.O.) b) Sublingual (S.L.) c)Rectal (P.R.).
2) Parenteral route: includes injection and S.C. implantation.
3) Inhalation: either for local action (as treatment of bronchial asthma), or for systemic
action (as inhalation general anaesthesia).
4) Topical (local): on skin and mucous membranes as eye, nose, ear, and vagina.

Route The drug Advantages Disadvantages

should be
1-Enteral: 1) Stable. 1) Easy. Not suitable for:
a)Oral 2) Not irritant. 2) Convenient. 1) Emergencies (due to
3) Absorbable (if 3) Economic. delayed onset of action).
systemic action is 4) Safe. 2) Unconscious patients (for
needed). 5) Suitable for most fear of aspiration
drugs. pneumonia).
3) Irritant drugs.
4) Unabsorbable drugs as
aminoglycosides
(streptomycin).
5) Uncooperative patients (as
children, insane patients).
6) In presence of vomiting.
7) Drugs with almost complete
first pass effect (as
lidocaine).
8) Absorption is affected by
the presence of food and
other drugs

b)Sublingual 1-Stable. 1-Rapid onset of

(S.L.): e.g. 2-Soluble in saliva. action.
nitroglycerin 3-Palatable. 2-Avoids first pass
pellets in 4-Effective in small effect.
acute anginal doses. 3-Overdose effects
attacks. can be avoided by
swallowing or
spitting.

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GENERAL PHARMACOLOGY 2011/2012

c)Rectal: In the form of Can be used if oral 1-Psychologically inconvenient

suppository and route is ineffective as for most patients.
enema. Enema is in: 2-may cause rectal
either:1-retention Unconscious- inflammation (proctitis).
enema (MgSO4, Vomiting-Irritant 3-variable absorption
glucose,steroids) drugs-Uncooperative especially when the rectum if
2-evacuant enema patients-Drugs with full of stools.
( in constipation). extensive first pass. 4-Not suitable in diarrhea.

2-Injection: All drugs should be

sterile and pyrogen-
free.
a)I.V.: 1)most drugs should 1)The most rapid 1)Allergic reactions as
(bolus or be slowly injected. route so useful in anaphylactic shock.
infusion) 2)Only aqueous emergencies. 2)Rapid injection of
solutions are allowed. 2)Achieves 100% aminophylline causes severe
bioavailability. hypotension and
3-)Useful for highly arrhythmias=velocity reaction.
irritant drugs. 3)Pyrogenic reaction may
4)Useful in occur.
unconscious 4)Thrombophlebitis.
patients. 5)Transmission of diseases as
5)Useful for drugs hepatitis B and C.
not absorbed orally. 6)Extravasation of the drug
6)Useful in vomiting. may cause necrosis (see
7)Large volumes can noradrenaline).
be given by I.V. 7)Avoid oily preparations and
infusion. suspensions to avoid
embolism.
b)I.M.: 1)Solutions. Rapid onset and high 1)Avoid highly irritant drugs (to
2)Suspensions. bioavailability. avoid inflammation).
3)Oily preparations. 2)Heparin should never be
4)Moderately irritant. given IM to avoid hematoma.
3)Pain, irritation.
4)Phenytoin and
benzodiazepines as Diazepam
strongly bind to muscle
proteins leading to irregular
absorption after IM injections.

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GENERAL PHARMACOLOGY 2011/2012

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.

3-Inhalation Gases-Volatile liquids- 1-Useful for systemic Irritation of bronchi by some

Aerosol (solution given actions as general drugs-irregular dosage.
by inhaler or anaesthesia and local
nebulizer)-finely actions as treatment
micronized powder of bronchial asthma.
(given by spinhaler). 2-Very rapid onset
and very high
bioavailability if
systemic action is
desired.
4-Topical:
A-Skin: 1-Ointments, creams, Absorption of some harmful
and powders are drugs as steroids (cortisol)
applied for local especially in children,
actions. organophosphorous
2-Transdermal compounds (in the form of
delivery system (TDS) insecticides), and nicotine (in
as transdermal workers collecting tobacco
patches which are leaves) may occur causing
applied for systemic systemic actions.
actions as
nitroglycerin. It
avoids 1st pass and
has long duration.

B-Mucous 1-Used for local Undesirable systemic actions

membranes: actions, e.g. eye may occur, e.g. timolol eye
1) Nose. drops in glaucoma. drops used in glaucoma may
2) Ear. 2-May be used for cause severe bronchospasm in
3) Eye. systemic actions as asthmatic patients.
4) Mouth. nasal vasopressin
(ADH) in treatment
of diabetes insipidus.
N.B.: Drugs given orally are liable to 1st pass metabolism, whereas drugs given S.L.,
injection, inhalation, and by TDS avoid 1st pass effect.
Skin absorption can be increased by:
1) Inunction (rubbing off oily drugs).
2) Iontophoresis (galvanic current for water soluble drugs).

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GENERAL PHARMACOLOGY 2011/2012

Other Routes of Administration:

Other methods of injection:
1) Intra-dermal: sensitivity tests and vaccines.
2) Intra-arterial: thrombolytics (fibrinolytics), angiography and in cancer chemotherapy.
3) Intra-cardiac: adrenaline in cardiac arrest (cardiac resuscitation).
4) Intra-articular: cortisol in treatment of arthritis.
5) Intra-peritoneal: in peritoneal dialysis.
6) Intra-thecal: in spinal anaesthesia and in treatment of meningitis.
7) Intra-cameral: injection into aqueous humor.
8) Intra-osseous: injection through the shaft of long bones.

Subcutaneous implantation: e.g. contraceptives as norgestrel which is in the form of a

solid capsule (pellet) implanted under the skin, from which the hormone is released for a
long period (up to 5 years).

How to prolong the duration of action of drugs:

1) Delay absorption by:
a) Add vasoconstrictors as adrenaline to local anaesthesia.
b) Add oil to the drug (as vasopressin).
c) Add gelatin to heparin.
d) Use suspensions as protamine zinc insulin.
e) S.C. implants as contraceptives (norgestrel).
f) Use long-acting preparations as sustained release (SR) preparations, also known as
controlled release (CR) and timed-release (TR) preparations.
2) Use preparations that are highly bound to plasma proteins (long acting sulphonamides).
3) Decrease metabolism by HME inhibitors.
4) Delay renal excretion e.g. by adding probenecid to penicillin.

Fundamental Principles of Pharmacokinetics:

1) Steady State Concentration (Css):
 To achieve the desired effect of any drug an almost constant (steady) plasma
concentration should be reached and maintained, known as the "steady state
concentration" or "Css".
 The most accurate method to achieve Css is by IV infusion.
 For any routes the dose regimen is designed so that the rate of drug administration
equals the rate of drug elimination.
 For most drugs Css is reached after 4-5 half-life times (t1/2) of the drug (see later).

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GENERAL PHARMACOLOGY 2011/2012

2) Plasma half-life =Elimination half-life (t1/2):

 It is the time needed by the body to reduce the plasma concentration of any drug by
50% (i.e. it is the time needed to eliminate 50% of the drug in plasma).
 It is constant for drugs following "first-order kinetics" but variable with few drugs
that follow "zero-order kinetics" (see later).
 Most drugs reach Css concentration after 4-5 t1/2.
 For most drugs, almost the entire drug (> 95%) is eliminated within 4-5 t1/2.
 For some drugs, the effect of the drug may be much longer than the plasma t1/2,
i.e. the biological t1/2 outlasts the plasma t1/2. Examples include the proton pump
inhibitors (PPIs as Omeprazole) which cause irreversible inhibition of H+/K+ ATPase
(proton pump), and Reserpine.

3) First order kinetics and Zero order kinetics:

Drug elimination follows one the following processes:
First order kinetics Zero order kinetics
(Linear kinetics) (Non-linear kinetics-Saturation kinetics)
1) A constant proportion (percent, fraction) 1) A constant amount (number of moles) of the
of the drug is eliminated /unit time. drug is eliminated /unit time.
2) The rate of elimination is proportional to 2) The rate of elimination is not proportional to
the drug plasma concentration. the drug plasma concentration.
3) Css (plateau) is reached after 4-5 t1/2. 3) Css is not necessarily reached after 4-5 t1/2.
4) Plasma t1/2 is constant whatever the 4) Variable plasma t1/2, it increases as the
plasma drug concentration (dose). plasma concentration (dose) increases.
5) No saturation of metabolizing enzymes or 5) Saturation of metabolizing enzymes or
carriers needed for renal excretion. carriers needed for renal excretion occurs.
6) Linear drug disappearance curves (log. 6) Non-linear drug disappearance curves (log.
Concentration-time curves). Concentration-time curves).
7) AUC is proportional to the drug plasma 7) AUC is not proportional to the drug plasma
concentration. concentration.
8) Less liable to cumulation and toxicity. 8) Cumulation occurs if the rate of drug intake
exceeds the rate of elimination and may lead
to toxicity.
9) Examples: most drugs (including small 9) Examples: large doses of aspirin, phenytoin,
doses of aspirin, phenytoin, and alcohol). and alcohol.

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GENERAL PHARMACOLOGY 2011/2012

Pharmacodynamics

Pharmacodynamics is usually referred to as "what the drug does to the body".

It includes:
A) Mechanism of action. B) Pharmacological actions.
A) Mechanism of action of drugs:
Mechanism of Action Examples
1-Physical:
a) Adsorption: 1) Kaolin adsorbs toxins in case of diarrhea.
2) Activated charcoal adsorbs other drugs in
treatment of acute toxicity.

b) Osmosis: 1) Osmotic diuretics as mannitol.

2) Osmotic saline purgatives as magnesium sulphate
(MgSO4).

c) Demulcent: The drug forms a soothing layer that covers and

forms a protective layer on mucous membranes, e.g.
Liquorice in pharnygitis and dry cough.

d) Astringent: The drug precipitates superficial proteins to form a

protective layer, e.g. tannic acid in treatment of
gingivitis.
2-Chemical:
a) Neutralization (Chemical 1) Antacids as NaHCO3 are used to neutralize HCl in
Antagonism) cases of hyperacidity.
2) Protamine sulphate is used to neutralize heparin
(protamine sulphate is the specific heparin
antidote).

b) Chelation: 1) Desferrioxamine to chelate Fe3+ iron.

Combination of organic 2) Dimercaprol (BAL) to chelate heavy metals as
compound with a heavy metal mercury, lead, and antimony.
to form non-toxic easily 3) Sodium edentate to chelate Ca2+ in cases of
excreted complex. hypercalcemia.
4) D-Penicillamine to chelate Copper in treatment of
Wilson's disease and Copper toxicity.

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GENERAL PHARMACOLOGY 2011/2012

3-Inhibition of cell division Cancer chemotherapy as Methotrexate and Nitrogen

(cytotoxic action): mustard.
4-Interference with normal Sulphonamides inhibit bacterial folic acid synthesis
metabolic pathway: by competition with PABA.
5- Interference with selective 1) Na+ channel blockers as lidocaine (lead to
passage of ions through ion membrane stabilization, used as local
channels: anaesthetics and antiarrhythmics).
2) Ca2+ channel blockers as verapamil which block
voltage gated Ca2+ channels, L-type (used as anti-
anginals, antiarrhythmics and antihypertensives).
6-Action on Enzymes (mostly by 1) Aspirin irreversibly inhibits cyclooxygenase (COX)
enzyme inhibition; which is either enzymes.
"reversible" or "irreversible") 2) Organophosphprous compounds irreversibly
inhibit cholinesterase enzyme.
3) Neostigmine and physostigmine inhibit reversibly
cholinesterase
4) Allopurinol inhibits reversibly xanthine oxidase
enzyme.
7-Action on Receptors: Acetylcholine (agonist) and atropine (antagonist) act
(The most important mechanism on muscarinic receptors.
of drug action). Adrenaline (agonist) and propranolol (antagonist) act
on β-receptors.
RECEPTORS:
 Receptors are specific chemo-sensitive, chemo-selective protein macromolecules
present on the cell membrane (e.g. α- and β-adrenergic receptors, and muscarinic and
nicotinic receptors), inside the cytoplasm (e.g. receptors for steroid hormones and
vitamin D), and inside the nucleus (e.g. receptors for thyroid hormones).
 Any chemical substance that has the ability to bind to a receptor is called a "ligand".
 Ligands may be: drugs, hormones, or chemical transmitters (neurotransmitters).
 The ability of the ligand to bind to the receptor is called "affinity".
 Affinity may be due to the fact that the shapes of the ligand and the receptor are
complementary (Key and Lock theory), which allows the drug to "fit" onto the receptor.

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GENERAL PHARMACOLOGY 2011/2012

 Drugs acting on receptors are classified into:

1) AGONISTS:
 Agonists are drugs that activate (stimulate) the receptors.
 They are characterized by having:
1) Affinity.
2) Efficacy (intrinsic activity): agonists have the ability to change the activity of the cell;
either by stimulation or inhibition (e.g. adrenaline acts as an agonist on β-receptors
in the heart causing stimulation of cardiac properties as heart rate, and acts on β-
receptors in the smooth muscles of the intestine causing inhibition or relaxation).
3) Rapid rate of association and dissociation:
Association
Ka
D+R▬▬▬▬►DR complex▬▬▬►drug response
◄▬▬▬▬
Dissociation
Kd
(D: drug- R: receptor –Ka: rate of association- Kd: rate of dissociation).

 Examples of agonists: Acetylcholine-Adrenaline-Noradrenaline.

 The response (effect or action) of the agonist depends on:
1) The number of receptors occupied by the agonist: the more the number the more
the response. This is known as "occupation theory ".
2) The rate of association / dissociation of the agonist with / from the receptors: the
more rapid the rate, the more the response of the agonist. This is known as "rate
theory of Paton".

N.B.: a number of receptors remains unoccupied even with maximum response of

an agonist and are called "spare receptors".

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".

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GENERAL PHARMACOLOGY 2011/2012

Dose-Response Curves of Agonists:

Graded Dose- Response Curves:

 The dose or log. dose of a drug is plotted versus response. If the dose if plotted versus
response; the curve is hyperbolic in shape, but if the log. dose is plotted versus
response, the shape of the curve becomes sigmoid.
 Efficacy = Emax: it is the maximum response obtained by the drug. Drugs with high
efficacy are known as "high ceiling" e.g. loop diuretics.
 Potency = ED50: it is defined as the dose that achieves 50% of the maximal response
(the lower the ED50 the more potent the drug).

Graded Dose-Response Curves

2-ANTAGONISTS = BLOCKERS:

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GENERAL PHARMACOLOGY 2011/2012

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.

Types of Pharmacological antagonists:

1) Competitive Antagonists: there is competition between the agonist and antagonist on
the same receptor, and excess agonist can displace the antagonist. Examples: Atropine-
Propranolol-Prazosin-Curare. Competitive antagonists cause "parallel shift to the right
with same efficacy" of the log dose/ response curve of the agonist.
2) Non-competitive Antagonists: the antagonist cannot be displaced by excess agonist.
They cause "non-parallel shift to the right with reduced efficacy" of the agonist
log dose/ response curve.
Non-competitive antagonists are further subdivided into:
a) Reversible Antagonists: the effect of the antagonist is of short duration because it is
rapidly metabolized, e.g. succinylcholine (non-competitive neuro-muscular blocker).
b) Irreversible Antagonists: the effect of the antagonist is prolonged because it binds to
the receptor by a "covalent bond", and its effect is terminated by synthesis of new
receptors, e.g. phenoxybenzamine (irreversible α-blocker).

Non-Parallel shift to the right. parallel shift to the right.

Lower efficacy (Emax). same efficacy (Emax is not reduced).
Agonist after Agonist after
Non-Competitive Antagonist competitive Antagonist
Graded Dose-Response Curves following different types of Antagonists

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3-PARTIAL AGONISTS (Dualists):

Few drugs act as partial agonists having the following characters:
1) Affinity.
2) Moderate efficacy (less than the agonist and higher than the antagonist).
3) Slow or moderate rate of association and dissociation (slower than the agonist).
Partial agonists are used clinically as antagonists. Examples: some
β-blockers as oxprenolol, pindolol, and acebutolol-Nicotine in large dose-Succinylcholine.
Types of Receptors and Signal-Transduction Mechanisms:
Receptors have 2 main functions; to bind ligands and to initiate a "response" or effect in
the cells by signal transduction.
There are (4) types of receptors according to the signal transduction mechanism
responsible for inducing the response of agonists:
1) Ion-channel linked receptors= Ligand-gated ion channels
They are located in the cell membrane on the gates of ion channels. Activation of this type
of receptors by specific agonists leads to change in the shape of the receptor
(conformational change) followed by opening of the gates of specific ion channels.
Examples include:
1) Nicotinic receptors (N): They are formed of 5 subunits: 2 α, 1 β, 1 γ, and 1 δ.
Activation of this receptor by acetylcholine (which binds to both α subunits) induces
opening of Na+-channels → Na+ influx and depolarization.
2) GABA receptors: There are 2 types of GABA receptors in CNS: GABAA receptors
which open Cl- channels leading to Cl- influx and hyperpolarization, and GABAB
receptors which open K+-channels also leading to K+ efflux and hyperpolarization
and may also block Ca2+-channels.
2) G-protein-linked receptors:
They are serpentine in shape, made up of 7 polypeptide loops that span the cell
membrane (7 α helical segments).
Type of G- Receptors Signal transduction
Protein
Gs 1) All β-receptors. Activation of adenyl cyclase and
2) H2-receptors. increase in c-AMP.
3) D1-receptors.
Gi 1) α2-receptors. Inhibit adenyl cyclase and
2) M2-receptors. decrease c-AMP, and may open
3) 5-HT1-receptors. K+-channels.
4) D2-receptors.
Gq 1) α1-receptors. Activation of phospholipase C
2) M1 and M3 (except on blood vessels). and increased DAG, IP3, and
3) H1-receptors (except on blood vessels). Ca2+.
4) 5HT2 receptors.

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3) Tyrosine kinase-linked receptors:

Examples include: growth hormone and insulin receptors.
Insulin receptors are made up of 4 subunits (domains): 2 α subunits on the cell membrane
and 2 β subunits transfixing the cell membrane (see endocrine pharmacology).

4) DNA- linked intracellular receptors (Gene active receptors):

Steroid hormones and vitamin D receptors are found in the cytoplasm whereas thyroid
hormones receptors are present in the nucleus.
They regulate gene transcription, translation of m-RNA, and protein synthesis, that is why
the have slow onset of action (see endocrine pharmacology).

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.

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GENERAL PHARMACOLOGY 2011/2012

Dosage of Drugs (Posology):

 Therapeutic Dose: It is the dose required to achieve therapeutic effect in an adult
male of average weight (70 Kg.).
 Loading Dose: It is the dose administered at the beginning of therapy in acute
conditions as acute heart failure to reach the steady state plasma concentration (Css)
rapidly. It is usually a large dose and it may lead to toxicity if applied to drugs with
low therapeutic index as digoxin.

Loading dose (LD) = Vd X Css

 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.

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Factors Modifying the Dose and Action of Drugs:

1) Age:
 Infants (younger than 2 years) and children require smaller doses than adults due to:
1) Underdevelopment of hepatic microsomal enzymes.
2) Lower level of plasma proteins and low binding capacity.
3) Reduced renal excretory function.
4) Immature B.B.B.
N.B. some drugs as digitalis are rapidly metabolized in children than in adults and
accordingly they need higher doses (children are more tolerant to digitalis than adults).
 Infant's dose is calculated according to Clark's Formula:
Infant dose = Adult dose X weight in pounds or weight in Kg
150 70
 Child dose is calculated according to Young' Formula:
Child dose =Adult dose X Age in years
Age in years +12
 Child dose can also be calculated according to Dilling's Formula:
Child dose = Adult dose X Age in years
20
 The dose can be also calculated by the percentage method:

Age Percent of Adult

Dose
1 month: 10%.
1 year: 25%.
3 years: 33%.
7 years: 50%.
12 years: 75%.

 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.

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GENERAL PHARMACOLOGY 2011/2012

3) Body Surface Area:

This is a more accurate parameter for calculation of doses than age and body weight and it
can be obtained from specific charts.
Infant's dose = Adult dose X infant's surface area_
1.73(Adult body surface area = 1.73 m2).
4) Sex (Gender):
 Females usually require smaller doses than males of the same age because:
1) Female sex hormones are hepatic microsomal enzyme inhibitors whereas male sex
hormones act as inducers.
2) Females contain higher body fat.
 Special situations in females:
1) During menstruation avoid drugs that may cause bleeding as aspirin and castor oil.
2) During pregnancy avoid teratogenic drugs (as aspirin, cortisone, ACE inhibitors,
cyclizine, meclizine) and uterine stimulants (oxytocic drugs as ergotamine, PG
analogs as misoprostol).
3) During lactation avoid harmful drugs excreted in breast milk as chloramphenicol,
antithyroid drugs, morphine, and oral anticoagulants.

5) Route and Time of Administration:

 Oral dose is higher than parenteral and S.L. doses to compensate for first pass effect
(GIT and hepatic).
 S.C. dose is higher than I.M. due to less vascularity of subcutaneous tissue compared to
skeletal muscles.
 The route of administration affects the action of some drugs as magnesium sulphate:
 It acts as a cholagogue (in small dose) and purgative (in large dose) if given orally.
 It acts as a dehydrating agent (as in acute glaucoma) if given rectally as retention
enema.
 It acts as an anticonvulsant and skeletal muscle relaxant if given by I.V. infusion.
 Most drugs are better given orally before meals because the presence of food may
reduce absorption, but irritant drugs as NSAIDs are better given after meals.

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GENERAL PHARMACOLOGY 2011/2012

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.

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GENERAL PHARMACOLOGY 2011/2012

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.

Drugs Idiosyncratic reaction

Succinylcholine 1-Succinylcholine apnea in patients with
pseudocholinesterase deficiency.
2-Malignant hyperthermia.
Halothane Malignant hyperthermia.

Aspirin, Primaquine, Phenacetin, Hemolytic anemia in patients with

Sulphonamides deficiency of G-6-PD.
Isoniazid- Hydralazine Peripheral neuritis in slow acetylators.

Hydralazine SLE- like syndrome in slow acetylators.

Corticosteroids Elevate IOP and induce glaucoma

11) Pathological state:

The action of the drug occurs only in the presence of pathological conditions, e.g. aspirin
lowers high body temperature to normal but does not lower normal body temperature
(aspirin is an antipyretic not hypothermic).

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12) Emotional state:

To distinguish between the real pharmacodynamic effect of a drug from the psychological
effect; a "Placebo" is used (dummy medication made of an inert substance as starch or
sugar).

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).

14) Drug-Drug Interactions (Drug Combinations):

When 2 or more drugs are administered together interactions may occur, which are either
beneficial (e.g. thiazide diuretics are combined with K+-sparing diuretics), or harmful (e.g.
loop diuretics and aminoglycosides are ototoxic drugs).
I-Pharmacoceutical interactions:
They occur before drug administration as during drug formulation (Calcium salts cause
chelation of tetracyclines in capsules) - mixing of drugs with IV fluids (Calcium salts with
NaHCO3)- mixing of drugs in the same syringe (Protamine zinc insulin with soluble insulin).
II-Pharmacokinetic interactions:
1) Absorption: antimuscarinic drugs as atropine and propantheline increase absorption of
digitalis- antacids decreases absorption of tetracyclines, digitalis and ACE inhibitors-
cholestyramine decreases absorption of any other drug if given concomitantly.
2) Distribution: a drug may displace other drugs from their plasma protein binding sites
leading to toxicity, e.g. NSAIDs as aspirin and loop diuretics as frusemide displace
warfarin causing bleeding, quinidine displaces digoxin leading to digitalis toxicity.
3) Metabolism: HME inducers (as nicotine, phenytoin, barbiturates, rifampicin, and
androgens) increase elimination of drugs metabolized by these enzymes; whereas HME
inhibitors (as cimetidine, female sex hormones, chloramphenicol, erythromycin, and
grape fruit) reduce clearance and may cause toxicity.
4) Excretion: quinidine and verapamil decrease renal excretion of digoxin, and probenecid
decreases active secretion of penicillin (prolongs the action of penicillin) and thiazides
and loop diuretics (antagonizes their diuretic action).
III-Pharmacodynamic Interactions: may lead to:
1) Addition = Summation: the result of 2 active drugs given together equals the algebraic
sum of their individual actions (1 + 1 = 2).
2) Potentiation: the result of an active drug with an almost inactive drug is more than the
action of the active drug alone (1 + 0 › 1), e.g. caffeine and barbiturates potentiate the
analgesic effect of aspirin.
3) Synergism: the result of adding 2 active drugs is more than the algebraic sum (1 + 1 › 2),
e.g. rifampicin + isoniazid in T.B. and penicillin + aminoglycosides in serious infections.

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GENERAL PHARMACOLOGY 2011/2012

4) Antagonism: which may be:

a) Pharmacological: agonist + antagonist; it may be competitive (as acetylcholine +
atropine, adrenaline + propranolol, noradrenaline + prazosin) or non-competitive
(noradrenaline + phenoxybenzamine).
b) Physiological: 2 different compounds act on 2 different receptors causing 2 opposing
actions as adrenaline and histamine.
c) Chemical: chemical antacids neutralize excess HCl, and protamine sulphate
neutralizes excess heparin.
5) Reversal of action: Adrenaline reversal after alpha1-blockers.
N.B.: "Drug-Food interaction": tyramine found in yoghourt and cheese leads to
hypertensive crisis in depressed patients treated by MAO inhibitors (cheese
reaction).
15) Biological variations.

Adverse Effects and Toxicity of Drugs

a) Unpredictable adverse effects:
1) Allergy. 2) Idiosyncracy.
b) Predictable adverse effects:
1. Side effect: unavoidable action of the drug not related to the dose, e.g. atropine causes
dry mouth.
2. Secondary effect: e.g. prolonged use of broad-spectrum antibiotics especially if
incompletely absorbed orally causes superinfection and vitamin B and K deficiency.
3. Overdose: e.g. hypoglycemia due to overdose of insulin.
4. Hepatotoxicity: e.g. by halothane.
5. Nephrotoxicity: e.g. by aminoglycosides.
6. Neurotoxicity = Nerve damage: e.g. ototoxicity by aminoglycosides and loop diuretics.
7. Teratogenicity.
8. Bone marrow suppression (blood dyscrasias).
9. Tolerance, dependence, and addiction.
10.Intolerance (supersensitivity).
11.Iatrogenicity: drug-induced (physician-induced) disease; e.g. aspirin causes peptic ulcer;
alpha methyldopa and reserpine cause parkinsonism.
12.Carcinogenicity: by tobacco smoking.
13.Drug interactions.

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GENERAL PHARMACOLOGY 2011/2012

Adverse drug effects are classified into:

Type A (Predictable undesirable side effects):

Include: side effects – overdose toxicity – Supersensitivity – Secondary effects –
Cytotoxicity (hepato-, nephro-, and neuro-toxicity) – Drug interactions.
Type B (Unpredictable side effects):
Include: Hypersensitivity and idiosyncracy.
Type C (Chronic effects):
Include: Tolearnce and dependence – Iatrogenicity.
Type D (Delayed effects):
Include: Teratogenicity – Mutagenicity – Carcinogenicity.
Type E (End of use effects):
Include: rebound effect after sudden withdrawal of clonidine and beta blockers – acute
Addisonian crisis after sudden withdrawal of corticosteroids – withdrawal symptoms
(abstinence syndrome) in addicts to morphine, heroin, alcohol, barbiturates, tobacco…
Type F (Failure of therapy):
1) Primary Failure: the drug did not prove the desired therapeutic effect from the start of
treatment.
2) Secondary Failure: failure to get the desired effect after a failure to get the desired
effect after a period of adequate response.
Example: oral insulin secretagogues as Sulfonylureas in treatment of non-insulin
dependent D.M.

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