General Pharmacology

GENERAL PHARMACOLOGY
Pharmacology
• It is the science that deals with drugs
• It is derived from the Greek terms; "Pharmacon" = drug and
"logos" = science
• It is divided into 2 branches: Pharmacokinetic and Pharmaccdynamic.
Drug
• It is a chemical substance that alters body functions
• It can be used for diagnosis, prevention or treatment of disease.
Drug Nomenclature

Chemical name Generic name Trade name

Acetylsalicylic acid Acetylsalicylic acid Aspirin, Aspocid,
(Official or approved name) Rivo

Pharmacodynamics
• These are the effects of the drugs on the body
Pharmacokinetics
• These are the effects of the body on the drugs.
•They include: Absorption, Distribution, Metabolism and Excretion
(ADME).

Pharmacodynamics

Pharmacokinetics

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 General Pharmacology

PHARMACOKINETICS
• Pharmacokinetic describes what the body does to the drug.
• It is the quantitative studying of drug Absorption, Distribution, Metabolism
and Excretion (ADME).

• Importance of Pharmacokinetics :
Dose adjustment according to :
1. Body size
2. Body functions (liver, heart, kidney)

Target Site Therapeutic effect

Other Sites Adverse effect

Fate of the drug in the body

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 General Pharmacology

Drug Absorption
Absorption is the passage of drug from the site of administration to the blood.
Factors affecting drug absorption

l) Drug properties :

a• Molecular Weight (MW):

- Low MW drugs have faster rate of absorption, while high MW drugs have
slower rate of absorption.
b• Solubility:
- Lipid soluble (Unionized ) drugs are more diffusible than water soluble
(ionized ) drugs Æ faster rate of absorption.
- The degree of drug ionization depends upon its pKa (dissociation constant)
and the pH of the solution. ( pKa is pH at which drug molecules are half
ionized & half unionized ).
Clinical significance of pKa :
• Salicylate (pKa 3.5) is mostly unionized in the acidic pH of stomachÆ
absorbed into the gastric wall causing gastric ulcers .
• Salicylate is ionized in the alkaline urineÆ easily excreted so alkalinisation
of urine is used in treatment of salicylate toxicity.
2) Drug Formulation
• Different formulations have different rates of absorption Æ
different plasma concentrations.
• Drugs with different rates of disintegration have different rates of
absorption e.g. Sustained (slow) release capsules and tablets.

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 General Pharmacology

Ad
dvantages of
o slow rellease prep
parations

(Drrug B) oveer ordinary preparaations

(drrug A):

• Longer acction
• Less frequuent adminnistration
• Less adverrse reactionn (low peaak level)

3) Conditions
C s at site off administrration :
a. Blood
B flow
w:

Deecreased bloood flow inn subcutanneous tissuee ↓ the ratee of drug abbsorption e.g.:
e

i.. Morphinee in shock should be given

g I.V.
ii. Addition of epinephhrine to loccal anestheticsÆ prollongs their action
eÆ cutaneous vasoco
because epinephrine
e onstriction..
b. GIT
G motiliity :

P
Prokinetic d
drugs ↑ thee gut motiliity Æ ↑ absorption off drugs e.gg.
mettoclopramiide ↑ absorrption of errgotamine in
i treatmennt of migraaine.

c. GIT
G conten
nt :

- Teetracyclinees ↓absoption of Ca+++ by its chelation.

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 General Pharmacology

Bioavailability
• The fraction of unchanged drugs reaching systemic circulation after any
route of administration.
• - IV bioavailability = 100%
• It is calculated by dividing the Area Under the blood concentration-time
Curve (AUC) after any route of administration by that after IVI.

IV

Oral

Concentration-Time curves after oral & IVI

Oral bioavailability AUC after Oral dose =

AUC after IV dose

Factors Affecting Bioavailability

I. Amount of drug absorbed (see before)
II. First-Pass Metabolism ( Presystemic Elimination)
• Metabolism of the drug in gut wall or liver before reaching systemic
circulation e.g. catecholamines as epinephrine are not effective orally due to
destruction by gut MAO.
• Nitroglycerin & propranolol undergo extensive 1st pass metabolism in liver.

Routes Bypassing the First-pass Effect

Sublingual - Parenteral - Rectal (to some extent)

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 General Pharmacology

Drugs Distribution
• After a drug is absorbed, it is distributed between blood and tissues. The
drug passes through body compartments (plasma, interstitial, intracellular)
which are separated by capillary walls and cell membranes.

Volume of Distribution (Vd)

• It is the apparent volume that would be occupied by the amount of drug in
the body if its concentration throughout the body equals its plasma
concentration.
• Vd is not a real volume, because the body is considered to be one
compartement including plasma, interstitium and tissues.
Vd = Amount of drug in the body
Plasma concentration

Drugs of large Vd Drugs of small Vd

• Highly tissue binding (low • Highly binding to plasma protein

binding to plasma protein). (low tissue binding).
• Lipophilic. • Hydrophilic.
• Require hepatic metabolism for • Excreted unchanged in the
elimination. kidney.
• Hemodialysis in drug toxicity is • Hemodialysis is useful in drug
not useful because of extensive toxicity because most of drug is
tissue drug distribution e.g. present in the circulation
Digoxin. e.g. Salicylate.

Importance of Vd
Vd can be used to calculate the loading dose (LD):

LD = Vd x Steady state plasma concentration (Css)

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 General Pharmacology

Binding of drugs to plasma proteins

Bound form (reservoir): Non diffusible, inactive, not liable for elimination.
Free form: Diffusible, active, liable for elimination

Importance of binding to plasma proteins:

1• ↑drug absorption by maintaining concentration gradient towards plasma

2• ↓ drug distribution (↓Vd)
3• ↓ drug elimination Æ ↑ duration of action ( ↑t1/2)
4• ↓ drug activity and toxicity
5• Drug Interactions : Drugs with higher affinity to plasma proteins can
displace drugs of lower affinityÆ ↑ free part of the drug and toxicity.

Example: Aspirin displaces warfarin (the oral anticoagulant) from plasma

proteinsÆ bleeding.

Importance of binding to plasma proteins

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 General Pharmacology
Drug Biotransformation

(Metabolism)
Definition.: Changes that occur to drugs after absorption until excretion.
Aim : to change lipid soluble drugs into water soluble (polar) metabolites Æ
easily excreted.
Results of drug metabolism :
Drug metabolism Æ formation of :
1• Inactive metabolites (most drugs).
2• Active metabolites like the parent drugs e.g. diazepam metabolites.
3• Active metabolites from inactive drugs (prodrugs) e.g. prednisone
(prodrug) Æ prednisolone. Thus prednisolone is used instead of
prednisone in liver disease or when applied locally.
Sites of drug metabolism:
• The Liver is the main site .
• Other sites include kidney, lung , GIT , plasma , brain ,eye and skin.

Enzymes responsible for drug metabolism :

1. Microsomal enzymes: present in smooth endoplasmic reticulum.They are
responsible for drug oxidation, reduction or hydrolysis. The most important is
oxidation by mixed function oxidase or cytochrome P450 system.
2. Non microsomal enzyme in cytoplasm or plasma . (e.g. Ach esterase)

Non-microsomal Enzyme Microsomal Enzyme

Plasma Enzyme Cytoplasmic Enzyme

e.g. Cyt. P450 oxidase

for oxidation
e.g. Ach
esterase e.g. xanthine
oxidase
e.g. glucuronyl transferase
for conjugation

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 General Pharmacology

Types of metabolic reactions :

a. Phase 1 (non synthetic) :
Oxidation , reduction or hydrolysis by microsomal enzymes to convert a drug
to polar (water soluble) metabolites which are easily excreted or conjugated in
phase II reaction (i.e.. if the formed metabolite is still insufficiently polar).

b. Phase II (synthetic) :
It is the addition of endogenous polar substance to a drug or metabolites of
phase I (conjugation) to form water soluble inactive metabolites e.g.
glucuronidation, acetylation, and methylation.

Factors affecting drug metabolism :

a) Age : Metabolism is ↓ in extremes of age, so doses are decreased.

b) Sex : estrogen inhibits while testosterone stimulates the drug metabolism.
Males are able to tolerate pollutants more than females .
c) Diseaeses : In liver diseases drug metabolism is decreased Æ↑ susceptibility
to drug toxicity e.g. the effect of diazepam is prolonged and it may cause coma
when given in ordinary doses.
d) Drugs: act on microsomal enzymes affecting of drug metabolism. They are:

- Enzyme inducing drugs (Enzyme inducers)

They stimulate drug metabolism e.g. Rifampicin, Phenobarbital. These drugs

↑metabolism of warfarinÆ need to ↑dose of warfarin to maintain its effect.

- Enzyme inhibiting drugs (Enzyme inhibitors)

They inhibit drug metabolism e.g. Erythromycin, Chloramphenicol. These

drugs ↓ metabolism of theophyline Æ ↑ its toxicity. So ↓ dose of theophyline.

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 General Pharmacology

Drug clearance
• Definition: clearance is the volume of plasma from which a drug is cleared
per unit of time.
• It determines the relation between drug elimination rate and drug
concentration.
• Clearance = Rate of elimination / Drug concentration

Types of elimination kinetics

First order Kinetics Saturable Kinetics

(Non-saturable)
1• Constant Fraction (percentage or 1• Constant Amount of drug is
ratio %) of drug is eliminated. eliminated
2• elimination system is unlimited 2• elimination system is limited
(unsaturable). (saturable)
3• Elimination rate is directly 3• Elimination rate is not directly
proportional to plasma proportional to plasma
concentration. concentration
4• Fixed half life with CSS. 4• Non- fixed half life without CSS.
5. More doses after CSS Æ No 5•More dosesÆ Marked ↑↑ in
further ↑ in its plasma plasma concentration to toxic
concentration level so measure plasma level of
drug frequently.
6• e.g. Most of drugs 6. e.g. Salicylate, Theophylline

The elimination organs:

1. Liver : Hepatic metabolism- biliary excretion.
2. Kidney : Renal glomerular filtration & tubular secretion.
3. Others : lung, GIT & Skin.

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 General Pharmacology
Steady State Concentraation (Csss)
It iss the conceentration of
o the drug in plasmaa when the rate of abbsorption = the
ratee of eliminaation.
Elim
mination half
h life ( t 1/2)
It iss the time required
r too reduce thee plasma concentratioon of the ddrug to the half
of its initial cooncentratioon.
C
Conc.

1/2 C

T im
me
{

t1/2

* Calculation
C : t1/2 = 0.6693Vd /Cl
* Im
mportancee of t1/2 :
1) t1/2 shows the
t time reequired forr a drug to reach CSS
S after its administraation
.Thhe drug neeeds 4-5 timees its half life
l to reacch its CSS.

m
mg/dl
18.75

1st order kin

netics :
Reepeated dooses at intervals = t 1/2 , each dose
d ↑ conccentration
n by 10 mg
g/dl

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 General Pharmacology
2) t1/2 shows the time required for a drug to be removed from blood after
stoppage of drug, usually it takes 4-5 time half life.

3) t1/2 determines dose interval (frequency) of drug administration:

• Most drugs are given at intervals equal to their t1/2 to avoid interdose
fluctuation in blood level away from CSS.

• Drugs with very short t1/2 e.g Na Nitroprusside (in treatment of

hypertensive emergency) → given by continuous infusion.

• Drugs with long t1/2 e.g Digoxin (in treatment of heart failure) → given
as initial loading dose followed by maintenance dose.

Loading dose (LD):

• The dose given at the onset of therapy to achieve target concentration (CSS)
i.e. the dose which saturate Vd.
• Loading dose = CSS x VD

Maintenance dose (MD):

• The dose given for maintaining the drug steady state concentration. It is
given at dose rate equal to elimination rate of the drug
• Maintenance dose = CSS x CL

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 General Pharmaco
ology

P
PHARMA
ACODY
YNAMIC
CS

• Itt describess what the drug doess to the bo

ody (pharm
macologiccal responsse).
• This
T responnse may be intendedd (therapeu
utic effectts) or
unnintendedd(adverse effects).
e

Dose-resp
ponse Reelationsh
hip
The dose-respoonse relationship can be
b represen
nted graphically by 2 types of cu
urves:
quanntitative (grraded) andd qualitative (All/Non
ne) dose-ressponse curvve:

I. Graded dosse-responsee curve is obtained

o iff the degreee of respoonse is dep
picted
a
against log the dose e.g. decreasses of blood
d glucose against
a the dose.

Paraameters th
hat can bee obtained from
f the graded
g doose-respon
nse curve:
1 Efficacy (Emax): iss the maxim
1. mal effect produced
p byy the drug
2 Potency of the drugg is assessedd from ED50
2.
ED500: it is dosee that produuces 50% of
o the maxim
mal responnse.
m potent the drug iss. 1
Thee lower the ED50 the more

1:
It shhould be noted that
t low ED50 means
m a more potent
p drug but it does not esseentially mean a more effective drug
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 General Pharmacology
II. All/None dose-response curve is obtained if the percentage of patients who
respond to the drug is depicted against log the dose.

Parameters that can be obtained from the All/None curve:

1. ED50: It is the dose that cures 50% of cases. It is used for comparison between
drugs e.g. drug with a lower ED50 is > potent than that with a higher ED50.

2. LD50: It is the dose,that kills 50% of animal. It gives an idea about the
absolute toxicity of the drug i.e. the drug with lower LD50 is considered more
toxic than the drug with higher LD50. The dose used should not exceed 10%
of the estimated LD50.

3. Therapeutic index (TI):

• It is the ratio between ED50 & LD50 → TI = LD50/ED50.

• It gives an idea about the safety of the drug: if the TI is large, i.e. the
LD50 is much higher than the ED50 Æ the drug is safer.

Some Drugs with narrow therapeutic index:

Aminoglycosides, anticoagulants, hypoglycemic agents,
theophylline.

efficacy of the drug is assessed by the Emax and not the ED50.
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 General Pharmacology

Mechanism (Mode) of Action of Drugs

• Drugs can induce a tissue response, initially through:
I. Receptor-mediated mechanisms involving interactions with particular
receptors at specialized sites within the body.
II. Nonreceptor-mediated mechanisms.

1. Receptor-Mediated Mechanisms
• Receptors2 are specific cellular macromolecules (usually proteins) that
interact with a ligand (binding) to produce a response.

SIGNALING MECHANISMS
• The most important signal transduction systems are:
1. Ion Channels (for fast neurotransmitters)
• Receptors are ion-selective channels in the plasma membrane.
Binding of agonist to the receptor →opening of the channel → alteration
in membrane potential or change in intracellular ion concentration, both
resulting in change in cell activity, e.g. nicotinic Ach receptors
(combined Na+/K+ channels)

2
The pharmacological actions mediated by the receptors are characterized by sensitivity (i.e. very small
conc. of ligand is enough to elicit the action), selectivity (i.e. each receptor has the type of ligand that
can interact with it) & specificity (i.e. they elicit the same response each time they interact with ligand).
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 General Pharmacology
2. Receptors linked to Tyrosine Kinase (RTKs)
• Binding of insulin causes 2 single tyrosine-kinases receptors to aggregate
into a dimmer with subsequent autophosphorylation → activation →
cellular response.

3. G protein-Coupled Receptors (for slow neurotransmitters)

• Receptors are linked to G proteins. The G protein is a trimer (α, β and γ).
• Agonist binding → dissociation of α subunit which regulates activity of
several effectors.

Examples of G Proteins
a. Gs (stimulatory) linked to β-receptors resulting in increased cAMP.
b. Gi (inhibitory) linked to α2 and M2 receptors resulting in decreased cAMP.
c. Gq linked to α1 and M1 & M3 receptors liberating (diacyl-glycerol) DAG
and inositol triphosphate-3 (IP3).

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 General Pharmacology

- Protein kinase A (PKA)

4. Receptors Regulating Transcription (very slow)

• Steroid hormones, thyroid hormones and vitamin D enter the target cell →
bind to intracellular receptor proteins associated with nuclear chromatin
(DNA) to activate or inhibit transcription certain gene → cellular response.

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 General Pharmacology
II. Nonreceptor-Mediated Mechanisms

1. Drugs Acting on Enzymes

• Drugs may inhibit or activate enzyme systems.
• Examples of drugs acting via enzyme inhibition:
- Choline esterase inhibitors (ChEIs) → inhibit ChE preserving Ach.
- Aspirin inhibits cyclooxygyenase → decreases prostaglandin synthesis.

2. Drugs Acting on Plasmatic Membranes

Drugs may affect permeability, carrier systems, transport processes or
enzyme systems in the plasmatic membrane. Example:
• Polyene antifungal drugs increase permeability of fungal plasmatic
membrane.

3. Drugs Acting on the Genetic Apparatus

• Antibiotics (e.g. aminoglycosides, chloramphenicol & tetracyclines)
inhibit bacterial protein synthesis.

4. Drugs Acting by Physical Means

• Demulcents (soothing): bismuth salts coat intestinal mucosa.
• Adsorbents: charcoal adsorbs gases and toxins in intestine.
• Lubricants: liquid paraffin is used in constipation.

5. Drugs Acting by Chemical Action

a. Antacids neutralize HCL in peptic ulcer.
c. Protamine neutralizes heparin by its positive charge in treatment of heparin
overdose.

6. Chelation; is the capacity of organic compounds to form complexes with

metals (chelates). The chelate may become more water-soluble and easily
excreted. It is useful in treatment of heavy metal poisoning. Example:
Desferrioxamine chelates iron and is used in iron toxicity.

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 General Pharmaco
ology

Ligaands bin
nding
Typ
pes of ligands
1. Agonist
A
I
Interacts w the recceptor (affinnity) activaating it (effficacy) → pharmaco
with ologic
e
effect, i.e. it has aff
ffinity and
d efficacy, e.g. acetyylcholine ((Ach) activ
vates
n
nicotinic reeceptors → depolarizzation → sk
keletal musscle contraaction.
2. Antagoniist
I
Interacts w
with the reeceptor wiithout activ
vation (aff hout efficacy),
ffinity with
T
There are 2 types of receptor
r anntagonists:

Com
mpetitive Antagonist
A t Noncomp
petitive An
ntagonist
• Antagonist
A competess with the
t • Anttagonist biinds irreveersibly to the
aggonist for the samee recognitiion reco
ognition sitte of the reeceptor or bind
b
siite of the reeceptor. to an
a allostericc site.
• Duration
D deepends on plasma
p connc. • Durration of antagonism
a m dependss on
off agonist annd antagonnist. the rate of turnnover of thhe receptor.
• Causes
C paraallel shift too the right in • Cau
uses downw
ward & nonn-parallel
doose-responnse curve & no changge shifft in the dose-responsse curve &
inn Emax decrrease in Emax
m (maxim
mum respon
nse)

• Examples:β Blockers. • Pheenoxybenzaamine (α bblocker).

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 General Pharmacology

3. Partial Agonist (Agonist-Antagonist)

• In absence of the agonist, it activates the empty receptor, but with lower
efficacy than that of a full agonist.
• In the presence of the agonist, it acts as an antagonist.
• Example: succinylcholine → initially activates nicotinic receptors →
fasciculations (agonistic effect) →followed by relaxation (antagonist effect).

N.B. the action of a ligand can also be reversed by non receptor antagonists
Examples:
• Chemical antagonists: interact chemically with the agonist away from
receptor, e.g. negative charges on heparin are neutralized by positive
charges on protamine sulfate (heparin antidote).
• Physiological antagonists: one drug antagonizes the effect of another
by acting on a different receptor to induce the opposite action e.g. β2-
bronchodilator effect of epinephrine antagonizes H1-bronchconstrictor
effect of histamine.

Receptor Cycling or Turnover

• The number of receptors is not constant but the receptors are cycling
(old receptors are internalized inside the cell and the new ones are
externalized to the outside) and their number is continuously
changing depending on the rate of recycling.
• Binding of the agonist → increases receptor internalization Æ ↓
number of recruited receptors [down regulation] while binding of the
antagonist Æ ↑ the number of recruited receptors [up regulation].

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 General Pharmacology

Tolerance
• It is reduced responsiveness to the drug on repeated administration so that
higher doses are needed to produce the same effect.

Pharmacokinetic tolerance: is tolerance due to decreased drug level e.g.

• ↓ Absorption e.g. furosemide tolerance due to gut edema in heart failure

• ↑ Elimination e.g. ↑ metabolism with enzyme inducers as phenobarbitone

Pharmacodynamic tolerance: is tolerance without decreased drug level e.g.

• Decreased sensitivity of the receptors e.g. opiates

• Decreased number of receptors [down regulation] e.g. ß2-agonists
• Increased number of receptors [up regulation] e.g. H2-receptor
antagonists.

Special types of tolerance

-Tachyphylaxis:
It is an acute tolerance but the same effect can not be obtained by ↑dose e.g.
amphetamine acts by releasing biogenic amines (NE) from their stores.
After repeated doses it cannot act due to depletion of the stores.
- Cross tolerance:
Tolerance to related drugs e.g. e.g. cross tolerance between different members of
opioids.

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 General Pharmacology

ADVERSE DRUG REACTIONS

• The term "adverse reactions" is used for harmful effects of a drug, which
require reduction of dose, drug withdrawal or immediate treatment.

Types of Adverse Reactions

Type A: Augmented (side effects and overdosage toxicity).
Type B: Bizarre (hypersensitivity, idiosyncrasy).
Type C: Continuous (reactions due to long-term use).
Type D: Delayed (teratogenesis and carcinogenesis).
Type E: Ending of use (adverse effects following drug withdrawal).

Type A (Augmented)
a. Intolerance (at doses < therapeutic): tinnitus after a single, small aspirin dose.
b. Side effect (occurs at therapeutic dose) e.g.
i. 1ry pharmacological action e.g. dry mouth from antihistamines.
ii. 2ry pharmacological action e.g. thrush3 while taking antibiotics.
c. Overdose (at doses slightly > therapeutic): seizure with lidocaine.
d. Toxic effect (at very high doses) e.g. hepatotoxicity with acetaminophen.

Type B (Bizarre)
1. Hypersensitivity (Allergic reactions)
• Immune-based adverse reactions. They are not dose-related but are
induced by prior contact with drugs that act as antigens.
2. Idiosyncrasy
• Genetically-mediated adverse effects e.g. Favism.
Type C (Continuous)
• Adverse effects occurring on chronic use of drugs e.g. analgesic nephropathy
or corticosteroids-induced diabetes.

3
Due to overgrowth of candidal infection.
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 General Pharmacology
Type D (Delayed):
• This adverse effect may occur even after stopping drug. There are 3 types
a. Mutagenicity: drug-induced gene abnormalities; with metronidazole.
b. Carcinogenicity: drug-induced neoplasme.g. radioactive drugs.
c. Teratogenesis (teratos = monster; genesis = production): induction of fetal
abnormalities. The most vulnerable period is weeks 3-10 intrauterine life.
e.g. Thalidomide→ phocomelia, Tetracyclines→ dental hypoplasia.

Type E (adverse effects following withdrawal of some drugs)

1. Abstinence (withdrawal syndrome) in drug-dependent persons (addicts)
following withdrawal of narcotics, alcohol, hypnotics...
2. Addisonian crisis on sudden withdrawal of chronic corticosteroid therapy.
3. Angina or infarction may follow sudden withdrawal of β-adrenoceptor
blockers (due to upregulation of β-adrenoceptors → ↑ heart activity).

Other Adverse Effects

1. Drug Abuse
• It is the use of a drug for non-therapeutic purpose.
• It is more common with drugs acting on CNS → dependence.
2. Iatrogenic Disease (Drug-Induced Disease)
• Drug prescribed for a disease → another disease, e.g. aspirin-induced
asthma or peptic ulcer.

PHARMACOGENETIC DISORDERS
These are genetic abnormalities that are revealed only by the effect of drugs.

Hemolytic Anemia due to G6PD Deficiency

• Congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD)
enzyme renders RBCs readily hemolyzed in presence of some oxidant drugs
as antimalarials, sulfonamides and fava beans (favism).

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 General Pharmacology
Succinylcholine Apnea
• The skeletal muscle relaxant succinyl choline may cause respiratory muscle
paralysis with apnea in genetically predisposed patients. This is due to failure
of its breakdown due to a genetic defect in pseudocholine esterase enzyme
responsible for its breakdown.

Malignant Hyperthermia
++
• Genetic disorder in which skeletal muscles fail to sequester Ca in
sarcoplasmic reticulum following administration of succinylcholine and
halothane. This results in marked muscle rigidity & rise of body temperature.

DRUG ALLERGY
• It is an acquired condition due to repeated exposure to the drugs mediated by
immunogenic mechanisms.
Mechanisms and Types of allergic reactions

Type I Reaction (immediate type; anaphylactic):

• Rapid IgE-mediated reaction: asthma, anaphylaxis
(with penicillins).
• Treatment:
Antihistaminic, Epinephrine, and corticosteroids (hydrocortisone Na
succinate).

Type II Reaction
• IgG or IgM antibodies are fixed to a circulating blood cell → complement-
dependent lysis. e.g., agranulocytosis (with chloramphenicol).

Type III Reaction (serum sickness)

• Antigen antibody (IgG) complex is deposited in capillary beds → e.g.
glomerulonephritis (with sulfonamides and penicillin).
Type IV Reactions (Delayed type; cell-mediated)
• Antigen stimulates T-cells to release lymphokines.
• It is involved in allergic contact dermatitis from topically applied drugs.
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 General Pharmacology

DRUG INTERACTIONS

• Drug interactions occur when one drug modifies the action of another drug in
the body. Clinically important drug interactions occur with:

1. Drugs that possess:

Important Examples
a. Low therapeutic index (TI).
• Oral anticoagulants.
b. Enzyme inducing or inhibiting properties.
• Oral hypoglycemics
c. Saturable kinetics.
• Cardiac glycosides.
2. Patients:
a. Receiving multiple drugs.
b. Severely ill - impaired liver or kidney function.
c. At extremes of age

Types of Drug Interactions

• Pharmaceutical incompatibilities occur outside the body e.g., precipitation
when drugs are mixed in solution for IV administration
• Pharmacokinetic:involving absorption, distribution, metabolism & excretion.
• Pharmacodynamic: interactions at the sites of action or nearby.

I. Pharmacokinetic Interactions
A. Interactions at site of absorption
• Tetracyclines chelate metals → ↓ absorption of Ca2+, Mg2+, &
Al3+containing antacids.

B. Competition for plasma protein binding sites

• A drug with higher affinity will displace another drug with less affinity
increasing its free concentration and hence its effect.

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 General Pharmacology

• Clinically important protein binding interactions necessitate that the drug

should have > 90% of the drug is plasma-protein-bound so that small
displacement of bound form → large increase in percentage of free form.

Examples of displacement interactions

• Aspirin displaces warfarin → bleeding.
• Sulfonamides displace bilirubin → hyperbilirubinemia →
kernicterus in the newborn.

C. Interactions involving metabolism

1. Enzyme Induction by enzyme inducers→
• ↑ Metabolism of drugs given simultaneously → ↓ level→ ↓effect
- Rifampicin →↑ metabolism of oral contraceptives → pregnancy.

2. Enzyme inhibition by enzyme inhibitors→

• ↓ Metabolism of drugs given simultaneously→ ↑ level → potentiation
- Erythromycin inhibits metabolism of theophylline, warfarin.

D. Interactions at Site of Excretion

• Alkalinization of urine→↑ionization of acidic drugs ( aspirin) →↓tubular
reabsorption →↑ excretion (useful in treatment of toxicity)
• Acidification of urine →↑ionization of basic drugs (amphetamines)
→↓tubular reabsorption →↑ excretion (useful in treatment of toxicity).

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 General Pharmacology

II. Pharmacodynamic Interactions

A. Enhancement Interactions
• Summation (1+1= 2) i.e. additive effect. Example: a barbiturate and
another sedative given together before surgery to relax the patient.
• Synergism4 (1+1= >2): when two drugs work together. Example:
sulfonamides plus trimethoprim act synergistically to block two sequential
steps in bacterial folic acid metabolism.
• Potentiation (a +b= B): occurs when two drugs are taken together and
one of them intensifies the action of the other. Example: beta lactamase
inhibitors with beta lactamase sensitive penicillins.

B. Antagonistic Interactions (1+1=0)

e.g. β Blockers or α blockers with their agonists. (see types of antagonism)

Beneficial Drug Interactions

• By combining drugs having different mechanisms of action or drugs that
correct undesirable reactions of each other.
• Examples: multiple drug therapy for treatment of hypertension, heart failure.

4
The word synergism comes from two Greek words: erg meaning "to work", and syn meaning
"together"; hence, synergism is a "working together".
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 General Pharmacology

Drug therapy during pregnancy

Passage of drugs to the fetus :

- Almost all drugs cross the placenta after multiple doses except heparin because
it has a large and polar molecule ( & insulin : large).
- During the 1st trimester (period of organogenesis) drugs may cause structural

abnormality (teratogenicity) . Examples of Teratogenic drugs :

1. Thalidomide: phocomelia ( short or absent long bones of limbs)

2 . Tetracyclines: teeth discoloration & hypoplasia

3. Antiepileptics (phenytoin): cleft palate

- During the 2nd and 3rd trimesters drugs may cause physiological
abnormality. Examples :
1-Morphine → neonatal respiratory depression (asphyxia neonatorum)

2-Oral anticoagulants → neonatal hemorrhage

3-Oral hypoglycemics → neonatal hypoglycemia

4-Aminoglycosides → 8th cranial nerve damage

FDA categorization of teratogenic risk of drugs :

Category A : Controlled studies showed no risk in humans e.g. folic acid

Category B : No studies in human. Animal studies showed no risk in animals.

e.g. penicillins and erythromycin.

Category C : No studies in human . Animal studies showed some risk e.g.

Acetaminophin, Acyclovir, dexamethasone.

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 General Pharmacology

Category D : Studies in human showed some risk, however the benefit of

therapy outweighs the potential for risk e.g. ACEIs in 2nd & 3rd
trimester & NSAIDS in 3rd trimester.
Category X : Studies in human & animal showed risk which outweigh the
benefit (i.e. contraindicated).e.g Misoprostol

Drug therapy during breast feeding

Passage of drugs through breast milk.

- Most drugs given to the mother pass from maternal plasma to breast milk by
passive diffusion except heparin & insulin which are too large .

- The milk is more acidic and contains more fat (than plasma ) → retention of
basic (ionized) and lipophilic drugs.
- Drugs are diluted in the mother's body Æthe dose of the drug reaching the baby
is usually low.

- Examples of drugs contraindicated during breast feeding :

1- Chloramphenicol ,tetracyclines & sulphonamides

2- Opioids , benzodiazepines, alcohol and nicotine
3 - Corticosteroids (↓ growth)

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