GENERAL PHARMACOLGY

Prepared by dean farhan abdi eid

 Introduction
 Pharmacology = pharmakon (drug ) + logos (study)
 The study of interactions b/n chemical agents (drugs) & living organisms
especially by binding to regulatory molecules and activating or inhibiting
normal body processes!(osmotic, G. anesth.?)
– Intentional (medical p’cology) or unintended exposure (T’cology)
 Different from pharmacy
 Important for rational use of drugs
 Two major aspects studied
– What the body does to this chemical agent (ADME)  Pharmacokinetics

– What the chemical agent (drug) does to the body  Pharmacodynamics

 Definition of a drug
 From French ‘’ drogue’’- dried herb
 Are chemical substances which modify living
processes and never create a new one
 In clinical practice, drug is "a chemical substance
used in the treatment, prevention, or diagnosis of
disease or used to otherwise enhance physical or
mental well-being,
in appropriate doses

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 Sources of Drugs
 A. Natural Sources

– Plants: - leafs, roots, barks

 Atropine from Atropa belladonna, Quinine form Cinchona bark,

Morphine from Papavarum somniferum, digoxin and digitoxin

from Digitalis lanata
 eucalyptus oil, ginger oil, castor oil, olive oil…

– Animal Sources – expensive and difficult

 Insulin, from pork and beef pancreas, Hormones (thyroid),

Vaccines , Heparin and Cod liver oil …

 Natural sources…
 Microorganisms
– Antibiotics: - e.g. penicillin from Penicillium notatum, chloramphenicol from
Streptomyces venezuelae, grisofulvin from Penicillium griseofulvum, neomycin
from Streptomyces fradiae, streptomycin from Streptomyces griseus, etc
 Mineral Sources
Ferrous sulfate is used in iron deficiency anaemia Magnesium
sulfate is employed as purgative Magnesium trisilicate,
aluminium hydroxide and sodium bicarbonate are used as antacids for
hyperacidity and peptic ulcer Kaolin (aluminium silicate) is used
as adsorbant in antidiarrheal mixture Radioactive isotopes of iodine, phosphorus
are employed for the diagnosis/treatment of diseases
 B. Synthetic sources

 Majority of drugs used in clinical practice are synthetic

– Aspirin , oral antidiabetics, antihistamines, amphetamine, chloroquine,
chlorpromazine, general and local anaesthetics, paracetamol, phenytoin,
synthetic corticosteroids, sulphonamides and thiazide diuretics. …..
 Advantages
– chemically pure

– Easy and cheap process of preparation

– Excellent quality control of the drug

– More effective and safer drugs can be prepared by modifying the chemical
structure of the prototype drug
 con’t
C. Semi synthetic sources
– When the synthesis of drugs (complex molecules) may be
difficult, expensive and uneconomical or when the natural
sources may yield impure compounds
– E.g Homatropine from atropine, 6-aminopenicillanic acid derivatives…

D. Biosynthetic sources (genetically engineered drugs)

– Genetically engineered novel vaccines (Recombinex HB - a
hepatitis-B vaccine), recombinant DNA engineered insulins
(Humulin- human insulin) and interferon-alpha-2a and
interferon-alpha-2b for hairy cell leukaemia.
 Drug Nomenclature
 Chemical name: - named according to the rules of chemical naming such as
IUPAC nomenclature
– Difficult and complex  Not used widely

– N-acetyl para amino phenol for paracetamol,

– 4-[2-hydroxy-3-[(1-methyl ethyl) amino] propoxy] benzene acetamid for atenolol

 Proprietary /Trade/Brand Name: - is unique name for particular

manufacturer
– Designate the manufacturer’s ownership of that pharmaceutical product.

– A single drug may be marketed under many brand names.

– Tylenol and Panadol for paracetamol

 Cont..
 Approved/official/generic names: - is a common name
drug that allows different product with the same ingredient

to be identified as such

– used uniformly all over the world by an international

agreement through the WHO

– Generic names of drugs are usually used in text books of

pharmacology, medical journals etc. …

– E.g. propranolol, paracetamol, omeprazole, atenolol etc.

 Braches of Pharmacology
 Pharmacotherapeutics: (Greek 'therapia' means
medical treatment)
– deals with the use of drugs in the diagnosis, treatment or
prevention of diseases.
 Toxicology: toxicon/toxikos
– deals with the adverse effects of drugs and poisonous
effects of various chemicals
– Clinical toxicology is the science of detection, diagnosis
and treatment of poisoning.
 Pharmacogenetics:
– deals with genetically mediated variations in drug responses.
 Pharmacogenomics:
– deals with the application of genomic technologies to new drug
discovery and further characterization of older drugs.
 Clinical Pharmacology:
– deals with the pharmacological effects of drugs in man.

– It gives information about potency, usefulness, doses & toxicity of

new drugs for their safe clinical use.
 Posology: - deals with dosing of medications
 Pharmacokinetics
 Drug in motion
 Evaluates factors that influence magnitude of drug
effects as a function of time
– Onset of action
– Duration of action depends on
 Plasma half life
 Determines frequency of administration
 Drugs with long plasma half lives get cumulated
 Has four components
– Absorption
– Distribution
– Biotransformation
– Excretion
 Drug absorption
• Transport of drugs from the site of administration into
circulation (blood/ lymph)
– All RA except iv

– Critical (systemic effect) vs not required (local effect)

• Involves passage across cell membranes via

1. Simple passive diffusion 2. Carrier-mediated transport 3. Ion pair
transport 4. Bulk flow 5. Endocytosis
• Sites of absorption depend on routes of administration
 Routes of drug adminstration
 A path by which a drug is brought into contact with body

 May be classified into : Entral, Parentral, Inhalational and Topical

 Entral

– to do with the GI track

– include all RA that involve the GI tract : oral, buccal, sublingual & rectal

 Parentral

– not through the GI tract

– all RA that do not envolve the GI tract

– commonly refers to injections (IV, IM and SC)

 Oral Route of Administration
 Advantages   Disadvantages
– The safest route – Variable absorption

– Economical – Gastric irritation  vomiting

– High patient compliance – Not useful if patient is vomiting

– No need for sterile equipment – Requires cooperation of patients

– Onset of action is slow
– Systemic effect
– Subjected to first pass effect
– Relatively reversible
 Absorption of drugs from the oral route

• Absorption from the Stomach

– The stomach is rich blood supply  potential site for
drug absorption
– vary from patient to patient & time to time

– The low pH of the gastric contents (pH 1–2) degree of

drug ionization  drug absorption
• WB vs WA drug

• WB drug may be trapped in gastric (ion trapping)

 Absorption of drugs from the oral route

 Absorption from the Small  Absorption from the Large

 Ideal site of absorption – Little absorption occurs from this

– large surface area site

 Small absorptive surface area
– high blood perfusion rate
 The relatively solid nature of the lumen
– single cell layer of epithelial lining,
– In distal portion of the large
villi and microvilli
intestine, the rectum,
 Most site proximal jejunum (first
 the extensive vascularity of the rectal
1–2 m) mucosa  absorption

 Simple passive lipid diffusion.

– Pka and PH affect absorption
 First Pass Effect
 All drugs that are absorbed from the intestine enter hepatic portal
vein and pass through the liver before they are distributed
systemically

 Some drugs are almost completely destroyed/ metabolized/ and

other to some extent on their first passage through the liver
Hepatic first pass effect

 Some drugs are also destroyed in the GI tract when administered

orally  by acids of the stomach, enzymes
 Gastrointestinal first pass effect.
 Buccal and Sublingual RA

• Advantages • Disadvantages
– Bypass first pass effect – Inconvenient
– Rapid absorption – If any is swallowed 
• Nitroglycerine subjected to first pass
– Drug stability effect
• Relatively neutral pH – Only small doses
 Rectal route
•  Advantages
– Approximately 50% of absorbed drug bypass
hepatic first-pass effect
– Useful when oral ingestion is precluded
• The patient is unconscious or when vomiting
• Young children and also in elderly
 Disadvantages
– Erratic absorption
 Irregular and incomplete

 Variation among individuals regarding the necessary dose.

– Delayed or limited absorption = the small surface area of the rectum.

– Small amount of fluid available

 Slow dissolution of tablets or capsules

 Instill 10ml of warm water before the tablet or capsule

– Absorption may be interrupted by defecation.

– Constipation may prevent contact of drug with rectal mucosa

– Many drugs can cause irritation of the rectal mucosa.

 Parentral route
i. IV
– Directly into vein → no absorption
– 100% bioavailability
– Accurate control of drug delivery
– Ideal for irritant drugs
– Fast action
– Drug has to be in form of solution
– Difficult to terminate action
– Repeated administration depends on patency of
veins
– Self administration not possible
 Parentral (cont.)
ii. IM
– Administration into sk. Muscles
– Sites of absorption (muscles)
– Absorption depends on rate of blood flow at the
injecting site
– Massaging/heating/exercise increases absorption
– Oily/suspension ppn makes absorption constant
– Irritating substance may sometimes be
administered
– Self administration not possible
 Parentral (cont.)
iii. SC
– Injection under skin
– Site of absorption: subcutaneous tissue
– Absorption is slower but constant
– Solid pellets can be implanted for longer effect,
e.g., contraceptives
– Vasoconstrictors retard absorption
– Only non-irritants
 Parentral (cont.)
• Intra-arterial
• Intradermal
• intra-artecular
• Intracardiac
• Intraperitoneal
• Intrathecal
 Inhalational
• Administration into lungs
• Site of absorption: alveoli
• Applicable for
– Systemic effect (volatile Anesthetics)
– Local effect (antiasthmatic drugs)
• Powders, volatile liquids, gases
• Bypasses 1st pass effect
• Can be regulated with metered dose inhaler
and reliable aerolizers
 Topical
• Mucus membrane
– Conjunctiva, oro and naso-pharynx, vagina, colon,
urethra, urinary bladder
– Site of absorption - mucus membrane
• Skin
– absorption from intact skin: less
– Absorption from broken skin: high
– Site of absorption- skin
– Enhanced by rubbing
– Controlled release topical patches can be kept on
skin for systemic use. E.g., scopolamine patch
placed behind ear for motion sickness
 Routes of administration
 The choice depends on
– Physicochemical property of drug
– Rate and extent of absorption
– Site of desired action
– First pass effect
– Desired onset of action
– Accuracy of dosage
– Condition of patient
 Pharmacology
PHARMACOKINETICS
• Absorption
• Distribution
• Metabolism
• Excretion
 Pharmacokinetics
Drug Absorption
 Transport of drugs from the site of administration into circulation
(blood/ lymph)
– All RA except iv
– Critical (systemic effect) vs not required (local effect)
 Involves passage across cell membranes via
– Simple passive diffusion
– Carrier-mediated transport
– Ion pair transport
– Bulk flow
– Endocytosis
 Simple passive diffusion
 Drug molecule penetrates by diffusion along ∆C
– Aqueous Diffusion: through aqueous pores

– Lipid Diffusion: across cell membrane

 No requirement of energy
 Most common mechanism of transport
 Rate α to the
– magnitude of the ∆C

– lipid-water partition coefficient of the drug

– membrane surface area

 Carrier-mediated transport
Facilitated Diffusion:
 A carrier–mediated transport system x’zed by
– Saturability, selectivity and competitive
– The driving force is ∆C
– No energy is required
 The rate first α ∆C then reaches a limiting or maximal
rate  constant
 More information at the bottom?????????????????
 Active transport

 Passage facilitated by an energy-dependent membrane carrier

mechanism
 Occur against a concentration gradient
 It exhibits
– Structural selectivity
– Saturability
– Competition
– Genetic variants
 Drugs that sufficiently resemble the endogenous s/bces
Characteristics Simple Facilitated Active
diffusion diffusion transport

Incidence Commonest Less common Least common

Process Slow Quick Very Quick

Movement vs ∆C Along Along Against

Carrier Not needed Needed Needed

Energy Not needed Not needed Needed

 Ion Pair Transport
 Absorption of some highly ionized cpds from the GI
– Despite their low lipid–water partition coefficients
 Highly lipophobic drugs + endogenous cpds (mucin)
 neutral ion pair complexes  penetrates the
lipid membrane passively
 Bulk Flow

 Most substances, lipid soluble or not, cross the

capillary wall at rapid rates
– >> rates of passage across other membranes
 Occurs through intercellular pores
 Major mechanism of passage of drugs across
most capillary endothelial membranes
– Except CNS (BBB)
 Endocytosis

• Involves passage into cell within membrane

invagination
• Important mechanism for
– Particulates

– High molecule weight compounds

• Proteins
 Pharmacology
FACTORS AFFECTING ORAL DRUG ABSORPTION:
• Physicochemical properties (molecular size and shape,
lipid solubility partition coefficient..)
• Routes of adminstration
• Dosage form
• Blood flow at the site of absorption
• pH
• Surface area: intestine vs stomach
• Contact time at absorption site (e.g increased GIT
motility and food in general decreases absorption)
 Pharmacology
BIOAVIALABILITY : It is the proportion of
the dose administered that is available at
the site of action
• It is the fraction of the drug absorbed and
reaches the systemic circulation.
• Intravenous route – bioavailability is ~ 1
or 100%.
 Pharmacology
Bioavailability of a drug
• The bioavailability of a drug (by a route
other than intravenous) is given by:
AUC (extra vascular)
• F= -----------------------------
AUC (intravenous)
 Pharmacology
Bioavailability of a drug:
 Pharmacology
• Amount of drug absorbed or
reaching plasma = F x Dose
• For example the oral bioavailability (F)
of digoxin (lanoxin) is 0.7
• For digoxin 250 ug given orally, the effective
or absorbed dose = 0.7 x 250 ug
= 175 ug
 Pharmacology
Bioavailability of a drug:
Oral dose = Intravenous dose / F
• For example, the oral bioavailability of
theophylline is close to complete (F =1) so
that oral and intravenous dose rates are about
the same.
• Morphine has an oral bioavailability of about
0.2, so to achieve similar plasma
concentrations as intravenous, oral dose rates
need to be 5 times intravenous dose
(intravenous dose / 0.2).
 Factors affecting BA
• Affected by
– Routes of administration
– Poor intestinal permeability
– First pass effect
– Nature of the drug formulation
• Represented by the AUC vs time plot
• Expressed as -
– an absolute and relative bioavailability
 Pharmacology
BIOEQUIVALENCE: For two drugs to be
bioequivalent, they must have the same
bioavailability and the same plasma profile, i.e.
the curve must have the same shape.
• They must have the same Cmax and Tmax.
• Cmax: The maximum plasma concentration
attained by a drug-administration.
• Tmax: The time at which maximum
concentration is reached.
 Pharmacology
BIOEQUIVALENCE:
 B. Distribution
 Is the delivery of drugs from systemic
circulation to tissues
 Distribution of drugs is random (every tissues
have equal chance)
 But concentration of drugs in different tissues
differ due to different factors:-
– Plasma protein binding
– Tissue uptake (affinity of drugs to tissue)
– Physiological barriers
– Tissue perfusion
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I. Plasma protein binding
• Drug in systemic circulation exist as bound
and unbound form
• Drug ordinarily bind with plasma protein in
reversible fashion and in dynamic
equilibrium
D + P →[DP] → D + P
– As free drugs leave the systemic circulation the
bound drug dissociate

51
 The extent of this binding will influence the
drug’s distribution and rate of elimination b/c
only the unbound drug can:
– Diffuse through capillary and cell membrane
– Produce pharmacological effect
– Produce toxic effect
– Be metabolized
– Be excreted
 The major binding macromolecules are:
Albumin
– Most drug binding glycoprotein
– Mainly acidic and hydrophobic drug bind
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Some factor affect the binding of drugs with
albumin:
Disease state:
Hypoalbuminemia, Liver disease
 α1 –acid glycoprotein
Binding site mainly for basic drug
Plasma protein binding is clinically important for
those drugs which have high plasma protein
binding and low excretion ….????
Warfarin
acetyl salicylic acid
Phenytoin ….

53
II. Tissue uptake
 some drug will be either considerably higher or
considerably lower in particular tissues: due to
tissue different affinity
o Adipose tissue : drugs with extreme lipid
solubility
 May result :–
 decrease therapeutic activity ( eg thiopental)
 Prolonged activity (eg fat depot preparation)
 Toxicity ( eg-DDT)
o Kidney : contain proteins that has high affinity
for metals
 Cadmium, Lead, Mercury accumulation -----toxicity

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o Eye – drugs which have affinity accumulate in the eye
Chlorpromazine (other phenothiazine) and chloroquine---
accumulate in eye
o Bone- TTC, Lead
TTC accumulation may cause poor bone development (binds
Ca2+)
Lead accumulation result bone brittleness (displace Ca2+)
o Teeth –TTC accumulation result yellow- brown
discoloration of teeth
o Liver – Chloroquine
Generally tissue accumulation of drug may have
 Advantageous effect ---( target tissue therapy eg
Chloroquine, iodine: sustained release effect, eg fat depot )
 Disadvantageous effect---mainly toxicity

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III. Physiological barrier
 Blood brain barrier (BBB)
 Transfer of drug to brain is regulated by BBB
Not pass BBB
Cross BBB
-- ionized drug
--unionized drug
-- Lipid insoluble
-- small size drug
drugs
-- unbound drug
-- Bound drug
 Inflammation such as due to meningitis increase the
permeability of BBB so permeating the passage of
ionized , lipid soluble drugs.
 Eg:- penicillin and ampicillin – not cross BBB ( highly
ionized) but inflammation– they can pass BBB --used for
antibiotic effect centrally

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Placental blood barrier
• Blood vessel of mother and fetus separated by
PBB
• Highly polar and ionized drugs do not cross
placenta readily
• Drugs with high lipid solubility shouldn't be
given to give pregnant mother
– Eg TTC –accumulate in bone and teeth of neonate
—↓development of bone and teeth
• Drugs which cross PBB and cause fetal
abnormalities called teratogenic drugs
57
IV. Tissue perfusion
• Different tissue have d/t rate and amount of
blood flow
– Highly perfused tissue:- heart, lung, brain, liver,
kidney
– Intermediate perfused tissue:- skeletal muscle
– Poorly perfused tissue:- skin, bone, nail, fat
tissue

58
 Pharmacology
Volume of distribution : It is defined as the
volume in which the amount of drug would
need to be uniformly distributed to produce the
observed blood concentration.
The volume of distribution (Vd)
of a drug is given by:
D D
• Vd = -------- Co = --------
Co Vd
D = Total amount of the drug in the body
C = Drug concentration in plasma at zero time
 Pharmacology
Drug Plasma concentration
dose Volume = 1 L

100 mg/L
100
mg

Volume = 10 L
10 mg/L
100
mg

Volume = 100 L
1 mg/L

100
mg
 Pharmacology
Volume of distribution of a drug indicates

• Vd of about 3 L: Distribution restricted to

the vascular compartment. e.g., Heparin.
• Vd of about 11 L: Distributed in extra
cellular fluid, but are unable to penetrate
cells. e.g., Mannitol. Intracellular
• Vd of about 42 L: Drugs are able to pass fluid 28L

most biologic barriers and are distributed in

total body water (extra and intracellular)
eg., Alcohol.
• Vd > 42 L: drugs are extensively stored
within specific cells or tissues e.g.,
Extracellular
fluid 11L

Chloroquine, digoxin
Plasma 3L
 Pharmacology
METABOLISM
• It is also called as biotransformation.
• It renders the lipid soluble drug to
water soluble drugs. (for ease of excretion)
• The primary sites for metabolism is
liver, others are --- kidney, intestine,
lungs and plasma
 Pharmacology
METABOLISM:
Biotransformation can be of two types:
• Phase I reactions – oxidation / reduction
reactions.
•Phase II reactions – conjugation
reactions.
 Pharmacology
Biotransformation can leads to ---
 Inactivation of parent drug-e.g,
phenobarbitol
 Conversion of drug to its toxic metabolite- e.g,
paracetamol
 Conversion of inactive drug (prodrug) to more
active drug e.g. Levodopa  dopamine

Enalapril  enalaprilat
 Maintenance of activiry e.g. diazepam 
desmethyldiazepam  oxazepam
Imipramine  desipramine
 Pharmacology
• Phase I reactions :
Oxidation reactions – carried by liver
cytochrome P 450 system.
e.g. : barbiturates, acetaminophen,
benzodiazepines
Reduction reactions – carried by liver
cytochrome P 450 system. e.g. :
chloramphenicol, methadone
Hydrolysis – carried by cyp 450 esters, amines,
e.g.: procaine, oxytocin
 Cytochrome P450 Enzyme System
 Most important cyp -450 include:
– CYP1A2, CYP2A6, CYP2C9, Cyp2C19CYP2D6, CYP2E1, and CYP3A4
 Nomenclature: for E.g. CYP 3A4
– CYP – abbreviation for cytochrome P450

– 3- designates family  40% sequence identity

– A- designates subfamily  55% sequence identity

– 4 – designates specific P450 gene

 More than one CYP isoform may be involved in metabolism of a drug
 CYP3A4 = metabolize over 50% of drugs
 CYP2D6 = metabolize about 30% of drugs
 CYP2C9 = metabolize  10% of drugs
 Enzyme Induction and Inhibition
 The level of CYP450 enzymes
– can be affected by the presence of other drugs, certain
food items, or by disease states.
 Enzyme inhibition
– impairs metabolism of drugs
– often leads to increase in pharmacological action & toxicity
  Induction
– results in an acceleration of substrate metabolism
– usually in a decrease in the pharmacologic action
 Pharmacology
 Phase II reactions :
It is the conjugation of a drug to form a polar
(ionized) drug which can be easily excreted.
Glucuronide conjugation
• Using glucuronosyl transferase (GTs) enzyme Eg drug:
Chloramphenicol (CAF), morphine aspirin

Acetylation rxn
Involve N-acetyl transferase
Eg isoniazide (INH), hydralazine, sulfonamides
Methylation – adrenaline, histamine
70
 Factors Affecting Biotransformation
 Age - Metabolism vs age
– children & oldies metabolize drugs in slow rate

e.g sulphonamide in neonates results in kernicterus

 Sex = Sex-dependent differences  Hormone-related differences
(alcohol Vs alcoholic dehydrogenase )
 Genetic variability - Gene  protein  enzymes
– Rapid vs slow metabolizers (isoniazid)
 Drug interaction - Enzyme induction and inhibition
 Diet - For example grapefruit juice is known to inhibit CYP3A4

- Poor nutrition  decrease the ability to synthesize enzymes

 Disease state: liver damage
72
 Elimination of Drugs
 Removal of drugs
– unchanged (excretion)
– converted to metabolites.
 Excretion + metabolism + tissue redistribution
– Determine rate of drug elimination
– Determine duration of drug action
 The principal organs involved
– kidneys, lungs, biliary system & intestines
 Renal Excretion
 The kidney

– primary organ of removal for water soluble drugs

 Depends up on

– Glomerular filtration (Affected by molecular size, charge, binding to plasma

proteins, and shape of drug)

– Tubular secretion (carrier-mediated transport Competitive  drug

interaction Probenecid vs penicillin

– Tubular reabsorption (mostly passive back-diffusion few drugs actively

reabsorbed.)
 Factors influencing renal drug excretion

 Gender -Female 80 % renal function of males

 Age - renal function ⇓50% with age (25 –75 yr)
  Pregnancy -Renal function ⇑50%
 Disease - Renal disease, heart failure
 Drugs
 Alteration of renal excretion of drugs

 Competitive inhibition of tubular secretion

– Eg, the renal clearance of penicillin is decreased90% by
probenecid
 Influence of pH
– Sodium bicarbonate used to alkalinize urine
 increase in pH  increases ionization of weak acids (eg salicylate;
methotrexate)  decreases tubular reabsorption increased excretion

– Ammonium chloride used to acidify urine

 enhance excretion of basic drugs (eg amphetamines)
 Other routes
• Faeces : purgatives – liquid paraffin
• Exhaled air : volatile anesthetics, alcohol
• Saliva and sweat : Rifampin
• Milk : Metronidazole, Phenytoin , TTC
 Quantification of drug elimination

Half-Life (t1/2)
 The time it takes for Cp or the amount of drug in the body
to be reduced by 50%.
 Determines
– the time required to reach steady state
 Usually after 4 t1/2

– the dosage interval

 Shouldn’t be > t1/2

– time for a drug to be removed from the body

 Usually after 7 t1/2
 Excretion
• Kinetics of elimination
– Zero order kinetics: fixed amount/time
– First order kinetics: fixed fraction/time
– Intermediate kinetics: between first and zero
order kinetics
 Pharmacology
LINEAR / FIRST ORDER KINETICS :
• The rate of elimination of the drugs is
proportional to the plasma concentration.
• Constant fraction of the drug is eliminated
in unit time.
• 80mg 40mg 20mg 10mg 5mg
• Most of the drugs follow first order
kinetics.
Pharmacokinetics
First order / Linear kinetics
 Pharmacology
SATURATION / ZERO ORDER KINETICS:
• The rate of the elimination of drug is
constant irrespective of the plasma
concentration.
• Constant amount of drug is eliminated in
unit time. Eg : Phenytoin, Alcohol,
Theophylline.
• 80mg 70mg  60mg 50mg 40mg
Pharmacokinetics
 Pharmacology
HALF LIFE :
• Plasma half life: It is the time required
for the drug to reduce to half its original
plasma value.
• Half life is a concept which is applied only
to drugs following first order kinetics.
 Pharmacology
The half-life of a drug is also called
elimination half‑life.
• The half‑life of a drug is given by:
0.693
t½ = --------------
Ke
Ke = Elimination constant
 Pharmacology
• Steady state is the state when the
Rate in = Rate out.

• The time to reach the steady state is

dependent only on half life of a drug and
is independent of the dose size and the
frequency of administration.
 Pharmacology
Time and the steady state :
• 100% steady state = ~ 7 half life
• 96.85% of the steady state = 5 half life
• 93.75% of steady state = 4 half life
• 90% of steady state = 3.3 half life
• 87.5% of steady state = 3 half life
• 75% of the steady state = 2 half life
• 50% of steady state = 1 half life
 Pharmacology
Rate of Infusion :
• Irrespective of the rate of infusion, it takes
the same amount of time to reach the
steady state.
• If the rate of infusion is doubled, then
the plasma level of the drug at steady
state is doubled.
Pharmacology
 Pharmacology
CLEARANCE :
It is the volume of the plasma from
which the drug is completely removed
in unit time.
 Pharmacology
• CLr of a drug can be used as a marker
of the process of renal drug
elimination
• CLr ~ 100-150 ml/min indicates GFR
• CLr > 150 ml/min indicates t. secretion
• CLr < 100 ml/min indicates tubular
reabsorption.
 Clearance (CL)
• The volume of plasma completely emptied of
drugs per unit time

• Elimination of drug may occur by

– GI tract, kidney, liver, and other organs.
• Cl of drug by several organs is additive
PHARMACODYNAMICS

100
 Pharmacodynamics
 The biochemical & physiological effects of drugs and
their MOA
  Action Vs Effect
– Action: is the property of a drug to alter conditions in a
biological entities
– Effect: is the result we observe when drugs act on this
biological entities
 Action  effect
 E.g., adrenaline by binding to alfa-receptor cause Camp
increment. Then finally cause vasoconstriction
cAMP increment: action
Vasoconstriction : effect
 Drugs do have selectivity on the system they act

– Minor & major actions

– Major action leads to major effect

– Minor action leads to minor (side) effect

 Aspirin

– Major action: analgesic, antipyretic, anti-inflammatory

– Minor action (SE): antiplatelet

 Drug can produce action via
– Physical means
 Chealation

 Osmotic action

 Adsorption

– Drugs may act through chemical reactions

 Antacid to neutralize gastric acid secretions

– Drug interact with biological means

 Drugs acting on enzyme: (Aspirin + Cyclooxygenase)

 Action through receptor: (Cimetidine + Histamine receptor)

104
 Receptors
 Generally denotes the component of the organism
with w/c chemical agent is presumed to interact
– Definition 1: “Any target molecule with which a drug
molecule interacts to produce the observed effect”.
 Ion channels, enzymes, carrier molecules and “the actual drug
targets”.

– Definition 2: The component of a cell or organism that

interacts with a drug and initiates the chain of events
leading to the drugs observed effects
106
 Properties of Receptors
 Sensitivity
– a small amount of drug/ligand is required to produce response.

– There is a signal amplification system

 Selectivity
– Receptors interact only with molecules that are complementary to them
 The molecular size, shape, and electrical charge

 Specificity
– The response obtained at a given receptor remains the same in spite of
the difference in the type of agonist. (e.g atenolol, timolol)
 Nature of Receptors

 Most receptors are proteins,

– provide both the necessary diversity and the necessary

specificity of shape and electrical charge

 Receptors have two functional domains: a ligand-

binding domain and an effector domain

Receptor Families
1. Cell surface/membrane bound receptor
– found embedded on cell membranes

– Based on molecular structure & the nature of signal

transduction mechanism
 Ion channel linked receptors

 G-protein coupled receptors (GPCRs)

 Receptor that are enzymes or linked enzymes

 Ion channel linked receptors/ Ligand-gated ion
channels

 Coupled to ion channels

 Binding of a ligand
– modulates the opening/closure or conductance of the
ion channel.
– Conformational changes
 A fastest effect is obtained.
 Example include:
– nACh receptor, GABA A receptor
 G-protein coupled receptors
 Coupled to intracellular effectors via a G-protein

– When they bind GDP the inactive

– when they bind GTP they will be active.

act as molecular switches

 Binding of ligand  activation of the receptor/

conformational changes  activation of a G protein 

change of effector activity
 Effectors controlled by G-proteins
 Adenylate cyclase (AC)/cAMP:
– AC catalyses formation of the intracellular messenger cAMP

– cAMP activates various protein kinases that control cell function by

causing phosphorylation
 Phospholipase C/inositol trisphosphate (IP3)/diacylglycerol (DAG)

– catalyses the formation of two intracellular messengers, IP3 and DAG,

from PL

– IP3 acts to increase free cytosolic Ca2+ by releasing intracellular Ca2+

– increased free Ca2+  contraction, etc

– DAG activates protein kinase C  phosphorylating

 Kinase-linked and related receptors

 Linked to an intracellular domain that

– Exhibit catalytic/enzymatic / activity

– tyrosine kinase activity

 Binding of a ligand change in receptor conformation 
receptor dimerization  brings together the protein kinase
domains  autophosphorylation of tyrosine residues 
enzymatically active  phosphorylate additional
downstream signaling proteins
2. Intracellular receptors:
– Found either in cytoplasm or nucleus & regulate gene
transcription
– Ligands have sufficiently lipid-soluble to cross the plasma
membrane.
– Mediate regulation of DNA transcription

– Consist of a conserved DNA-binding domain, ligand-binding and

transcriptional control domains
– E.g Aldosterone receptor, Steroid hormones,
 Pharmacodynamics

Adrenergic
receptors

Eg., Nicotinic
Ach receptor
Eg., Insulin Eg., Steroids
ANP
 Receptor agonism and antagonism
 Potency: is a measure of much drug is
required to elicit a given response (the lower
the dose required for a given response the more potent
the drug is)
 Affinity: It is the ability of the drug to bind
to the receptors
 Intrinsic activity: It is the ability of a
drug to activate the receptor and produce the
response.
AGONIST : It binds to the receptors and it
will activate the receptor.
 It has both affinity and intrinsic activity.
 Eg : epinephrine
 Cont..
ANTAGONIST : It binds to the receptor but it
will not activate the receptor.
• It has affinity but no intrinsic activity
• Eg : atenolol, metoprolol, prazosin
PARTIAL AGONIST : It activates the
receptor and produce sub maximal response.
• It antagonizes the action of pure agonist.
Eg : Pindolol
INVERSE AGONIST
 Drug receptor theories
1. Occupation theory
– Classical (Clark – Ariens)
 Linear relationship
 Emax occurs if only all receptors are occupied
– Modified (Stephenson)
 Nonlinear relationship
 Emax achieved without occupancy of all receptors
2. Rate theory
– The response elicited by a drug is proportional to the rate
of drug-receptor interaction, rather than to the number of
receptor occupied
 Pharmacology
Graded Dose Response Curve (DRC) :
• Potency: It refers to the amount of drug
needed to produce the response.
• The position of the curve on the dose axis
is an index of drug potency.
• The dose required to produce half the
maximum response is an index used to
determine the potency.
 Pharmacology
• Efficacy : It refers to the maximum
response of the drug.
The upper limit of the drug
response curve is an index of efficacy of
the drug.
• Steepness of the curve indicates the
dose range – steep slope indicates that a
small increase in the dose markedly
increase the response.
• Slope of the curve is related to the
mechanism of action of a drug.
Graded dose response curve
Graded dose response curve
 Graded dose response curve
E max

Effect
%
50

Potency

Concentration (Log)
Drug Response Curve
 Pharmacology
Therapeutic index is the ratio of median
lethal dose (LD 50) and the median effective
dose (ED 50).
• It indicates the safety of the drug.
Therapeutic index

Cumulative or
Quantal dose
response curve
 Carbamazepine; digoxin;
levothyroxine; lithium;
phenytoin; theophylline;
valproic acid; warfarin

128
 Pharmacology
Drug antagonism : when one drug
decrease the effect of the another drug .
• Physiological : the two drugs acting
through different receptors produce
opposite effects. eg : Glucagon and
beta blockers.
• Physico-chemical : two drugs react
chemically and form an inactive product
eg : EDTA complex with heavy metals
 Pharmacology
Drug receptor antagonism :
• Competitive/Reversible antagonist:
• Antagonist and Agonist compete to bind
to the same receptor.
• Parallel shift of DRC to the right side
• Decrease the potency not efficacy
• Eg : Acetylcholine and Atropine,
Prazosin and Epinephrine
Competitive antagonist

                            
          
 
 
 
F
i
g
.
3

                               
          
 Pharmacology
• Noncompetitive/irreversible
antagonist :
• The antagonist binds irreversibly or to
site other than that of agonist.
• Non parallel shift of DRC to right side.
• It decrease the efficacy.
• Eg : Phenoxybenzamine and Epinephrine
Noncompetitive antagonist
 

  
      
   
 
Fig.
4

                                        

           
 Pharmacology
FACTORS MODIFYING DRUG ACTION:
• Age
• Sex
• Race/Genetics
• Psychological/Pathological factors
• Other drugs
• Tolerance: It is the requirement of higher
dose than usual dose to produce the
effect
 Pharmacology
• Natural: Individual is inherently less
sensitive to the drug
Eg : Certain race are tolerant to mydriatics
• Acquired : repeated use of drug in an
individual who was responsive initially results
in less response later on.
• Tachyphylaxis: When a drug is repeated in
very quick succession, it results in marked
reduction in response.
• Usually seen with indirectly acting drugs like
ephedrine
TACHYPHYLAXIS
 Adverse drug reactions
Definition: noxious unwanted effect at therapeutic
dose
 Could be
– Mild: no intervention
– Moderate: change in drug
– Severe: life threatening/drug withdrawal
– Lethal: contribute to death
 Results from interaction between
– Characteristics of the drug
– Characteristics of patient
 Adverse Drug Reactions (ADR)
 Any noxious or unintended reaction to a drug that is
administered
– in standard doses
– by the proper route of administration
– for the purpose of prophylaxis, diagnosis or treatment
 An undesirable effect of a drug beyond its
anticipated therapeutic effect occurring during
clinical use.
• ADR may be related to

– Directly b/c of medicines

– Poor product quality

– Medication error
 ADR may require

– discontinuing the medicines

– Changing the therapy

– Modification of dose

– Admission to hospital

– Prolonged stay in hospital

– Supportive treatment
 Types of ADR
 Type A ADRs
– These are dose related ADRs

– Exaggerated but normal PA

– Cause significant morbidity but rarely severe

– Often predictable

– Most common  at least 2/3 of ADRs

– Treated by reducing the dose or withholding the drug and

considering alternative therapy
– Side effects and toxic effects
• E.g
 Type B (bizarre) ADRs

 Rare but severe

 Often unpredictable and not related to the dose
 Are not extension of the PA of the drug.
 Only few ADRs (  5 %)
 Occur in few individuals due to their susceptibility
– genetic difference
 Treated by stopping the medicine & avoiding its use in
future
• Classified into two:
– Hypersensitivity reactions
• Immune mediated

– Idiosyncratic reactions
• Gene mediated
 Type C (chronic) ADRs
 These are associated with long-term use of drug
 Related to cumulative Dose
 Often involve dose accumulation
 They are well known and can be anticipated
 E.g. ocular toxicity by antimalarials
 Treated by reducing the dose or withholding drug
 E.g. osteoporosis with oral steroids
 Type D (delayed) ADRs

• Delayed in onset or have lag time

• Uncommon and difficult to treat

• Are dose independent

• Example
– Teratogenicity

– Carcinogenesis

– Tadive dyskinesia
 Type E (end of use ) ADRs
 Occur soon after end of use/withdrawal
 Uncommon
 Treated by
– reintroducing the medicines  slowly withdrawing it
 Example
– BZD

– Opiate

– Beta blockers
 Type F (failure) ADRs
 Common and occur when there is a failure of efficacy
 May be dose related & often caused by drug
interaction
 Treated by
– Increase dose
– Considering the effects of concomitant therapy
 Example
– Resistance to antimicrobial
– Failure of contraception
 Causes of ADR

 Allergy/hypersenitivity rxn
 Genetics
 Drug interaction
 Nutritional deficiency
 Alcohol consumption
 Smoking
 Environmental pollutants
 Over dosage toxicity
 Refers to the toxic effects of drugs when taken in
excess
 Related to the pharmacological property of drug
 Direct extension of the drugs PA
 Is predictable
 Paracelsus (the father of toxicology)
 “all things are poison and not without poison; only the

dose makes a thing not a poison”

 Rational prescribing
Clinical pharmacology lecture
 Introduction
 A rational use of drugs is a tool
– maximize the beneficial effects
– minimize the potential ADRs
 achieved through the commitments and
collaboration of the three groups of people
(Prescribers, dispensers and drug consumers)
with the support of policy makers
 Healthy communication among these groups is
absolutely essential in the promotion of rational
drug use
 Introduction (Cont.)

Prescriber

Dispenser Consumer
∆
Policy Maker
 Rational prescribing

• Prescribers are health professionals who

diagnose and order drugs to patients
• there are different levels of prescribers
ranging from health assistants to sub-
specialists
• Rational prescribing is a process of safe,
effective and economic ordering of drugs for
the benefit of consumers
 Principles of rational prescribing

• Identifying level of prescribers

• Proper diagnosis
• Exhausting non drug therapy
• Relevant information on the drug to be
prescribed
• Updating knowledge on drugs
• Consulting drug specialists
 Principles of rational prescribing
(cont.)
 Following STG
 Considering emergence of resistance
 Smooth communication with consumers and
dispensers
 Writing correct prescription
– on standard format
– legible prescription
– in generics
– not multiple
– not ambiguous
 Examples of irrational prescribing
 Prescribing antibiotics for nonspecific diarrhea
 Prescribing antidiarrheal drugs for childhood
diarrhea
 Prescribing injections for malaria indiscriminately
 Prescribing antibiotics for mild, non-bacterial
infection, e.g., URI
 Prescribing Tonics and multivitamins for
malnutrition
 Prescribing cephalosporins while penicillins can do
 Steps in rational prescribing
(1) Defining patient’s problem;
(2) Specifying therapeutic objective;
(3) Verifying the suitability of the P-drug and
choose treatment for individual patient;
(4) Writing a prescription;
(5) informing and instructing patient; and
(6) Monitoring and/or stop treatment
 General protocol for overdose poison
management
 ABC stabilization
 Clinical evaluation
 Decontamination
– Decrease further absorption
– Enhance excretion
 Use antidote
– PCM?, morphine?, diazepam?, iron?,
organophaspate?, Pb?, Methanol? etc
 Development of New drugs

• General approaches for new drugs discovery

– Random screening for biological activity

– Chemical modification of a known molecule

– Rational drug design

–  Biotechnology
 New compound (Synthetic / Natural

Identification and characterization

 
General screening in animals
(Pharmacological evaluation in experimental models of
the disease)

Preclinical studies
(Pharmacodynamics/ Pharmacokinetics Toxicity)
 Preclinical Toxicity Studies
 Acute toxicity studies
 Chronic toxicity studies
 Limitations of preclinical studies
– time-consuming and expensive

– Extrapolations of animal data to humans may not be

accurate/ possible
– Large number of animals are required to obtain a valid data

– Animal models of some human diseases may not exist

 Clinical Testing Of Drugs
 The actual safety and efficacy of new drugs
 Ethical issue
 Informed consent
 Conducted step by step
– Phase I
– Phase II
– Phase III
– Phase IV
 Phase I clinical trial
 Objective: to study the safety of the drug in healthy human
subjects.
– To establish the dose level at which signs of toxicity first appear
 Conducted on small number of healthy volunteers (20 to 80)
 Initially a single low dose of the test drug PO  increased
 If no untoward effects from single doses  short-term multiple-
dose
 Volunteer patients are used for the study
– Pharmacokinetic measurements of absorption, half-life, and metabolism
are also studied.
 Phase II clinical trial

• Conducted on small number of patients ( 80

-100)
• The major objectives are
– To evaluate efficacy and establish an optimal dose
range
– To monitor adverse drug reactions
 Phase III clinical trial
 Conducted on a relatively large number of patients (thousands)
 The major objectives
– To verify the efficacy of the drug in a large study population

– To detect effects unobserved in the phase I and II trials,

 At the end of phase III study
– the documents are reviewed by regulatory bodies

– the drug is approved for market.

 For drugs being developed for the treatment of life threatening illnesses
(e.g. cancer and AIDS) phase II studies may suffice for approval
Phase IV study (Post-Marking Surveillance)

 Conducted on a large number of patients who

are actually taking drug
 Major objectives are:
– To investigate rare side effects not reveled by
previous studies
– To investigate for new beneficial effects/
indication/ of the drug