Pharmacology: Is a term derived from the Greek word pharmakon

(a drug) and logos (the science). It is the science that deals with drugs.

Drug: Is defined as a substance that is used for

prevention, diagnosis, treatment and cure of the disease in animals and humans.

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PharmacokineticPharmacodynamic

A- Therapeutic

B- Toxic

Aspects of Drug Actions

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Pharmacokinetic aspects

Drug absorption.

Routes of administration OralInjection (IV, IM, IA)TopicalInhalationRectal

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Absorption

TABLET

CAPSULE

SYRUP

AEROSOL

SUB-LINGUAL

TRANSDERMAL

SUPPOSITORYIV IM

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PHARMACODYNAMICS

Pharmacodynamics means study of the drug action on the body.

Mechanisms of drug action could be:

On the cell membrane by:a) Acting on specific receptors e.g. histamine.b) Interfering with selective passage of ions across membranes e.g. calcium channel blockers.c) Inhibiting the membrane bound enzymes and pumps e.g. cardiac glycosides.d) Physicochemical interaction e.g. general & local anaesthetics and alcohol.

On metabolic processes within the cell by:a) Enzyme inhibition e.g.allopurinol that inhibits xanthine oxidase.b) Inhibition of transport processes that carry substances across cells e.g. probenecid delays excretion of penicillin.

Outside the cell:Direct chemical interaction e.g. antacids

RECEPTORSDefinition:A receptor is a macromolecular site on the cell with which an

agonist binds to bring about a change

Affinity Affinity is the ability of a drug to bind to a receptor. Intrinsic activityIt is the ability of a drug to elicit a response after binding to the

receptor. Agonist It is a substance that binds to the receptor and has affinity and

intrinsic activity e.g. adrenaline AntagonistIt is a substance that binds to the receptor and It has affinity but

no intrinsic activity. Partial agonist It binds has low intrinsic activity. e.g. pentazocine

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Partial Agonist •Affinity and weak efficacy•Therefore, it may sometimes act as an agonist or antagonist.

If no agonist is present, then partial agonist

produces some response.

If agonist and partial agonist are present then less agonist can bind so total response is less – like antagonist

Drug Mechanisms

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Graded Dose Responses

•Types of drug actions

–Agonist = bind and produce a response

•Affinity and efficacy (Drug A or B)

–Antagonist = bind but don’t produce response (block agonist,

however)•Affinity but no efficacy (Drug D)

–Partial Agonist = bind and produce weak response

•Affinity and weak efficacy (Drug C)

Antagonists:

Antagonists are drugs that decrease the actions of another drug or endogenous ligand.

Antagonism may occur in several ways:1- Receptor antagonists act on the identical receptor as the

agonist.They have affinity without efficacy• competitive. prazosin competes with phenylephrine • == competitive antagonist characteristically causes a shift of

the agonist dose-response curve to the right. • == noncompetitive2- chemical antagonist protamine ionically binds to heparin,

rendering it inactive 3- Functional antagonism: An antagonist may act at a

completely separate receptor in the sane system giving opposite effects e.g epinephrine and histamine producing bronchodilation and bronchoconstriction respectively

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• Agonist Antagonist

Competitive antagonist = a drug that binds to but does not activate specific receptors

• Affinity no efficacy

•

MEDC 603 Fall 200714

Theory of Drug Action Fischer’s ‘Lock and Key’ Hypothesis

Every ‘lock’ has its own ‘key’ If the ‘key’ is not precise, the ‘lock’ does

not open The ‘drug’ is the key that has to fit the

target specifically and productively

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Theory of Drug Action

Corollary of ‘Lock & Key’ Hypothesis

OHCH3

OH

O

OOH O

OH

CH3

OH

OCH3

OH

OH

CHC

CH2

CH2OH CH3

CH3 OH

O

N

CH3

CH3CH2

CH3

Types of receptors

1. Ligand-gated ion channels.

2. G-protein coupled receptors.

3. Enzymatic receptors (kinase linked receptor).

4. Nuclear receptors (Transcription factors or receptors that regulate gene transcription).

Types of receptors

Ligand-gated ion channels

The activity of these channels is regulated by the binding of a ligand (drug) to the channel. ExamplesNicotinic receptor: Na + channels γ-aminobutyric acid (GABA) receptor: Cl - channels

Some drugs like Benzodiazepines, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell.

B- G protein coupled receptors

A second family of receptors consists of G protein coupled receptors. These receptors are linked to a G protein (Gs and others)

Having three subunits, an α- subunit that binds guanosine triphosphate (GTP) and γ- β subunit

Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α- subunit.

Dissociation of the G protein occurs leading to activation of second messengers giving response

Second messengers:

→ activation of adenylyl cyclase by alpha-GTP subunits, which results in the production of cyclic adenosine monophosphate (cAMP)

→ activation of phospholipase C, which is responsible for the generation of inositol-1,4,5-trisphosphate (IP3) and

Diacylglycerol (DAG).

These messengers are responsible for the regulation of intracellular free calcium concentrations.

(norepinephrine, dopamine, serotonin, and acetylcholine). → activation of guanylyl cyclase, which converts GTP to

cyclic guanosine monophosphate (cGMP), a fourth second messenger that stimulates cGMP-dependent protein kinase. (intestinal mucosa and vascular smooth muscle, where it causes relaxation)

C. Enzyme-linked receptors

These receptors have cytosolic enzyme activity as an integral component of their structure or function.

Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity.

Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form.

For example, when insulin binds to two of its receptor subunits, causes autophosphorylation which activate IP3 and protein kinase system giving an effect.

D. Intracellular receptors

These receptors are entirely intracellular and the ligand must diffuse into the cell to interact with the receptor.

ligands being lipid soluble, are transported in the body attached to plasma proteins, such as albumin.

Example: steroid hormones, exert their action on target cells via this receptor mechanism.

DRUG TOLERANCE

Repeated dosing can result in: Tolerance --- Tachyphylaxis

Tolerance: Tolerance is the requirement of higher doses of a drug to

produce a given response. Tolerance may be natural or acquired.

Natural tolerance: The species/race shows less sensitivity to the drug, e.g.

Rabbits show tolerance to atropineAcquired tolerance: Develops on repeated administration of a drug. The

patient who was initially responsive becomes tolerant, e.g. barbiturates, opioids, nitrites produce tolerance.

Mechanisms of tolerance

Pharmacokinetic: e.g. barbiturates induce microsomal enzymes

and enhance their own metabolism.

Pharmacodynamic: Changes in the target tissue may make it less

responsive to the drug. It could be due to down regulation of receptors as in opioids or due to compensatory mechanisms of the body, e.g. decreasing the response to some antihypertensives due to salt and water retention.

Cross tolerance:

The development of tolerance to pharmacologically related drugs,

i.e. to drugs belonging to a particular group. Thus chronic alcoholics also show tolerance to

barbiturates and general anesthetics.

Tachyphylaxis Is the rapid development of tolerance. When some drugs are administered repeatedly at short

intervals, tolerance develops rapidly and is known as tachyphylaxis or acute tolerance, e.g. ephedrine, amphetamine, tyramine and 5-hydroxytryptamine.

This is thought to be due to depletion of norepinephrine stores as the above drugs act by displacing norepinephrine from the sympathetic nerve ending.

Other mechanisms is decreasing the total number of receptors available (down regulation).

Potency Vs. Efficacy►Potency refers to the strength of a drug.

► Efficacy refers to its effectiveness in treatment. ♥Potency is the relationship between the dose of a drug and

the therapeutic effect. A drug is considered potent when a small amount of the drug achieves the intended effect, most commonly fifty percent of the maximum (ED 50 or EC 50.)

♥ Efficacy is the ability of a drug to produce the desired therapeutic effect. Efficacy means that the drug is effective.

• When comparing two drugs that work equally, the one with the lower dose has a higher potency. They have equal efficacy.

• example

• both 500 mg of acetaminophen and 200 mg of ibuprofen resolve a headache.

• ibuprofen is more potent because it requires a lower amount of drug

• Scince both drugs eliminate the headache. They are equally effective (efficacious)

Dose Response Relationships:

An agonist is defined as an agent that can bind to a receptor and elicit a biologic response.

The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug pharmacokinetic profile, such as rate of absorption, distribution, and metabolism.

As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases.

The response is a graded effect, meaning that the response is continuous and gradual.

Dose (ml)

Response

)mm (or (cm)

0.05

0.1

0.2

0.4

0.8

00.5

11.5

22.5

33.5

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

DoseR

espo

nse

Remember that the dose (final bath concentration) is expressed as: weight / volume, Molar, % , etc…

Therapeutic indexThe therapeutic index (TI) in broadest sense is defined as:

the ratio of the dose required to produce a toxic effect and the dose needed to elicit the desired therapeutic response.

The therapeutic index is expressed by the median doses:

Median effective dose, (ED 50) is the dose that produces certain pharmacological effect in 50% of experimental animals.

Median lethal dose is the dose that produces lethal effect in 50% of the experimental animal (LD 50) as

LD 50 ED 50

The larger the ratio, the greater the relative safety. However the use of the median effective & median lethal doses is not

without disadvantages because median doses tell nothing about the slopes of the dose response curves for therapeutic &

toxic effects.

Adverse Drug Reactions and Drug Interactions

Adverse Drug Reaction

• Response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis and therapy (WHO)

• Unwanted or harmful reaction experienced after the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to drug

RISK BENEFIT

When prescribing drugs a doctor must assess risk to benefit ratio in the individual patient by

•Choosing an appropriate class of drug then an appropriate individual agent

•Is it effective ?

•What are the chances of adverse effect ?

•Are there features in this patient which affect choice eg other drugs, organ failure, aged

•Tailoring the dose

•Considering duration of treatment

The Risk to Benefit Ratio

Type of adverse reactions

• Type A (Augmented)

• Type B (Bizarre, strange)

• Type C (Chronic)

• Type D (Delayed)

• Type E (End of use)

• Type F (Therapeutic failure)

• Type G (Genetic/genomic)

Type AType AType BType B

PharmacologicaPharmacologically predictablelly predictable

YesYes NoNo

Dose Dose dependentdependent

Yes Yes NoNo

IncidenceIncidenceHighHighLowLow

MorbidityMorbidityHighHighLowLow

MortalityMortalityLowLowHighHigh

ManagementManagementDosage Dosage adjustmentadjustment

STOPSTOP

• Type A ADRs – intrinsic to the drug effects

• Type B ADRs - idiosyncratic

Predisposing factors

• Multiple drug therapy

• Age

== Elderly

== Neonates- chloramphenicol, morphine,

Reye’s syndrome - ?

Hepatotoxicity – Aspirin

Predisposing factors

• Gender

- Females have 1.5-1.7 folds of developing ADR than males

- Women are prone to develop blood dyscrasias with phenylbutazone & chloramphenicol

• Presence of disease

- HIV –skin reactions with co-trimoxazole

Predisposing factors

• Race and genetic polymorphism

- Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers)

- Drug receptors

- Drug transporters (P-glycoproteins, P-gp )

Mechanism of dose related (Type A) reactions

• Pharmaceutical cause

-pharmaceutical aspects of a dosage form

Indomethacin – GI bleeding

Mechanism of dose related (Type A) reactions

• Pharmacokinetic causes

1. Absorption

GI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in liver & gut wall, concomitant drugs

2. Distribution

Plasma-protein and tissue binding

Mechanism of dose related (Type A) reactions

• Pharmacokinetic causes

3. Metabolism

Enzyme induction or inhibition – efficacy??

Genetic variants – oxidation, hydrolysis, acetylation

Drugs competing for glucoronidation

4. Elimination

-digoxin

Examples of type B

Primaquine• Quinolones (ciprofloxacin, nalidixic acid,

norfloxacin, ofloxacin)• Sulfonamides (Cotrimoxazole)

These drugs cause hemolysis in patients with G6PD deficiency

* anesthetics and muscle relaxants (succinylcholine) cause Malignant hyperthermia treated with dantrolene

Chronic type©

• Paracetamol hepatotoxicity

Delayed adverse effects (D)

• Vaginal carcinoma in female child in mothers taking diethylestilbosterol

Adverse effects associated with drug withdrawal (E)

• Benzodiazepine withdrawal syndrome

• Clonidine Rebound hypertension –

• Acute adrenal insufficiency - corticosteroids

Type F

• One of these drugs, Tamoxifen, a prodrug that must be activated by hepatic CYP450 will fail in presence of abnormal enzyme.

• Drug interactions • I. Pharmaceutical interactions (incompatibilities)• II. Pharmacological interactions• [A] Pharmacokinetic drug interactions:• Absorption:• Change in GI pH: Raising gastric pH by cimetidine can

markedly reduce the absorption of ketoconazole.• Adsorption: Activated charcoal/many drugs. This is

beneficial in management of toxicity.of overdosage.• Chelation: Metalic ions (Ca++, Al+++) found in dairy

products and antacids and iron form complex with tetracyclins that is poorly absorbed.

•

• Ddistribution:

• Alteration of plasma protein binding

• Phenylbutazone and aspirin displace warfarin bleeding tendency

• Sulphonamides displace bilirubin Kernicterus in newborn

• Phenylbutazone displace tolbutamide risk of hypoglycemia

• Metabolism:

• Enzyme induction:

• Phenobarbitone induces metabolism of almost all drug metabolism by CYP450 as well as its own metabolism (auto-induction).

• Enzyme inhibition

• Cimetidine inhibits metabolism of carbamazepine, leading to elevation of its blood level.

• Grapefruit juice inhibits metabolism of CCBs. Thus, the juice increases the bioavailability

Excretion:Probenecid inhibits active renal tubular secretion of many acidic drugs e.g. penicillin, leading to prolongation of its duration. [B] Pharmacodynamic drug interactions Addition (summation): 1+1=2: Aspirin + paracetamol

Synergism: 1+1= >2: Barbiturates + alcohol

Potentiation: 0 +1= >1: Beta lactamase inhibitors + beta lactam antibiotics Barbiturates + aspirin.

Antagonism: 1+1= <1

• Chemical antagonism: Protamine/heparin

• Physiological (functional) antagonism: Adrenaline/histamine.

• Pharmacological antagonism:

- Competitive: NA/phentolamine

- Non competitive: Acetylcholine/succinylcholine