pharmacodynamics pharmacodynamics includes the experimental study of : mechanism of drug action....

Pharmacodynamics

Pharmacodynamics includes the experimental study of :

Mechanism of drug action.Pharmacological effects.

Mechanism of ActionA drug may produce its effect through:• Receptor mediated action.• Non-receptor mediated action.

Receptor Mediated Action• Receptor: receptor is a special molecular component of

the cell (protein macro-molecule or DNA) which is capable of selectively recognizing and binding a drug, hormone, mediator or neurotransmitter, thereby eliciting a cellular response.

•Kd = dissociation constant = concentration of drug at 50% binding to the receptors.

)(Re/)(Re)( sponseComplexRDRceptorDDrug Kd

DRUG RECEPTORS AND PHARMACODYNAMICSDRUG RECEPTORS AND PHARMACODYNAMICS

RECEPTORSSpecific molecules in a biologic system with which drugs interact to produce changes in the function of the system


RECEPTORSDetermine the quantitative relations between dose or concentration of drug and pharmacologic effects


RECEPTORSSelective in choosing a drug molecule to bind to avoid constant activation by promiscuous binding of many different molecules


RECEPTORSChanges its function upon binding in such a way that the function of the biologic system is altered in order to have pharmacologic effect


RECEPTORSSelective in ligand-binding characteristics (respond to proper chemical signals and not to meaningless ones)Mediate the actions of both pharmacologic agonists and antagonists


RECEPTORSMajority are proteins which provide the necessary diversity and specificity of shape and electrical charge


RECEPTORSRECEPTOR SITE/RECOGNITION SITE

Specific binding region of the macromoleculeHigh and selective affinity to the drug molecule


Interaction between the drug and the receptor is the fundamental event that initiates the action of the drug


CLASSIFICATION OF RECEPTORSREGULATORY PROTEIN

Best characterized drug receptorsMediates the action of endogenous chemical

signals like neurotransmitters, autacoids andhormonesMediates the effects of the most useful

therapeutic agents


CLASSIFICATION OF RECEPTORSENZYMES

Inhibited (or less commonly, activated) by binding a drugEg, dihydrofolate reductase, the receptor formethotrexate


CLASSIFICATION OF RECEPTORSTRANSPORT PROTEINS

Eg, Na+/K+ ATPase, the membrane receptor for digitalis


CLASSIFICATION OF RECEPTORSSTRUCTURAL PROTEINS

Eg, tubulin, the receptor for colchicine, an anti-inflammatory drug


EFFECTORSMolecules that translate the drug-receptor interaction into a change in cellular activityEg, adenyl cyclase


EFFECTORSSome receptors are also effectorsA single molecule may incorporate both the drug binding site and the effector mechanism

Dose

Response

AffinityAffinity:: it is the ability of a drug to bind a it is the ability of a drug to bind a

receptor. It is determined by the dissociation receptor. It is determined by the dissociation

constant (Kd) (the lower the Kd the higher the constant (Kd) (the lower the Kd the higher the

affinity).affinity).

EfficacyEfficacy: : it is the ability of a drug receptor it is the ability of a drug receptor

complex to produce an effect. Maximal effect complex to produce an effect. Maximal effect

produced if a maximal dose is given. It is produced if a maximal dose is given. It is

determined by the graded dose- response curve.determined by the graded dose- response curve.

Graded dose-response curve

�

A BResponse

50%

ED50 ED50Dose

Drug A > drug B

Potency: Potency: it refers to the it refers to the

concentration (EC50) or dose concentration (EC50) or dose

(ED50) of a drug producing 50% of (ED50) of a drug producing 50% of

the maximum effect. It depends on the maximum effect. It depends on

the Kd which determines the the Kd which determines the

receptor affinity to bind that drug. receptor affinity to bind that drug.

The lower the ED50, the more The lower the ED50, the more

potent drug.potent drug.


GRADED DOSE-RESPONSE CURVEResponse of a particular receptor-effector system is measured against increasing concentration of a drugGraph of the response versus the drugdose


GRADED DOSE-RESPONSE CURVESigmoid curveEfficacy (Emax) and potency (EC50) are

derived from this curveThe smaller the EC50, the greater the

potency of the drug


Emax

Maximal response that can be produced by a drugAll receptors are occupiedNo response even if the dose is increased


EC50

Concentration of drug that produces 50% of maximal effectSmaller EC50–more potent

DRUG RECEPTORS and PHARMACODYNAMICSDRUG RECEPTORS and PHARMACODYNAMICS

Drug effect

5

10

EC50

Emax

Drug dose


Bmax

Total number of receptor sitesAll receptors have been occupied


KD

Equilibrium dissociation constantConcentration of drug required to bind 50% of the receptors


KD

Measure of the affinity of a drug for its binding site on the receptor

Smaller KD–greater affinity of drug

to receptor


Receptor bound drug

5

10

KD

Bmax

Drug dose

• Therapeutic Index (TI) = Margin of Safety:

• LD50 = lethal dose to 50% of the population in animal experiments.

• ED50 = the effective dose in 50% of animals.• The higher the TI, the safer the drug e.g. barbiturate (TI=10)• The lower the TI, the greater the possibility of toxicity e.g.

digitalis (TI=3), so death may occur if only 3mg has been administered because the usual therapeutic dose of cardiac glycoside is one mg.

50

50

ED

LDTI

General classification of drugs

• Agonist = stimulant.• Partial agonist.• Antagonist = blocker.• Agonist: a drug has affinity, high efficacy and rapid rate of

association and dissociation with its receptor e.g. adrenaline, morphine and histamine.

• Partial agonist: a drug has affinity, weak efficacy and moderate association and dissociation. It produces an effect < the full agonist when it has saturated the receptors. It acts as antagonist in the presence of full agonist e.g. nalorphine, ergotamine, succinylcholine and oxprenolol.

• Antagonist: a ligand having affinity, but no efficacy and slowly associated and dissociated from the receptor.

Signal Transduction Mechanism • Signal transduction is the subcellular cascade of

events that occurs after binding of a ligand with a

receptor to produce a unique cellular function.

Types of Receptors & Their Signaling Mechanisms

• Channels-linked receptors: e.g. nicotinic receptor &

GABA receptors. When acetylcholine (on nicotinic

receptor), or GABA (on GABAA receptor), bind their

receptors, a conformational change occurs in the

channel resulting in altering of ion distribution across

the cell membrane and a unique cellular function

produced.

Na+

G-protein coupled receptors:• The receptors for catecholamines,

prostaglandines and many peptide hormones are linked to G-protein (Gs , Gi , Gq , …) evolving in stimulation or inhibition of a second messenger

R

G

Second messenger

Examples • Stimulation of β1 & β 2 adrenergic receptors

stimulate Gs increase cAMP.• Stimulation of α1 adrenergic receptors Gq

increase DAG, IP3.• Stimulation α2 adrenergic receptors Gi

decrease cAMP.

Kinase-linked receptors:

• When insulin, EGF and PDGF)bind their

surface receptors, a tyrosine-kinase (on the

inner part of the receptor) is activated. This

leads to phosphorylation of certain protein

on its tyrosine residue producing the specific

cellular function.

T.K

R

Nuclear Receptors = Gene active receptors:

• The steroid hormones.

• Thyroid hormones.

• vitamin D and vitamin A.

• These hormones can easily pass the cell membrane and

bind with cytoplasmic mobile receptors.

• Drug-receptor complex enters the nucleus and bind to

DNA response element, which in turn regulates RNA

transcription with production of unique protein

concerned with the cell response.

Non-Receptor Mediated Mechanisms

Drugs act on enzymes:• Nitric oxide (NO) penetrates the cell membrane stimulating

cytoplasmic guanylyl cyclase enzyme leading to increase of intracellular cGMP.

• Digitalis inhibits Na+/ K+ ATPase enzyme.

Drugs Act on Plasma Membrane:• Polymixins and amphotricin B increase the permeability of

bacterial plasma membrane.

Drugs Act on Subcellular Structures:• Erythromycin and chloramphenicol inhibit protein synthesis in

bacteria by binding to 50 S ribosomal subunit. Tetracyclines and aminoglycosides bind 30 S ribosomal subunit.

Drugs Act by Chemical Action:• Antacids neutralize gastric acid secretion.• Protamine (alkaline & +ve charge) antagonizes

heparin (acid & -ve charge).

Drugs Act by Physical Means: • Osmosis e.g. mannitol.• Lubricant e.g. liquid paraffin.• Adsorbent e.g. kaolin and charcoal.

Chelation:

• Chelation is mainly employed in the treatment of heavy

metal poisoning. A chelating agent holds the toxic metal ion

to form a drug-metal complex, which is non-toxic, water-

soluble and easily excreted in urine e.g.:

• EDTA chelates calcium, lead and digitalis.

• Dimercaprol (BAL) chelates mercury and copper.

• Penicillamine chelates copper & used in treatment of

Wilson’s disease.

• Desfferioxamine chelates iron in cases of iron toxicity.

Sex: males need higher doses than females owing to the higher bulky

muscles and androgen which is an enzyme inducer. Drugs should be

administered cautiously during pregnancy and lactation (see latter)

Route of administration:

• MgSO4 orally on empty stomach

(4g.) cholagogue

(15g.) saline purgative.

• i.v inhibits the CNS and used in eclampsia seizures.

• retention enema dehydration and used in cerebral edema and

eclampsia.

Disease states: long duration of action or toxic effect of

a drug may be related to liver or kidney disease and

long period of time for absorption and distribution

related to heart disease.

Immune factors: a drug may stimulate the immune

system causing urticaria or shock. From now on this

patient should not received this drug or its related

preparations e.g. penicillin and cephalosporins.

.

Psychological factors:

• the hopes, fears and expectation of the individual

often affect the drug action.

• Patients may even improve with placebo (tablet or

capsule containing sucrose or lactose).

• This may be due to release of endogenous

substances like endorphins and enkephalins in the

brain and other body parts

Timing of dosage:

• A single dose of antacid or ranitidine taken at

bedtime is more effective than two or three

doses taken during the day.

• Absorption is better on empty stomach.

• Irritant drugs should be given after meals.

• CNS stimulants never be given at bed time.

Cumulation:. • A drug is designated as cumulative when its

elimination and/or detoxification are slow • E.g. digitalis, diazepam, amiodarone and large

doses of aspirin or phenytoin. • The toxicity could be avoided by decreasing

the dose

Tolerance

It is a decrease or failed response to the usualtherapeuticdose of a drug.Types of Tolerance:

• Congenital tolerance: existing from birth examples:

• Negroes are tolerant to the mydriatic action of ephedrine.

• Eskimos are highly tolerant to fat diet (not develop acidosis).

• Biological variation i.e. individual tolerance within any population. This may be related to genetic factors.

• Rabbits are tolerant to large doses of atropine , probably due to the presence of atropine esterase in the liver (species tolerance).

• Acquired tolerance: an acquired resistance to the usual dose of a drug repeatedly administered and more drugs are needed to produce the same effect.

• It is reversible when the drug is stopped for a period of time.Causes: • It may be due to increased metabolism of the drug.• or decreased sensitivity and number of receptors (down

regulation). • Addiction is a phenomenon which often, accompanies the

development of tolerance. Examples: cocaine, heroine, morphine, alcohol, nicotine,

barbiturates, nitrates and xanthines.

• Tachyphylaxis: • It is an acute form of acquired tolerance • Occurring within few minutes.• Usually occurs if a drug is given repeatedly, at short intervals

& generally by i.v route.• Tachyphylaxis probably occurs due to a transient saturation of

the cell receptors with the drug.• Increasing the dose cannot produce the same effect. Examples:• Disappearance of the hypertensive effect of ephedrine

repeatedly administered i.v in an anesthetized dog. • Disappearance of the hypertensive effect of tyramine which

releases and displaces noradrenaline from the adrenergic neurons.

• Cross-tolerance: tolerance to a drug may extend to the related drugs. Example: nicotine/lobeline, morphine / pethidine, and between members of barbiturates

pharmacodynamics pharmacodynamics includes the experimental study of : mechanism of drug action....

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