Dr. NurhidayatiDepartmen of Pharmacology

School of MedicineMataram University

2004-2005

Drug Receptors and Pharmacodynamics

(how drugs work on the body)

The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action.

PharmacodynamicsThe biochemical and physiologic mechanisms

of drug action

What the drugWhat the drugdoes when it gets there.does when it gets there.

What the drugWhat the drugdoes when it gets there.does when it gets there.

Drug MechanismsReceptor interactionsNon-receptor mechanisms

Drug ActionsMost drugs bind to cellular receptors

Initiate biochemical reactionsPharmacological effect is due to the alteration

of an intrinsic physiologic process and not the creation of a new process

2004-2005

Drug Receptor

A macromolecular component of a cell with which a drug interacts to produce a response

Usually a protein

Major Classes of ReceptorsLigand-Gated Ion ChannelsTyrosine Kinase-Linked ReceptorsG-Protein Coupled ReceptorsLigand-Activated Transcription Factors

Location of ReceptorsMembran cellIntracellular receptor

CytosolicNuclear

The Lock and Key Model of Ligand-Receptor Interaction

a ligand such as a hormone or neurotransmitter (the "key") bind to specific receptors (the "lock”)

this binding "unlocks" the cell's response.

many drugs work by mimicking a naturally occurring hormone or neurotransmitter

if the drug causes the receptor to respond in the same way as the naturally occurring substance, then the drug is referred to as an agonist

these are drugs that can “pick the lock”.

other drugs work in the opposite way as antagonists.

these drugs bind to the receptor, but do not produce a response.

because the drug prevents the receptor from binding to the normal hormone or neurotransmitter, it has an inhibitory effect on the naturally occurring substance.

Na+

Choline

Ca++

Receptor

Acetylcholinesterase

Acetylation

TERMS AGONIST

FULL AGONISTPARTIAL AGONIST

ANTAGONISCOMPETITIVE REVERSIBLENON-COMPETITIVE IRREVERSIBLEPHYSIOLOGICALCHEMICAL

SELECTIVE AND NON-SELECTIVEDIRECT AND INDIRECT (???)

Agonist Receptor

Agonist-Receptor

Interaction

Lock and key mechanism

Receptor

Perfect Fit!

Induced Fit

Antagonist Receptor

Antagonist-Receptor

ComplexDENIED!

CompetitiveInhibition

Agonist Receptor

Antagonist

‘Inhibited’-ReceptorDENIED!

Non-competitive Inhibition

Chemistry of Drug-Receptor InteractionsMost drug-receptor

interactionsReversibleweak chemical bonds

Irreversible drug-receptor interactionsnot commonstrong chemical bonds

(covalent)e.g. aspirin, anti-tumour drugs

usually undesirable reversal of effects/toxicity mutagenicity/

carcinogenicity

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agonist has affinity plus intrinsic activity

antagonist has affinity but no intrinsic activity

partial agonist has affinity and less intrinsic activity

competitive antagonists can be overcome

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Agonist Drugsdrugs that interact with and activate receptors; they possess both affinity and efficacy

two typesFull – an agonist with maximal efficacy

Partial – an agonist with less then maximal efficacy

Pharmacological Antagonists

Competitive AntagonistsNon-Competitive Antagonists

2004-2005

Antagonist Drug

Antagonists interact with the receptor but do NOT change the receptor

they have affinity but NO efficacy

two typesCompetitiveNoncompetitive

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Competitive Antagonistcompetes with agonist for receptor

surmountable with increasing agonist concentration

displaces agonist dose response curve to the right (dextral shift)

reduces the apparent affinity of the agonist i.e., increases 1/Ke

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Noncompetitive Antagonist

drug binds to receptor and stays boundirreversible – does not let go of receptorproduces slight dextral shift in the agonist

DR curve in the low concentration rangethis looks like competitive antagonist but, as more and more receptors are

bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect

Chemical antagonism

interaction of two drugs in solution such that the effect of active drug is lost

e.g. metal chelators plus toxic metalsProtamin against heparin effectDimercaprol against efect of toxic

metals

Physiological Antagonism interaction of two drugs with opposing

physiological actionse.g.

histamine: lowers arterial pressure through vasodilation (H1 receptors); and epinephrine raises arterial pressure through vasoconstriction (α-adrenergic receptors)

Relationship of Drug Concentration and Receptor Binding

2004-2005

Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves

Agonist Types: Its All RelativeA: full agonist

maximum potency, maximum efficacy

B: partial agonistmaximum potency,

reduced efficacyC: full agonist

reduced potency, maximum efficacy

D: partial agonistreduced potency,

reduced efficacy

Competitive Antagonists - Effect on Dose Response Curves

Aagonist + no

antagonistagonist has maximum

potency, maximum efficacy

Bagonist + competitive

antagonistagonist has reduced

potency, but maximum efficacy

Non-Competitive Antagonists - Effect on Dose Response Curves

Aagonist + no

antagonistagonist has maximum

potency, maximum efficacy

B agonist + non-

competitive antagonist

agonist has maximum potency, but reduced efficacy

Non-receptor MechanismsActions on Enzymes

Enzymes = Biological catalysts Speed chemical reactions Are not changed themselves

Drugs altering enzyme activity alter processes catalyzed by the enzymes

Examples Cholinesterase inhibitors Monoamine oxidase inhibitors

Non-receptor MechanismsChanging Physical Properties

MannitolChanges osmotic balance across membranesCauses urine production (osmotic diuresis)

Non-receptor MechanismsChanging Cell Membrane Permeability

Lidocaine Blocks sodium channels

Verapamil, nefedipine Block calcium channels

Bretylium Blocks potassium channels

Adenosine Opens potassium channels

Non-receptor MechanismsCombining With Other Chemicals

AntacidsAntiseptic effects of alcohol, phenolChelation of heavy metals

Non-receptor MechanismsAnti-metabolites

Enter biochemical reactions in place of normal substrate “competitors”

Result in biologically inactive productExamples

Some anti-neoplastics Some anti-infectives

Drug Response RelationshipsTime ResponseDose Response

Latency

Duration of Response

Maximal (Peak) Effect

Effect/

Response

Time

Effect/

Response

Time

IVSC

IM

Dose Response RelationshipsPotency

Absolute amount of drug required to produce an effect

More potent drug is the one that requires lower dose to cause same effect

Effect

Dose

A B

Which drug is more potent?

A!A!Why?Why?

TherapeuticEffect

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EfficacyDegree to which a drug is able to produce the desired response

Max effect of Drug Aeffect Max effect of Drug B

A B DoseA = FurosemidB = Thiazid

Max effect of Drug A Max effect of Drug B

effect

A B Dose

Dose Response RelationshipsThreshold (minimal) dose

Least amount needed to produce desired effects

Maximum effectGreatest response produced regardless of dose

used

Which drug has the lower threshold dose?

Effect

Dose

A

B

Which has the greater maximum effect?

AA

BB

TherapeuticEffect

Dose Response RelationshipsLoading dose

Bolus of drug given initially to rapidly reach therapeutic levels

Maintenance doseLower dose of drug given continuously or at

regular intervals to maintain therapeutic levels

Effective Concentration 50% (ED50)Concentration of the drug which induces a

specified clinical effect in 50% of subjects

Lethal Dose 50% (LD50)Concentration of the drug which induces death

in 50% of subjects

Therapeutic Index• A measure of drug safety• Considers dose required for a toxic effect versus that required for the desired beneficial effect

In general, a larger T.I.indicates a clinically saferdrug

Therapeutic dose

Toxic dose

Therapeutic index = Toxic dose

Therapeutic dose

Why don’t we use adrug with a TI <1?

Why don’t we use adrug with a TI <1?

ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!ED50 < LD50 = Very Bad!

Some drugs with a low therapeutic index 

Lithium Digoxin

Carbamazepine Cyclosporin

Phenytoin Phenobarbitone

Theophylline (Aminophylline)

Warfarin

 

Beneficial versus Toxic Drug EffectsNo drug causes only a single, specific effect Selectivity in clinical actions is limited to a

specific dose range (T.I.)

1.Effects mediated by identical receptors in the same tissue.

2.Effects mediated by identical receptors in different tissues.

3.Effects mediated by different receptors.

Drug Desensitizationeffect of a drug often

diminishes when given continuously or repeatedly

desensitization, tachyphylaxis, refractoriness, resistance, tolerance

receptor-mediated and non-receptor-mediated mechanisms

Receptor Mediatedloss of receptor functionreduction of receptor number

Non-Receptor Mediatedreduction of receptor-coupled

signaling componentsreduction of drug

concentrationphysiological adaptation

Receptor Mediated Desensitization1. Loss of Receptor Functionrapid desensitization due to

change in receptor conformation

usually due to feedback of cellular effects of agonist

Example: phosphorylation of specific amino acids in G-protein coupled receptors blocks coupling to G-proteins

2. Reduction of Receptor Number

slower, long-term desensitization due to change in receptor number

usually due to feedback of cellular effects of agonist

Example: phosphorylation of specific amino acids in G-protein coupled receptors causes removal from cell surface

Non-Receptor Mediated Desensitization1. Reduction of Receptor-Coupled Signaling

Componentsdepletion of signaling molecules required for biological

responseExample: prolonged stimulation of G-protein coupled receptors

can lead to depletion of intracellular secondary messengers2. Increased Metabolic Degradation

increase in the rate of metabolism and/or elimination of drug lowers plasma drug concentrations

Example: barbiturates induce the expression of metabolic enzymes (cytochrome P450s) that degrade this drug

3. Physiological Adaptationreduction or amelioration of drug effects due to opposing

homeostatic responsevery few well characterized mechanisms

**all of these receptor and non-receptor dependent factors can also contribute to interindividual differences in drug response**

Factors Altering Drug ResponsesAge

Pediatric or geriatricImmature or decreased hepatic, renal

functionWeight

Big patients “spread” drug over larger volume

GenderDifference in sizesDifference in fat/water distribution

Factors Altering Drug ResponsesEnvironment

Heat or coldPresence or real or perceived threats

FeverShock

Factors Altering Drug ResponsesPathology

Drug may aggravate underlying pathologyHepatic disease may slow drug metabolismRenal disease may slow drug eliminationAcid/base abnormalities may change drug

absorption or elimination

Influencing factorsGenetic effects

Lack of specific enzymesLower metabolic rate

ImmunityBody rhythms(cortisol levels, active immunity

is cyclic)Diet and NutritionPsychological factors

Placebo effect

Pediatric PatientsHigher proportion of waterLower plasma protein levels

More available drugImmature liver/kidneys

Liver often metabolizes more slowlyKidneys may excrete more slowly

Geriatric PatientsChronic disease

statesDecreased plasma

protein bindingSlower metabolismSlower excretion

Dietary deficienciesUse of multiple

medicationsLack of compliance

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Drug interactionsDrug interactions

occurs whenever the diagnostic, preventive therapeutic or toxic action of a drug is modified in or on the body by another pharnmacologically acting chemical substance, whether that be a prescription drug, an over the counter drug, or something in the diet or the environment.

Impact of Drugs interactionAdventage Disadventage

Mechanism Drug interactionsPharmaceutical interaction (invitro )

Pharmacokinetic interactionsPharmacodynamic Interactions

Pharmaceutical interaction (invitro )

Drug incompatibilitieschemical or physical reactions that occur

among two or more drugs and can occur during mixing outside the body or inside the body

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Chemical incompatibilities-between two drugs and

change the molecular structure of the drugs or solutions, altering pharmacologic properties.

A precipitate may form, or a color change may occur

Physical incompatibilities-occur when two drugs

are loosely bound to each other, but still retain their original pharmacologic properties.

The end result of a physical incompatiblity is usually a precipitate

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Pharmacokinetic interactions

Major mechanisms of pharmacokinetic interactions include interactions in which:GI absorption of a drug is affected absorption Plasma Protein binding is m odified

distribution Drug metabolism is stimulated or inhibited

biotrasformation/metabolismDrugs Elimination elimination

ADME

Altered Absorption (Availability)

Change in gastrointestinal pH Ketoconazole needs acidic conditions in gut H-2 blockers + ketoconazole H-2 blockers + ketoconazole dissolution of ketoconazole is dissolution of ketoconazole is

decreased, resulting in reduced absorptiondecreased, resulting in reduced absorptionDrug binding in GI tract

E.g. tetracycline and calciumChange in gastrointestinal flora

Antibiotics with OCs         Change in gastrointestinal motility

Metoclopramide and digoxinMalabsorption caused by other drugs

Orlistat (Xenical) and fat soluble vitamins

Enzyme InhibitionOften rapid, reversible and relatively short

acting.E.g. erythromycin and cyclosporin

erythromycin is a substrate and an inhibitor of CYP 3A4

May be prolonged due to long half- life of drug.E.g. amiodarone and S-Warfarin

amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

Enzyme Activation

Phenobarbital + warfarin Phenobarbital + warfarin phenobarbital phenobarbital increases the metabolism of warfarin, increases the metabolism of warfarin, resulting in reduced anticoagulationresulting in reduced anticoagulation

Plasma

TissueDrug A

protein bound

Drug Afree

Drug Afree

Drug B

Drugs A and B both bind to the same plasma protein

phenytoin + valproic acid phenytoin + valproic acid protein binding of valproic acid is reduced protein binding of valproic acid is reduced and total Css decreasedand total Css decreased

ExcretionDrug A increases or reduces the excretion

(usually renal) of Drug B.Blood levels of B fall below or rise above normal

therapeutic range.Becomes either ineffective or toxic.

Hydralazine + digoxin Hydralazine + digoxin hydralazine increases the renal hydralazine increases the renal clearance of digoxin clearance of digoxin via via Increase in Renal Blood Flow

antacids + aspirin antacids + aspirin antacids reduce the tubular antacids reduce the tubular reabsorption of salicylate reabsorption of salicylate via an increase in urine pHvia an increase in urine pH

probenecid + penicillin probenecid prolongs the half-life of penicillin, allowing single dose therapy via Inhibition of Active Tubular Secretion

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Pharmacodynamic InteractionsAdditive effect

occurs when two or or more drugs having the same effect are combined and the result is the sum of the individual effects relative to the doses used.

This additive effect may be beneficial or harmful to the client.

Synergistic effectoccurs when two or more drugs, with or without the

same overt effect, are used together to yield a combined effect that has an outcome greater than the sum of the single-drugs active components alone

Response

Hi

Lo

Time

Cumulative Effects

Drug A

Drug B

Response

Hi

Lo

Time

A B

Additive Effects

A + B

Response

Hi

Lo

Time

A B

A + B

Synergistic Effects

Pharmacodynamic Interactions 2

Potentiationdescribes a particular type of synergistic effect-a

drug interaction in which only one of two drugs exerts the action that is made greater by the presence of the second drug.

Antagonisticreactions have the opposite effect of synergism

and result in a combined effect that is less than either active component alone.

eg. Protamine administered as an antidote to anticoagulant action of heparin

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Drug-Food Interactions Food is known to induce physiologic changes

in the GI system that may decrease, increase, or delay the absorption of drugs; or the drug may take longer to reach peak blood levels after a doseFoods decreasing drug effectiveness Foods increasing drug effectiveness

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Patient-related factors that affect drug interactionsFactors that may

influence the response to drug interactions are:

Chronic disease states

Dietary excess or insufficiencies

Various drugsAlcohol intakeEnvironmental

factorsGenetic make up?Age

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Adverse Drug ReactionsAdverse Drug Reactions (Adverse effect, side

effect) Describes the potential unwanted effects that a

patient may experience as a result of a drugAdverse drug reactions are divided into two

categories’ : Type A reactions

produce 70-80% of all reactions, are dose dependent, and are often predictable and preventable

Type B reactions immunologic in nature or idiosyncratic, are not

dose dependent, usually not preventable or avoidable

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Type A reactionsPrimary Reactions

Expected extensions of a drug’s known pharmacologic properties

eg. Drowsiness and lethargy from sedatives and hypnotics

Secondary Reactionsundesirable

secondary reactions including severe drowsiness and sleepiness from antihistamines, excessive tiredness and impotence from antihypertensives

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Type B reactionsand Idosyncratic reactions

Allergic Reactions (Drug allergies or hypersensitivity reactions) range from very mild to very severe uticaria to true anaphylaxis type reactions

types of allergic reactionsType I-anaphylactic or atopic reactionType II- Cytotoxic reactionType III-Autoimmune reactionType IV-Cell-mediated hypersensitivity

Idosyncratic reactionsan unexpected, abnormal, or peculiar reaction to a

drug occurring in a small portion of the population