Dose-Response Relationship

Dr. Sanooz Raheem

Objectives 1. Describe dose response relationship2. Explain therapeutic window phenomenon 3. Define a. drug potency b. drug efficiency 4. Define therapeutic index and its clinical importance

Dose-Response Relationship• When a Drug administered systemically

• Dose-plasma concentration relationship (determined by pharmacokinetic properties)

• Plasma concentration (dose)-response relationship• Intensity of response increases with increase in dose / concentration at the

receptor • Drug-receptor interaction obeys law of mass action

Emax * [D]

E=KD +[D]

E- observed effectD- dose Emax- maximal response Kd- dissociation constant of the drug-receptor complex

Dose-Response CurveE =

Emax X [D]

Kd + [D]

Dose-response and log dose-responsecurves

Dose- Response curve• Response is proportional to an exponential function(log) of the dose • Advantages:- A wide range of drug doses can be easily displayed on a graph- Comparison between agonists and study of antagonists becomes

easier

Drug Potency and efficacy• Potency: amount of drug required to produce a certain response

DRC positioned rightward indicates a lower potency Relative potency is more meaningful than absolute potency Relative potency: comparing the dose of two agonists at which they elicit half

maximal response (EC50)Ex: 10mg of morphine= 100 mg pethidine as analgesic , morphine is potent • Potency for therapeutic effect should increase over the potency for adverse effects • Potency of a drug important to choose a dose

• Efficacy: Maximal response that can be elicited by the drug Ex: morphine produces analgesia not reached with any dose of aspirin.

Morphine is more efficacious than aspirin.

Efficacy is an important factor in the choice of a drug

Illustration of drug potency and drug efficacy.Dose-response curve of four drugs producing the samequalitative effect

Potency and efficacy1.Compare drug A&B2.A&C3.D vs A,B,C

Note:Drug B is less potent but equally efficacious as drug A.Drug C is less potent and less efficacious than drug ADrug D is more potent than drugs A, B, & C, but less efficaciousthan drugs A & B, and equally efficacious as drug C

Potency and efficacy - Examples• Aspirin is less potent as well as less efficacious than Morphine• Pethidine is less potent analgesic than Morphine but equally efficacious• Diazepam is more potent but less efficacious than pentobarbitone• Furosemide is less potent but more efficacious than metolazone

• Depending on the type of drug, both higher efficacy or lower efficacy could be clinically advantageous.

Slope of DRC• Steep slope – moderate increase in dose markedly increase the response (dose needs

individualization)• Flat DRC – little increase in response occurs in wide range of doses (standard dose can be given to

most patients)• Example: Hydralazine and Hydrochlorothiazide DRC in Hypertension

Steep and flat dose-response curves illustratedby antihypertensive effect of hydralazine and hydrochlorothiazide

Therapeutic efficacy • Depends on- Relative potency and efficacy - Pharmacokinetic variables- Pathophysiological variables

• Expressed in terms ofa.Degree of benefit/ relief afforded by the drug orb.Success rate in achieving a defined therapeutic end point Ex: a drug which makes a higher percentage of epileptic patients totally

seizure free than another drug is the more therapeutically effective antiepileptic.

Drug Selectivity • Some drugs may produce different actions • DRCs for different effects of drug may be different • Extent of separation of DRCs of a drug for different effects is a

measure of its selectivity Ex: Isoprenaline vs salbutamol

Illustration of drug selectivity.Log dose-response curves of salbutamol for bronchodilatation(A) and cardiac stimulation (D)Log dose-response curves of isoprenaline for bronchodilatation(B) and cardiac stimulation (C)

Therapeutic index (TI)/ Safety margin

Gap between the therapeutic effect DRC and adverse effect DRC Median effective dose- dose which

produces the Specified effect in 50% individuals Median lethal dose- dose which kills 50% of the recipients

Therapeutic index (TI)

Therapeutic window/ therapeutic range • Bounded by the dose which produces minimal therapeutic effect and

the dose which produces maximal acceptable adverse effect• Individual variability: effective dose may be toxic for others • Defining the therapeutic range is difficult • Few drugs higher therapeutic response and adverse effects in higher

dosesEx: Prednisolone in Asthma

Illustrative dose-response curves for therapeuticeffect and adverse effect of the same drug

Risk-benefit ratio• Judgment between estimated harm and the expected advantages • Estimated harms:- Adverse effects- Cost - Inconvenience • Expected advantages:- Relief of symptoms- Cure - Reduction in complications/mortality - Improvement in quality of life

• Prescribe when benefit outweighs the risks• Difficult to measure accurately • Should rely on pharmacoepidemiology and experience

Drug specificity • Refers to range of actions produced by a drug • Drugs may show – - One / limited number of actions- Widespread effects on many organs of the body • Depends on:a.Whether drug acts on single/many receptors/targets and b.How widely the target is distributed in the body Ex:Omeprazole- highly selectiveChlorpromazine- D2, muscarinic cholinergic, H1, 5-HT Dexamathasone- involves many organs due to receptors widespread in the

body

Combined effects of drugs

objectives• Describe the combined effects of drug action• Explain synergism with few examples• Explain antagonism with few examples

Combined effects of drugs • If two/ more drugs given simultaneously/ in quick succession, they

may be either indifferent to each other or exhibit synergism/ antagonism.

• Interaction may take place at- Pharmacokinetic level- Pharmacodynamic level

Synergism • Action of one drug is facilitated or increased by the other • In a synergetic pair- Both drugs can have action in same direction or- One may be inactive and enhancing the effect of other • Two types - Additive- Supraadditive/ potentiation

Additive • Effect of two drugs in same direction and simply adds up

Effects of drugs A+B= effect of drug A+ effect of drug BSide effects do not add up Better tolerance than high dose of one component

Supraadditive • Effect of combination is greater than the individual effects

Effects of drug A+B > effect of drug A+ effect of drug B When one component given alone produces no effect, but

enhances the effect of the other.

Antagonism • One drug decreases or abolishes the action of the other

Effects of A+B < effect of drug A+ effect of drug B • One drug is inactive and decreases the effect of the other

Drug Antagonism1. Physical2. Chemical3. Physiological antagonism4. Receptor antagonism:

a. Competitive antagonism (equilibrium)b. Non-competitivec. Non-equilibrium

Physical antagonism • Based on the physical property of the drug

- charcoal : adsorbs alkaloids (used in alkaloidal poisonings)

Chemical antagonism • Two drugs react chemically and form an inactive product

Physiological/ functional antagonism • Two drugs act on different receptors or by different mechanisms • Have opposite effects on the same physiological function

Receptor antagonism • One drug/ antagonist blocks the receptor action of the other

drug/agonist • Receptor antagonists are relatively selective

Receptor antagonism - curvesCompetitive:

o Antagonist is chemically similar to agonist and binds to same receptor molecules

o Affinity (1) but IA (0), Result – no responseo Log DRC shifts to the righto antagonism is reversible – increase in concentration of agonist overcomes

the blocko Parallel shift of curve to the right side when the concentration of antagonist

increases o Extent of shift depends on affinity and concentration of antagonist

Plot on a DRC for competitive antagonists A&B. Antagonism A>B, Agonist notify as C

Dose-response curves showing competitive (a) antagonismA—agonist, B—competitive antagonist,

* Partial agonist- have affinity for the same receptor competes with and antagonizes a full agonist & produces a submaximal response

Non-competitive/ allosteric antagonism:o Allosteric site binding- altering receptor not to bind with

agonist/ unable to transduce the response o Chemically unrelated to antagonist o No competition between them – no change of effect even

agonist concentration is increasedo Increasing concentration of antagonist progressively flatten DRCo Not in clinical use

Plot on a graph for non-competitive antagonists A&B, Antagonism A>B, Agonist notify as C

• Non – equilibrium:• Antagonists Binds receptor with strong bond• Dissociation is slow and agonists cannot displace antagonists• Irreversible antagonism develops• DRC shifts to the right and Maximal response lowered• Phenoxybenzamine is a non-equilibrium antagonist of adrenaline

at the alpha adrenergic receptors

Plot on a DRC for agonist A and non-equilibrium antagonist B

Compare between competitive and non-competitive antagonists?

THANK YOU