Pharmacodynamics

Drug

• Chemical substance of known structure

• Produces biological effect

• When administered to living organism

• Not nutrient or essential dietary ingredient

-cology V -codynamics V -cokinetics

• -Cology → effects of drugs on living systems

• -Codynamics → effects of drug on body

• -Cokinetics → effects of body on drug

Therapeutics

Use of drugs + method of admin

Why choose a drug?

1. Availability in target area

2. Competition from other drugs (which can also access target)

3. Efficacy of drug (magnitude of action)

4. Pharmacodynamics (e.g. Vd)

Drug actions

When bind to receptor

• reduce effect of natural mech → increased opposite effect

• reduce formation (enzyme/protein inhibition)

• mimic natural analogue

Agonist

• Mimics natural ligand

• Causes an effect when binding to target

Full agonist

• Maximum response even when small proportion of target bound

• High efficacy

Partial agonist

• Cause submaximal response

• Lower efficacy

Inverse agonist

• Binds to receptor but reduces response

Constitutive activation

• Intracellular signalling due to ligand absence

• Continual low level of activity

• Targetted by inverse agonists

Agonism is Dynamic

Agonist dissociates rapidly fromreceptor

more agonists bind → effect maintained

association & dissociation until sufficient agonist removed from vicinity

Scope to later interaction

• antagonists compete with agonist

Antagonist

• Bind to ligand to block effect

• Zero efficacy

• Most are reversible

Irreversible antagonist (aspirin → competitive irreversible)

• Strongly covalently bonds to COX-1 (preferential)

• Competes with arachidonic acid for COX-1 binding site

Competitive reversible antagonist

Competes with agonist by blocking active site of same target receptor

Noncompetitive antagonist

• Same physiological effect but different target

• Ca2+ channel blocker V Beta blockers → -ve chronotropes

Pharmacokinetic antagonism

• Drug reduces action of another drug

• Impacts: (effects body has on drug)

  • Absorption

  • Distribution

  • Metabolism

  • Elimination

• E.g. binding to receptor stimulates other drug to be metabolised quickly

Chemical antagonism

1 drug directly interacts with another to directly reduce its activity

• Drug breaks other drug down

• Drug complex no longer binds to receptor

Tachyphylaxis (self antagonism, desensitisation)

Rapid loss of responsiveness to drug when it repeatedly binds to receptor

• Target disappears in response to agonist (receptor endocytosis - endosome binds with lysosome)

• Change in receptor

• Physiological adaptation

Tolerance

Gradual (long term) decrease in drug responsiveness

Resistance

Loss of effectiveness of antimicrobial or anticancer drugs

• Target changed

Physiological antagonism

• Drug promotes opposite effect of original agonist

• Often binds to different receptor for opposite result

Drug dosage

• Response proportional to dose and free drug concentration in target tissue

• Different affinities

  • Low affinity (less potent) → effect at higher conc

Drug Efficacy

response drug produces

• measures irrespective of potency

• requires known maximum effect

Drug potency

concentration of drug required to bring about a response

ID50

C → concentration

inhibitory dose → dose of ANTAGONIST that causes 50% reduction in response

ED50

C → concentration

effective dose → how much AGONSIT that causes 50% reponse

How is potency measured

Compared ED50 or EC50

• most potent requires lowest concentration

Partial vs full agonist

partial → lower effiacy

potency is not effected

• lower affinity can produce a more potent response (at a lower concentration than a higher affinity drug)

  • earlier but lower peak

Therapeutic index/window

• low index = narrow window

• dose/concentration that produces desired effect = very similar to dose/concentration that produces undesirable effects (side effects, toxicity, adverse reaction etc)

Agonist in presence of competitive angtagonist

same efficacy

• lower potency

Antagonist

baseline activity vs log antagonsit conc

• zero → zero efficacy

Inverse Agonist vs Agonist

• negative baseline activity → binds to reduce a response

Inverse agonist in presence of competitive agonist

• reduction in response but at a lower potency (higher log dose)

Antagonist in presence of agonist

reduction from effect of full agonist → tends towards 0

Antagonist in presence of inverse agonist

• brings response back to baseline

• reduces response of agonist but antagonist reducing its ability to bind

Dose Response curves

• see whether agonist, antagonist, inverse agonist

  • whether competitive for target

• dose response curves - maximal response always reached → determined max efficacy

• response conc → plateau at max

• response-log conc → sigmoidal

  • see difference btw doses and responses they deliver