ANTAGONISTS

Clinical uses of antagonists

Inhibit actions of endogenous agonists (hormones, neurotransmitters etc), reverse effects of administered agonists

IC50

Inhibitory concentration of antagonist required to inhibit response of agonist by 50% (determines potency of antagonist)

Factors affecting tachyphylaxis

Internalisation of receptors (short-term), down-regulation of signalling pathways

low ic50 value

Lower the value, more potent the antagonist; lower concentrations of drug required to inhibit maximal biological response (therefore fewer side effects)

Buprenorphine

Partial agonist of opioid receptors (weak morphine-like activity), used to reverse morphine addiction (alternative to methadone for drug addiction)

Types of antagonism

Reversible competitive, irreversible competitive, non-competitive, uncompetitive, physiological (functional), pharmacokinetic, self-antagonism

Tachyphylaxis

Self-antagonism/desensitisation; repeat administration can reduce effects of agonist

Reversible competitive receptors

Activity depends on relative affinity of each molecule at site and their relative concentrations

Relationship between concentration and response

Amount of inhibition depends on amount of antagonist administered i.e fixed concentration of agonist plus unlimited concentration of antagonist - response will gradually decrease

Allosteric antagonists

Another name for non-competitive antagonists

Self-antagonism/desensitisation

Another name for tachyphylaxis

Non-competitive antagonism

Antagonists bind at distinctly separate binding site to agonists, exerting action from different site - no amount of agonist can overcome inhibition (as not competitive)

Irreversible competitive antagonism

Antagonists covalently bind to receptors, cannot be removed i.e inactivate receptor for duration (effects determined by rate of receptor turnover/synthesis)

Uncompetitive antagonism

Antagonists require receptor activation by an agonist before being able to bind at separate allosteric binding site (i.e. memantine for Alzheimers disease)

Partial agonists (working with full agonists)

At high conc, partial agonists (spare receptors) will reduce response of full agonists i.e act as irreversible competitive antagonist if co-administered with full agonist by competing for receptor occupancy

Features of antagonists

Bind to target molecules (like receptors), have affinity but NOT efficacy (i.e bind but provoke no response)

Reversible competitive antagonism

Binds competitively with agonist to receptors (doesn't alter maximal response of agonist i.e. no efficacy as drug reversibly binds)

Identifying irreversible competitive antagonism

Decrease in slope and decrease in maximal response of agonist (due to reduction in available binding sites, so more concentration required for reduced response) - no shift of curve to left or right

Degree of inhibition

Depends on concentration of agonist/antagonist, number of available receptors, affinity of antagonist

Identifying non-competitive antagonism

Depression of maximal response curves (agonist dose-response)

Antagonist potency

Determined by IC50 value - concentration of antagonist required to elicit half inhibition of maximal biological response of agonist

Antagonist

Drug that doesn't provoke a biological response, but blocks/dampens actions of agonist-mediated responses (inhibits agonists)

Pharmacokinetic antagonism

Drugs reduce/increase absorption of another drug, increase/decrease rate of drug metabolism (breakdown), increase/decrease rate of drug excretion, displace another drug from plasma binding sites

Physiological antagonism

Endo/exogenous i.e. opposing effects - bronchoconstriction vs bronchdilation (using agonist to activate another/opposite signalling pathway for example B-agonist for obstructive lung disease)

Inhibit actions of endogenous agonists

Example, allergic rhinitis; use antihistamines (loratadine) to prevent excess mucus secretion/itchy eyes

Reverse effects of administered agonists

Example, overdose of sedative; use benzodiazepine receptor antagonist

Increased drug dosage

Increased likelihood of adverse side-effects (drugs are selective but not specific in action i.e. antihistamines cause a dry mouth because they also block acetylcholine receptors)

Identifying reversible competitive antagonism

Visible parallel shift of dose-response curve to RIGHT with added antagonist i.e. more concentration required due to competition with agonist at binding sites