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