SN2 SHORT NOTE 5M ★ High-yield

Define partial agonist and inverse agonist. Give examples and their clinical significance.

Pharmacology · 2nd Professional — Para-Clinical

Definitions

Term	Affinity	Intrinsic activity	Effect alone	Effect with a full agonist
Full agonist	Yes	1	Maximal response	—
Partial agonist	Yes	Between 0 and 1	Submaximal response — acts as an agonist	Reduces the response — acts as an antagonist
Antagonist	Yes	0	No effect	Blocks it
Inverse agonist	Yes	−1	Opposite effect to the agonist	Blocks and reverses

CLINICAL PEARL

A partial agonist is an agonist or an antagonist depending entirely on what else is present. Given alone it produces a modest effect — agonism. Given alongside a full agonist it occupies receptors that would otherwise have been fully activated, so the total response falls — antagonism. This dual behaviour is not a contradiction; it follows directly from submaximal intrinsic activity, and it is the single most examined point in the topic.

Partial Agonists — Examples and Uses

Drug	Receptor	Clinical use of the partial agonism
Buprenorphine	Mu opioid	Analgesia with a ceiling on respiratory depression, so it is safer in overdose; used in opioid substitution therapy, where it also precipitates withdrawal if given to a patient dependent on a full agonist
Pindolol, acebutolol	Beta adrenergic (intrinsic sympathomimetic activity)	Cause less resting bradycardia and less worsening of lipids; useful where bradycardia limits a conventional beta-blocker
Tamoxifen	Oestrogen receptor	Antagonist in breast tissue (hence its use in breast cancer) but agonist in bone and endometrium — which protects bone but raises the risk of endometrial carcinoma
Raloxifene	Oestrogen receptor	Agonist in bone, antagonist in breast and endometrium — used for osteoporosis
Aripiprazole	Dopamine D2	Stabilises dopamine transmission, with fewer extrapyramidal effects
Nalbuphine, pentazocine	Opioid receptors	Analgesia with lower abuse potential
Varenicline	Nicotinic	Reduces craving while blunting the reward of smoking

Inverse Agonists

Require the receptor to have constitutive (spontaneous) activity in the absence of any ligand
An antagonist blocks that constitutive activity but does not reduce it; an inverse agonist actively suppresses it by stabilising the inactive conformation
Examples — most H1 and H2 antihistamines (cetirizine, ranitidine), beta-carbolines at the GABAA–benzodiazepine site (causing anxiety and convulsions, the opposite of a benzodiazepine), and some beta-blockers
Clinical relevance — inverse agonists may be more effective than neutral antagonists where constitutive activity contributes to the disease

Comparison of Partial Agonist and Antagonist

Feature	Partial agonist	Competitive antagonist
Effect alone	Submaximal response	None
Intrinsic activity	Greater than 0	Zero
Effect on a full agonist	Reduces the maximum toward its own ceiling	Shifts the curve right; the maximum is preserved
Withdrawal after long use	Less rebound, as some receptor stimulation persists	Rebound is common, from receptor up-regulation

Applied Aspects

Never give buprenorphine to a patient recently dosed with a full opioid agonist — it displaces the full agonist from the receptor and precipitates acute withdrawal
Buprenorphine’s ceiling on respiratory depression makes it safer in overdose, but also means its effect cannot be escalated for severe pain
Tamoxifen requires endometrial surveillance and any postmenopausal bleeding must be investigated, because of its agonist effect on the endometrium
Beta-blockers with intrinsic sympathomimetic activity are avoided after myocardial infarction, where full blockade gives the mortality benefit
The same molecule can be agonist and antagonist in different tissues, depending on receptor subtype and the local balance of co-activators — which is the basis of the selective oestrogen receptor modulators

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