3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.1.4 Receptor binding profiles of commonly utilised agents

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Written by Resident Doctor Committee · Published

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  • Higher-affinity sites are occupied at lower concentrations, so a drug's effects change with dose: quetiapine is antihistaminic at low doses and blocks D2 at higher doses.

  • Transporter inhibition is a different action from receptor antagonism.

Side effects by receptor

Receptor blocked

Effect

Dopamine D2

Antipsychotic benefit, parkinsonism, hyperprolactinaemia

Histamine H1

Sedation; weight gain together with 5-HT2C blockade

Alpha-1 adrenergic

Postural hypotension and falls

Muscarinic

Dry mouth, constipation, urinary retention, blurred vision, cognitive impairment

Antipsychotics

  • Antipsychotics fall into four groups by their relative affinity at dopamine D2 and serotonin (5-HT) 5-HT2A receptors.

  • Risperidone, olanzapine and loxapine have high affinity at both D2 and 5-HT2A.

  • Lurasidone has negligible affinity for H1 receptors, so it causes little sedation and weight gain. It is also a 5-HT1A partial agonist.

Clozapine

  • Alpha-1 adrenergic is clozapine's highest-affinity receptor, with lower affinity at 5-HT2A, D4, D2 and 5-HT1A.

  • Clozapine also binds muscarinic receptors with high affinity, alongside H1 and 5-HT2C.

  • Clozapine binds D4 about tenfold more tightly than D2, but selective D4 antagonists were ineffective, so D4 binding does not explain its unique benefit.

  • Clozapine binds D2 weakly and dissociates quickly, giving striatal D2 occupancy of about 40 to 60%.

  • This occupancy sits well under the 78 to 80% threshold for extrapyramidal effects, so clozapine causes few motor side effects.

  • Clozapine changes glutamate release indirectly. It does not bind NMDA (N-methyl-D-aspartate) receptors.

Look at where the curve crosses the red line: extrapyramidal side effects rise sharply above about 78 to 80% striatal D2 occupancy, well above the 40 to 60% that clozapine reaches. Drawn for MRCPsychiatrist

Vortioxetine

Vortioxetine is a multimodal antidepressant.

Target

Action

Serotonin transporter

Inhibition

5-HT3 and 5-HT7

Antagonism

5-HT1A

Agonism

5-HT1B

Partial agonism

5-HT1D

Antagonism

Pregabalin

  • Pregabalin is a structural analogue of GABA (gamma-aminobutyric acid) but does not act at any GABA receptor.

  • It binds the alpha-2-delta subunit of voltage-gated calcium channels and reduces excitatory transmitter release.

Pregabalin differs from benzodiazepines by its site: benzodiazepines enhance GABA-driven channel opening at GABA-A receptors.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.

3.3.1.4 Receptor binding profiles of commonly utilised agents | MRCPsychiatrist