2004B01 Briefly describe how drugs produce their pharmacological effects.
Illustrate each mechanism with examples.



·      Receptor – ion permeability

·      Receptor – second messenger

·      Receptor – gene transcription

·      Other: physicochemical, enzyme inhibition, voltage-gated ion channel


Receptor -> ↑↓ ion permeability:


e.g. sevoflurane at GABA-A receptor

·   Binds receptor beta subunit

·   ↑Cl- conductance through ionophore

·   Hyperpolarisation

·   ↓action potential

Ionotropic glutamate

e.g. ketamine at NMDA receptor

·   Binds PCP site

·   ↓Ca2+>Na+=K+ conductance

·   ↓ICF [Ca2+] -> ↓action potential

Ionotropic purinergic

e.g. ATP at P2X, P2Y

·   Binds receptors

·   ↑Na+ = K+ > Ca2+ conductance


Receptor -> second messenger:

G protein-coupled receptor

e.g. adrenaline agonist at β1 adrenoceptor, a Gs GPCR

·   Binds ECF domain

·   Conformational change

·   GTP displaces GDP; α-GTP dissociates from βγ dimer

·   α-GTP activates adenylyl cyclase -> ↑cAMP -> ↑activity PKA -> Phosphorylation of:

o L-Ca2+: ↑Ca2+ influx on excitation

o Myosin -> ↑rate of cycling

o Troponin I and phospholamban-> ↑rate of relaxation


*Note G inhibitory (↓cAMP) and Gq (↑IP3, DAG), others exist

Receptor tyrosine kinase

e.g. insulin agonist at insulin receptor

·   Binds ECF α-subunits

·   ICF β-subunits autophosphorylate

·   Activation of tyrosine kinase activity

·   ↑PI3K activity (e.g. ↑GLUT4 expression)

·   ↑MAPK activity (growth)


Receptor -> ↑↓Gene transcription:

Transcription factor

e.g. thyroxine at thyroid hormone receptor

·   Unbound receptor in cytosol

·   Bound receptor migrates to nucleus

·   ↑↓gene transcription



Voltage-gated ion channel inhibition

·   e.g. lignocaine at VDNaC

·   ↓Action potential formation

Enzyme inhibition

·   Reversible: e.g. neostigmine + AChE -> carbamylate ester

·   Irreversible: e.g. organophosphate + AChE -> phosphorylated ester


·   Alter pH: e.g. sodibic for GORD

·   Chelation: e.g. g-cyclodextrin + rocuronium

·   Osmosis: lactulose -> stool softening

·   ?Charge neutralization: heparin (negative) + protamine (positive) -> stable salt

Structural analogy

·   e.g. azathioprine for purine


·   e.g. imatinib for BCR-ABL in chronic myeloid leukaemia