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

List:

· Receptor – ion permeability

· Receptor – second messenger

· Receptor – gene transcription

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

Receptor -> ↑↓ ion permeability:

Pentameric

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 G_s 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

Other: