22B19: Exam Report

Outline the effects of critical illness on drug pharmacokinetics, including examples

31% of candidates passed this question.

The description of a receptor was worth 20% thus it was expected that detailed information on the different forms of receptors, their structure, the resultant conformational change when activated and where they are found would be provided for full marks.

Most candidates were able to correctly define an agonist, antagonist, partial agonist and inverse agonist.

Unfortunately, this was the limit of most answers. Candidates were expected to provide details of drug or agonist/receptor interaction discussing the terms affinity/intrinsic activity and how different mechanisms of binding and interacting with the receptor alters these terms.

Ci / Civ / 22B19: What are receptors? (20% marks). Discuss the relationship between the properties of a drug and potential receptor response under the following headings: agonists, partial agonists, inverse agonists and antagonists (80% marks)

Receptors are protein molecules to which ligands bind in order to effect the regulation of a cellular process. In vivo, they function to recognise and respond to endogenous chemical signals.

4 Main Types of Receptors

Ligand Gated Ion Channels

GPCR

Kinase Linked

Nuclear Receptors

Structure

Ligand Gated Ion Channels

Oligomeric (often pentameric) assembly of subunits surrounding a central pore on cell membrane

GPCR

Serpentine proteins consisting of 7 transmembrane helices with intracellular G protein coupling domain

Kinase Linked

Large proteins consisting of a single membrane spanning helical region with a large extracellular ligand binding domain

Nuclear Receptors

Monometric structure with separate receptor and DNA binding domains

Effect after ligand binding

Ligand Gated Ion Channels

Opening of central pore → nerve hyperpolarisation OR depolarisation due to ionic flux

GPCR

Binding of ligand causes the receptor to activate the G protein (composed of α, β, γ subunits) which bind GDP.

Upon stimulation, GTP replaces GDP → α-GTP subunit dissociates to activate/inhibit  an effector protein

Kinase Linked

Binding of ligand causes dimerisation leading to autophosphorylation of tyrosine residues on the intracellular domain → flow on signal transduction via intracellular protein kinases

Nuclear Receptors

Binding of ligand effects changes in gene transcription

Site

Ligand Gated Ion Channels

Membrane of nerves / muscles

GPCR

Cell membrane

Kinase Linked

Cell membrane

Nuclear Receptors

Intracellular

Example

Ligand Gated Ion Channels

Nicotinic ACh receptors, GABA-A, NMDA and AMPA receptors

GPCR

Muscarinic ACh receptors, adrenoreceptors

Kinase Linked

JAK kinases

Nuclear Receptors

Steroid hormone receptors

Agonists

Agonists are drugs that bind to physiological receptors to elicit the same response as the endogenous ligand

  • A full agonist which drug which produces a maximal response at the receptor site. i.e. high affinity and an intrinsic activity of 1
    • Affinity is how avidly a drug binds to its receptor. Described by the association constant, Ka
    • Intrinsic activity (IA) is the ability of a bound agonist to cause a maximum response. Maximum IA is 1
    • g. morphine at opioid receptors

Partial Agonist

A partial agonist is a drug which is unable to induce maximal activation of a receptor population, regardless of the amount of drug applied

  • High affinity but intrinsic activity between 0 and 1
  • g. buprenorphine at opioid receptors

Inverse Agonist

An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist

  • This is due to the agonist being relatively more selective for the resting state of the receptor

High affinity but intrinsic activity between -1 and 0

Author: Andrew Wang