23B12: Exam Report

List the effects of stimulation of adrenoreceptors on target organs and tissues (60% marks). Describe the mechanism of action and pharmacokinetics of metoprolol (40% marks)

74% of candidates passed this question.

This question required a list of effects of the stimulation of adrenoreceptors, thus detailed description of downstream effects and exact mechanisms was not required.

Using a systems based structure with a subdivision into each receptor (or vice versa) meant that important GIT, GUT, endocrine and metabolic effects were not omitted. Given the need for little depth, this part of the question required breadth particularly within cardiovascular effects. Venoconstriction, dromotropy and lusitropic effects should also be covered.

The second part of the question required a detailed description of the mechanism of action and pharmacokinetics only, thus dose, pharmaceutics and pharmacodynamic information was not required.

Here it would be important to elaborate on the downstream effects of blocking the beta adrenergic receptors as compared with the information required in the first part of the question.

M2ii / 23B12: List the effects of stimulation of adrenoreceptors on target organs and tissues (60% marks). Describe the mechanism of action and pharmacokinetics of metoprolol (40% marks)

Receptor

Mechanism

Physiological effect at target site

Receptor​

α 1

Mechanism

  • Gq
  • Increases PLC and IP3

Physiological effect at target site​

  • Vascular Smooth Muscle – Contraction
  • Blood Vessel – Vasoconstriction = increases SVR
  • Urinary Sphincter – increase tone
  • Uterine – Contraction
  • Pupillary radial muscle – Contraction
  • Pilomotor smooth muscle – contraction

Receptor​

α 2

Mechanism

  • Gi
  • Reduces cAMP

Physiological effect at target site​

  • Presynaptic nerves – inhibits neurotransmitter release
  • Adrenergic & Cholinergic nerve terminals – inhibits neurotransmitter release
  • Platelets – aggregation
  • Vascular smooth muscle – constriction
  • Fat cells – inhibits lipolysis
  • Pancreatic B cells – inhibits insulin release
  • Ciliary epithelium – Reduces humor secretion

Receptor​

β 1

Mechanism

  • Gs
  • Increases cAMP

Physiological effect at target site​

  • Heart – positive ino & choronotropy, increases automaticity and conduction velocity
  • Kidney – Stimulates Renin release

Receptor​

β 2

Mechanism

  • Gs
  • Increases cAMP

Physiological effect at target site​

  • Liver – stimulates glycogenolysis
  • Pancreatic b cells – stimulates insulin release
  • Skeletal muscle – contraction
  • Heart – Positive chrono & inotropy
  • Ciliary epithelium – increases humor secretion
  • Airway, uterine & vascular smooth muscle – relaxation
  • Uterus – inhibits contraction

Receptor​

β 3

Mechanism

  • Gs
  • Increases cAMP

Physiological effect at target site​

  • Adipocytes – stimulates lipolysis

Metoprolol

β 1 cardioselective competitive antagonist

MoA (mechanism)

  • β1 receptor is a Gs-coupled receptor
  • Competitive antagonism of this receptor will
    • Inhibit Adenylate cyclase
    • Reduce intracellular cAMP
  • At target organ:
    • Negative inotropy
    • Negative chronotropy
  • Clinically:  Reduce HR and CO
  • The β -blocking effect is linearly related to the logarithm of the dose and drug plasma concentration

PK

A

  • 50% OBA

D

  • 10% PPB

M

  • Hepatic; 60% 1st pass metabolism
  • Inactive metabolites
  • Cirrhosis will increase the bioavailability and reduce the clearance of metoprolol

E

  • Metabolites cleared in urine
  • <10% unchanged
  • T1/2b 6 hrs
  • Renal impairment will affect the renal excretion of metabolites but they are dialysable