2018A Question 08

Outline the pharmacology of intravenous metoprolol.

Examiner Report

50% of candidates achieved a pass in this question.

This question required an application of physiological and pharmacological knowledge, specific to metoprolol. The pass rate was 50% but there were few high-scoring answers.

Errors were often related to confusion about the effect of specific beta receptors, or incorrect information specific to metoprolol as a beta-blocker. Most candidates had a good system for answering a question on a medication, however many candidates wrote vague information under these headings. Candidates are not expected to know detailed pharmacokinetic values for a medication such as metoprolol, but they are expected to know important pharmacokinetic points.

Model Answer

Structure:

  • PC
  • PK
  • PD

Physicochemical

Factor Details
Enantiomers

R-metoprolol

S-metoprolol

Presentation

IV solution

Tablets as tartrate (quick) or succinate (slow)

Pharmacokinetics

Factor Details
Administration - IV: 1-2mg q2 mins, max 10mg
Time course

- Onset 1-2 mins

- Duration 5-8 hours

Absorption

- Oral bioav 50% single dose, 70% if repeated (?)

Distribution

- Plasma protein binding 10%

- Moderate lipid solubility

- Crosses blood-brain barrier

Metabolism

- CYP2D6 O-demethylation > CYP3A4 α-hydroxylation

- t1/2β 3-7 hours

Excretion

- Metabolites → Urine

Pharmacodynamics

Factor Details
Generation

- 2nd

Receptor activity

- β adrenoceptor antagonist

- Fairly β1 selective

- No intrinsic sympathomimetic activity (ISA)

- Weak membrane stabilizing activity (MSA)

Receptor activation

- Gs G protein coupled receptor

- ↓ CAMP → ↓ PKA activation → ↓ Phosphorylation of intracellular targets

Cardiac pacemaker cells

- ↓ HCN channel activation → ↓ Slope phase 4 → ↓ HR

Ventricular myocyte

- ↓ Phosphorylation of:

 - Membrane L-Ca2+ and SR Ryanodine-sensitive Ca2+ channel (↓ Ca2+ influx)

 - Myosin (↓ rate at which cross-bridge cycling can occur)

 - Troponin I and phospholamban (↓ rate of relaxation)

CVS effects

- ↓ HR, ↓ atrial tachyarrhythmias, ↓ AV node conduction

- ↓ Contractility, ↓ remodelling in LV failure

- ↓ Cardiac output, ↓ MAP acutely (offset by ↑ SVR)

- +/- Worsen peripheral vascular disease (more a problem if non-selective)

- +/- rebound effects if abrupt cessation

Resp effects

- Risk bronchospasm (some β2 antagonism)

CNS effects

- ↓ Tremor, depression, fatigue, insomnia, sexual dysfunction, migraine prophylaxis

Metabolic effects

- ↑ Risk diabetes, ↓ autonomic response to ↓ BSL, ↓ symptoms of ↓ BSL (tremor, ↑ HR)

Renal effects

- ↓ Renin release → ↓ Na+/H2O retention → ↓ MAP long term

Other

- Hair loss

Caution if

- Severe LV failure

- Atrioventricular conduction delay

- Asthma, COPD

- Diabetes

MSA toxicity

As for local anaesthetic systemic toxicity:

- CNS: Excitation (seizures) then depression (coma)

- CVS: Hypotension, arrhythmia, death


Last updated 2021-08-23

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