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 |