2018A08 Outline the pharmacology of intravenous metoprolol.

 

List:

·      PC

·      PK

·      PD

 

Physicochemical:

Enantiomers

R-metoprolol

S-metoprolol

Presentation

IV solution

Tablets as tartrate (quick) or succinate (slow)

 

Pharmacokinetics:

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:

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:

o Membrane L-Ca2+ and SR Ryanodine-sensitive Ca2+ channel: ↓Ca2+ influx

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

o 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

 

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