Outline the pharmacokinetics, and mechanism of action of carvedilol and spironolactone.
Carvedilol and spironolactone are common drugs used in the management of cardiac
failure. They have different mechanisms of action and pharmacokinetics. Both are drugs
listed in the Syllabus as Level B and thus candidates are expected to have a general
understanding of their pharmacology. Many candidates gave class specific information
about beta blockers rather than demonstrating an understanding of carvedilol`s particular
properties. Most candidates were able to score marks by commenting upon the results of
aldosterone antagonism suggesting an understanding of the physiology of this hormone but appeared to know little more about the pharmacology of spironolactone. Overall there was
insufficient information provided by most candidates for both drugs.
Yes, it feels super weird to be comparing a beta blocker and a diuretic. It's a bit like asking somebody to compare a kitten to a video card. Both may have a positive effect on your quality of life, but they are structurally and functionally quite dissimilar, making it harder to produce a comparison.
|Class||Beta blocker||Potassium-sparing diuretic|
|Routes of administration||Oral only||Oral only|
|Absorption||25-35% oral bioavailability||Excellent GI aborption (90%); when taken with food, bioavailability is ~ 95%|
|Solubility||pKa 8.77, good lipid solubility||Minimal water solubility; pKa -4.9 and 18|
|Distribution||VOD 2 L/kg; 95% protein bound||Massive VOD, ~ 150L; 90% protein-bound|
|Target receptor||Nonselective β1 and β2 receptor blocker, with some anti-α1 effects; also some sodium channel blocker (membrane stabilising) effects||Aldosterone receptors|
|Metabolism||Mainly hepatic clearance||Extensively metabolised, into metabolites which all have some aldosterone antagonist activity|
|Elimination||minimal renal excretion; half-life 7-10 hrs||Half-life is about 15-20 hours for the primary drug and its active metabolites.; excreted mainly in the urine|
|Time course of action||Clinical effects persist for longer than the half life would suggest, because they are mainly determined by drug-receptor affinity||Duration of action is similar to half-life, ~ 12hrs|
|Mechanism of action||By binding to Gs-protein coupled β1 and β2 receptors, blocks cAMP synthesis||Acts by competitive binding of aldosterone receptors at the distal convoluted tubule. This causes sodium and water to be excreted, while potassium is retained.|
|Clinical effects||β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolci coronary fillng, and decreased arrhythmogenicity.
β2 effects: increased peripheral vascular resistance, bronchospasm, decreased insulin release, increased bladder and uterine tone
α1 effects: afterload reduction, vasodilation
Membrane-stabilising (sodium channel blocker) efect
|Decreased blood pressure and circulating volume, hyponatremia, hyperkalemia, metabolic acidosis (Type 4 RTA) and gynaecomastia (by cross-reactivity with other steroid receptors, eg. sex hormones)|
|Single best reference for further information||Oliver et al (2019)||FDA data|