Calcium channel blockers as a class

β-blockers in the Cardiovascular section of the 2023 CICM Primary Syllabus Pharmacopeia appear as "Beta Blockers – not listed above" in the sweaty depths of the crowded "Level 3" section. The "listed above" are only esmolol and labetalol. Others are either missing or reshuffled, for example (understandably) sotalol appears apart in the antiarrhythmic section, and (weirdly) carvedilol is listed even deeper below as a "Mixed Antagonist". 

Class Calcium channel blocker
Chemistry
Non-dihydropyridines (diltiazem and verapamil) and dihydropyridines (the rest)
Routes of administration

Verapamil nimodipine and diltiazem are available in both IV and oral forms; clevidipine is IV only (like esmolol)
Absorption
Bioavailability ranges from 64% for amlodipine to 10% for lercanidipine.
Solubility
All have a high-ish pKa, in the 8-10 range. For the most, these drugs are highly protein-bound (>90%), and extremely lipophilic.
Distribution
Most of these drugs have a relatively large volume of distribution (5-20 L/kg), except clevidipine which is confined to extracellular fluid (VOD = 0.56 L/kg)
Metabolism
All calcium channel blockers ungergo extensive hepatic metabolism, except clevidipine which is hydrolysed by plasma esterases, giving it an extremely short half-life (1-2 min) Clevidipine All of the liver-metabolised cCCBs are substrates for CYP3A4. Additionally, verapamil and diltiazem inhibit CYP3A4.
Elimination
None are dependent on renal excretion.
Time course of action
Clinical effect is much longer than half life, and is completely unrelated to it; eg for amlodipine, elimination half-life is 30-50 hrs
Target receptor

All calcium antagonists bind to the α1c subunit of the L-type calcium channel

Dihydropyridines are selective for the L-type calcium channels in the vascular smooth muscle, whereas verapamil and diltiazem are non-selective and therefore also have cardiac effects. 
Mechanism of action

By binding to the α1c subunit of the L-type calcium channel, these drugs

  • Prevent or delay the opening of voltage-gated calcium channels; 
  • Thus, decrease intracellular calcium influx during depolarisation (eg. Phase 2 plateau of the normal cardiac action potential)
  • Thus, decrease calcium-stimulated flow of calcium from the SR
  • Thus, decrease the availability of intracellular calcium for cardiac myocytes, decreasing their contractility, and for vascular smooth muscle cells, decreasing their resting tone.
  • Increase the length of Phase 0 of the pacemaker potential, slowing the rate of automatic depolarisation

Additionally 

  • Dihydropyridine binding depends on the resting membrane potential of the smooth muscle cells
  • This resting potential is different in different vascular beds
  • This confers vascular territorial selectvity to these drugs, eg. nimodipine is selective for the cerebral circulation
Clinical effects

  • Relaxation of vascular smooth muscle, thereby decreasing peripheral vascular resistance and afterload (in the case of all CCBs, but especially the dihydropyridines)
  • Decreased cardiac contractility and decrease heart rate, thereby decreasing myocardial oxygen demand (in the case of verapamil and diltiazem)
Literature reference

Oliver et al (2019)
CICM details of understanding Level 3
Mentioned around Deranged Physiology

 Calcium channel blockers; also Classification and summary of antihypertensive agent classes
Related SAQs

Question 8 from the second paper of 2017 (calcium channel blockers, nimodipine)

Question 2 from the first paper of 2014  (calcium channel blockers, verapamil)

Question 17 from the second paper of 2011 (calcium channel blockers)

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