Classify calcium channel blockers, and give an example for each classification. (30% of 
marks) Describe the pharmacology of verapamil. (70% of marks)

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College Answer

Most candidates managed to provide a classification of calcium anatagonists. The 
pharmacology of verapamil was less well understood. The structure for answering a 
pharmacology question was often poor and there was commonly a lack of precision in 
pharmacokinetics. We suggest that candidates look at a general pharmacokinetic structure
when answering these questions. One approach would be a structure that covers drug name 
and description, pharmaceutics (chemistry/ ampoule contents), Pharmacokinetics, 
Pharmacodynamics (Think CNS/CVS/Resp/GIT etc. if relevant), Dose and Side effects then 
Indications and Contraindications can help organize the information

Discussion

Classification of calcium channel blockers:

  • Phenylalkylamines:
    • Verapamil
  • Benzothiazepines:
    • Diltiazem
  • 1,4-dihydropyridines:
    • Nifedipine
    • Nimodipine
    • Amlodipine
    • Lercanidipine
    • Clevidipine

Pharmacology of verapamil

Class Calcium channel blocker
Chemistry Phenylalkylamine
Routes of administration Oral or IV
Absorption oral bioavailability 24%
Solubility pKa 8.73, excellent lipid solubility
Distribution Highly lipid soluble: octanol/water partition coefficient 67, 84-91% protein bound. VOD =3.8 L/kg
Target receptor α1c subunit of the L-type calcium channel (non-selective, affecting both myocardial and smooth muscle isoforms)
Metabolism Mainly hepatic clearance, by CYP3A4 (which it inhibits)
Elimination Time to peak effect = 0.5-1.0 hrs; elimination half-life 4.5-12 hrs
Time course of action Clinical effects persist for longer than the half life would suggest, because they are mainly determined by drug-receptor affinity
Mechanism of action Modulates the opening of voltage-gated calcium channels, which prevents intracellular calcium influx during depolarisation. This decreases the availability of intracellular calcium for vascular smooth muscle cells, decreasing their resting tone. In cardiac myocytes, this decreases contractility as well as the automaticity of pacemaker cells.
Clinical effects Relaxation of vascular smooth muscle, thereby decreasing peripheral vascular resistance and afterload. Decreased cardiac contractility and decrease heart rate, thereby decreasing myocardial oxygen demand. Side effects include flushing and constipation.
Single best reference for further information Abernethy & Schwartz (1999)

References

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Drapak, Iryna, et al. "Cardiovascular calcium channel blockers: historical overview, development and new approaches in design." Journal of Heterocyclic Chemistry 54.4 (2017): 2117-2128.

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Godfraind, Théophile. "Discovery and development of calcium channel blockers." Frontiers in pharmacology 8 (2017): 286.

Tang, Lin, et al. "Structural basis for inhibition of a voltage-gated Ca 2+ channel by Ca 2+ antagonist drugs." Nature 537.7618 (2016): 117-121.

Morel, Nicole, and Theophile Godfraind. "Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine." British journal of pharmacology 102.2 (1991): 467-477.

Yatani, A. T. S. U. K. O., DIANA L. Kunze, and ARTHUR M. Brown. "Effects of dihydropyridine calcium channel modulators on cardiac sodium channels." American Journal of Physiology-Heart and Circulatory Physiology 254.1 (1988): H140-H147.

Godfraind, Theophile. "Cardioselectivity of calcium antagonists." Cardiovascular drugs and therapy 8.2 (1994): 353-364.

Kelly, John G., and Kevin O’Malley. "Clinical pharmacokinetics of calcium antagonists." Clinical pharmacokinetics 22.6 (1992): 416-433.