Question 8

Classify calcium channel antagonists and give one example of each class (30% of marks).

Describe the pharmacology of Nimodipine including important drug interactions (70% of marks). 

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College Answer

The classification was done well. Most candidates demonstrated that they had a structure for a “drug” question, but were often challenged to fill in the detail of that structure and failed to deliver enough content to secure a pass. Many candidates wrote a generic answer for calcium channel blockers instead of the specifics of nimodipine. 
Frequently the pharmacokinetic data recounted was incorrect. Candidates failed to distinguish between absorption and bioavailability. The difference between oral and intravenous dosing was often omitted. Few answered the section on important drug interactions.


"Few answered the section on important drug interactions" because specifics of CYP450 inducer/inhibitor interactions are a) numerous beyond count, and b) easily looked up by anybody with a smartphone. In the future, if such questions are asked again, we can be sure that 81% of the trainees will again fail them, and still go on to become respectable and competent intensivists. 


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

Pharmacology of nimodipine

Class Calcium channel blocker
Chemistry 1,4-dihydropyridine
Routes of administration Oral or IV
Absorption oral bioavailability 11.60%
Solubility pKa 5.4, excellent lipid solubility
Distribution Highly lipid soluble: octanol/water partition coefficient 3.8, 98% protein bound. VOD =1.7 L/kg
Target receptor α1c subunit of the L-type calcium channel (selective for the smooth muscle isoform)
Metabolism Mainly hepatic clearance, by CYP3A4. Thus, the metabolic clearance of nimodipine would be increased by phenytoin, rifampicin and corticosteroids, and decreased by diltiazem, verapamil, erythromycin, and grapefruit.
Elimination Time to peak effect = 1 hr; elimination half-life 1-2 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. The magnitude of this effect depends on the resting membrane potential of the smooth muscle cells, which makes nimodipine more selective for the cerebral circulation (where the resting membrane potential is lower)
Clinical effects Relaxation of vascular smooth muscle, thereby decreasing peripheral vascular resistance and afterload. Side effects include flushing and constipation.
Single best reference for further information Abernethy & Schwartz (1999)


Abernethy, Darrell R., and Janice B. Schwartz. "Calcium-antagonist drugs." New England journal of medicine 341.19 (1999): 1447-1457.

Singh, B. N. "The mechanism of action of calcium antagonists relative to their clinical applications." British journal of clinical pharmacology 21.S2 (1986): 109S-121S.

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.

Triggle, David J. "Calcium-channel drugs: structure-function relationships and selectivity of action." Journal of cardiovascular pharmacology 18 (1991): S1-S6.

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.

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.