Classify the calcium channel blockers and provide one example of a drug for each class (20% marks). Compare and contrast the pharmacology of nimodipine and verapamil (80% marks).
Most candidates were able to classify the calcium channel blockers well (Type I :
Phenylalkylamines eg verapamil, Type II : Dihydropyridines eg nimodipine and Type III :
Benzothiazepines eg diltiazem) However, the comparison of the pharmacology of nimodipine and
verapamil was in general answered poorly. Few candidates demonstrated an organised
approach to this part of the question. The two drugs’ presentation, routes of administration,
indications and dosing were poorly answered considering that nimodipine in particular is used
frequently in intensive care units. Mode of action was well answered, but important principles
relating to pharmacokinetics (such as a basic outline of protein binding, bioavailability, and
metabolism) were expected, but common omissions. More knowledge than ‘metabolism in the
liver’ is required. Few candidates mentioned interactions, adverse effects, or predictable effects
of over dosage of these drugs
Classification:
Most modern textbooks produce this sort of breakdown:
For some reason, the examiners had offered numbered Types instead of chemical classes ("Type I :
Phenylalkylamines eg verapamil, Type II : Dihydropyridines eg nimodipine and Type III :
Benzothiazepines eg diltiazem"). This seems to be an alternative naming strategy which you only see in some of the older papers (eg. Singh, 1986), and it will not be used here because it fails as nomenclature (i.e. numbered class names describe nothing useful) and because it might breed confusion with the already confusing number-based classification of antiarrhythmic agents.
A comparison of verapamil and nimodipine:
| Name | Nimodipine | Verapamil |
| Class | Calcium channel blocker | Calcium channel blocker |
| Chemistry | 1,4-dihydropyridine | Phenylalkylamine |
| Routes of administration | Oral or IV | Oral or IV |
| Absorption | oral bioavailability 11.60% | oral bioavailability 24% |
| Solubility | pKa 5.4, excellent lipid solubility | pKa 8.73, excellent lipid solubility |
| Distribution | Highly lipid soluble: octanol/water partition coefficient 3.8, 98% protein bound. VOD =1.7 L/kg | 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 (selective for the smooth muscle isoform) | α1c subunit of the L-type calcium channel (non-selective, affecting both myocardial and smooth muscle isoforms) |
| Metabolism | Mainly hepatic clearance, by CYP3A4 | Mainly hepatic clearance, by CYP3A4 (which it inhibits) |
| Elimination | Time to peak effect = 1 hr; elimination half-life 1-2 hrs | 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 | 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) | 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. Side effects include flushing and constipation. | 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. |
| Best references for further information | Abernethy & Schwartz (1999); Kelly & O'Malley (1992) | |
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.