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).
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.
Classification:
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) |
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