2.4.2 Med Chem CCBs

Voltage‑sensitive Ca2+ channels mediate extracellular Ca2+ entry into VSM, cardiac myocytes, and nodal cells in response to __________.

Electrical depolarization

Ca2+ influx triggers contraction and increases blood pressure and positive __________ and __________ effects.

Inotropic; Chronotropic

Ca2+ channel blockers inhibit Ca2+ influx and therefore __________ blood pressure.

Lower

The three structural classes of CCBs are __________, __________, and __________.

1,4‑Dihydropyridines; Phenylalkylamines; Benzothiazepines

Verapamil and diltiazem share overlapping binding sites located in the pore, whereas 1,4‑DHPs bind to a site oriented __________ from the pore.

Away

1,4‑DHPs are primary __________, whereas verapamil and diltiazem are vasodilators plus cardiodepressants.

Vasodilators

Compensatory sympathetic responses such as __________ are observed with 1,4‑DHPs.

Tachycardia

Using a beta‑blocker with a 1,4‑DHP can minimize reflex tachycardia in hypertension, but combining beta‑blockers with __________ or __________ is discouraged due to additive cardiodepression.

Verapamil; Diltiazem

A 1,4‑DHP requires the intact __________ ring; pyridines or piperidines abolish activity.

Dihydropyridine

The phenyl ring at C4 of a 1,4‑DHP prefers __________ and/or __________ substitution, with orientation more important than electronics.

Ortho; Meta

Esters at C3 and C5 are optimal in 1,4‑DHPs, and asymmetrical derivatives introduce a chiral center at C4 with the active __________ isomer of amlodipine marketed as levamlodipine.

S

Amlodipine and nicardipine possess basic amines on side chains that are __________ at physiologic pH.

Ionized

Most 1,4‑DHPs undergo extensive first‑pass metabolism as CYP3A4 substrates and can be affected by __________, which increases plasma concentrations.

Grapefruit juice

Verapamil is metabolized to norverapamil (≈20% activity), while diltiazem is hydrolyzed to __________ (25-50% activity) and also undergoes N‑ and O‑demethylation.

Deacetyldiltiazem