indication

For the management of vasospastic angina, chronic stable angina, hypertension, and Raynaud's phenomenon. May be used as a first line agent for left ventricular hypertrophy and isolated systolic hypertension (long-acting agents).

pharmacology

Nifedipine, the prototype of the dihydropyridine class of calcium channel blockers (CCBs), is similar to other dihydropyridines including amlodipine, felodipine, isradipine, and nicardipine. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, nifedipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives nifedipine additional arterial selectivity. At therapeutic sub-toxic concentrations, nifedipine has little effect on cardiac myocytes and conduction cells. By blocking the calcium channels, Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, results in a increase of myocardial oxygen supply and a decrease in systemic blood pressure.

mechanism of action

Nifedipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. The vasodilatory effects of nifedipine result in an overall decrease in blood pressure.

toxicity

Symptoms of overdose include dizziness, drowsiness, nausea, severe drop in blood pressure, slurred speech, and weakness. LD₅₀=494 mg/kg (orally in mice); LD₅₀=1022 mg/kg (orally in rats)

biotransformation

Hepatic metabolism via cytochrome P450 system. Predominantly metabolized by CYP3A4, but also by CYP1A2 and CYP2A6 isozymes.

absorption

Rapidly and fully absorbed following oral administration.

half life

2 hours

route of elimination

Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites accounting for 60 to 80% of the dose excreted in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion.

drug interactions

Amobarbital: The barbiturate, amobarbital, decreases the effect of the calcium channel blocker, nifedipine.

Aprobarbital: The barbiturate, aprobarbital, decreases the effect of the calcium channel blocker, nifedipine.

Butabarbital: The barbiturate, butabarbital, decreases the effect of the calcium channel blocker, nifedipine.

Butalbital: The barbiturate, butalbital, decreases the effect of the calcium channel blocker, nifedipine.

Butethal: The barbiturate, butethal, decreases the effect of the calcium channel blocker, nifedipine.

Cimetidine: Cimetidine may increase the effect of the calcium channel blocker, nifedipine.

Cisapride: Cisapride may increase the effect and toxicity of nifedipine.

Cyclosporine: Increased risk of gingivitis

Dihydroquinidine barbiturate: Decreased quinidine effect, increased nifedipine effect

Ginseng: Ginseng increases the effect and toxicity of nifedipine

Heptabarbital: The barbiturate, heptabarbital, decreases the effect of the calcium channel blocker, nifedipine.

Hexobarbital: The barbiturate, hexobarbital, decreases the effect of the calcium channel blocker, nifedipine.

Imatinib: Imatinib increases the effect and toxicity of nifedipine

Melatonin: Melatonin can possibly decrease the effect of nifedipine

Methohexital: The barbiturate, methohexital, decreases the effect of the calcium channel blocker, nifedipine.

Methylphenobarbital: The barbiturate, methylphenobarbital, decreases the effect of the calcium channel blocker, nifedipine.

Pentobarbital: The barbiturate, pentobarbital, decreases the effect of the calcium channel blocker, nifedipine.

Phenobarbital: The barbiturate, phenobarbital, may decrease the effect of the calcium channel blocker, nifedipine.

Primidone: The barbiturate, primidone, decreases the effect of the calcium channel blocker, nifedipine.

Quinidine: Decreased quinidine effect, increased nifedipine effect

Quinidine barbiturate: Decreased quinidine effect, increased nifedipine effect

Quinupristin: Synercid increases the effect of ziprasidone

Rifampin: Rifampin decreases the effect of the calcium channel blocker, nifedipine.

Secobarbital: The barbiturate, secobarbital, decreases the effect of the calcium channel blocker, nifedipine.

St. John's Wort: St. John's Wort decreases the effect of nifedipine

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by Nifedipine, a CYP1A2 inhibitors. Monitor the efficacy and toxicity of Tacrine if Nifedipine is initiated, discontinued or if the dose is changed.

Tacrolimus: The calcium channel blocker, Nifedipine, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nifedipine therapy is initiated, discontinued or altered.

Talbutal: The barbiturate, talbutal, decreases the effect of the calcium channel blocker, nifedipine.

Telithromycin: Telithromycin may reduce clearance of Nifedipine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Nifedipine if Telithromycin is initiated, discontinued or dose changed.

Thiopental: The CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Nifedipine, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Nifedipine if Thiopental is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Nifedipine. Monitor for changes in Nifedipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.

Tizanidine: Nifedipine may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of nifedipine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nifedipine if voriconazole is initiated, discontinued or dose changed.