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Nifedipine has been formulated as both a long- and short-acting 1,4-dihydropyridine calcium channel blocker. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, nifedipine prevents calcium-dependent myocyte contraction and vasoconstriction. A second proposed mechanism for the drug’s vasodilatory effects involves pH-dependent inhibition of calcium influx via inhibition of smooth muscle carbonic anhydrase. Nifedipine is used to treat hypertension and chronic stable angina.

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• Chase laboratories inc
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• Mylan pharmaceuticals inc
• Osmotica pharmaceutical corp
• Pfizer inc
• Pfizer laboratories div pfizer inc
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• Pfizer Inc.
• Pharmaceutical Utilization Management Program VA Inc.
• Pharmacy Service Center
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• Warrick Pharmaceuticals Corp.
• Watson Pharmaceuticals

Synthesis Reference

Not Available

General Reference

Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000 Jul 29;356(9227):366-72. Pubmed Poole-Wilson PA, Kirwan BA, Voko Z, de Brouwer S, van Dalen FJ, Lubsen J: Safety of nifedipine GITS in stable angina: the ACTION trial. Cardiovasc Drugs Ther. 2006 Feb;20(1):45-54. Pubmed Odou P, Ferrari N, Barthelemy C, Brique S, Lhermitte M, Vincent A, Libersa C, Robert H: Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms. J Clin Pharm Ther. 2005 Apr;30(2):153-8. Pubmed Grossman E, Messerli FH, Grodzicki T, Kowey P: Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA. 1996 Oct 23-30;276(16):1328-31. Pubmed Takahashi D, Oyunzul L, Onoue S, Ito Y, Uchida S, Simsek R, Gunduz MG, Safak C, Yamada S: Structure-activity relationships of receptor binding of 1,4-dihydropyridine derivatives. Biol Pharm Bull. 2008 Mar;31(3):473-9. Pubmed Varon J, Marik PE: Clinical review: the management of hypertensive crises. Crit Care. 2003 Oct;7(5):374-84. Epub 2003 Jul 16. Pubmed

Type	small molecule

Classes

Nitrobenzenes

Substructures

Dihydropyridines Carboxylic Acids and Derivatives Nitrobenzenes Acetates Oxoazaniums Ethers Benzene and Derivatives Nitro compounds Enamines Heterocyclic compounds Aromatic compounds Anilines

;Angina Pectoris 心绞痛;ANTIHYPERTENSIVES 降血压;

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).
Pharmacodynamics	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.
Absorption	Rapidly and fully absorbed following oral administration.
Volume of distribution	Not Available
Protein binding	92-98%
Metabolism	Hepatic metabolism via cytochrome P450 system. Predominantly metabolized by CYP3A4, but also by CYP1A2 and CYP2A6 isozymes. Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us. Substrate Enzymes Product Nifedipine Cytochrome P450 3A4 dehydronifedipine Details
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.
Half life	2 hours
Clearance	Not Available
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)
Affected organisms	Humans and other mammals
Pathways	Pathway Name SMPDB ID Nifedipine Pathway SMP00379

Properties
State	solid
Experimental Properties	Property Value Source melting point 172-174 °C PhysProp water solubility Insoluble Not Available logP 2.20 MASUMOTO,K ET AL. (1995)
Predicted Properties	Property Value Source water solubility 1.77e-02 g/l ALOGPS logP 2.49 ALOGPS logP 1.82 ChemAxon logS -4.3 ALOGPS pKa (strongest basic) 5.33 ChemAxon physiological charge 0 ChemAxon hydrogen acceptor count 5 ChemAxon hydrogen donor count 1 ChemAxon polar surface area 110.45 ChemAxon rotatable bond count 6 ChemAxon refractivity 92.16 ChemAxon polarizability 33.85 ChemAxon

Drug	Interaction
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
Etravirine	Nifedipine, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to monitor nifedipine therapy for reduced effectiveness.
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.

• Avoid alcohol.
• Avoid natural licorice.
• Grapefruit down-regulates post-translational expression of CYP3A4, the major metabolizing enzyme of nifedipine. Grapefruit, in all forms (e.g. whole fruit, juice and rind), can significantly increase serum levels of nifedipine and may cause toxicity. Avoid grapefruit products while on this medication.
• Take with low fat meal.