Nifedipine

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Nifedipine
Nifedipine.svg
Nifedipine-from-xtal-3D-balls.png
Systematic (IUPAC) name
3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Trade names Adalat, Procardia, others
AHFS/Drugs.com Monograph
MedlinePlus a684028
Pregnancy
category
  • C: (USA)
Routes of
administration
Oral, Topical
Pharmacokinetic data
Bioavailability 45-56%
Protein binding 92-98%
Metabolism Gastrointestinal, Liver
Biological half-life 2 hours
Excretion Kidneys: >50%, Biliary: 5-15%
Identifiers
CAS Number 21829-25-4 YesY
ATC code C08CA05 (WHO)
PubChem CID 4485
IUPHAR/BPS 2514
DrugBank DB01115 YesY
ChemSpider 4330 YesY
UNII I9ZF7L6G2L YesY
KEGG D00437 YesY
ChEBI CHEBI:7565 YesY
ChEMBL CHEMBL193 YesY
Chemical data
Formula C17H18N2O6
Molar mass 346.335 g/mol
Physical data
Melting point 173 °C (343 °F)
  (verify)

Nifedipine, sold under the brand names Adalat among others, is a medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor.[1] It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lungs and time to transfer the mother to a well qualified medical facility before delivery. Nifedipine is taken by mouth and comes in fast and slow release formulations.[1]

Common side effects include lightheadedness, headache, feeling tired, leg swelling, cough, and shortness of breath. Serious side effects may include low blood pressure and heart failure.[1] There is tentative evidence that its use in pregnancy is safe; however, it is not recommended during breastfeeding.[2] It is a calcium channel blocker of the dihydropyridine type.[1]

Nifedipine was discovered in 1969 and approved for use in the United States in 1981.[1][3] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[4] It is available as a generic medication.[1] The wholesale price in the developing world for the slow release form is about 1.90 to 3.80 USD per month.[5] In the United States it is about 40 to 60 USD a month depending on the dose.[1]

Medical uses[edit]

High blood pressure[edit]

The approved uses for are the long-term treatment of hypertension (high blood pressure) and angina pectoris. In hypertension, recent clinical guidelines generally favour diuretics and ACE inhibitors, although calcium channel antagonists, along with thiazide diuretics, are still favoured as primary treatment for patients over 55 and African American patients.[6]

Sublingual nifedipine has previously been used in hypertensive emergencies. It was once frequently prescribed as needed to people taking MAOIs for real or perceived hypertensive crises.[7] This was found to be dangerous, and has been abandoned. Sublingual nifedipine causes blood-pressure lowering through peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, the FDA reviewed all data regarding the safety and efficacy of sublingual nifedipine for hypertensive emergencies in 1995, and concluded that the practice should be abandoned because it was neither safe nor efficacious.[8][9] An exception to the avoidance of this practice is in the use of nifedipine in the treatment of hypertension associated with autonomic dysreflexia in spinal cord injury.[10]

Early labor[edit]

Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it is comparable with magnesium sulfate and beta-agonists (such as ritodrine) with fewer side-effects.[11][needs update] Its role vis à vis atosiban is not established.

Other[edit]

Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.[12]

Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures.[13]

Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema.[14]

Other uses include painful spasms of the esophagus such as from cancer or tetanus. It is also used for the small subset of people with pulmonary hypertension.

Side effects[edit]

Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine (such as Adalat OROS). A more novel release system is GITS (Gastro-Intestinal Therapeutic System), which - according to Bayer - provides 24-hour continuous release through an osmotic push system. Recent trials with GITS include INSIGHT (for blood pressure)[15] and ACTION (for angina).[16]

Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the lowering of CYP3A4 activity.[17]

Overdose[edit]

A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or parenteral administration. The adverse effects include lethargy, bradycardia, marked hypotension and loss of consciousness. The drug may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Analytical methods usually involve gas or liquid chromatography and specimen concentrations are usually in the 100-1000 μg/L range.[18][19]

Mechanism[edit]

Nifedipine is a calcium channel blocker. Although nifedipine and other dihydropyridines are commonly regarded as specific to the L-type calcium channel, they also possess nonspecific activity towards other voltage-dependent calcium channels.[20][21]

Nifedipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.[22]

History[edit]

Nifedipine (initially BAY a1040) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s.[23]

The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine.[24] This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctations in blood pressure) and at high doses of 80 mg a day and more.[25]

See also[edit]

References[edit]

  1. ^ a b c d e f g "Nifedipine". The American Society of Health-System Pharmacists. Retrieved Dec 19, 2015. 
  2. ^ "Nifedipine Pregnancy and Breastfeeding Warnings". Retrieved 25 December 2015. 
  3. ^ Corey, E.J. (2013). Drug discovery practices, processes, and perspectives. Hoboken, N.J.: John Wiley & Sons. p. 172. ISBN 9781118354469. 
  4. ^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015. 
  5. ^ "Nifedipine". International Drug Price Indicator Guide. Retrieved 25 December 2015. 
  6. ^ Hypertension: management of hypertension in adults in primary care. Clinical guideline CG34. National Institute for Health and Clinical Excellence (NICE), June 2006. Fulltext index. ISBN 1-86016-285-1.
  7. ^ "Nifedipine for MAOI Hypertension? Reversing a Previous Recommendation". Biological Therapies in Psychiatry. March 1997. Retrieved 22 Jan 2015. 
  8. ^ Grossman E, Messerli FH, Grodzicki T, Kowey P (1996). "Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies?". JAMA. 276 (16): 1328–31. doi:10.1001/jama.276.16.1328. PMID 8861992. 
  9. ^ Varon J, Marik PE (2003). "Clinical review: The management of hypertensive crises". Critical care (London, England). 7 (5): 374–84. doi:10.1186/cc2351. PMC 270718free to read. PMID 12974970. 
  10. ^ Campagnolo, DI. "Autonomic Dysreflexia in Spinal Cord Injury". eMedicine. Retrieved 2011-07-14. 
  11. ^ King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B (2003). Flenady, Vicki, ed. "Calcium channel blockers for inhibiting preterm labour". Cochrane database of systematic reviews (Online) (1): CD002255. doi:10.1002/14651858.CD002255. PMID 12535434. 
  12. ^ Thompson AE, Pope JE (2005). "Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis". Rheumatology (Oxford, England). 44 (2): 145–50. doi:10.1093/rheumatology/keh390. PMID 15546967. 
  13. ^ Ezri T, Susmallian S (2003). "Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure". Dis. Colon Rectum. 46 (6): 805–8. doi:10.1007/s10350-004-6660-8. PMID 12794583. 
  14. ^ Ali, Mir Omar & Qazi, Samia (2007-09-19). "Pulmonary Edema, High-Altitude". eMedicine. Retrieved 2007-11-25. 
  15. ^ Brown MJ, Palmer CR, Castaigne A, et al. (2000). "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. 356 (9227): 366–72. doi:10.1016/S0140-6736(00)02527-7. PMID 10972368. 
  16. ^ Poole-Wilson PA, Kirwan BA, Vokó Z, de Brouwer S, van Dalen FJ, Lubsen J (2006). "Safety of nifedipine GITS in stable angina: the ACTION trial". Cardiovas Drugs Ther. 20 (1): 45–54. doi:10.1007/s10557-006-6312-4. PMID 16552473. 
  17. ^ Odou P, Ferrari N, Barthélémy C, et al. (2005). "Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms". Journal Clinical Pharm Ther. 30 (2): 153–8. doi:10.1111/j.1365-2710.2004.00618.x. PMID 15811168. 
  18. ^ Nifediac package insert, TEVA Pharmaceuticals, Sellersville, Pennsylvania, August, 2009.
  19. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA: Biomedical Publications. pp. 1108–1110. ISBN 0-9626523-7-7. 
  20. ^ Curtis, Tim M.; Scholfield, C. Norman (May 2001). "Nifedipine blocks Ca2+ store refilling through a pathway not involving L-type Ca2+ channels in rabbit arteriolar smooth muscle store refilling through a pathway not involving L-type Ca2+ channels in rabbit arteriolar smooth muscle". The Journal of Physiology. 532 (3): 609–623. doi:10.1111/j.1469-7793.2001.0609e.x. Retrieved 19 August 2016. 
  21. ^ McDonald, TF; Pelzer, S; Trautwein, W; Pelzer, DJ (April 1994). "Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells.". Physiological reviews. 74 (2): 365-507pmid=8171118. 
  22. ^ Luther, James M. (2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension. 23 (5): 456–461. doi:10.1097/MNH.0000000000000051. ISSN 1062-4821. 
  23. ^ Vater W, Kroneberg G, Hoffmeister F, et al. (1972). "[Pharmacology of 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (Nifedipine, BAY a 1040)]". Arzneimittel-Forschung (in German). 22 (1): 1–14. PMID 4622472. 
  24. ^ Furberg CD, Psaty BM, Meyer JV (1995). "Nifedipine. Dose-related increase in mortality in patients with coronary heart disease". Circulation. 92 (5): 1326–31. doi:10.1161/01.cir.92.5.1326. PMID 7648682. 
  25. ^ Opie LH, Messerli FH (1995). "Nifedipine and mortality. Grave defects in the dossier". Circulation. 92 (5): 1068–73. doi:10.1161/01.cir.92.5.1068. PMID 7648646. 

External links[edit]