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Ranolazine



Ranolazine
Systematic (IUPAC) name
N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)
propyl]piperazin-1-yl]acetamide
Identifiers
CAS number 142387-99-3
ATC code C01EB18
PubChem 56959
DrugBank APRD01300
Chemical data
Formula C24H33N3O4 
Mol. mass 427.537 g/mol
Pharmacokinetic data
Bioavailability 35 to 50%
Protein binding 62%
Metabolism Hepatic, CYP extensively involved
Half life 7 hours
Excretion Renal (75%) and fecal (25%)
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status

-only(US)

Routes Oral

Ranolazine, sold under the trade name Ranexa™ by CV Therapeutics, is an antianginal medication. On January 31, 2006, ranolazine was approved for use in the United States by the FDA for the treatment of chronic angina.[1]

Additional recommended knowledge

Contents

Mechanism of action

Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia.[2] Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.[3]

Indications for use

Ranolazine is indicated for use in the treatment of chronic stable angina in individuals with angina which is refractory to more standard anti-anginal medications. It has been shown to decrease angina episodes in individuals with coronary artery disease on maximal doses of amlodipine.[4] In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem.[5]

Unlike other antianginal medications such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina that is refractory to maximal tolerated doses of other anti-anginal medications.

While it would seem from the mechanism of action that ranolazine may be of benefit in individuals with non-ST-elevation acute coronary syndromes and acute myocardial infarction (heart attack), the recently completed Merlin/TIMI-36 trial showed no benefit in this population.[6]

Contraindications

Ranolazine is known to increase the QT interval on the electrocardiogram. While the mean increase in the QTc is approximately 6 msec, about 5 percent of individuals may have QTc prologations of 15 msec or longer.[7]

Because of this, caution should be used when ranolazine is used in combination with other medications that increase the QT interval. In addition, because the effect of ranolazine on the QT interval is increased in the setting of liver dysfunction, it is contraindicated in the setting of mild, moderate, or severe liver disease.[1]

Metabolism

Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450 system.[8]

Drug interactions

While ranolazine is not significantly metabolized by cytochrome CYP2D6, it does inhibit this enzyme.[8] Because of this, the doses of medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.

Drugs that may interact with ranolazine include:[9]

While caution should be used when administrating ranolazine in combination with any of the above medications, some combinations may be considered relatively safe. For instance, in the CARISA trial, ranolazine was used in individuals taking diltiazem without any adverse events attributable to the combination.[5]

References

  1. ^ a b "FDA Approves New Treatment for Chest Pain", FDA News, 2006-01-31. Retrieved on 2007-02-04. 
  2. ^ Hale SL, Kloner RA. (2006). "Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit". J Cardiovasc Pharmacol Ther 11 (4): 249-55. PMID 17220471.
  3. ^ Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. (2006). "Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts". J Mol Cell Cardiol 41 (6): 1031-8. PMID 17027025.
  4. ^ Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. (2006). "Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial". J Am Coll Cardiol 48 (3): 566-75. PMID 16875985.
  5. ^ a b Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. (2004). "Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial". JAMA 291 (3): 309-16. PMID 14734593.
  6. ^ Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al (2007). "Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial". JAMA 297 (16): 1775-83. doi:10.1001/jama.297.16.1775. PMID 17456819.
  7. ^ What is Ranexa. CV Therapeutics. Retrieved on 2007-02-04.
  8. ^ a b Jerling M. (2006). "Clinical pharmacokinetics of ranolazine". Clin Pharmacokinet 45 (5): 469-91. PMID 16640453.
  9. ^ Patient information sheet: Ranolazine. FDA (2006-06-14). Retrieved on 2007-02-04.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Ranolazine". A list of authors is available in Wikipedia.
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