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pravastatin (Pravachol)

Tradename: Pravachol. Indications: - hyperlipidemia - hypercholesterolemia - hyperlipoproteinemia type 3 - arteriosclerosis - coronary artery disease - myocardial infarction - prevention of cardiovascular disease - transient ischemic attack - may reduce risk of stroke in women [7] - may reduce all-cause mortality in women [7] - treatment of proteinuria in conjunction with ACE inhibitor [6] - statin of choice for use with HIV protease inhibitors or to avoid cytochrome P450 interactions [8] Contraindications: - pregnancy (potentially teratogenic, risk may be small) Dosage: 1) start 10 mg QHS 2) usual dose 20-40 mg QHS 3) maximum: 80 mg/day; 40 mg in elderly 4) lower dose recommended for moderate renal impairment [5] Tabs 10, 20 & 40 mg. Pharmacokinetics: 1) oral absorption is poor, bioavailability is 17% 2) extensive 1st pass metabolism in liver; -> extraction ratio 0.66 [4] 3) transported into hepatocytes (primary site of action), less so into other cells 4) maximum plasma levels in 1-1.5 hours [12] 4) metabolized in the liver a) isomerization to inactive 3-alpha hydroxy isomer (major metabolite) b) oxidation (not metabolized by cyt P450) [12] c) conjugation 5) does not require activation via lactone hydrolysis as do lovastatin, simvastatin, & mevastatin 6) protein binding is 50% 6) elimination 1/2life is 2-3 hours; 1.8 hours [12]; 77 hours for metabolites - no active metabolites [12] 7) 8% excreted unchanged in the urine 8) according to ref [9], pravastatin metabolized by kidney Monitor: (see HMG CoA reductase inhibitor) Adverse effects: 1) gastrointestinal - nausea/vomiting, dyspepsia - diarrhea, constipation, abdominal cramps, flatulence - hepatitis - increased serum transaminases 2) musculoskeletal a) myopathy - myalgias - increased serum creatine kinase - rhabdomyolysis - renal failure b) arthropathy 3) CNS: headache, dizziness, 4) ocular: lens opacity, blurred vision 5) skin: rash 6) Respiratory: cough 7) potentially teratogenic 8) risk for diabetes mellitus may be lowest among statins - pravastatin improves insulin sensitivity & inhibits gluconeogenesis Drug interactions: 1) avoid use in combination with gemfibrozil [12] 2) limit dose of pravastatin to 40 mg QD with coadministration of cyclosporine, tacrolimus, everolimus, sirolimus [12] 3) drugs that inhibit cyt P450 3A4 do not increase pravastatin levels significantly [5] 4) any drug which induces cyt P450 3A4 can diminish pravastatin levels 5) may NOT interact with warfarin as do other HMG CoA reductase inhibitors 6) increased effect with cholestyramine 7) increased effect of warfarin 8) concurrent use may increase risk of rhabdomyolysis -> cyclosporine, gemfibrozil, clofibrate, erythromycin, clarithromycin, troleandomycin, itraconazole, protease inhibitors 9) close monitoring for myalgia with coadministration of colchicine [12] Mechanism of action: 1) inhibition of HMG CoA reductase 2) maximal effect (40 mg/day) a) total cholesterol: decrease of 25% b) LDL cholesterol: decrease of 34% c) HDL cholesterol: increase of 8% d) triglycerides: decrease of 25% 3) reduces proteinuria in patients with controlled hypertension [6]

Interactions

drug interactions drug adverse effects (more general classes) monitor with HMG CoA reductase inhibitors (statins)

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (Mega Study) Prospective Study of Pravastatin in Elderly People at Risk (PROSPER)

General

hydrophilic statin

Properties

INHIBITS: HMG CoA reductase MISC-INFO: elimination route LIVER protein-binding 50% 1/2life 1.6-3 HOURS pregnancy-category X safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1990. pg 882
  3. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  4. Physician's Desk Reference (PDR) 54th edition, Medical Economics, 2000
  5. Prescriber's Letter 9(1):1 2002
  6. Prescriber's Letter 9(9):49 2002
  7. Mizuno K et al. Usefulness of pravastatin in primary prevention of cardiovascular events in women: Analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA study). Circulation 2008 Jan 29; 117:494. PMID: 18172039
  8. Prescriber's Letter 16(8): 2009 Clinically Significant Statin Drug Interactions Detail-Document#: 250812
  9. Medical Knowledge Self Assessment Program (MKSAP) 16, American College of Physicians, Philadelphia 2012
  10. Carter AA et al. Risk of incident diabetes among patients treated with statins: Population based study. BMJ 2013 May 23; 346:f2610. PMID: 23704171 - Huupponen R and Viikari J. Statins and the risk of developing diabetes. BMJ 2013 May 23; 346:f3156 PMID: 23709567
  11. Deprecated Reference
  12. Wiggins BS, Saseen JJ, Page RL 2nd et al Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease. A Scientific Statement From the American Heart Association. Circulation. 2016;134:00-00 PMID: 27754879 http://circ.ahajournals.org/content/circulationaha/early/2016/10/17/CIR.0000000000000456.full.pdf

Component-of

aspirin/pravastatin (Pravigard PAC)