Drugs Facts and Comparison

Statins

Statins (Antilhyperlipidemic Agent).

Mechanism of Action: They act by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate limiting step of cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism. They have pleotropic effects.

Uses: Treatment of dyslipidemia or primary prevention of cardiovascular disease (atherosclerotic) as detailed: 1) Primary prevention of cardiovascular disease (high risk for CVD): To reduce the risk of MI or stroke in patients without evidence of heart disease who have multiple CVD risk factors or type 2 DM. 2) Treatment of dyslipidemia: To reduce elevation in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with elevation of one or more components, and/or to increase HDL-C as present in Fredrickson type IIa, IIb, III, and IV hyperlipidemias.

Side effects: 1) Statins are generally well-tolerated and have only two major side effects that occur relatively rarely: raised liver enzymes and skeletal muscle pain or damage which include myositis and myopathy, with the potential for rhabdomyolysis leading to acute renal failure. 2) Headache, paraesthesia, and gastrointestinal effects including abdominal pain, flatulence, constipation, diarrhea, nausea and vomiting. 3) Rash and hypersensitivity reaction have been rarely reported.

Pharmacokinetics: Initial change: 3-5 d; Maximal reduction in Ch & TG after: 2 weeks. Pravastatin & Fluvastatin are completely absorbed orally and active as such. Lovastatin & Simvastatin are absorbed 30-50% after oral dose. Simvastatin & Lovastatin are pro-drugs (lactones) that are hydrolyzed to active metabolites. They are metabolized by the liver. All are biotransformed, with some of the products retaining activity. Excretion takes place principally through the bile and feces, but some urinary elimination also occurs. Their half-lives varies from 2 hours (Pravastatin, Fluvastatin) to 14 hours (Atorvastatin). Examples: Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, and Simvastatin.

Examples: (cont.) Cerivastatin was withdrawn from the market in 2001 because of the high rate of serious side-effects. Mevastatin is not used in therapy of hyperlipidemias because of multiple side effects but it is the only source for production of another statin - pravastatin. Pitavastatin is a novel member of the medication class of statins. It has been available in Japan since 2003, and is being marketed under license in South Korea and in India.

Potency: Cerivastatin is the most potent, followed by rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.

Dosing: In general, HMG-CoA Reductase inhibitors should be administered in the evening or at bedtime to counteract the peak cholesterol synthesis which occur in the early morning hours. Atorvastatin, Simvastatin ( 10-20mg OD, max 80 mg OD ) Lovastatin, Fluvastatin ( 20-40mg OD, max 40mg BID ) Pravastatin, Rosuvastatin ( 10-20mg OD, max 40mg OD ) It is better to administer Pravastatin & Simvastatin with food to reduce dyspepsia and Lovastatin with food to increase bioavailability.

Monitoring Parameter: Lipid profile every 4-8 weeks, also after dose changes. Liver function test: can be performed prior and at 12 weeks following both initiation of therapy, and elevation in the dose, and periodically thereafter. CPK level: for myopathy ( > 3ˣ normal ).

Pregnancy risk factor: Class X

Drug interaction: With gemfebrozil, fibric acid derivatives and niacin. When coadministered with hepatic enzyme inhibitors ( Cyclosporine ). Statins (Lovastatin increase the prothrombintime with concurrent warfarin).

Contraindication: Active liver disease. Pregnancy & Lactation. Comparative pharmacology of statins

Increase in HDL Reduction in TG Reduction in TC Drug Reduction in LDL (%) (%) (%) (%)

Atorvastatin 26 - 60 5 - 13 17 - 53 25 - 45

Lovastatin 21 - 42 2 - 10 6 - 27 16 - 34

Simvastatin 26 - 47 8 - 16 12 - 34 19 - 36

Fluvastatin 22 - 36 3 - 11 12 - 25 16 - 27

Rosuvastatin 45 - 63 8 - 14 10 - 35 33 - 46

Pravastatin 22 - 34 2 - 12 15 - 24 16 - 25 Comparative pharmacokinetic of statins

Variable Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Prodrug No No Yes No No Yes

Effect of No No Yes No No No food on absorption

Protein >98 98 >95 55-60 88 95 binding %

Active Yes No Yes No No Yes metabolites Water No No No Yes Yes No solubility Elimination Hepatic Hepatic Hepatic Hepatic / Hepatic / Hepatic Renal Renal Plasma 14 0.5-3 2-3 1.3-2.6 19 4 elimination half life T1/2

Major CYP3A4 CYP2A9 CYP3A4 Sulfation CYP2A9 CYP3A4 metabolic CYP2A19 Isozyme Doses adjustment and Time of administration .

Adjustment in Adjustment in Adjustment with Drug Time of administration renal failure hepatic failure concomitant drugs

Do not use in Without regard to time Atorvastatin No active liver ------of day, with food if disease desired.

CrCl Need dose adjustment with <30ml/min: cyclosporine, fibrates, With dinner or at Lovastatin use doses ------niacin, amiodarone and bedtime. >20mg/day verapamil with caution

Use with caution in severe impairment Need dose adjustment with CrCl cyclosporine, fibrates, With dinner or at Simvastatin ------<10ml/min: niacin, amiodarone and bedtime initial dose: verapamil 5mg/day with close monitoring

Use with caution in severe impairment Use with caution in severe Additive effect with bile acid binding resin or niacin; QHS Fluvastatin impairment administer 2 hrs following these drugs

Rosuvastatin CrCl ------Need dose adjustment with Without regard to time <30ml/min: initial 5mg/day, not cyclosporine of day exceed 10mg OD

Initial: Initial: Need dose adjustment with Without regard to time Pravastatin 10mg/day 10mg/day cyclosporine of day or QHS.

Availability in KAUH. Simvagen ® ( Simvastatin 10mg film coated tablets ), Price = 59.8 SR. Vasta ® ( Simvastatin 20mg film coated tablets ), Price = 78.1 SR.

:Done By

Roaa Matouq H. Khinkar