HMG COA reductase inhibitors

HMG COA reductase inhibitors:

Overview

Mechanism of action: Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

**Comparative efficiency and pharmacology of the statins.**
Drug	Reduction in LDL-C (%)	Increase in HDL-C (%)	Reduction in TG (%)	Reduction in TC (%)	Metabolism	Protein binding (%)	T1/2 (h)	Hydrophilic
Atorvastatin	26 - 60	5 - 13	17 - 53	25 - 45	CYP3A4	98	13-30	No
Lovastatin	21 - 42	2 - 10	6 - 27	16 - 34	CYP3A4	>95	2 - 4	No
Simvastatin	26 - 47	8 - 16	12 - 34	19 - 36	CYP3A4	95 - 98	1 - 3	No
Fluvastatin	22 - 36	3 - 11	12 - 25	16 - 27	CYP2C9	98	0,5 - 3,0	No
Rosuvastatin	45 - 63	8 - 14	10 - 35	33 - 46	CYP2C9	88	19	Yes
Pravastatin	22 - 34	2 - 12	15 - 24	16 - 25	Sulfation	43 - 67	2 - 3	Yes
Source: Vaughan CJ, Gotto AM Jr. Update on statins: 2003. Circulation. 2004 Aug 17;110(7):886-92.

**Comparison of lipophilicity of HMG-CoA Reductase Inhibitors at pH 7.4**
	Cerivastatin	Simvastatin	Fluvastatin	Atorvastatin	Rosuvastatin	Pravastatin
Log D Class	1,50-1,75	1,50-1,75	1,00-1,25	1,00-1,25	-0,25-(-0,50)	-0,75-(-1,0)
					Hydrophilic	Hydrophilic
White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol. 2002 Sep;42(9):963-70.

Atorvastatin (Lipitor ®)	Fluvastatin (Lescol ®)
Lovastatin (Mevacor ®)	pitavastatin - (LIVALO®)
Pravastatin (Pravachol ®)	Rosuvastatin (Crestor ®)
Simvastatin (Zocor ®)
Combination products
Advicor ® (lovastatin + niacin SR)	Vytorin ® (simvastatin +ezetimibe)
Other
ezetimibe (Zetia ®)	Niacin (Vitamin B3 )
Adult Treatment Panel (ATP) III Analysis
Adult Treatment Panel (ATP) III Calc	Impact of drug therapy

Atorvastatin (Lipitor ®)

Supplied: 10 mg, 20 mg, 40 mg, 80 mg
Dosing: Hyperlipidemias: Adults: Oral: Initial: 10-20 mg once daily. Patients requiring >45% reduction in LDL-C may be started at 40 mg once daily. Range: 10 to 80 mg once daily.
Adjustments should be made at intervals of 2-4 weeks.

Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or a Combination of Ritonavir plus Saquinavir or Lopinavir plus Ritonavir
In patients taking cyclosporine, therapy should be limited to LIPITOR 10 mg once daily. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of LIPITOR exceeding 20 mg, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of LIPITOR is employed

Fluvastatin (Lescol ®)

Supplied: Capsule: 20 mg, 40 mg. Tablet, extended release (Lescol® XL): 80 mg

Dosing: Dyslipidemia: Oral: (Adults): Patients requiring >/= 25% decrease in LDL-C: 40 mg capsule once daily in the evening, 80 mg XL tablet once daily (anytime), or 40 mg capsule twice daily. Patients requiring <25% decrease in LDL-C: Initial: 20 mg capsule once daily in the evening; may increase based on tolerability and response to a maximum recommended dose of 80 mg/day, given in 2 divided doses (capsule) or as a single daily dose (XL tablet).

Lovastatin (Mevacor ®)

Supplied: Tablet: 10 mg, 20 mg, 40 mg. Tablet, extended release: 20 mg, 40 mg, 60 mg
Dosing: Dyslipidemia: Oral: (Adults): Initial: 20 mg with evening meal, then adjust at 4-week intervals; maximum: 80 mg/day immediate release tablet or 60 mg/day extended release tablet.

Dosage modification/limits based on concurrent therapy: Cyclosporine and other immunosuppressant drugs: Initial dose: 10 mg/day with a maximum recommended dose of 20 mg/day.
Concurrent therapy with fibrates, danazol, and/or lipid-lowering doses of niacin (>1 g/day): Maximum recommended dose: 20 mg/day. Concurrent use with fibrates should be avoided unless risk to benefit favors use. Concurrent therapy with amiodarone or verapamil: Maximum recommended dose: 40 mg/day of regular release or 20 mg/day with extended release.

Pravastatin (Pravachol ®)

Supplied: 10 mg, 20 mg, 40 mg, 80 mg
Dosing: Hyperlipidemias: Oral: (Adults): Initial: 40 mg once daily; titrate dosage to response (usual range: 10-80 mg) (maximum dose: 80 mg once daily).

Dosage adjustment based on concomitant cyclosporine: Oral: Initial: 10 mg/day, titrate with caution (maximum dose: 20 mg/day).

Rosuvastatin (Crestor ®)

Supplied: 5 mg, 10 mg, 20 mg, 40 mg

Dosing: Hypercholesterolemia; mixed dyslipidemia: Oral: (Adults): Initial dose: 10 mg once daily (20 mg in patients with severe hypercholesterolemia). Conservative dosing: Patients requiring less aggressive treatment or predisposed to myopathy (including patients of Asian descent): 5 mg once daily. Titration: After 2 weeks, may be increased by 5-10 mg once daily; dosing range: 5 to 40 mg/day (maximum dose: 40 mg once daily).

Dosage adjustment for persistent, unexplained proteinuria while on 40 mg/day: Reduce dose and evaluate causes.

Use with Concomitant Therapy
Patients taking cyclosporine
The dose of CRESTOR should not exceed 5 mg once daily

Patients taking gemfibrozil
Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily.

Patients taking lopinavir and ritonavir or atazanavir and ritonavir
Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily

Simvastatin (Zocor ®)

Dosing:
Simvastatin Dose Limitations
When used with simvastatin, the following medications can raise the levels of simvastatin in the body and increase the risk of myopathy. Taking no more than the recommended dose of simvastatin with these medications will help keep simvastatin levels in the body at a safer level.

Previous simvastatin label	New simvastatin label
Avoid simvastatin with: Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone	Contraindicated with simvastatin: Itraconazole Ketoconazole Posaconazole (New) Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol
Do not exceed 10 mg simvastatin daily with: Gemfibrozil Cyclosporine Danazol	Do not exceed 10 mg simvastatin daily with: Amiodarone Verapamil Diltiazem (Note: These drugs are contraindicated with Simcor as Simcor is only available with 20 mg or 40 mg of simvastatin.)
Do not exceed 20 mg simvastatin daily with: Amiodarone Verapamil	Do not exceed 20 mg simvastatin daily with: Amlodipine (New) Ranolazine (New)
Do not exceed 40 mg simvastatin daily with: Diltiazem
Avoid large quantities of grapefruit juice (>1 quart daily)	Avoid large quantities of grapefruit juice (>1 quart daily

Oral: (Adults): [See dosage restrictions above]
Prevention of cardiovascular events, hyperlipidemias: Oral: 20-40 mg once daily in the evening; range: 5 to 80 mg/day.
Homozygous familial hypercholesterolemia: Oral: 40 mg once daily in the evening or 80 mg/day (given as 20 mg, 20 mg, and 40 mg evening dose).
Patients requiring only moderate reduction of LDL-cholesterol: May be started at 10 mg once daily
Patients requiring reduction of >45% in low-density lipoprotein (LDL) cholesterol: May be started at 40 mg once daily in the evening.
Patients with CHD or at high risk for CHD: Dosing should be started at 40 mg once daily in the evening; simvastatin may be started simultaneously with diet.

Dosage adjustment for simvastatin with concomitant medications: Cyclosporine or danazol: Patient must first demonstrate tolerance to simvastatin >/= 5 mg once daily: Initial: 5 mg, should not exceed 10 mg/day. Fibrates or niacin: Dose should not exceed 10 mg/day. Amiodarone or verapamil: Dose should not exceed 20 mg/day.

Mechanism Of Action
Simvastatin is a prodrug and is hydrolyzed to its active

-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Supplied: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Combination products:

Advicor ® (lovastatin + niacin SR)

Indicated for the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Dosing (Adults):
Usual initial dose: 500 mg/20 mg. The dose of Advicor should not be increased by more than 500 mg daily (based on the niacin component) every 4 weeks. Doses > 2000 mg/40 mg daily are not recommended.

Supplied: 20/500, 20/750mg, 20/1000mg tablet.

Vytorin ® (simvastatin + ezetimibe )

HMG-CoA reductase inhibitor + cholesterol absorption inhibitor.

Dosing (Adults):
Usual initial dose: Ezetimibe 10 mg and simvastatin 20 mg once daily in the evening. Patients who require >55% reduction in LDL-C: Initial: Ezetimibe 10 mg and simvastatin 40 mg once daily.

Renal dosing: In severe dysfunction, start only if patient tolerates 5 mg daily of simvastatin. Monitor closely.

Supplied: ( Ezetimibe / simvastatin) 10/10 , 10/20, 10/40, 10/80.

Other:

ezetimibe (Zetia ®)

Selective cholesterol absorption inhibitor.
Adult (usual): Hypercholesterolemia: 10 mg po qd.

Moderate reductions in low-density lipoprotein (LDL) cholesterol (less than 20%) have been reported with monotherapy in patients with hypercholesterolemia. As add-on therapy, it may enable reduced doses of statins. The drug is approved for primary hypercholesterolemia, for homozygous familial hypercholesterolemia (combined with atorvastatin or simvastatin), and for homozygous sitosterolemia.

Supplied: 10 mg tablet.

Niacin (Vitamin B3 )

Hyperlipidemia:
Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin. OTC preparations that are marketed as causing "no flush" may have no free nicotinic acid and are ineffective in treating dyslipidemia.

Dosing (Adults):
Regular release formulation (Niacor®): Initial: 250 mg once daily (with evening meal); increase frequency and/or dose every 4-7 days to desired response or first-level therapeutic dose (1.5-2 g/day in 2-3 divided doses); after 2 months, may increase at 2- to 4-week intervals to 3 g/day in 3 divided doses

Extended release formulation (Niaspan®): 500 mg at bedtime for 4 weeks, then 1 g at bedtime for 4 weeks; adjust dose to response and tolerance; can increase to a maximum of 2 g/day, but only at 500 mg/day at 4-week intervals.

Administer with food. Administer Niaspan® at bedtime. Niaspan® tablet strengths are not interchangeable. When switching from immediate release tablet, initiate Niaspan® at lower dose and titrate.
MONITORING— Blood glucose; liver function tests (dyslipidemia, high dose, prolonged therapy) pretreatment and every 6-12 weeks for first year then periodically; lipid profile.

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David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.