Drug Information

Drug Interaction:

Simvastatin-

Most clinically important drug interactions with simvastatin occur when the drug is combined with agents that through various mechanisms resulyt in an increased incidence of myopsathy.

This is particularly true with cyclosporin ( upto 30% of patients) and gemfibrozil

Other drugs commonly used in combination with statins include the bile acid sequestrants, which have been shown to bind the statins in the gut. These drugs shoulds not be taken at the same time as the statins

All drugs which induce or inhibit cytochrome P450 system, particularly those afectiing CYP3A4 should be considered as potentially interacting agents. However, wideespread clinical use of these compounds fotr the past decade have resulted in few dramatic interactions and must be avoided

Ezetimbe-

Coasdmin of ezetimibe with cholestyramine results in decrease mean AUC of total ezetimbe, with a mean redduction of approximately 55% and 80%

Combination of ezetimibe with simastatin shoud be administered > 2 hrs before or > 4 hrs after injection of bile and sequestrant such as chlotestyramine. When treating hyperlipidemia in patients receiving cyclosporin therapy ezetimibe /simvastain should be titrated above the starting dose of 10/10 mg/day

Indication:

Hypercholesterolemia, hyperlipdemia

Adverse Reaction:

Ezitimbe appears to be well tolerated with adverse effects being mild and transcient. Most common adverse effects are abdominal discomfgort, disarrhea, back pain, arthalgia, respiratory infection, cough, headache, musculoskeletal pain, and fatigue

Myopathy and rhabdomyolysis arte known adverse efects to stains, therefore caution should be used when ezitibe is used as a combination with statin

Contra-Indications:

Hypersensitivity ,pregnancy and lactation

Dosages/ Overdosage Etc:

Hypercholesterolemia, hyperlipdemia

Dosage-

Recommended starting dose of ezitimbe /simvastatin is 10/20mg /day but it can be adjusted on the individual patient needs ie. 10/10 mg in patients with a relatively less aggresive LDL/C target.

Pharmacology/ Pharmacokinetics:

Pharmacology-

Simvastatin-

Simvastatin is a reversible competitive 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase inhibitor.HMG CoA reductase is the rate limiting step for cholesterol biosynthesis. The primary site of action of simavastatin is within the hepatocyte. Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations.

The mechanism of the LDL lowering effect of simavastain may involve both reduction of VLDL chloesterol concentration and induction of the LDL receptor leadinfg to reduced production and/or increased catabolism of LDL-C

Ezetimibe-

Ezetibe localizes at the brush border of the small intestine where it inhibits the absorption of cholesterol without interfering with the absorption of fatty acids or fat slouble vitamins thus decreasing the delivery of intestinal chloesterol to the liver. Ezetimibe inhibits exogenous chloesterol entry into blood stream. This decreases the cholesterol stores in the liver and ultrimately increases the clearance from the blood.

Clinical efficacy-

When statins and ezetimibe are administered together the satins inhibits the compensatory increase in hepatic chloestrol biosynthesis. The combination therapy of satin and slective inhibition of chloesterol absorption with ezetimibe results in more enhanctive effect on removal of chloesterol from circulation. A number of studies demonstrate increased efficacy for LDL-C and triglyceride reduction and HDL-C elevation when ezetimibe is used in combination with simvastatin

Pharmacokinetics-

Simvastatin-

Simvastain is an inactive prodrug and must be hydroxylated by the cytochrome P450 system in the

liver to the acid metabolite(simvastain acid) to be pharmacologically activeDespite the short half-lfe

simvastain ( like all statins ) is dosed once daily usually in the evening because the pharmcological

effect of the drug is associated with the curculating plasma concentrations but activity primarily in the

hepatocyte

Ezetimibe -

Following oral administrationof 20mg of ezetimibe was rapidly absorbed and extensively conjugated.

The main circulating metabolite in plasma was the glucuronide congugate of ezetimibe.

Soon after intake of ezetimbe a large portion of it is converted to glucoronyl drivative in small intestine.

After 10 days of admin approx 78% of ezetimbe dose is excreted in the feces as parent drug and 11%

in urine in conjugated form.

Significant amonuts of (69% of the dose) of ezetimbe were present in the feces.

Pregnancy and lactation:

Contraindicated in pregnancy and lactation

Simvastatin + Ezetimibe

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Pharmacology/ Pharmacokinetics

Pregnancy and lactation