Hypolipidemic Agent

Hypolipidemic AgentHypolipidemic Agent1. Fibric Acid Derivatives2. Resin3. HMGCoA Reductase Inhibitor4. Nicotinic Acid5.

Fibric Acid DerivativesFibric Acid Derivatives1. Gemfibrozil

- It is absorbed quantitatively from the intestine- It is tightly bound to plasma protein- Undergoes enterohepatic circulation ; passes the placenta- Plasma half-life is 1,5 hours- 70% is eliminated through the kidney, mostly unmodified- The liver modifies some of the drug to hyfroxymethyl, carboxyl, and quinol derivatives.- Usual dose : 600 mg ovally twice daily- Absorption if taken with food

- Side EffectGastrointestinal disorders (diarihea,

nausea)MyopathyHypokalemiaHigh blood levels of aminotransgereses or

alkaline phosphataseDecrease in white blood count or

hematocritRhabdomyolysis- ContraindicationHepatic or renal dysfunctionBiliary tract disease

2. Klofibrat- It is absorbed from the intestine- Peak plasma cincentration in several hours after oral administration- Plasma half life is 20 hours- 60% is excreted in the urine as the glucoronide ; 25% in feces- Mechanism of action :

Increase lipolysis of lipoprotein triglyceride via LPL intracellular lipolysis in adipose tissue level of VLDL decrease- Klofibrat available in capsule 500 mg.- The dosage of klofibrat : 2 – 4 times/day with maximum dosage is 2 gr.- Contraindication : Hepatic or renal dysfunction, pregnancy, laktation period.

ResinResin- Consist of Colestipol,

cholestyramine,- These agents are large polymeric

cationic ; water insoluble- It is not absorbed- Mechanism of action :

Mechanism of Action :Mechanism of Action :Resin binds bile acids in the intestinal lumen

Prevent reabsorption of bile acid

Decrease of bile acid levels

Bile acid production from cholesterol

Resin Disturb enterohepatic circulation Inhibit absorption of Cholesterol from intestine Excretion of steroid

Decrease of Cholesterol in the liver

- Increase of LDL receptors ; LDL catabolism - HMGCoA reductase activity

Therapeutic Uses and Therapeutic Uses and DosageDosage- Resins are used in treatment of

hypercholesterolemia- Therapeutic dose is 12 – 16 g

daily, maximum dose : 30 – 32 g/d- Resins are available as granular

preparation- Granular resins are mixed with

juice or water- Resins should be taken in two or

three doses with meals

Adverse EffectAdverse Effect- Constipation and Bloating

Can be relieved by increasing dietary fiber- Heart burn and diarrhea- Steatorrhea in patient with preexisting

bowel diseases or cholestasis- Malabsorption of vitamen A,D,K- Hypoprothrombonemia- Increasing duration of protrombin time- Absorption of certain drugs (digitalis,

thiazides, phenylbutazone) may be impaired by resins

HMGCoA Reductase HMGCoA Reductase InhibitorInhibitor These compounds are structural

analogs of HMGCoA This groups include :

Locastatin Simvastatin Pravastatin

Most effective in reducing LDL Decreased oxidative stress &

vascular inflammation

PharmacokineticsPharmacokinetics Lavastatin & simuastatin : inactive lactone

produgs. Hydrolized in the GI tract active -hydroxyl

derivates Pravastatin has an active lactone ring Absorption varies from 40% to 75% All have high first-pass extraction by the

liver Most of the absorbed dose is excreted in the

bile 5 – 20% is excreted in the urine Plasma half life range from 1 hour to 3 hours

Mechanism of ActionMechanism of Action HMGCoA reductase mediates the first

commited step in sterol biosynthesis Reduce plasma LDL levels

HMGCoA reductase clearly induce an increase in high-affinity LDL receptors increases both the fractinomal catabolic rate of LDL and the liver’s extraction of LDL Precursor (VLDL) reducing plasma LDL

HMGCoA reductase is not effective for patient with homozygot familiab hypercholesterolemia

Therapeutic Uses & Therapeutic Uses & DosageDosage- Reductase inhibitors are useful alone or

with resins, miacins- Should be given in the evening if a single

dose is used- Daily doses of lovastatin : 10 mg – 80 mg- Dosage of pravastatin : 80 mg, simuastatin :

5 – 80 mg daily.- Divided dose of lovastatin is effective- Lovastatin : drug of choice for

Patient with hypercholesterolemia high risk for Myocardial Infarc

Patient with cholesterol total > 300 mg/dl- Contraindication : woman who are

pregnant, lactating.

ToxicityToxicity- Elevation of serum aminotransferase

activity cup to three times the normal level) aminotrasferase activity should be measured at 1 – 2 month and then every 6 month

- Hepatic parenchymal disease- Minor increases in creatini kinase

activity- Myopathy- Lupus – like disorder- Peripheral neuropathy

ra’re

NIACIN (Nicotinic Acid)NIACIN (Nicotinic Acid)- Decreases VLDL & LDL levels, increases HDL

levels.- Niacin is converted in the body to the amide- It is excreted in the urine unmodified and as

several metabolites- Mechanism of action Niacin inhibits VLDL secretion decreasing

production of LDL Increased clearance of VLDL via the LPL pathway

triglyceride reduction- Niacin has no effect on bile acid production- Niacin inhibits the intra cellular lipase of adipose

tissue via receptor mediated signaling decreasing the flux of free fafty acids to livers reducing VLDL production.

Therapeutic Uses & Therapeutic Uses & DosageDosage Niacin combined with resin or reductase

inhibitor normalize LDL in patient with heterozygous familial hypercholesterolemia

Dosage in niacin 2 – 6 daily For other types of hypercholesterolemia

& hypertriglyceridemia : 1,5 – 3,5 g daily Should be given in divided doses with

meals Starting dose 100 mg, 2 or 3 times daily,

increasing gradually

ToxicityToxicityRash, flush, pruritusEritema of skinHepatic dysfunction : increasing

alkali phosphatase levelsGI dysfunction : nausea, diarrheaHyperuricemiaReversible toxix amblyopia (blurring

of distance vision)Dryness of mucous membranesSevere peptic disease

Treatment With Drug Treatment With Drug CombinationsCombinationsCombined drug therapy is useful :1. When VLDL levels are

significantly increased during treatment of hypercholesterolemia with a resin

2. When LDL and VLDL levels are both elevated initially

3. When LDL or VLDL levels are not normalized a single agent

4. When elevated levels of Lp (a) or HDL deficiency coexist with other hyperlipidemias

a.Fibric acid Derivates & Bile Acid – Binding Resin- Useful for patients with fimilial combined hyperlipidemia who are intolerant of niacin- May increase the risk of cholelithiasis

b.HMGCoA reductase inhibitors & Bile Acid-Binding Resin- Highly synergistic combination for patient with familial hypercholesterolemia- HMGCoA reductase inhibitor : 1 hour before or 4 hours after resin intake to ensure their absorption

c.Niciacin & Bile Acid Binding Resins- Effective for controls VLDL levels during resin therapy- Effective for other disorders involving both increased VLDL & LDL levels- Used for heterozygotis familial hypercholesterolemia- Combined dose : 6,5 g of niacin with 24 – 30 g of resin daily

d.Niacin & Reductase InhibitorEffective for treating familial hypercholesterolemia.

Sites of Action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and Resin used in treating hyperlipidemias. LDL receptors (R) are increased by treatment with resins and HMG-CoA reductase inhibitors