Antihyperlipedemic Agents Introduction
Lipids are organic compounds and are the scientific terms of fats. The most common lipids are triglycerides, cholesterol and phospholipids. These lipids are insoluble in plasma. They combine with special proteins called apoproteins also called apolipoproteins to form lipoproteins and this process makes the lipids soluble in plasma. The major apolipoproteins required for the solubilization of lipoproteins like HDL, LDL are Apo A-1 and Apo B respectively.
Table of Contents
All lipoproteins including HDL, LDL have an outer layer of phospholipids, cholesterol, apolipoproteins and an inner core consisting of triglycerides and cholesterol esters. Depending on their density, lipoproteins are classified chylomicrons (CM), low density lipoproteins (LDL), very low density lipoproteins (VLDL) and high density lipoproteins (HDL).
Out of these, HDL is generally considered to be “good” cholesterol, while LDL is considered “bad” because LDL is responsible for delivering cholesterol to peripheral tissues, including the adrenal glands, ovary and testes whereas HDL is involved in reverse cholesterol transport.
The pharmacological agents which reduce the concentration of plasma lipids are called antihyperlipidemic agents. An increase in plasma lipids, particularly cholesterol is a common feature of atherosclerosis, a condition involving arterial damage which may lead to ischemic heart disease, myocardial infarction and cerebral vascular accidents.
Classification
Hypolipidemic agents are classified as:
- HMG CoA reductase inhibitors: eg. Lovastatin, Simvastatin, Metastatin, Pravastatin, Fluvastatin, Atorvastatin, Pitavastatin, Rosuvastatin
- Fibric acid derivatives : eg. Clofibrate, Fenofibrate, Gemfibrozil, Ciprofibrate, Benzafibrate, Fluvestain.
- Bile acid sequestrants : eg. Cholestyramine, Colestipol.
- LDL oxidation inhibitor : eg. Probucol.
- Pyridine derivatives : eg. Nicotinic acid, Nicotinamide.
- Cholesterol absorption inhibitors: eg. Ezetimibe.
- Miscellaneous agents : eg. ẞ- Sitosterol, Dextrothyroxine.
HMG-CoA Reductase Inhibitors
These agents block the conversion of HMG- CoA to mevalonic acid in the synthetic pathway for the synthesis of cholesterol.
Lovastatin (Lova, Lovastat, Rovacor)
Lovastatin is obtained from the fermentation product of fungi Aspergillus terreus and Monascus ruber. It is a prodrug and it must be hydrolyzed at lactone ring to open heptanoic acid for active metabolite.
ADR: Increased creatinine phosphokinase, flatulence and nausea.
Dose: 20mg/day given with the evening meal.
Use: Antihyperlipoproteinemic agent.
Simvastatin (Simvin, Simvotin, Simlo)
It is a prodrug and it is metabolized into active open-ring hydroxy acid.
ADR: Headache, nausea, flatulence, heartburn and abdominal pain.
Dose: 10 to 20mg daily, to be taken in the evening.
Use: It is used as antihyperlipidemic agent.
Pravastain Sodium (Prastatin, Pravator)
The sodium salt of B-hydroxy acid is more active because of its hydrophilic nature, which results in less CNS penetration. Pravastatin was isolated from Absidia coerula.
ADR: GI disturbances, headache, insomnia, chest pain and rash.
Dose: 10 to 40mg daily at night, adjusted according to response at 4 weeks interval. Use: It is used as antihyperlipoproteinemic agent.
Atorvastatin (Atorva, Atocor)
ADR: Headache, flatulence and diarrhea.
Dose: Initially, 10 or 20mg daily may increase at 4 weeks interval.
Use: It is used to treat primary hyperlipidemia as well as as for secondary hypercholesterolemia.
Rosuvastatin (Rosuvastat, Rostar)
ADR: Headache, dizziness, constipation, nausea and vomiting.
Dose: 5 to 10mg daily may increase dose at 4 weekly intervals to 20mg daily if necessary.
Use: It is used for the treatment of high LDL cholesterol, total cholesterol and triglycerides.
Pitavastatin (Livalo, Flovas)
ADR: Back pain, muscle pain, constipation and diarrhea.
Dose: Initially 2mg daily and increased after 4 weeks up to maximum of 4mg/day.
Use: It is used to treat hypercholesterolaemia and for patients with metabolic syndrome.
Fibric acid Derivatives
Fibrates are chemically classified as analogues of phenoxy isobutyric acid. They have the following general structure.
The isobutyric acid is essential for activity. Compounds containing ester group like Clofibrate and Fenofibrate are prodrugs. Substitution at the p-position of the aromatic ring with the chloro group or chlorine containing isopropyl ring produces compounds with significant half lives.
The spacer group is mostly, propyl group. They reduce the plasma concentration of triglyceride and cholesterol. Fibric acid derivatives increase the activity of lipoprotein, lipase an enzyme that degrades chylomicrons and VLDL. Other mechanism includes; decrease hepatic clearance of VLDL and LDL causing lower LDL cholesterol level.
Clofibrate (Atromid, Lipinorm)
Synthesis
ADR: Cholecystitis, gall stone, eosinophilia and pneumonia.
Dose: 200mg, three times a day with food.
Use: It is a drug of choice for the treatment of type – III hyperlipoproteinemias.
Gemfibrozil (Gempar, Lopid)
Synthesis
ADR: Myositis syndrome, cholelithiasis, GI disturbances, rash and headache.
Dose: 1.2gm daily in two divided doses.
Use: It is used in the treatment of hyperlipidemia.
Benzafibrate (Beza, Bezalip)
Synthesis
ADR: GI upset, pruritus, urticaria and alopecia.
Dose: 200mg tid, may increase dose gradually over 5 to7 days.
Use: It is a highly potent antihyperlipidemic agent.
Fenofibrate (Fenacor, Fibral)
Synthesis
ADR: Headache, dizziness, asthaenia, fatigue and arrhythmia.
Dose: 67mg tid or 200mg once daily may reduce to 67mg bid or increase to 67mg four times daily.
Use: It is more potent hypocholesterolemic and tri-glycerides lowering agent.
Bile-Acid Sequestrants
Cholestyramine Resin (Questran)
It is a styrene co-polymer with divinylbenzene with quaternary ammonium functional group. The resin is insoluble in water, remains unchanged in the intestinal tract, unaffected by digestive enzymes and is not absorbed. In small intestine, the cholestyramine resin exchange chloride for bile acid, cationic ion exchange resin simply binds anionic bile acids.
This form of insoluble complex result in increased loss of fecal bile acid and prevents its reabsorption into liver. The decrease in body content of bile acids is compensated by an increase in conversion of cholesterol to bile acids.
ADR: Constipation, skin rashes and hemorrhoids.
Dose: 4 to 8gm once or twice daily.
Use: It reduces cholesterol level without affecting triglycerides and effective in the treatment of type III hyper-lipoproteinemias.
Colestipol (Colestid)
Colestipol is a high-molecular weight, insoluble granular copolymer of tetra ethylene pentamine and epichlorohydrin. It functions as anion exchange resin sequestering agent in a similar manner.
ADR: Constipation, heart burn, flatulence and nausea.
Dose: 2 to 16gm/day.
Use: It is effective in the treatment of type II hyperlipoproteinemia.
LDL Oxidation Inhibitor
Probucol (Lesterol, Lorelco)
It is the only drug used to increase the HDL-C in higher properties than any other drugs available in the market
ADR: GI disorders and prolongation of GI intervals.
Dose: 500mg daily given with morning and evening meals.
Use: It is used as antihyperlipoproteinemic agent.
Pyridine Derivatives
Nicotinic acid (Neasyn, Nialip, Nicocin)
It is the only drug used to increase the HDL-C in higher proportion than any other drug available in the market currently.
Synthesis
ADR: Vomiting, diarrhea, peptic ulceration and jaundice.
Dose: Initially 600mg daily in three divided doses gradually increased over 2 to 4 weeks to a maximum of 6gm daily.
Use: It is used to lower triglycerides, cholesterol and to enhance HDL-C. Serious deficiency of it may lead to pellagra.
Cholesterol Absorption Inhibitors
Ezetimibe (Ezee, Ezibloc)
ADR: Abdominal discomfort, headache, dizziness and sinusitis.
Dose: 10mg once daily.
Use: It is an adjunct to dietary measures in the management of hypercholesterolaemia, homozygous sitosterolemia.
Miscellaneous Agent
B-Sitosterol
B-Sitosterol is a plant sterol, whose structure is identical with cholesterol, except for the substituted ethyl group on C24 of its side chain.
B-Sitosterol acts by inhibiting the absorption of dietary cholesterol from the GIT.
ADR: Diarrhea, constipation and GI disturbances.
Dose: 800 to 6000mg per day
Use: It is used as anticholesteremic agent and also used in the treatment of prostatic adenoma.
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