HYPERLIPIDEMIA
Hyperlipidemia is a broad term, it is also called hyperlipoproteinemia, it is a common disorder in developed countries and a major cause of coronary heart disease.
It is a result of abnormalities in lipid metabolism or plasma lipid transport or a disorder in the synthesis and degradation of plasma lipoprotein.
Causes of Hyperlipidemia:
- Most of the time hyperlipidemia is caused due to lifestyle habits or treatable medical conditions.
- Obesity, not exercising, and smoking, diabetes, obstructive jaundice, and an underactive thyroid gland inherit hyperlipidemia.
THE BIOCHEMISTRY OF PLASMA LIPIDS
Lipids: Lipids are the heterogeneous mixtures of fatty acids and alcohol that are present in the body. The major lipids in the bloodstream are cholesterol and its esters, triglycerides, and phospholipids.
Cholesterol: It is a C27-Steroid that serves as an important component of all cell membranes and an important precursor molecule for the biosynthesis of bile acids, steroid hormones, and several fat-soluble vitamins.
Normal functions of cholesterol in the body:
- New cells must form and for older cells to repair themselves after injury.
- It is also used by the adrenal glands to form hormones such as cortisol, by the testicles to form testosterone, and by the ovaries to produce estrogen and progesterone.
Normal functions of triglycerides and phospholipids in the body.
- Triglycerides supply energy for the body. Triglycerides are required to meet immediate energy needs in muscles or to store fat for future energy requirements.
- Phospholipids are compounds that are used to make cell membranes, generate second messengers, and store fatty acids for use in the generation of prostaglandins.
Lipoproteins:
- Blood and other body fluids are watery, so fats require a special transport system to travel around the body.
- Fats are traveling from one place to another mixing with protein particles, called lipoproteins.
- Four (or five) types of lipoproteins are there, each having a particular distinct job.
- A lipoprotein contains both proteins and lipids, bound to another protein which is called apolipoproteins, which allow fats to move through the water inside and outside cells. Provide structural support and stability, binds to receptors.
Classification of Lipoproteins:
| Classification | Composition | Primary function |
| Chylomicrons | Triglyceride TGs 99%, 1% protein. | Transport dietary TGs to adipose tissue and muscle. |
| VLDL | Newly synthesized TGs. Lipid 90%, 10% protein. | Transport endogenous TGs to adipose tissue and muscle. |
| IDL | Intermediate between VLDL and LDL. | They are not usually detectable in the blood. |
| LDL | Lipid 80%, 20% protein. | Transport endogenous cholesterol from the liver to tissues. |
| HDL | Lipid 60%, 40% protein. | Collect cholesterol from the body’s tissues, and take it back to the liver. |
CLASSIFICATION OF ANTIHYPERLIPIDEMIC DRUGS
| Sr. No. | Class | Example |
| 1. | HMG CoA Reductase Inhibitors | Lovastatin, Simvastatin, Metastatin, Pravastatin, Fluvastatin, Atorvastatin, Pitavastatin, Rosuvastatin |
| 2. | Fibrates | Clofibrate, Fenofibrate, Gemfibrozil, Ciprofibrate, benzafibrate, Fluvestatin. |
| 3. | Bile acid sequestrants | Cholestyramine, Colestipol |
| 4. | LDL oxidation inhibitor | Probucol |
| 5. | Pyridine derivatives | Nicotinic acid, Nicotinamide |
| 6. | Cholesterol absorption inhibitors | Ezetimibe |
| 7. | Miscellaneous agents | β-Sitosterol, Dextrothyroxine |
1. HMG- CoA Reductase inhibitors (STATINS):
- 3-hydroxy-3-Methylglutaryl-coenzyme A (HMG-CoA).
- The enzyme that catalyzes the conversion of HMG-CoA to mevalonate.
- This reaction is the rate-determining step in the synthetic pathway of cholesterol.
Statins:
- Lovastatin was isolated from Aspergillus terreus.
- There are two classes of statins:
Natural Statins: Lovastatin(mevacor), Pravastatin (pravachol), Simvastatin (Zocor).
Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol).
- Statins are competitive inhibitors of HMG-CoA reductase. They are bulky and “stuck” in the active site.
- Statins prevent the binding of the enzyme with its substrate, HMG CoA.
| Drug | ADR | Uses |
| Lovastatin | Increased creatinine phosphokinase, Flatulence, Nausea. | Antihyperlipoproteinemic agent. |
| Simvastatin | Headache, nausea, flatulence, heartburn, abdominal pain. | Antihyperlipidemic agent. |
| Pravastatin | GI disturbances, headache, insomnia, chest pain, rash. | Antihyperlipoproteinemic agent. |
| Atorvastatin | Headache, flatulence, diarrhea. | Primary hyperlipidemia and secondary hypercholesterolemia. |
| Rosuvastatin | Headache, dizziness, constipation, nausea, vomiting. | High LDL, total cholesterol, TGs. |
2. Fibrates:
- Fibrates are antihyperlipidemic agents, these are used in the treatment of various forms of hyperlipidemia and hypercholesterolemia.
- These are 2-phenoxy-2-methyl propanoic acid derivatives.
- These drugs stimulate β-oxidation of fatty acids in mitochondria.
- These are especially using for decreasing plasma levels of fatty acid and triacylglycerol.
MOA:
- Fibrates are decreasing plasma TGs levels.
- This class of drugs acting through lowering the blood triglyceride levels by decreasing the production of the liver’s VLDL (the triglyceride-carrying particle that circulates in the blood) by activation of lipoprotein lipase and enhances the removal of TGs from the blood. It is due to the activation of PPAR-α.
- These drugs are acted by increasing blood HDL cholesterol and not effective in lowering LDL cholesterol.
| Drug | ADR | Uses |
| Clofibrate | Cholecystitis, gall stone, eosinophilia, pneumonia. | Type III Hyperlipoproteinemias. |
| Gemfibrozil | Myositis syndrome, Cholelithiasis, GI disturbances, rash, and headache. | Hyperlipidemia. |
| Fenofibrate | Headache, dizziness, asthenia, fatigue, arrhythmia. | More potent hypercholesterolemic and triglycerides lowering agent. |
3. Bile Acid Sequestrants:
- Cholestyramine (Questran)
- Colestipol hydrochloride (Colestid)
- Colesevelam (tablet form)
Also called bile acid-binding resins and ion-exchange resins.
4. Cholesterol Absorption Inhibitor:
Ezetimibe (Zetia):
It is a drug that lowers plasma cholesterol levels. It acts by decreasing cholesterol absorption in the intestine.
MOA:
- Ezetimibe lowers plasma cholesterol levels by inhibiting the absorption from the intestine.
- This drug decreases the cholesterol delivery to the liver which in turn clears more cholesterol from the blood.
- It has selective action (( not interfere with TGs, lipid-soluble vitamins absorption)
- The levels of LDL-C in the serum are reduced by bile acid sequestrants.
Therapeutic Uses:
- As monotherapy or in combination with HMGRI for reduction of elevated total cholesterol.
5. Pyridine Derivatives:
- Nicotinic Acid (Niacin): Nicotinic acid is a water-soluble vitamin of the B family; after converted into the amide, it is incorporated as NAD. For effective action, the dose should be 1.5 to 3.5 gm daily. It is available as a sustained release dosage form.
Vitamin B3:
- For Lipid-lowering action it requires higher doses than when used as a vitamin.
- Effective, inexpensive, also used in combination with other lipid-lowering drugs.
MOA:
- It Increases the activity of lipase, which breaks down the lipids.
- It decreases the metabolism of cholesterol and triglycerides.
Indications:
- It is effective in the lowering of triglycerides, total serum cholesterol, and LDL levels.
- It also increases the HDL levels.
- It is also effective in the treatment of types IIa, IIb, III, IV, and V hyperlipidemias
Adverse Effect:
- Flushing (due to histamine release)
- Pruritus
- GI distress
- Liver dysfunction and jaundice. Serious liver damage is the most important risk.
6. LDL Oxidation Inhibitor:
Probucol:
- Probucol has two tertiary butyl phenol groups linked by the help of the dithiopropylidene bridge and gives a high lipophilic character along with high antioxidant properties.
- In humans, it reduces both liver and serum cholesterol levels and does not alter plasma triglycerides.
- It reduces LDL levels.
- It decreases the extent of HDL levels by a unique mechanism that is still not delineated.
- The decreased HDL level may be caused by the ability of probucol to inhibit the synthesis of apoprotein A-1, a major protein component of HDL.
- It is effective in reducing the levels of LDL and it is also used in hyperlipoproteinemias characterized by increased LDL levels.
ADR:
- GI disorders and prolongation of GI intervals.
Use:
It is used as an anti-hyperlipoproteinemic agent.
7. Miscellaneous Agent:
β-Sitosterol:
- Sitosterol is a plant sterol, whose structure is identical to that of cholesterol, except for the substituted ethyl group on C-24 of its side chain.
- Its hypolipidemic effect is not clearly understood, it is claimed that the drug inhibits the absorption of dietary cholesterol from the gastrointestinal tract.
- It is absorbed poorly from the mucosal lining and it is competing with cholesterol for absorption site in the intestine.
ADR:
- Diarrhea, constipation, GI disturbances.
Use:
- Anti cholesteric agent and treatment of prostatic edema.
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