1. Hypolipidemic Drugs
Classification:
1-HMG CoA Reductase Inhibitors: ( Lovastatin,  Mevastatin,  Pravastatin,  Simvastatin,  Rosuvastatin,  Atorvastatin,  Fluvastatin and  Cerivastatin)
2-Fibric Acid Derivatives: (Clofibrate,  Fenofibrate,  Bezafibrate,  Ciprofibrate and
 Gemfibrozil)
3-Bile Acid Binding Resins: (Cholestyramine,  Colestipol and  Colesevelam)
4- Niacin (Nicotinic Acid)
5-Cholesterol Absorption Inhibitors: (Ezetimibe)
6- Omega-3 marine triglycerides

2. Statins
-Statins are the most effective and best-tolerated agents for treating dyslipidemia.
Mechanism of action:
- Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis. By reducing the conversion of HMG-CoA to mevalonate inhibit hepatic cholesterol biosynthesis.
- Reduced free cholesterol content within hepatocytes → ↑ synthesis of LDL receptors →↑ removal of LDL from the blood, thereby lowering LDL-C.
-Statins also enhance the removal of LDL precursors (VLDL and IDL).
-Higher doses of the more potent statins (e.g., atorvastatin, simvastatin, and rosuvastatin) also can reduce triglyceride levels caused by elevated VLDL levels.

3. Biosynthesis of Cholesterol
HMG CoA synthase
CH3-C-SCoA OOC-CH2-C-CH2-C-SCoA O OH
CH3
acetyl coenzyme A hydroxy-3-methyl-glutaryl-CoA
Statins
HMG CoA
reductase
cholesterol
-OOC-CH2-C-CH2-CH2-OH OH
CH3
mevalonate

4. other Statins dynamics
improved endothelial function
reduced vascular inflammation and platelet aggregability
antithrombotic action
stabilisation of atherosclerotic plaques
increased neovascularisation of ischaemic tissue
enhanced fibrinolysis
-The efficacy and safety of the statins in reducing fatal and non-fatal CHD events, strokes, and total mortality are well established.
Depending on the dose , they
↓LDL 18-55%
↑HDL 5-15%
↓TG 7-30%
 Maximal effects on plasma cholesterol levels are achieved within 7–10 days. The statins are effective in almost all patients with high LDL-C levels.

5. Absorption, fate and elimination
After oral administration absorption of the statins varies between 30% -85%
- peak in 1–4 hours
All of the statins, except simvastatin and lovastatin, are administered as active b-hydroxy acids. -Simvastatin and lovastatin are administered as inactive lactones that must be transformed in the liver to their respective b-hydroxy acids.
-There is extensive first-pass hepatic uptake of all statins, but they enter the liver by different mechanisms.
-Due to extensive first-pass hepatic uptake, systemic bioavailability of 5%-30%
-Except for fluvastatin and pravastatin, the metabolites of all statins are active.
-In the plasma, >95% of statins and their metabolites are protein bound with the exception of pravastatin (50% bound).
-The half-lives 1–4 hours, except for atorvastatin and rosuvastatin, ~20 hours.
-Metabolized in the liver , and >70% of statin metabolites elimination in the feces.

6. Adverse effects:
Hepatotoxicity :
Myopathy:
Proteinuria:
Safety during pregnancy:
-The safety of statins during pregnancy has not been established.
-Women wishing to conceive should not take statins. During their childbearing years, women taking statins should use highly effective contraception.
- Nursing mothers also are advised to avoid statins.

7. Therapeutic uses:
-Each statin has a recommended starting dose. It is advisable to start each patient on a dose that will achieve the goal for LDL-C lowering according to level of LDL-C before the treatment.
-Hepatic cholesterol synthesis is maximal between midnight and 2:00 AM. Thus, statins with half-lives of 4 hours or less (all but atorvastatin and rosuvastatin) should be taken in the evening.
-The initial recommended dose of lovastatin is 20 mg and is slightly more effective if taken with the evening meal than if it is taken at bedtime. The dose may be increased every 3–6 weeks up to a maximum of 80 mg/day.
-The starting dose of simvastatin for most patients is 20 mg at bedtime unless the required LDL-C reduction exceeds 45% or the patient is a high-risk secondary prevention patient, in which case a 40-mg starting dose is indicated. The maximal dose is 80 mg, and the drug should be taken at bedtime. In patients taking fibrates, or niacin, the daily dose should not exceed 20 mg.
-Pravastatin therapy is started with a 20- or 40-mg dose that may be increased to 80 mg; it should be taken at bedtime. Since pravastatin is a hydroxy acid, it is bound by bile-acid sequestrants, which reduce its absorption. This is rarely a problem since the resins should be taken before meals and pravastatin should be taken at bedtime.
-The starting dose of fluvastatin is 20 or 40 mg, and the maximum is 80 mg/day. Atorvastatin has a long t1/2, which allows dosing at any time of the day. The starting dose is 10 mg, and the maximum is 80 mg/day.
-Rosuvastatin is available in doses ranging between 5 and 40 mg. It has a t1/2 of 20–30 hours and may be taken at any time of day. Treatment initiated with 5–10 mg daily, increasing stepwise if needed. If the combination of gemfibrozil with rosuvastatin is used, the dose of rosuvastatin should not exceed 10 mg.

8. Bile-Acid Sequestrants
cholestyramine , colestipol and Colesevelam
Mechanism of action:
The bile-acid sequestrants are highly positively charged and bind negatively charged bile acids.
The y are anion exchange resins , insoluble in water , not absorbed, and the bound bile acids are excreted in the stool. Since >95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids and increases hepatic bile-acid synthesis. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase. Inhibition of reductase activity by a statin substantially increases the effectiveness of the resins.

9. The two established bile-acid sequestrants or resins (cholestyramine and colestipol) are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently.
They ↓LDL 15-30%, ↑HDL 3-5%, TG No change
Colesevelam is a newer bile-acid sequestrant that is prepared as an anhydrous gel and taken as a tablet. It lowers LDL-C by 18% at its maximum dose.
The reduction in LDL-C by resins is dose-dependent.
Doses of 8–12 g of cholestyramine or 10–15 g of colestipol are associated with 12–18% reductions in LDL-C. Maximal doses (24 g of cholestyramine, 30 g of colestipol) may reduce LDL-C by as much as 30%, but will cause GI side effects that are poorly tolerated by most patients.

10. Adverse effects:
Associated with unacceptable gastrointestinal (GI) side effects (bloating and constipation) that limit compliance.
Since they increase triglyceride levels, severe hyper-triglyceridemia is a contraindication to the use of cholestyramine and colestipol.
Cholestyramine and colestipol both are available as a powder that must be mixed with water and drunk as a slurry. The gritty sensation is unpleasant to patients initially but can be tolerated.
Colestipol is available in a tablet that reduces the complaint of grittiness but not the GI symptoms.
Colesevelam is available as a hard capsule that absorbs water and creates a soft, gelatinous material that minimizes the potential for GI irritation.

11. Therapeutic uses:
The powdered forms of cholestyramine (4 g/dose) and colestipol (5 g/dose) are either mixed with a fluid (water or juice) and drunk as a slurry or mixed with crushed ice in a blender. Ideally, patients should take the resins before breakfast and before evening meal, one packet twice daily, and increasing the dosage after several weeks or longer as needed and as tolerated.
Colesevelam hydrochloride (WELCHOL) is available as a solid tablet containing g of colesevelam. The starting dose is either three tablets taken twice daily with meals or all six tablets
taken with a meal. The tablets should be taken with a liquid. The maximum daily dose is 7 tablets (4.375 g).

12. Niacin (Nicotinic Acid), Vit B3
The hypolipidemic effects of niacin require larger doses than are
required for its vitamin effects.
Its effects : LDL ↓ 5-25%, HDL ↑15-35%, TG ↓ 20-50%
In adipose tissue, niacin inhibits the lipolysis of triglycerides by
hormone-sensitive lipase, which reduces transport of free fatty
acids to the liver and decreases hepatic triglyceride synthesis.
Reduced triglyceride synthesis decreases hepatic VLDL production, which reduces LDL levels.
Niacin also promoting the clearance of chylomicrons and VLDL
Niacin raises HDL-C levels by decreasing clearance and enhancing HDL synthesis.

13. Absorption , fate and excretion:
The doses of regular (crystalline) niacin used to treat dyslipidemia are almost completely absorbed
Peak plasma concentrations are achieved within 30–60 minutes. The t1/2 is ~60 minutes , which accounts for the necessity of twice- or thrice-daily dosing. At lower doses, most niacin is taken up by the liver; only the major metabolite, nicotinuric acid, excreted in the urine. At higher doses, a greater proportion of drug is excreted in the urine as unchanged nicotinic acid.

14. Cutaneous effects include flushing , pruritus and rash of the face and upper trunk.
Flushing and associated pruritus are prostaglandin-mediated.
Flushing is worse when therapy is initiated or the dosage is increased, but ceases in most patients after 1–2 weeks of a stable dose.
Aspirin alleviates the flushing in many patients. Flushing recurs if only one or two doses are missed and is more likely to occur when niacin is consumed with hot beverages (coffee, tea) or with ethanol-containing beverages.
Flushing is minimized if therapy is initiated with low doses (100–250 mg twice daily) and if the
drug is taken after breakfast or evening meal.
Dry skin, a frequent complaint, can be dealt with by using skin moisturizers, and acanthosis nigricans can be dealt with by using lotions or creams containing salicylic acid.
Dyspepsia and rarer episodes of nausea, vomiting, and diarrhea are less likely to occur if the drug is taken after a meal.
Patients with any history of peptic ulcer disease should not take niacin because it can reactivate ulcer disease.
The most common serious side effects are hepatotoxicity, manifested as elevated serum
transaminases and hyperglycemia. Both regular (crystalline) niacin and sustained-release niacin
have been reported to cause severe liver toxicity, and sustained-release niacin can cause hepatic failure.
In patients with diabetes mellitus, niacin should be used cautiously, since niacin-induced
insulin resistance can cause severe hyperglycemia. Niacin use in patients with diabetes mellitus
often mandates a change to insulin therapy.
Niacin also elevates uric acid levels; a history of gout is a relative contraindication for niacin use.
Niacin, at doses used in humans, has been associated with birth defects in animal models and should not be taken by pregnant women.

15. Fibric Acid Derivatives:
Clofibrate, Gemfibrozil and a number of fibric acid analogs (fenofibrate, bezafibrate, and ciprofibrate).
LDL ↓ 5-20%, HDL ↑10-20%, TG ↓ 20-50%
The mechanisms:
Fibrates increasing triglyceride clearance and decreasing hepatic triglyceride synthesis.

16. Absorption, fate and excretion:
All of the fibrates are absorbed rapidly and efficiently (>90%) when given with a meal but less efficiently when taken on an empty stomach.
The ester bond is hydrolyzed rapidly, and peak plasma concentrations are attained within 1–4 hours.
More than 95% of these drugs are bound to plasma protein, mainly to albumin.
The half-lives of fibrates differ significantly, ranging from 1 hour (gemfibrozil) to 20 hours (fenofibrate).
The drugs distribute widely throughout the body, and concentrations in liver, kidney, and intestine exceed the plasma level. Gemfibrozil is transferred across the placenta.
The fibrate drugs are excreted predominantly as glucuronide conjugates; 60–90% of an oral dose is excreted in the urine, with smaller amounts appearing in the feces. Excretion is impaired in renal failure and fibrates are contraindicated in such patients.

17. Adverse effects:
Fibric acid compounds usually are well tolerated. Side effects, most often GI-related, may occur in 5–10% of patients but most often are not sufficient to cause drug discontinuation.
Other infrequent side effects include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia. Minor increases in liver transaminases and alkaline phosphatase have been reported.
Myopathy occasionally occurs in subjects taking clofibrate, gemfibrozil, or fenofibrate, and may occur in up to 5% of patients treated with a combination of gemfibrozil and higher doses of statins. Statin doses therefore should be reduced when a statin plus a fibrate are combined.
All fibrates increase the lithogenicity of bile. Clofibrate has been associated with increased risk of gallstone formation; gemfibrozil and fenofibrate reportedly do not increase biliary tract disease.
Renal failure and hepatic dysfunction are relative contraindications to fibrate therapy. Combined statin-fibrate therapy should be avoided in patients with impaired renal function.
Fibrates should not be used by children or pregnant women.

18. • Reduces cholesterol absorption by approximately 50%
Inhibition of Dietary Cholesterol Uptake
Ezetimibe:
Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorption by enterocytes in the small intestine.
• Reduces cholesterol absorption by approximately 50%
Therapeutic Effects : LDL ↓ 15-20%, HDL ↑ 1-2%, TG ↓ 5-10%

19. Absorption, fate and excretion:
-Ezetimibe (ZETIA) is available as a 10-mg tablet that may be taken at any time of day irrespective of food
-Ezetimibe is highly water insoluble.Oral administration gave variable bioavailability(35-60%)
- After ingestion, it is glucuronidated in the liver and intestin. ~70% is excreted in the feces and ~10% in the urine (as a glucuronide conjugate).
-Bile acid sequestrants inhibit its absorption, and the two agents should not be coadministered.

20. Adverse effects:
-Better tolerated than bile acid binding resins, Does not affect absorption of other compounds, such as fat-soluble vitamins
-GI effects: diarrhea, abdominal pain
-Infection and respiratory system disorders: sinusitis, pharyngitis, viral infections, coughing