| What are antihyperlipidemic drugs? | administration of drugs lowers plasma concentration either by reducing production of lipoproteins or reducing absorption of lipids or enhancing efficiency of their removal from plasma. |
| What are classes of antihyperlipidemic drugs? | 1. HMGCoA reductase inhibitors or (Statins)
2. Bile acid–binding resins or Bile acid sequestrants (Cholestyramine)
3. Nicotinic acid (Niacin)
4. Fibric acid derivatives (Fibrates)
5. Cholesterol absorption inhibitor (Ezetimibe)
These agents may be used alone or in combination.
However, drug therapy should always be accompanied by lifestyle modifications, such as exercise and a diet low in saturated fats |
| What is mechanism of action of statins? | Statin inhibit HMG-CoA reductase, leading to a decreased concentration of cholesterol within the cell.
Low intracellular cholesterol stimulates the synthesis of LDL receptors
Increased number of LDL receptors promotes uptake of LDL from the blood
Low intracellular cholesterol decreases the secretion of VLDL |
| What are effects of statins? | LDL and TG
HDL
CRP levels ➔anti-inflammatory role
Statin use might reduce platelet activation ➔ inhibit of platelet thrombus formation
Improve endothelial function (hypercholesterolemia adversely affects the process by which endothelium modulates vascular tone) |
| How are pharmacokinetics of statins? | Oral absorption is variable and High plasma protein binding
Metabolism:
Atorvastatin, Lovastatin and simvastatin are primarily metabolized by CYP3A4
Pravastatin and Rosuvastatin: insignificantly metabolized by CYP
Plasma half life:
Atorvastatin (14 h) and Rosuvastatin (19h) have long t1/2, the others 1-2 h |
| What are classes of statins? | Originally isolated from fungi and classified into:
① Natural: Lovastatin
② Semisynthetic:
➢ Simvastatin (ZOCOR)
➢ Pravastatin
③ Synthetic:
➢ Fluvastatin
➢ Atorvastatin (LIPITOR)
➢ Rosuvastatin (CRESTOR) |
| What are statins side effects? | LIPITOR
Liver effects, increased blood sugar, pain (muscles), impaired memory, tiredness/fatigue, others (headache, nausea), Rhabdomyolysis
Common ones are GI discomfort, headcahe, diarrhea, fatigue, nausea.
Serious are dose related hepatotoxicity elevated AST/ALT, myopathy and rhabdomyolysis. |
| How are drug interactions with statins? | Side effects may be exacerbated by interactions with other drugs like CYP3A4 inhibitors:
Antiretrovirals, ketoconazole, cimetidine, grapefruit, Fibrates, erythromycin and macrolides |
| What is the mechanism of action of bile-acid binding resins? | The bile-acid sequestrants are highly positively charged and bind negatively charged bile acids
Because of their large size, the resins are not absorbed, and the bound bile acids are excreted in the stool
95% of bile acids are normally reabsorbed ➔ interruption of this process depletes the pool of bile acids
hepatic bile-acid synthesis increases (cholesterol hydroxylase catalyzes the rate-limiting step in
conversion of cholesterol to bile acids) hepatic cholesterol content declines, production of LDL receptors increases and lead to the increase of the LDL clearance and decrease LDL levels from the blood |
| What are bile acid sequestrants drugs? | The two established bile-acid sequestrants or resins are (1) cholestyramine and (2) colestipol
They are among the oldest and safest of the hypolipidemic drugs
These resins are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently.
Cholestyramine therapy reduces LDL-C by 20% |
| How is pharmacokinetics, adverse effects and drug interactions for bile acid sequestrants? | Pharmacokinetic
Cholestyramine is taken orally. Because it is a very large (high molecular weight), it is neither absorbed nor
metabolically altered by the intestine. It is totally excreted by the feces.
Adverse Effects
Gastrointestinal disturbances such as constipation, nausea and flatulence.
Drug-Drug Interactions
Cholestyramine bind and decrease the absorption of many drugs, including: Some Thiazides, Digoxin, Warfarin, some
statins (Pravastatin and Fluvastatin)
NB: these drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after |
| What is Niacin? | Is a water soluble vitamin B3 (found in beans, green vegetables, mushrooms, peanuts)
Is a precursor to NAD+/NADH and NADP+/NADPH, which play essential metabolic roles in living cells
Is involved in both DNA repair, and the production of steroid hormones in the adrenal gland
Is administered orally
Is converted to Nicotinamide in the body (same activity as Niacin) |
| What is mechanism of action of Niacin? | -Niacin strongly inhibits lipolysis in adipose tissue, the primary producer of circulating free fatty acids (FFA).
The liver normally utilizes these circulating fatty acids as a major precursor for TG synthesis. Thus, niacin causes a decrease in liver TG synthesis, which is required for VLDL production
LDL (the cholesterol-rich lipoprotein) is derived from VLDL in the plasma. Therefore, a reduction in the VLDL concentration also results in a decreased plasma LDL concentration.
Thus, both plasma TG (in VLDL) and cholesterol (in VLDL and LDL) are lowered
Niacin treatment increases HDL cholesterol levels by reducing the CETPdependent transfer of cholesterol from HDL to VLDL and LDL
- By boosting secretion of tissue plasminogen activator and lowering the level of plasma fibrinogen, niacin can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis |
| What are therapeutic uses of niacin? | Particularly useful in the treatment of familial Hyperlipidemias.
Potent antihyperlipidemic agent for raising plasma HDL level |
| What are side effects of niacin? | Flushing (prostaglandin mediated) (in the face and upper trunk) affects compliance (ceases in most patients after 1 to 2 weeks of a stable dose )
Dyspepsia
Diarrhea
Increased uric acid levels (by inhibiting tubular secretion of uric acid)
Hepato toxicity have also been reported. The drug should be avoided in hepatic disease. |
| What are fibrates? | Fibrates activate PPAR (peroxisome proliferator-activated receptors)
The PPARs are a class of intracellular receptors that regulates carbohydrate and fat metabolism and adipose tissue differentiation
Activation of PPARs causes transcription of a number of genes that facilitate lipid metabolism
Upon binding to its natural ligand (fatty acids or eicosanoids) or hypolipidemic drugs ➔PPARs are
activated
In particular, PPARs regulates the expression of genes encoding for proteins involved in lipoprotein structure and function
Fibrates bind to PPARα- mainly in liver and adipose tissue |
| What is the mechanism of action of fibrate? | Fibrates bind to PPARα- mainly in liver and adipose tissue
Increased LPL Lipoprotein lipase synthesis: increase hydrolysis of Chylomicrons and VLDL
Stimulated synthesis of Acyl-CoA dehydrogenases involved in fatty acid oxidation: decrease of TGs liver synthesis so decrease of VLDL production
Stimulation of apoA-I and apoA-II expression so increase HDL levels |
| What are adverse effects of fibrates? | GI complaints: these lessen as the therapy progresses.
Gallstones: Because these drugs increase level of cholesterol in the bile, there is a predisposition to form
gallstones.
Myositis (inflammation of a voluntary muscle) can occur, and with muscle weakness or tenderness should be evaluated. |
| What are contraindications of fibrates and drug drug interactions? | Contraindications:
Myopathy and rhabdomyolysis have been reported in patients taking gemfibrozil and statins together.
The use of gemfibrozil is contraindicated with simvastatin.
Drug-Drug Interactions
Potentiate the action of oral anticoagulants and some hypoglycemic drugs displacing them from plasma
proteins binding sites
NB: Not used in pregnant or lactating women |
| What is mechanism of action of Ezetimibe? | Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver.
This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.
It lowers LDL cholesterol by 17 % and TG by 6%,
It increases HDL cholesterol by 1.3 %
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a Phase II reaction), with subsequent biliary and renal excretion |
| Table of all antihyperlipidemic drugs? | . |
| How is tx by statins in combination with other antihyperlipidemic? | It is often necessary to use two antihyperlipidemic drugs to achieve treatment goals in plasma lipid levels.
1. The combination of an HMG CoA reductase inhibitor
(lovastatin) with a bile acid–binding agent (colestipol) has
been shown to be very useful in lowering LDL-C levels
2. simvastatin and niacin as well as simvastatin and ezetimibe, are currently available combined in one pill to treat elevated
LDL cholesterol.
3. A fixed combination of simvastatin and ezetimibe decreases LDL-C levels by up to 60% at 24 weeks |
