ANTIHYPERLIPIDEMIC AGENTS Flashcards
What do antihyperlipidemic agents do?
promote the reduction of lipid levels in the blood by either
1) Lowering levels of low-density lipoprotein (LDL) cholesterol: this prevents primary and secondary symptoms of coronary heart disease.
2) reduce triglyceride levels.
What are lipoproteins?
What can lipoproteins be separated into?
How are lipid disorders related to hyperlipoproteinemia?
cholesterol/triglycerides noncovalently bound with protein and carbohydrate.
separated by ultracentrifugal techniques into chylomicrons, very–low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Lipid disorders are related to problems of lipoprotein metabolism that create conditions of hyperlipoproteinemia.
There are 6 types of this condition.
What are the types and characterisics of hyperlipoproteinemia?
What is the drug of choice to treat Type III?
What is the drug of choice to treat Type IIa
type I: caused by decrease in activity of lipoprotein lipase. There are no drugs for this.
Type II: Type IIa has elevated LDL and normal levels of triglycerides. Treat with Cholestyramine resin
Type IIb has elevated VLDL and LDL levels.
Type III: rare disorder with broad band of Beta lipoprotein. Treat with Clofibrate
type IV: high VLDL
Type V: high chylomicrons and VLDL, plasma triglycerides
Reduce anticoagulants dosage, if used with Clofibrate to keep prothrombin time within the desired limits.
CLASSIFICATION OF ANTIHYPERLIPIDEMIC AGENTS
- HMG CoA Reductase Inhibitors.
- Fibrates
- Bile Acid Sequestrants
- LDL Oxidation Inhibitor: Probucol
- Pyridine Derivatives: Nicotinic acid, Nicotinamide
- Cholesterol Absorption Inhibitors: Ezetimibe
- Miscellaneous Agents: β-Sitosterol, Dextrothyroxine
HMG CoA Reductase Inhibitors
Lovastatin
Simvastatin
Metastatin
Pravastatin
Fluvastatin
Atorvastatin
Pitavastatin
Rosuvastatin
These are statins.
Lovastatin and simvastatin are lactones and prodrugs.
Pravastatin administered as the sodium salt of the Beta-hydroxy acid.
Fluvastatin and Atorvastatin have heptanoic acid side chain that is critical for HMG CoA reductase.
Atorvastatin combination therapy with amlodipine for management of high cholesterol and high blood pressure
Fibrates
Clofibrate
Fenofibrate
Gemfibrozil
Ciprofibrate
Benzafibrate
Fluvastatin
Bile Acid Sequestrants
Cholestyramine
Colestipol
Colesevelam
Cholestyramine resin for type IIa with controlled diet to reduce Beta- lipoproteins.
Colestipol hydrochloride reduces cholesterol levels without affecting triglycerides. effective for type II.
Both Cholestyramine resin and Colestipol are anion-exchange resin bile-sequestering agents but Colesevelam is not an anion-exchange resin.
METABOLISM OF
ANTIHYPERLIPIDEMIC AGENTS
1)In the body, Clofibrate is converted by esterases into Clofibric acid. This Binds to serum albumin, Circulates in the blood and Is the active form responsible for hypolipidemic effect
2) Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, is metabolised in the liver to 2-hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile.
3) Lovastatin made by fermenting fungi:
Aspergillus terreus and Monascus ruber is a prodrug given in an inactive lactone form.
In the body, it is converted to Beta-hydroxy acid with an open ring structure. This active form causes competitive, reversible inhibition of HMG CoA reductase, the rate limiting enzyme in cholesterol synthesis
4) Rosuvastatin is metabolized mainly by CYP2C9 & approximately 10% is recovered as metabolite N-desmethyl rosuvastatin.
MOA OF
ANTIHYPERLIPIDEMIC AGENTS
1) Clofibrate inhibits cholesterol synthesis between the steps of Acetate → Mevalonate by inhibiting the enzyme sn-glyceryl-3-phosphate acyltransferase. Clofibrate also affects the liver’s cholesterol regulation by Inhibiting the enzyme HMG-CoA reductase.
2) D-thyroxine increasing the breakdown (catabolism) of cholesterol in the liver by stimulating 7-α-cholesterol hydroxylase. This enzyme is rate-limiting—it controls the speed of converting cholesterol into bile acids.
3) Ezetimibe decreases cholesterol absorption in the intestine by blocking the absorption of the sterol at the Brush boarder. The β-lactam ring binds to the NPC1L1 protein responsible for absorbing cholesterol. Used in combination with simvastatin
DRUG INTERACTIONS OF
ANTIHYPERLIPIDEMIC AGENTSt
1) D-Thyroxine boosts the effect of anticoagulants e.g. warfarin/dicumarol. So reduce the anticoagulant dose by 1/3 to keep the prothrombin time (blood clotting time) in the right range.
2) D-Thyroxine can increase the need for insulin or oral hypoglycemic medications.
3) Pravastatin absorption can be reduced if taken with resins like cholestyramine because pravastatin has a carboxylic acid group
4) Cholestyramine has less effect on Lovastatin and Simvastatin
5) People taking atorvastatin/simvastatin and other statin drugs metabolized via CYP3A4 should avoid consuming grapefruit since it contains components (flavonoid naringin, or the furanocoumarin bergamottin) that inhibit the CYP3A4 enzyme in the intestines. It increases Cmax and AUC, blood levels of atorvastatin, which could increase the risk of adverse effects
