HYPOLIPIDAEMIC DRUGS

Dr Anshuman ParidaDepartment of Pharmacology

Introduction

•Hypolipidemic agents, or antihyperlipidemic agents

•A diverse group of pharmaceuticals used in T/t of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia).

•They are also called lipid-lowering drugs.

Lipid transport and metabolism• Lipids originate from two sources:

▫Endogenous lipids : synthesized in the liver, ▫Exogenous lipids: ingested and processed in

the intestine.

• Dietary cholesterol & triglycerides : packaged into chylomicrons in the intestine into bloodstream via lymphatics.

• Liver synthesizes TG and cholesterol packages them as VLDLs before releasing them into the blood

• VLDLs in muscle and adipose blood vessels, their TG are hydrolyzed by LPL to fatty acids.

• The fatty acids that are released are taken up by the surrounding muscle and adipose cells.

• During this process, the VLDLs become progressively more dense and turn into LDLs

• Most LDLs taken up by Liver for disposal, • some circulate and distribute cholesterol to the rest of the

body tissues.

• HDLs, which are also secreted from the liver and intestine, have the task of preventing lipid accumulation.

• They remove surplus cholesterol from tissues and transfer it to LDLs that return it to the liver.

Hyperlipidemia • Elevated concentrations of lipid i.,e,

Hyperlipidemia development of atherosclerosis and CAD.

• Dyslipidemia can be primary or secondary.

• Primary forms : genetically determined

• Secondary forms : Consequence of other conditions such as Diabetes mellitus,

Alcoholism, Nephrotic syndrome,

Chronic renal failure, Administration of drug…

• Minor (and emerging) factors include: obesity, physical inactivity, athrogenic diet, lipoprotein (a), homocysteine, prothrombotic and proinflammatory factors, impaired fasting glucose.

Management of Dyslipidemia

• Drug therapy to lower plasma lipids is only one approach to treatment

• Used in addition to dietary management And

• Correction of other modifiable cardiovascular risk factors

• Several drugs are used to decrease plasma LDL-CHO

CLASSIFICATION 1/2•HMG - Co A Reductase inhibitors

( Statins ) : Atorvastatin, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, Rosuvastatin

•Bile acid binding resins : Cholestyramine, Colestipol, Colesavelam.

•Inhibitors of intestinal absorption of cholesterol : Stanol esters , Ezetemibe

CLASSIFICATION 2/2•Activators of Lipoprotein lipase (LPL)

(Fibrates) : Gemifibrozil, Bezafibrate, Fenofibrate, and Ciprofibrate

•Inhibitor of VLDL secretion and lipolysis : Niacin (Nicotinic acid)

•New drugs (CETP Inhibitors) : Torcetrapib, Anacetrapib

Class: HMG-CoA reductase inhibitors

• Mechanism: ↓rate-limiting step in cholesterol synthesis.

• Clinical use: ↓ LDL, ↓ triglycerides

• Side effects: H : Hepatotoxicity M : Myositis,rhabdoMyolysis G : ↑ FPG C : ↑ Creatinine phosphokinase A : HeadAche, Joint pain

R : Rash

Drug Fluvastatin

Pravastatin

Rosuvastatin

Lovastatin

Simvastatin

Pitavastatin

Atorvasatin

Dose mg/day

10-80 10-40 5-40 10–40 5–20 1–4 mg 10-80

Absorptio

complete

Incomplete, Varies from 45-75%

T ½(hours)

1-3 1-3 18–24 1-4 2-3 12 14

CYP CYP2C9 CYP3A4

DRC Non linear linear

LDL-CH lowering efficacy

35% <25% 51-55% 40% 40% 40% 51-55%

Special features

↓ Plasma

Fibrinogen

Max ↑ HDL

First clinically used

Inactive pro

drug C/I - 80

mg

Latest & Most Potent

Antioxidant

property

InteractionsCYP3A4 CYP2C9

INHIBITORS INDUCERS INHIBITORS

Macrolide Phenytoin Ketoconazole

Cyclosprin Gresiofulvin Metronidazole

Tacrolimus Thiazolidinediones Cimetidine

Ketoconazole Rifampicin Sulphinpyrazone

Protease inhibitor

Barbiturates

Paroxetine

Venlafexine

Verapamil

Amiodarone

Contraindications•Pregnancy & lactation•Children < 7-8 years•Active liver diseases

Class: Fibrates• Mechanism: binds with PPAR α

↑ lipoprotein lipase → ↓ VLDL ↓TG

• Clinical use: Elevated TG and remnants.

• Side effects: GI upset (dyspepsia), Cholelithiasis,

Myositis Hepatitis Rare

• Drug interaction: Warfarin ,OHA

Drug Gemfibrozil Fenofibrate Benzafibrate Clofibrate

Dose 600 mg BD 145mg QID 200 mg TDS

T ½ (hours) 1.5 20 18-24

Absorption Intestine, Enterohepatic circulation

Completely intestine

Distribution Tightly bound to plasma protein

Excretion Kidney, liver urine, faeces Kidney

Special feature

Trial for Cancer, Alzheimer

Discontinued

Interactions•Increased risk of myopathy when combined

with statins.(fenofibrate)

•Displace drugs from plasma proteins( e.g. oral anticoagulants and oral hypoglycemic drugs).

Contraindications:

•1- Patients with impaired renal functions.•2- Pregnant or nursing women.•3-Preexisting gall bladder disease

Class : Nicotinic Acid •Mechanism: ↓ fatty acid release from

adipose tissue, ↓ hepatic synthesis of LDL

•Clinical use: ↑ HDL, ↓ LDL, ↓TG

•Side effects: Skin flushing, paresthesias, pruritus, GI upset, ↑LFTs, hyperglycemia, hyperuricemia

•Prevention of side effects: Aspirin

•Wide spectrum antilipidemic drugs

•Most effective in reducing TG level.

•Dose: Start with 100 mg TDS, gradually increase to 2–4 g per day in divided doses.

•To be taken just after food to minimize flushing and itching.

Class: Cholesterol absorption inhibitors

•Ezetinib

•Mechanism: inhibits the luminal cholesterol uptake by inhibiting the

transport protein on NPC1L1

•Clinical use: ↓ LDL

•Side effects: Diarrhea, abdominal pain Angioedema.

•Reduces both dietary and billiary cholesterol.

•Dose : 10 mg OD

•T 1/2 ~ 22 hours

•Long half-life:▫Permits once-daily dosing▫May improve compliance

Class: Bile acid resins• Mechanism: Bind intestinal bile acids → ↓bile acid

stores & ↑ catabolism of LDL from plasma.

• Clinical use: ↓ LDL

• Side effects: Constipation, ↑ Gallstone formation, GI upset, LFT abnormalities, Myalgias. ↓ Absorption of drugs ADEK vitamins from the small intestine.

• Dose : 4 to 8 g OD/BD, max dose 24 g/d.

• Drug interactions : due to the risk of decreased absorption of these drugs. Digitalis, Estrogens and progestins,Oral diabetes drugs, Penicillin G,Phenobarbital,Spironolactone,Tetracycline Thiazide-type diuretic pills,Thyroid medication Warfarin,Leflunomide

• Contraindication ▫ 1- Complete biliary obstruction( because bile is not secreted into the intestine).▫ 2- Chronic constipation.▫ 3-Severe hypertriglyceridemia(TG >400 mg/dL)

Class : CETP INHIBITORS• Torcetrapib and Anacetrapib banned.

• Dalcetrapib (Clinical trails)

• Anacetrapib – Increases HDL-C by 129%

• Obicetrapib (TA-8995), Phase II results reported in 2015

• Cholesteryl ester transfer protein (CETP) Facilitates transfer of cholesteryl esters (CE)

from HDL-C to LDL-C, VLDL-C during “reverse cholesterol transport”

Antihyperlipedemic combinationsIndications:

• Increased VLDL during treatment of hypercholesterolemia with resins.

• Combined increase in LDL & VLDL.

• High LDL or VLDL not normalized with a single drug.

• Severe hypertriglycerdemia or hypercholesterolemia.

• To take lower doses of each drug

SUMMARY

Thank you……