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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……