Hypolipidemic Drugs

Introduction• Dyslipidemia is a general term associated with

high cholesterol and/or high triglyceride (TG) levels in plasma.

• Cases where both cholesterol (>200 mg/dL) and TGs are elevated, are considered to be Combined Dyslipidemias.

• Two major clinical sequlae of hyperlipidemia are acute pancreatitis and atherosclerosis.

Atherosclerosis• Atherosclerosis is the deposit of plaques containing

cholesterol and lipids on the innermost layer of the walls of arteries.

• Atherosclerosis is the leading cause of death due to (MI, hypertension, death)

• A key risk factor in the development of atherosclerosis is high blood cholesterol.

Triglycerides and Cholesterol are the two most common lipids

•Triglycerides – used for fat storage and as an energy source•Can be synthesized by the cells or obtained from the diet•Are the major fat in human diet because thesis the most common animal and plant fat•Require bile salts to be absorbed.

Cholesterol•Metabolism• Obtained from the diet or synthesized in liver, intestine, and endocrine glands.

• Acetyl CoA is its precursor

• HMG-CoA reeducates is the major rate-limiting enzyme in cholesterol synthesis

• Cholesterol synthesis is controlled in most tissues by negative feedback to most tissues by negative feedback to HMG-CoA reeducates

Cholesterol

•Functions:•Serves as a stabilizing component of cell membranes

•Serves as a precursor to bile salts

•Serves as a precursor for all steroid hormones

Is Cholesterol good or bad?

•Cholesterol is essential for life

•All steroid hormones are formed formed from it including:

•Calcitriol (Vitamin D hormone) – essent for life

•Aldosterone and mineralocorticoids (essential for life)

•Androgens and estrogens(not essential for life, but many people think it is essential)

•Cortisol and related glucocorticoids (essential for life)

Cholesterol in bile salts is highly recycled

•Bile Salts•Synthesized by liver from cholesterol.•Secreted into duodenum via gall bladder and biliary tract.•Bile salts are 95% reabsorbed, mostly in ileum.•Reabsorbed bile salts return to the liver where they are excreted again.•5% of bile salts are excreted in the feces.

Definitions Chylomicrons

The largest of the lipoproteins, formed in the intestines and carry triglycerides (TG) of dietary origin.

Very Low Density Lipoproteins (VLDL) Secreted by the liver, provide a means for TG from liver to

peripheral tissues. (Mostly TG’s) Liver synthesizes cholesterol and secretes it as

VLDL (→IDL→LDL) Low Density Lipoproteins (LDL) (mostly cholesterol

So called “bad cholesterol” transports cholesterol from liver to the blood stream. High levels in the blood are associated with an increased risk of atherosclerosis and coronary artery disease. (Normal is <100 mg/dL)

Definitions (con’t)

• High-Density Lipoprotein (HDL)• So called “good cholesterol”, HDL’s acquire cholesterol

from peripheral tissues i.e. arterial walls. Low HDL levels are a risk factor for cardiovascular disease. (< 40 mg/dL)

Primary Dyslipidemias Brief Summary

B. Secondary Dyslipidemias These are conditions in which hyperlipidemia is a

symptom of a primary disease:

› A) Diabetes – most common cause of combined dyslipidemia (Both high TG and high cholesterol)

› B) Hypothyroidism – patients tend to have high cholesterol but normal triglycerides

› C) Birth Control Pills – patients tend to have high cholesterol and high triglycerides.

› D) Drug Induced Dyslipidemia – anti-HIV drugs, thiazide diuretics

Treatments for Elevated Lipids• First and foremost, before drug intervention is employed, treatment

should involve lifestyle modification. ( Exercise, Diet) • Reducing cholesterol levels and increasing dietary fiber can improve lipid

profiles. (mono-unsaturated and polyunsaturated fats)

• Daily exercise and weight control also can improve lipid levels.

• If these things do not sufficiently treat the dsylipidemia, then pharmacological intervention can begin.

Treatments for Elevated Lipids

Fibrates

Others

Resins

Statins

LIPID-LOWERING DRUGS

LIPID-LOWERING DRUGS

StatinsStatinsHMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase

inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acid

Simvastatin + pravastatin + atorvastatin decrease hepatic CHO synthesis

increase in synthesis of CHO receptors increase in synthesis of CHO receptors + increased clearance of LDL+ increased clearance of LDL

Several studies demonstrated positive effects on morbidity and mortality

LIPID-LOWERING DRUGS StatinsStatins

PPharmacodynamic actions:harmacodynamic actions: improved endothelial functionimproved endothelial function reduced vascular inflammation and platelet aggregabilityreduced vascular inflammation and platelet aggregability antithrombotic actionantithrombotic action stabilisation of atherosclerotic plaquesstabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissueincreased neovascularisation of ischaemic tissue enhanced fibrinolysisenhanced fibrinolysis immune suppressionimmune suppression osteoclast apoptosis and increased synthetic activity in osteoclast apoptosis and increased synthetic activity in osteoblastsosteoblasts

LIPID-LOWERING DRUGStatinsStatins

Pharmacokinetics- well absorbed when given orally- extracted by the liver (target tissue), undergo

extensive presystemic biotransformation

Simvastatin is an inactive pro-drug

LIPID-LOWERING DRUGStatinsStatins

C l i n i c a l u s e s• Secondary prevention of myocardial infarction and stroke

in patients who have symptomatic atherosclerotic disease (angina, transient ischemic attacks) following acute myocardial infarction or stroke

• Primary prevention of arterial disease in patients who are at high risk because of elevated serum CHO concentration, especially it there are other risk factors for atherosclerosis

Atorvastatin lowers serum CHO in patients with homozygous familiar hypercholesterolemia

LIPID-LOWERING DRUGStatinsStatins

A d v e r s e e f f e c t s:- mild gastrointestinal disturbances

- increased plasma activities in liver enzymes - severe myositis (rhabdomyolysis) and angio-oedema (rare)

LIPID-LOWERING DRUGS

FibratesFibrates- stimulate the beta-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle

- increase the activity of lipoprotein lipase, hence increasing hydrolysis of triglyceride in chylomicrons and VLDL particles

- reduce hepatic VLDL production and increase hepatic LDL uptake

LIPID-LOWERING DRUGS FibratesFibratesO t h e r e f f e c t s :

improve glucose tolerance inhibit vascular smooth muscle inflammation

fenofibrate clofibrate gemfibrozil ciprofibrate

LIPID-LOWERING DRUGS FibratesFibrates

A d v e r s e e f f e c t s:A d v e r s e e f f e c t s:

in patients with renal impairment myositis in patients with renal impairment myositis (rhabdomyolysis) (rhabdomyolysis) myoglobulinuria, acute renal failure myoglobulinuria, acute renal failure Fibrates should be avoided in such patients and also in Fibrates should be avoided in such patients and also in alcoholics)alcoholics)

mild GIT symptoms

LIPID-LOWERING DRUGS FibratesFibrates

C l i n i c a l u s e sC l i n i c a l u s e s

mixed dyslipidemia (i.e. raised serum TG and CHO)

patients with low HDL and high risk of atheromatous disease (often type 2 diabetic patients)

patients with severe treatment- resistant dyslipidemia (combination with other lipid-lowering drugs)

LIPID-LOWERING DRUGS Bile acid bindingBile acid binding resinsresins

sequester bile acids in the GIT prevent their reabsorption and enterohepatic recirculation

The r e s u l t is: decreased absorption of exogenous CHO and increased

metabolism of endogenous CHO into bile acid acids

increased expression of LDL receptors on liver cells

increased removal of LDL from the blood

reduced concentration of LDL CHO in plasma (while an unwanted increase in TG)

LIPID-LOWERING DRUGS Bile acid binding resinsBile acid binding resins

C l i n i c a l u s e s:C l i n i c a l u s e s: heterozygous familiarheterozygous familiar hypercholesterolemiahypercholesterolemia an addition to a statin if response has been an addition to a statin if response has been

inadequateinadequate hypercholesterolemiahypercholesterolemia when a statin is when a statin is contraindicatedcontraindicated uses unrelateduses unrelated to atherosclerosis, including: to atherosclerosis, including: pruritus pruritus in patients with partial biliary obstructionin patients with partial biliary obstruction bile acid diarrheabile acid diarrhea (diabetic neuropathy) (diabetic neuropathy)

LIPID-LOWERING DRUGS Bile acid binding resinsBile acid binding resins

A d v e r s e e f f e c t sA d v e r s e e f f e c t s::

GITGIT symptoms symptoms - - nauzea, abdominal bloating, nauzea, abdominal bloating, constipation or diarrheaconstipation or diarrhea resins are resins are unappetisingunappetising. This can b. This can b minimized byminimized by suspending them in fruit juicesuspending them in fruit juice interfere with the absorption of fat-soluble interfere with the absorption of fat-soluble vitamins vitamins andand drugs (chlorothiazide, digoxin, warfarin) drugs (chlorothiazide, digoxin, warfarin)

These drugs should be given at last 1 hour before or 4-6 hours after a These drugs should be given at last 1 hour before or 4-6 hours after a resin resin

LIPID-LOWERING DRUGS OthersOthers

Nicotinic acid inhibits hepatic TG production and VLDL secretion modest reduction in LDL and increase in HDL

A d v e r s e e f f e c t s:flushing, palpitations , GIT disturbances

LIPID-LOWERING DRUGS OthersOthers

Fish oil (rich in highly unsaturated fatty acids)the omega-3 marine TG - reduce plasma TG but increase CHO (CHO is more strongly associated wih coronary artery disease)-the effects on cardiac morbidity or mortality is unproven( although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)

SUMMARY (HYPOLIPIDEMICS)

• Niacin ↓ Synthesis of VLDL ↓Triglycerides ↓ Synthesis of LDL ↓ LDL ↑ HDL

Statins ↓Cholesterol synthesis ↓ LDL ↑LDL receptor ↓Triglycerides

Fibric acid ↓vLDL synthesis ↓ Triglycerides

derivatives ↑LPL ↑ HDL ↑triglyceride hydrolysis ↑LDL catabolism

SUMMARY (con’t)

• Ezetimibe ↓Intestinal absorption of ↓ LDL

cholesterol ↓Triglycerides

Bile acid binding Interrupts enterohepatic ↓ LDL

resins circulation of bile acids. ↑ HDL

↑Synthesis of bile acids ↑ Triglycerides

↑Synthesis of LDL receptors

SIDE EFFECTS

Bile acid-binding constipation, gastric resins discomfort, nausea,

hemorrhoidal bleeding

Niacin acid flushing, nausea, pruritus, ↑gout, diarrhea, hepatic dysfunction

HMG-CoA reductase abnormal liver functioninhibitors myositis, muscle breakdown,

teratogenic effects

Fibric acid derivatives nausea, abnormal liver function, myositis

Ezetimide well tolerated

THE END!!

Thank you.