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 TGs)

Liver synthesizes cholesterol and secretes it as VLDL (IDLLDL)

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 (cont)
High-Density Lipoprotein (HDL)
So called good cholesterol, HDLs 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

Statins

Fibrates

LIPID-LOWERING DRUGS

Resins

Others

LIPID-LOWERING DRUGS

Statins
HMG-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 + increased clearance of LDL

Several studies demonstrated positive effects on morbidity and mortality

LIPID-LOWERING DRUGS
Statins Pharmacodynamic actions:
improved endothelial function reduced vascular inflammation and platelet aggregability antithrombotic action stabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissue enhanced fibrinolysis immune suppression osteoclast apoptosis and increased synthetic activity in osteoblasts

LIPID-LOWERING DRUG
Statins
Pharmacokinetics
- well absorbed when given orally - extracted by the liver (target tissue), undergo extensive presystemic biotransformation Simvastatin is an inactive pro-drug

LIPID-LOWERING DRUG
Statins
Clinical uses 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 DRUG
Statins
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

Fibrates
- 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
Other effects: improve glucose tolerance inhibit vascular smooth muscle inflammation

Fibrates

fenofibrate clofibrate gemfibrozil ciprofibrate

LIPID-LOWERING DRUGS
Fibrates

A d v e r s e e f f e c t s:
in patients with renal impairment myositis (rhabdomyolysis) myoglobulinuria, acute renal failure Fibrates should be avoided in such patients and also in alcoholics) mild GIT symptoms

LIPID-LOWERING DRUGS
Fibrates

Clinical uses

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 lipidlowering drugs)

LIPID-LOWERING DRUGS

Bile acid binding resins

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 resins

C l i n i c a l u s e s: heterozygous familiar hypercholesterolemia

an addition to a statin if response has been inadequate

hypercholesterolemia

when a statin is contraindicated

uses unrelated to atherosclerosis, including:

pruritus in patients with partial biliary obstruction bile acid diarrhea (diabetic neuropathy)

LIPID-LOWERING DRUGS
Adverse
Bile acid binding resins e f f e c t s:

GIT symptoms - nauzea, abdominal bloating,

constipation or diarrhea resins are unappetising. This can b minimized by suspending them in fruit juice interfere with the absorption of fat-soluble vitamins and drugs (chlorothiazide, digoxin, warfarin)
These drugs should be given at last 1 hour before or 4-6 hours after a resin

LIPID-LOWERING DRUGS

Others
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

Others
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
Synthesis of LDL

Triglycerides LDL HDL

LDL Triglycerides

Statins

Cholesterol synthesis
LDL receptor

Fibric acid derivatives

vLDL synthesis LPL triglyceride hydrolysis LDL catabolism

Triglycerides HDL

SUMMARY (cont)
Ezetimibe

Intestinal absorption of
cholesterol

LDL

Triglycerides LDL HDL Triglycerides

Bile acid binding resins

Interrupts enterohepatic circulation of bile acids.

Synthesis of bile acids Synthesis of LDL receptors

SIDE EFFECTS
Bile acid-binding resins constipation, gastric discomfort, nausea, hemorrhoidal bleeding flushing, nausea, pruritus, gout, diarrhea, hepatic dysfunction abnormal liver function myositis, muscle breakdown, teratogenic effects nausea, abnormal liver function, myositis well tolerated

Niacin acid

HMG-CoA reductase inhibitors Fibric acid derivatives Ezetimide

THE END!!
Thank you.