Arteriosclerosis= hardening of the arteries.

• ↑Serum cholesterol (above 4mmol/L) ↑risk of coronary heart disease• <4mmol/L level of plasma cholesterol is considered to be safe• ↑LDL ↑risk of coronary heart disease while,• ↑HDL ↓risk of coronary heart disease

• ↑Serum cholesterol (above 4mmol/L) ↑risk of coronary heart disease• <4mmol/L level of plasma cholesterol is considered to be safe• ↑LDL ↑risk of coronary heart disease while,• ↑HDL ↓risk of coronary heart disease

Dyslipidemia vs. hyperlipidemiaDyslipidemia: increase or decrease in specific types of lipoproteins. Hyperlipidemia: increase in level of plasma lipid in general.

Classification of lipoproteinsFraction%ProteincholesterolTriacylglycerol

(TG)PL

HDL, α-lipoproteins

4521826

LDL, β-lipoproteins

2151)cholesterol

carrier(

1018

VLDL,pre β-lipoproteins

12154)TG carrier(

9

Chylomicron2685)TG carrier(

7

If a drug acts on TAG then it affects

VLDL

Drugs acts on cholesterol it affects

LDL

If a drug acts on TAG then it affects

VLDL

Drugs acts on cholesterol it affects

LDL

Lipids & cholesterol are transported in the plasma as lipoproteins.

Lipophilic components (cholesterol ester and TG) inside the core of

lipoprotein

Hydrophilic components are on

the lipoprotein’s surface

Chylomicron:- transport of exogenous dietary TG

VLDL:- transport of endogenous dietary TG from liver to tissue

LDL:- transport of cholesterol to tissues

HDL:- transport of cholesterol out of the tissues to the liver.

• Type I has no pharmacologic treatment (only dietetic treatment).

• The most severe type is type II (whether IIa or IIb).

• Type IIb is mixed or combined (VLDL& LDL).

• Type III has abnormal elevated lipid (β VLDL)

• Both types IV&V have modest risk for atherosclerosis.

1-HypertriglyceridemiaDiabetes mellitus, obesity ,alcoholism (release VLDL), estrogens

(e.g.oral contraceptives), chronic renal & liver failure

2-Hypertriglyceridemia with hypercholesterolemia

Diabetes mellitus, renal transplantation, nephrotic syndrome

3-Hypertriglyceridemia with reduced HDLDrug-induced like: Non- selective β-blockers,

isoretinoin(derivative of Vit A) and norgestrel (contraceptive).

Classification of Cholesterol levels

Total Cholesterol mmol/l

LDL cholesterol mmol/l

Desirable<5.2<3.4

Borderline high

>5.2< 6.2>3.4<4.1

High>6.2>4.1

For managing patients with no need for pharmacologic therapy.

Cholesterol, saturated fats and trans fats→↑ LDL and (decrease HDL trans particularly)

Acute ↑ in carbohydrates intake →↑ VLDL.

Alcohol ↑triglycerides by inducing the secretion of VLDL from the liver.

Some forms of dietary fiber reduce LDL modestly.

Cis bond can converted to trans bond by increasing temperature

cistrans

Omega-3 fatty acids found in fish oils ↓triglycerides in

patients with endogenous or mixed lipidemia.

Supplementation with antioxidant vitamins such as

ascorbic acid (250 mg) and vit.E (50 IU on alternate

days) may be beneficial.

↓Calories & loss of weight →↓LDL & VLDL.

Cigarette smoking is a major risk factor for coronary disease.

It is associated with reduced levels of HDL,

impairment of cholesterol retrieval, Cytotoxic effects on the endothelium,

Increased oxidation of lipoproteins,

Stimulation of thrombogenesis.

Before getting to drugs, here’s a revision about lipoprotein and lipid metabolism

Lipids are digested and absorbed in the small intestine to simple fats

carried as chylomicron

Lipids are digested and absorbed in the small intestine to simple fats

carried as chylomicron

Peripheral tissues take up fats from chylomicron via the enzyme

lipoprotein lipase which converts TAGs to fatty acids leaving cholesterol

in chylomicron

Peripheral tissues take up fats from chylomicron via the enzyme

lipoprotein lipase which converts TAGs to fatty acids leaving cholesterol

in chylomicron

Chylomicron now is called chylomicron remnant is absorbed by

the liver

Chylomicron now is called chylomicron remnant is absorbed by

the liver

Cont’d

The liver distributes TAGs to different tissues in the form of VLDL

The liver distributes TAGs to different tissues in the form of VLDL

VLDL is digested by tissues with the help of lipoprotein lipase

VLDL is digested by tissues with the help of lipoprotein lipase

Then it’s called LDL which transports cholesterol to the tissues and liver

(bad cholesterol)

Then it’s called LDL which transports cholesterol to the tissues and liver

(bad cholesterol)

IDL

Enterohepatic circulation

The liver synthesizes bile from cholestrol

Bile is secreted in the duodenum to help fat

digestion

85-95% of the bile returns to the liver to be modified and released

again

85-95% of the bile returns to the liver to be modified and released

again

Nicotinic acid is not related to nicotine, yet it was first synthesized from it.

Nicotinic acid(niacin) is vit.B3

Ni ac in

nicotin acid vitamin

Mechanism of action:-Niacin inhibits VLDL’s secretion from the liver, thus concomitantly decreasing circulating LDL & hence ↑ HDL.Converted in the body to nicotinamide. Excreted in the urine as nicotinamide.

Nicotinamide has no antihyperlipidimic activity, yet it retains its vitamin’s physiologic

activity .

Has a slow onset of action

)2 months(

Harmless cutaneous flush due to vasodilatation resulting from the release of PG.

Pruritus, rash, and dry skin.

Impairment of glucose tolerance in patients with latent diabetes. Thus, niacin is used with caution in diabetic patients.

This manifestation

can be alleviated by taking aspirin.

This phenomenon is less seen in long-term

use of niacin .

Cont’d Nausea & abdominal discomfort.Reversible elevations in aminotransferases (liver toxicity).

Hyperuricemia, thus contraindicated in gout patients.

Supplied as the free acid form Undergoes enterohepatic circulationTightly bound to plasma albuminReadily passes the placenta

(thus contraindicated in pregnant women)

70% is excreted unchanged in the urine

T1/2 = 1.5 hr

Is a methylethyl ester that is hydrolyzed completely in the intestine.

T1/2 = 20 hr

60% is excreted in the urine as a glucuronide conjugate and about 25% in feces.

Fenofibrate is uricosuric (decreases uric acid in the blood by increasing the excretion of uric acid in the urine) used with gout

patients accompanied with dyslipidemia.

So it stimulate gene expression of lipoprotein lipase.Effect on chylomicron & VLDL

chylomicron remnant LDL

They potentiate the action of coumarins (e.g. warfarin)

They have toxic effect on

the liver

The risk of myopathy increases when fibrates are given along with statins.

↑ risk of cholesterol gallstone formation taken carfully in patients with biliary tract

diseases.

This group is not first line treatment.

They are polymers.

They bind bile acids in the intestine preventing their absorption.

In hypercholesterolemia it →↓LDL cholesterol,

If used to ↓ LDL in patients with combined (mixed) hyperlipidemia →↑VLDL .

They increase bile acid excretion

Little bile goes back to the liver

The liver needs more

cholesterol for bile synthesis

The liver increases LDL receptors in order

to get more cholesterol from the

plasma

↓LDL in plasma

Resins should be taken in two or three doses with meals, where they are

ineffective when taken between meals.

Resins should be taken in two or three doses with meals, where they are

ineffective when taken between meals.

Toxicity

They are devoid of systemic side effects.

Common complaints are constipation & bloating sensation.

Heart burn

Malabsorption of vit. A,D,E,K (lipid soluble vitamins)

Dry flaking skin

Lead to ↓ Absorption of thiazides, tetracyclines, & folic acid

Formation of gallstone (less than fibrates)

They are structural analogs of HMG-CoA reductase enzyme.

e.g. Lovastatin, atorvastatin, fluvastatin, pravastatin,simvastatin, & rosuvastatin.

HMG-CoA reductase mediates the first step in steroid genesis.

They are most effective in reducing LDL.

They decrease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions.

Lovastatin and simvastatin are prodrugs, due to the inactive closed lactone ring.

The closed ring is opened, becoming active, when drugs are passing through the GIT.

Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners that are active as given (due to the already open lactone ring).

Abosorption of statins is 40% to 75% with the exception of fluvastatin 100%.

Absorption of statins are enhanced when taken with food with the exception of pravastatin.

All have high first-pass metabolism in the liver.

Most of the absorbed dose is excreted in the bile; about 5–20% is excreted in the urine.

T1/2 range from 1 hour to 3 hours except for atorvastatin, which has a t1/2 of 14 hours, and rosuvastatin, 19 hours.

Because cholesterol occurs predominantly at night, reductase inhibitors-except atorvastatin and rosuvastatin- should be given in the evening.

catabolism of lovastatin, simvastatin, and atorvastatin → cytochrome P450 3A4

fluvastatin and rosuvastatin → CYP2C9.

Pravastatin is catabolized through other pathways, including sulfation.

Drug interactions:-Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. inhibit P450 3A4

Adverse effect ↑level of serum transaminase, may produce liver toxicity in patient with liver disease or a history of alcohol abuse.Minor increases in creatine kinase activity in plasma.Myopathy may occur when used in combination with fibrates.Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy.↑Lenticular opacity

Ezetimibe inhibits intestinal absorption of cholesterol and phytosterols (plant sterols).

Reduces LDL

Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours.

It undergoes enterohepatic circulation.

t1/2 = 22 hours

80% excreted in feces

Plasma ezetimibe concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine.

Therapeutic Uses

Primary hypercholesterolemia, effective in patients with phytosterolemia.

ADR

Reversible impaired hepatic function

Up regulation of LDL receptor

VLDL)VLDL(