hyperlipidemia hyperlipoproteinemia hyperlipoproteinemia (cholesterol, triglyceride, ldl-c, vldl)...

HyperlipidemiaHyperlipidemia

Hyperlipoproteinemia Hyperlipoproteinemia

(cholesterol, Triglyceride, LDL-C , VLDL)(cholesterol, Triglyceride, LDL-C , VLDL)

Lead to atherosclerosis and Coronary Lead to atherosclerosis and Coronary artery disease (CAD)artery disease (CAD)

Hyperlipidemia

Endothelial injuryThrombosis

Atherosclerosis

Smooth muscle cell proliferation

Macrophage inflammatory/immunologic mechanism

AtherosclerosisAtherosclerosis

Atherosclerosis is a disease which Atherosclerosis is a disease which characterized by intimal thickening and characterized by intimal thickening and lipid deposition.lipid deposition.

Definition

AtherosclerosisAtherosclerosis

Hypolipidemic drugsHypolipidemic drugs Bile Acid Sequestering resinsBile Acid Sequestering resins

HMG CoA Reductase InhibitorsHMG CoA Reductase Inhibitors

Fibric Acid DerivativesFibric Acid Derivatives

Nicotinic Acid (Niacin)Nicotinic Acid (Niacin) ProbucolProbucol

CE= cholesteryl ester

Colestyramine, colestipol

Mechanism of action

Binds to bile acid in intestine and prevents its transformation into cholesterol

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

** hypercholesterolemia when a statin is contraindicated

** uses unrelated to atherosclerosis, including:pruritus in patients with partial biliary obstruction

(bile acids that deposit into the skin is responsible for the pruritus)

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

GIT symptoms - nauzea, abdominal bloating,نفخ constipation or diarrhea, because resins not absorbed.resins are unappetizing. This can be 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 resin

Effect on LipidsEffect on Lipids

LDL

20-30%

HDL

2-8%

TG

10% (Esp.TG>250mg/dl )

2. HMG CoA Reductase 2. HMG CoA Reductase Inhibitors (Statin)Inhibitors (Statin)

lovastatinatorvastatinpravastatinsimvastatinFluvastatin

Rosuvastatin

Mechanism of StatinMechanism of Statin

Specific competitive inhibitor to HMG CoA Specific competitive inhibitor to HMG CoA Reductase Enzyme which is the rate limiting Reductase Enzyme which is the rate limiting step in cholesterol biosynthesisstep in cholesterol biosynthesis

The synergism effect of statin The synergism effect of statin and resinand resin

Effect on LipidsEffect on Lipids

LDL

25-55%

HDL

5-10%

TG• 10-20% (triglycerides < 250 mg/dl)

• 35-45% (triglycerides > 250 mg/dl)

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

- mild gastrointestinal disturbancesmild gastrointestinal disturbances

- increased plasma activities in liver increased plasma activities in liver enzymesenzymes

- severe myositis (rhabdomyolysis) severe myositis (rhabdomyolysis)

andand angio-oedema (rare) angio-oedema (rare)

Clinical Use

• Hyperlipidemia

•In atherosclerosis

3. Fibric acid derivatives 3. Fibric acid derivatives (fibrates)(fibrates)

Clofibrategemfibrozil fenofibratebezafibrate ciprofibrate

Mechanism of actionMechanism of action

- - - increase the activity of lipoprotein lipase, - increase the activity of lipoprotein lipase, hence increasing hydrolysis of triglyceride in hence increasing hydrolysis of triglyceride in

chylomicrons and VLDL particles. chylomicrons and VLDL particles. - reduce hepatic VLDL production reduce hepatic VLDL production andand increase increase

hepatic LDLhepatic LDL uptake.uptake.- Produce a modest decrease in LDL (~ 10%) and Produce a modest decrease in LDL (~ 10%) and

increase in HDL (~ 10%).increase in HDL (~ 10%).- But, a marked decrease in TGs (~ 30%).But, a marked decrease in TGs (~ 30%).

Effect on LipidsEffect on Lipids

TGTG

25-40%25-40% HDLHDL

5-15%5-15% LDLLDL

15-20% 15-20%

ToxicityToxicity

GIGI nausea., vomiting, gall stonenausea., vomiting, gall stone

Skeletal MuscleSkeletal Muscle Myopathy, weakness (Myopathy, weakness (Esp. with Esp. with StatinsStatins))

LiverLiver Increase aminotransferaseIncrease aminotransferase

Hematologic changeHematologic change Anemia, leukopeniaAnemia, leukopenia

Uses: Uses:

1st-line defense for:1st-line defense for:

*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).* Indicated in patients with VERY HIGH [TG]s who are at risk for pancreatitis

nicotinic acid (vitamin B3) Water soluble vitamin Nicotinic acidNicotinic acid acts by acts by decreasingdecreasing esterification of esterification of hepatichepatic

TGTG, and increasing the activity of , and increasing the activity of lipoproteinlipoprotein lipase .lipase . It decreasesIt decreases hepatic TG production hepatic TG production andand VLDL Secretion VLDL Secretion

(by ~ 30-50%) (by ~ 30-50%) modest reduction in LDL modest reduction in LDL andand increase in increase in HDLHDL.. Nicotinic Nicotinic

acid was the 1st lipid-lowering drug to acid was the 1st lipid-lowering drug to decrease decrease mortality mortality in in patients with CAD.patients with CAD.

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: flushing, palpitations , GIT disturbances.flushing, palpitations , GIT disturbances.

Currently, nicotinic acid is rarely used.Currently, nicotinic acid is rarely used.

OtherOther LIPID-LOWERING DRUGS

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)

Ezetimibe:Ezetimibe:

Inhibitors of Intestinal CHO Absorption:

Reduces CHO absorption and decreases LDL with little change in HDL

May be synergistic with statins: so good for combination therapy.

A potent lipophilic antioxidantA potent lipophilic antioxidant

Probucol

A t h e r o g e n e s i s involves several stages:- endothelial dysfunction with altered PGI2 and NO synthesis-endothelial cells monocyte attachment- bind LDL- oxidatively modified LDL is taken up by macrophages- having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially- atheromatous plaque formation- rupture of the plaque

HDL Prevent Foam Cell FormationHDL Prevent Foam Cell Formation

LDLLDL

LDLLDL

EndotheliumEndothelium

Vessel LumenVessel LumenMonocyteMonocyte

Modified LDLModified LDL

MacrophageMacrophage

MCP-1MCP-1AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux

Foam Foam CellCell