Plasma Lipids
• Chylomicrons = Dietary triglycerides +
Cholesterol (10:1)
• VLDL = Endogenous TG + Cholesterol (5:1)
• IDL = Endogenous TG + Cholesteryl esters (1:1)
• LDL = Cholesteryl esters
• HDL = Phospholipids + Cholesteryl esters
Agents that lower the levels of lipids and lipoproteins in
blood
Clinical Terms
Hyperlipidemia – used collectively for raised level of
high cholesterol and triglycerides (TG) levels in
plasma
Hyperlipoproteinaemia – increased level of any
lipoprotein
Hypercholesterolaemia - cholesterol levels
Hypertriglyceridaemia/hyperlipaemia - TGs
Hyperlipidemia
• Primary • Secondary
– Familial – Diabetes
(single gene defect) – Myxoedema
– Nephrotic syndrome
– Multifactorial – Chronic alcoholism
(multiple gene defects) – Oral contraceptives
Two major clinical sequelae of
hyperlipidemia and atherosclerosis
These drugs thus retard Atherosclerosis
& prevent cardiovascular disease
Risk Factors for Coronary Heart Disease
• Age: > 45 yrs for males, >
55 yrs for females
• Family history
• Smoking
• Hypertension
• Low HDL cholesterol
• Obesity
What is Atherosclerosis?
Atherosclerosis is the
deposit of plaques
containing cholesterol
and lipids on the
innermost layer of the
walls of arteries.
A key risk factor in the
development of
atherosclerosis is high
blood cholesterol.
Classification of Hypolipidemics
1. HMG-CoA Reductase Inhibitors (Statins)
2. Bile acid sequestrants (Resins)
3. LPL activators (Fibric acid derivatives)
4. Inhibitor of TG synthesis and lipolysis
5. Inhibitor of intestinal sterol absorption
HMG-CoA Reductase Inhibitors (STATINS)
• Most efficacious & best tolerated
• Lovastatin, Pravastatin, simvastatin,
ATORVASTATIN, rosuvastatin,
pitavastatin
• HMG-CoA Reductase activity maximum at
midnight, statins given at bedtime except
atorvastatin and rosuvastatin (long t½)
• Competitive inhibitors of
Mechanism of Action HMG CoA reductase (rate-
limiting step)
• Thus conversion of HMG
CoA to mevalonate is
blocked ↓ cholesterol
synthesis
• ↑ No. of LDL
receptors removal
of LDL from blood
↓ LDL cholesterol
• ↓ VLDL synthesis
Actions
• Reduction in LDL cholesterol, Plasma TG and HDL
cholesterol
• Anti-atherosclerotic: Enhance production of NO in
endothelium, reduced LDL oxidation
• Additional antioxidant property- Atorvastatin
Adverse Effects
– Muscle aches – commonest
– Rise in serum transaminase
– GI complaints usually mild
– Headache, Sleep disturbance uncommon
--Not be given in pregnancy (no data on safety)
Therapeutic Uses
• First choice for primary hyperlipidemias
(raised LDL and total CH with or without raised
TG levels)
• Secondary hypercholesterolemia (DM/
nephrotic syndrome)
Bile acid sequestering agents
(RESINS)
Cholestyramine , Colestipol
Mechanism of Action: • Binds to bile acids in the
intestine & inhibit their
enterohepatic circulation
• Increased excretion of
bile salts and CH
(absorbed with help of
bile salts)
• Enhanced conversion of
CH to bile acids &
increase in no. of hepatic
LDL receptors
• Increased clearance of
IDL, LDL & indirectly of
VLDL
Adverse Effects
Not clinically popular because
• Unpalatable
• Nausea and vomiting
• Flatulence, Steatorrhoea
• Deficiency of fat soluble vitamins
• interfere with absorption of many drugs
Used in
• hyperlipidemias that are associated with
raised LDL cholesterol
Lipoprotein Lipase (LPL) Activators (FIBRATES)
Gemfibrozil,Benzafibrate and fenofibrate
Mechanism of Action: Peroxisome Proliferator
Activated Receptor (PPARα)
– increased LPL synthesis
(key enzyme in VLDL
degradation) and fatty acid
oxidation
– Reduce hepatic TG synthesis
& increase clearance of TGs
– Enhanced LDL receptor
expression in liver
– Decrease in TG (20-50%),
LDL (10-15%) and Increase in
HDL cholesterol levels (10-
15%)
Gemfibrozil:
Also decreases coagulation, promotes fibrinolysis –
contributes to antiatherosclerotic effect
Combination with statin increases risk of myopathy
CI in pregnancy
Fenofibrate
Most suitable for combining with statins (minimally
affects statin metabolism)
Adverse Effects
• Epigastric distress, skin rashes, headache, blurred vision
• Lithogenic effect (increased CH content of bile) – risk of CH
gall stones
• Myalgia
Uses
- Hypertriglyceridemias with / without
hypercholesterolemia
Inhibitor of TG synthesis & Lipolysis
NIACIN / NICOTINIC ACID
• Inhibits synthesis of TGs
Mechanism of and VLDL
Action
• Reduction in plasma TG
level,IDL & LDL also
reduced
• MOST EFFECTIVE
DRUG TO RAISE HDL
CHOLESTEROL
LEVEL
• Inhibits lipolysis in adipose
tissue
• Group B vitamin, in high doses, reduces
plasma lipids
• Affects all types of lipoproteins
• Action unrelated to vitamin activity, not
seen with nicotinamide
Adverse Effects
• Cutaneous vasodilatation –marked flushing, heat and
itching after every dose
• GI symptoms – dyspepsia, V, D, peptic ulcer
• Dryness & hyperpigmentation, hepatotoxicity
• Hyperglycemia, Hyperuricemia and Gout
Uses
Wide spectrum hypolipidemic drug
Adjunctive drug to statins/ fibrates
Inhibitor of intestinal sterol absorption
EZETIMIBE
• Selective inhibition of
dietary cholesterol and
phytosterol absorption
from the intestine
• A/E allergic reactions
• Uses Hyperlipidemia
along with statins
Treatments for Hyperlipidemia
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.
Summary
Drug Effect on Lipid Use
Profile
Statins ↓↓↓ LDL – CH Primary IIa, IIb,
↑ HDL – CH V
↓ TG Secondary
Bile acid ↓↓ LDL – CH Primary IIa, IIb,
sequestering ↑ HDL – CH V
agents
↔ TG
Drug Effect on Lipid Use
Profile
Fibrates ↓↓↓ TG Primary Type III,
↑↑ HDL - CH IV, V
↓ LDL - CH
Nicotinic Acid ↑↑↑ HDL - CH Primary Type III,
↓↓ TG IV, V
↓ LDL – CH
