Antihyperlipidemics Flashcards
ATHEROSCLEROSIS AND HYPERCHOLESTEROLEMIA
+ tx
•Increased risk of atherosclerosis is
associated with hypercholesterolemia
● Increases risk of cardiovascular (CV) and
cerebrovascular diseases
-Statins:
• lower plasma cholesterol
• Reducing CV events by 25–50% and prolonging life
ATHEROMA + what do risk factors cause
Focal disease of the intima of large and medium-sized arteries
Many of the risk factors cause endothelial dysfuntion
Healthy endothelium produces nitric oxide (NO) and other mediators that protect against atheroma
ATHEROGENESIS: what happens
-Endothelial dysfunction
-Altered NO biosynthesis
-Injury of endothelium leads to expression of adhesion molecules
-Monocyte attachment and migration into the intima -Low-density lipoprotein (LDL) cholesterol oxidised(oxLDL)
ATHEROGENESIS (oxLDL)
•oxLDL is taken up by macrophages (foam cells) •oxLDL activates macrophages
-Releases proinflammatory cytokines
•Foam cells and T lymphocytes form fatty streaks •Proliferation of smooth muscle
-Deposition of connective tissue components
-Atheromatous plaque
•Plaque can rupture
•Forming a substrate for thrombosis
Exogenous pathway (from diet)
•Cholesterol and triglycerides absorbed from ileum •Transported as chylomicrons to muscle and adipose tissue
•Triglycerides are hydrolysed by lipoprotein lipase
-Tissues take up the resulting free fatty acids and glycerol
•Chylomicron remnants pass to the liver
•Undergo endocytosis via receptors on hepatocytes •Cholesterol liberated in hepatocytes
Stored
Oxidised to bile acids
Secreted unaltered in bile
Enters into the endogenous pathway
Endogenous pathway
•Cholesterol and newly synthesised triglycerides are transported from the liver as VLDL to muscle and adipose tissue
-Triglycerides are hydrolysed to fatty acids and glycerol; these enter the tissues
• Lipoprotein particles become LDL particles
-Key in atherogenesis
•Cells take up LDL by endocytosis via LDL receptors that recognise apoB-100
•Reverse cholesterol transport
Cholesterol can return to plasma from the tissues in HDL particles
Endo pathway cholesterol, lipoprotein
·Cholesterol esterified with long-chain fatty acids in HDL particles
·Resulting cholesteryl esters are transferred to VLDL or LDL particles by a transfer protein present in the plasma cholesteryl ester transfer protein (CETP)
·Lipoprotein(a),Lp(a), LDL species associated with atherosclerosis
-Localised in atherosclerotic lesions
/-May promote thrombosis
PREVENTION OF ATHEROMATOUS Dx
What tx prevents this
•Treatment of hypertension and, to a lesser extent, diabetes mellitus reduces incidence of symptomatic atheromatous disease
•Antithrombotic drugs reduce arterial thrombosis
•Reducing LDL is also effective
Main agents used clinically for lipid-lowering drugs
•Statins
•Fibrates
•Inhibitors of cholesterol absorption
•Nicotinic acid or its derivatives
•Other novel therapies
What are STATINS
They are HMG-CoA Reductase Inhibitors.
The rate-limiting enzyme in cholesterol synthesis.
STATINS examples
•Examples: simvastatin, lovastatin, pravastatin •Atorvastatin and rosuvastatin: long-lasting inhibitors
High-intensity statins at high doses: may reduce LDL by more than 50%
STATINS MoA
•Decreased hepatic cholesterol synthesis
•Upregulates LDL receptor synthesis
-Increasing LDL clearance from plasma into liver cells
•Main biochemical effect of statins is therefore to reduce plasma LDL
•Some reduction in plasma triglyceride and increase in HDL
•Positive results on morbidity and mortality
ADVERSE EFFECTS of statins
•Statins are well tolerated
Mild unwanted effects:
•Muscle pain (myalgia)
•Gastrointestinal disturbance
•Hepatotoxicity (raised LFTs)
•Insomnia
•Rash
More serious adverse effects are rare
•Severe myositis (rhabdomyolysis)
•Angio-oedema
-Contraindicated in pregnancy
Drug interactions:
• w/ Gemfibrozil: increase risk of rhabdomyolysis
• w/ CYP450 inhibitors: increase toxicity
CLINICAL USES of statins (revision)
- Secondary prevention of MI+ stroke who have symptomatic atherosclerotic dx. (Angina, transient ischaemic attacks)
- Primary prevention of arterial dx in pts who are at high risk b/c of elevated serum cholesterol conc., especially w/ other risk factors (diabetes)
3,. Atorvastatin lowers cholesterol. In pts w/ homozygous Familial hypercholesterolaemia - In severe drug resistant dyslipidaemia, ezetimibe is combined w: statin tx
- CI in pregnancy
Fibrates examples
Bezafibrate, ciprofibrate, gemfibrozil, fenofibrate, clofibrate
What do Fibrates do
Markedly reduce circulating VLDL and triglycerides
Modest (approximately 10%) reduction in LDL
Approximately 10% increase in HDL
(Statins on the other hand are good at reducing LDL levels)
(Fibrates: good at reducing VLDL + triglycerides)
Fibrates MoA
•Agonists at PPARα nuclear receptors
•Increase transcription of the genes for lipoprotein
lipase, apoA1 and apoA5
•They increase hepatic LDL uptake
Also:
•Reduce plasma C-reactive protein and fibrinogen
•Improve glucose tolerance
•Inhibit vascular smooth muscle inflammation
Fibrates Adverse Effects
•Rhabdomyolysis is unusual but can be severe
-Occurs particularly in: •Renal impairment •Alcoholics
•Combined use of fibrates with statins is generally
inadvisable (sometimes undertaken by specialists)
•GI symptoms, pruritus and rash are more common than with statins
•Clofibrate (and other fibrates to a lesser extent) predispose to gallstones
-Clofibrate use is limited to patients who have had a cholecystectomy (i.e. removal of the gall bladder)
DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION
1. Bile acid-binding resins
Examples
Colestyramine, colestipol, colesevelam
Bile acid-binding resins MoA
•Sequester bile acids in the intestine
• Prevent their reabsorption and enterohepatic recirculation
• Excretion in feces
•Decreased absorption of cholesterol
• Increased metabolism of endogenous cholesterol into bile acids in the liver
•Increased LDL receptor expression on hepatocytes
Evidence on survival is lacking, although effective at
reducing cholesterol levels
Bile acid-binding resins
(HDL,LDL, triglycerides)
•HDL is unchanged, triglycerides are increased (CI in
hypertriglycemia)
•Increased clearance of LDL from the blood and a
reduced concentration of LDL in plasma
•Interfere with absorption of fat-soluble vitamins, thiazide diuretics, digoxin and warfarin
Bile acid-binding resins
Adverse Effects:
May cause unacceptable constipation and bloating
Bile acid-binding resins
Clinical uses
Additional treatment in patients with severe disease (e.g. FH)- Not commonly used
Bile salt-associated symptoms of pruritus (itch) and diarrhea
DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION
2. Ezetimibe
MoA
•Inhibits absorption of cholesterol (and of plant stanols) from the duodenum
-Blockade of a transport protein (NPC1L1) •Decreased LDL: stimulates LDL receptor synthesis •No effect on the absorption of fat-soluble vitamins, triglycerides or bile acids
•Results on CV outcomes in primary prevention lacking
