Transcript drugs in Dyslipidaemias

Drugs in dyslipidaemias
Dr Sanjeewani Fonseka
Department of Pharmacolgy
Atheroma
• Focal disease of
intima
• Deposition of C in
arterial wall
Atheromatous disease
• myocardial infarction
• Cerebo vascular accidents
chy
remnant
chy
TAG
Exo
Lipids
FFA
FFA
Skeletal, cardiac and adipose
Endo
tissue
(+ cholesterol)
Synthesized
VLDL
LDL
by liver
Cleared
by
liver
Liver - bile
Cell
membrane
HDL
Dyslipidaemias
• Hypercholesterolaemia
• Hypertriglyceridaemia
• Mixed dyslipidaemia
Dyslipidaemias
Primary
Secondary
• Genetically
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• Cassify according to
lipoprotein particle
DM
Alcohol
Nephrotic
CRF
Hypothyroidism
Liver disease
Drugs
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Statins
• Competitive inhibition of HMG CoA reductase
• HMG Co A
HMG Co A
reductase
• Reduced C in the liver
• ↑ Expression of LDL receptor
• Increased LDL clearance
mevalonic acid
• Activation of sterol
regulatory element
binding protein 2
(SREBP2)
• ↑ Expression of gene
encoding LDL receptor
statin cont;
Other effects of statins
• Improve endothelial function
• Decreased coagulation
• Decreased inflammation
• Improved stability of atherosclerotic
plaques
statin cont;
• Well absorbed
• Metabolized in liver
• Extensive pre- systemic
metabolism
statin cont;
Statins
• ↓ LDL-cholesterol by 25-55%
• ↑ HDL-cholesterol by 5%
• ↓ triglycerides by 10-35%
• Given once daily (nocte)
statin cont;
Statins
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Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Rosuvastatin
statin cont;
Clinical use
• Primary prevention
• Secondary prevention
statin cont;
Statins: adverse effects
• Hepatotoxicity
• Myotoxicity
• Dyspepsia, abdominal pain, diarrhoea
• Angioedema
statin cont;
Statins: hepatotoxicity
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Asymptomatic
↑ ALT, AST
First 6 months
Discontinued if ALT / AST > 3
times the upper limit of normal
range
statin cont;
Statins: myotoxicity
• Pain / tenderness, weakness
• ↑ CK > 10 times upper limit of normal
• Reversible
• ↑ risk with concurrent fibrate therapy,
hypothyroidism, renal insufficiency
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Fibrates
• Activate peroxisome proliferatoractivated receptor-α (PPARα)
• Heterodimer binds to peroxisome
proliferator response elements
(PPREs) in the promoter regions of
specific genes
Fibrates cont
Fibrates cont:
• Gemfibrozil, fenofibrate
• ↓ LDL-cholesterol by 5-20%
• ↑ HDL-cholesterol by 10-35%
• ↓ triglycerides by 20-50%
Fibrates cont
Clinical use
• Mixed dyslipidaemia
• Low HDL
Fibrates cont
• Well absorbed
• Elimination renal
Fibrates cont
Fibrates: adverse effects
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Gastrointestinal discomfort
Myopathy
↑ liver transaminases
Gallstone formation (Gemfibrozil)
Displace warfarin from albumin
binding sites
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Bile acid binding resins
• Cationic polymer resins that bind
non-covalently to negatively-charged bile
acids in small intestine
• Enterohepatic circulation of bile acids
interrupted causing up-regulation of 7αhydroxylase in hepatocytes
Bile acid binding resins cont;
Bile acid binding resins cont
• Increased expression of the LDL
receptor
• Concurrent up-regulation of hepatic
cholesterol and triglyceride synthesis
Bile acid binding resins cont
• Cholestyramine, colestipol
• ↓ LDL-cholesterol by 15-30%
• ↑ HDL-cholesterol by 3-5%
• Triglycerides: no effect or ↑
Bile acid binding resins cont
• Not absorbed from GIT
• Bloating & dyspepsia
• Decreased absorption of digoxin,
warfarin, fat-soluble vitamins
• Take one hour before or 4 h after
colestyramine
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Niacin
• Also known as nicotinic acid
• ↓ LDL-cholesterol by 5 – 25%
• ↑ HDL-cholesterol 15 – 35%
• ↓ Triglycerides by 20 – 50%
Niacin cont;
• ↓ adipocyte hormone-sensitive lipase activity
• ↓ availability of FFA to liver for TG (VLDL)
synthesis
• ↑ half-life of apoA-I (major apolipoprotein in HDL)
Niacin cont;
adverse effects
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Cutaneous flushing & pruritus
Release of prostaglandins D2 & E2
Prevented by aspirin
Extended-release formulations associated
with less flushing
• hyperuricaemia, impaired insulin sensitivity,
myopathy
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Inhibitors of cholesterol absorption
• Ezetimibe
• Decreases cholesterol
transport from micelles
into enterocytes by
inhibiting brush border
protein NPC1L1
• Reduces cholesterol
incorporation into VLDL in
liver
Inhibitors of cholesterol absorption
• rapidly absorbed by enterocytes
• Eliminated in bile
• Undergoes enterohepatic circulation
• Clinical benefit uncertain
Drugs in dyslipidaemias
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Statins
Fibrates
Bile acid binding resins
Niacin
Inhibitors of cholesterol absorption
Omega-3 fatty acids
Omega-3 fatty acids
• Eicosapentaenoic acid (EPA)
• Docosahexaenoic acid (DHA)
• Reduce triglycerides
• Increase C
• Benefit - uncertain
Summary
• Most important hyperlipidaemia is
hypercholesterolaemia
• Most effective drug – statin
• Drugs reduce risk of MI