58 - Drug Regulation of Serum Lipids Flashcards
Treatment for dyslipidaemia 1) 2) 3) 4)
1) Establish baseline fasting plasma lipid profile
2) Consider cardiovascular status and risk factors
3) Treat secondary causes (EG: obesity, diabetes)
4) Manage modifiable risk factors
Sources of cholesterol
1)
2)
1) Diet (animal fats)
2) De novo synthesis in liver (probably sufficient for body’s cholesterol needs)
Where do statins originally come from?
Fungi
Mevastatin from Penicillium citrinum
Effects of statins 1) 2) 3) 4) 5)
1) Decrease mevalonic acid, therefore cholesterol synthesis
2) Compensatory increase in hepatic LDL receptors
3) Increased clearance of LDL from blood
4) Decreased plasma total cholesterol as well as LDL
5) Increased plasma HDL:LDL ratio
Effect of increasing statin dose
Doubling dose leads to significantly lesser percentage decreases in serum LDL
Pharmacological action of statins
HMG-CoA inhibitors
How long does it take for statin therapy to reach maximum effectiveness?
1-2 years
Precautions to take with statin therapy
1)
2)
3)
1) Grapefruit juice involves cytochrome P450 metabolism in liver. So does statin, so increases toxicity of statins
2) Some antibiotics, antifungals also use P450
3) Barbituates decrease statin levels
4) Minor increases in creatine kinase (from muscle breakdown, can lead to muscle pain and tenderness)
Common contraindications of statins 1) 2) 3) 4)
1) Mild GI symptoms
2) Headaches
3) Insomnia
4) Dizziness
Rare, serious side effects of statins 1) 2) 3) 4)
1) Myopathy (minimised with coenzymeQ10 therapy)
2) Rhabdomyolysis
3) Renal failure
4) Hepatitis, liver failure (~2% of patients have mild increase in serum aminotransferase)
Effect of statins on foeti
Impair myelination
When are statins not to be prescribed?
Pregnancy, pre-surgery, post-trauma
Treatment options for hypercholesterolaemia 1) 2) 3) 4) 5)
1) Statins
2) Bile acid sequestrants/resins
3) Nicotinic acid (niacin)
4) Fibrates
5) Fish oils
Examples of bile acid sequestrants
1) Cholestyramine
2) Cholestipol
How do bile acid sequestrants work? 1) 2) 3) 4)
1) Non-absorbable macromolecules, ingested as a granular preparation.
2) Bind bile acids, preventing gut absorption of lipids
3) This results in an up-to-10-times increase in bile acid secretion
4) As bile acid requires cholesterol to synthesise, this causes upregulation of hepatic LDL receptors, removal of LDL from plasma, more cholesterol metabolism
Common adverse effects of bile acid sequestrants 1) 2) 3) 4)
1) Abdominal discomfort
2) Bloating
3) Constipation
4) Flatulence
What are bile acid sequestrants used to treat?
Hypercholesterolaemia, mixed hyperlipidaemia
Rare adverse events of bile acid sequestrants 1) 2) 3) 4)
1) Increased TGs
2) Faecal impaction
3) Decreased absorption of fat soluble viamins
4) Steatorrhoea
Effect of resins on absorption of other drugs
Decreases absorption of anionoic, cationic, neutrally-charged drugs.
When should resins be taken?
Hours before or after other drugs taken, as decrease absorption of other drugs
Drug that lowers LDL by binding to a sterol transporter
Ezetimibe
Ezetimibe effect
Binds to a sterol transporter in the intestine. This inhibits cholesterol absorption, lowers LDL.
Possible ezetimibe side effects
Diarrhoea, tiredness, headache,allergic reactions, joint, stomach pain
How is ezetimibe used?
1)
2)
1) Alone in statin-intolerant patients
2) Used together with statins to lower statin dose
Other names for niacin
Nicotinic acid, vitamin B3
Mechanism by which niacin decreases LDL
Unclear.
Effects of niacin 1) 2) 3) 4)
1) Decrease secretion of VLDL particles from liver
2) Reduces plasma LDL and triglycerides (so also for mixed hyperlipidaemia)
3) Increases HDL
4) Lowers potentially atherogenic lipoprotein (a) -
Lp(a) formed from LDL is found in plaques, inhibits thrombolysis
Common adverse effects of niacin
–vasosodilation, flushing, hypotension
–nausea, vomiting
–tolerance develops to flushing as gastric upsets
Rare adverse effects of niacin
–itching
–glucose intolerance
–uric acid retention
–may increase hepatic impairment
When is niacin used?
Rarely used alone. Often in combination
Examples of fibrates
Gemfibrozil, fenofibrate
Mechanism of action of fibrates
1)
2)
3)
1) Agonists at nuclear receptors
2) Bind peroxisome proliferator activated receptor alpha
3) Increased synthesis of lipoprotein lipase
Effect of increasing lipoprotin lipase levels 1) 2) 3) 4)
1) Increase lipolysis of lipoprotein triglyceride
2) Moderate reduction in plasma triglycerides
3) Moderate increase in HDL
4) Variable effects on LDL
Use of fibrates for cholesterol treatment
Generally used as adjunct to dietary changes for high TGs, mixed hyperipidaemia, and second line therapy for hypercholesterolaemia
PPARa
Peroxisome proliferator activated receptor alpha.
A nuclear receptor, which encodes lipoprotein lipase.
Precautions to take with fibrates
Mild elevation of serum aminotransferase can present.
Monitor levels at three-month intervals. Reduce dose or discontinue fibrates if necessary
Common adverse events with fibrates 1) 2) 3) 4)
1) Nausea
2) Dry mouth
3) Headache
4) Rash
Rare adverse events with fibrates 1) 2) 3) 4) 5)
1) Arrhythmias
2) Gallstones
3) Photosensitivity
4) Impotence
5) Depression
Effect of fish oil omega-3 fatty acids on bloop lipid composition
Reduce TAGs and VLDL
Possible side effects of fish oils
Diarrhoea, abdominal discomfort
BLood-thinning effect
Drugs that decrease LDL 1) 2) 3) 4) 5) 6)
1) Statins (biggest decrease)
2) Bile acid resins
3) Ezetimibe
4) Niacin
5) Fibrates
6) Fish oil (also decreases VLDL)
Drugs that increase LDL receptor expression in liver
1)
2)
3)
1) Statins
2) Bile acid resins
3) Niacin
Drugs that increase HDL levels 1) 2) 3) 4)
1) Statins
2) Niacin (biggest increase)
3) Fibrates
4) Fish oil
Drugs that decrease TAG levels 1) 2) 3) 4)
1) Statins
2) Niacin
3) Fibrates (increase lipoprotein lipase)
4) Fish oil
Effects of statins on blood lipid concentrations 1) 2) 3) 4)
1) Decrease LDL
2) Increase LDL receptor
3) Increase HDL
4) Decrease TAGs
Effects of ezetimibe on blood lipid concentrations
Decreases LDL
Effects of bile acid resins on blood lipid concentrations
1)
2)
1) Decrease LDL
2) Increase LDL receptor
Effects of niacin on blood lipid concentrations 1) 2) 3) 4)
1) Decrease LDL
2) Increase LDL receptor
3) Increase HDL
4) Decrease TAGs
Effects of fibrates on blood lipid concentrations 1) 2) 3) 4)
1) Decrease LDL
2) Increase HDL
3) Decrease TAGs
4) Increase lipoprotein lipase
Effects of fish oils on blood lipid concentrations
1)
2)
3)
1) Decrease LDL and VLDL
2) Increase HDL
3) Decrease TAGs
Dyslipidaemia drugs that act on intestine
Ezetimibe, bile acid resins
Dyslipidaemia drugs that act on capillaries
Fibrates
Dyslipidaemia drugs that act on extrahepatic tissues
Statins
