Drug Regulation of Serum Lipids Flashcards
Explain the concept of dyslipidaemia?
Dyslipidaemia:
- In the 1950s and 60s it was recognised that high blood cholesterol correlated with increased risk of IHD
- dyslipidaemia = abnormal lipid profile
– can lead to atherosclerosis, increased risk of MI, stroke
– hypercholesterolaemia
(high risk > 7.5 mmol/L total cholesterol, treatment target
What are the principles behind treating dyslipidaemia?
- establish fasting plasma lipid profile for diagnosis
- consider cardiovascular status and risk factors
- treat secondary causes
- obesity, diabetes, hypothyroidism
- manage modifiable risk factors
- stop smoking
- avoid alcohol
- weight reduction
- increase exercise
- these can all reduce risk of cardiovascular events independently of lipid lowering
- modify diet
What are some targets for treating hypercholesterolaemia?
Targets for Hypercholesterolaemia:
Diet
– reduce saturated fat intake
– introduce
- Mediterranean diet – reduces risk, not LDL (bad) cholesterol
- plant sterol esters – reduce LDL cholesterol
- fish oils – reduce triglycerides, increase HDL (good) cholesterol
– lifestyle/diet intervention for people at low risk
Synthesis, transport and uptake
– Drug targets for intervention for people at > moderate risk
What are some sources of cholesterol?
Cholesterol derived from:
– diet (in animal fat, eggs - absorbed via intestine)
– no Recommended Daily Allowance (RDA) set
– de novo synthesis (primarily in liver) adequate
What is the fate of cholesterol in the body?
- stored in liver for export in VLDL (very low density lipoproteins)
- converted to bile acids, stored in gall bladder to emulsify fat
- used for membrane synthesis
Explain cholesterol transport and metabolism?
- transported in plasma lipoproteins
– chylomicrons - from small intestine through lymph cells
– Very low density lipoproteins (VLDL)
– Intermediate density lipoproteins (IDL)
– Low density lipoproteins (LDL = “bad” cholesterol)
– High lipoproteins (HDL = “good” cholesterol) - complex metabolism
- lipoproteins that contain apolipoprotein (apo) B-100 can transport lipids into artery walls = “bad”
– LDL, IDL, VLDL - HDL can retrieve cholesterol from artery wall = “good”
- “normal” total cholesterol levels not necessarily healthy
Explain the principles behind treatment of serum lipid levels with statins.
Statins
(Lova, atorva, fluva, prava, simvastatin)
- HMG- CoA reductase Inhibitors
- decrease mevalonic acid and therefore cholesterol synthesis
– compensatory increase in hepatic LDL receptors
– increased clearance of LDL (with bound cholesterol) from blood
– decreased plasma total cholesterol and LDL (and TGs to lesser extent)
– increased plasma HDL
What are some indications associated with statin treatment?
- Indications:
- hypercholesterolaemia (high LDL)
- mixed hyperlipidaemia (high LDL, TGs)
- Greater benefit after 1-2 years use
- Poor compliance related to perceived lack of efficacy rather than side effects
What are some precautions associated with statin treatment?
- avoid grapefruit juice (common metabolic pathway increases toxicity of statins) - drug-drug interactions due to cytochrome pathways
- statin levels are:
– increased by some antibiotics, antifungals and fibrates
– decreased by phenytoin, barbiturates, glitazones - mild elevation of serum aminotransferase = transaminase
–
What are some adverse effects of statins?
- common adverse effects
– mild GI symptoms, headache, insomnia, dizziness - rare but serious adverse effects
– myopathy (minimised by UQ10 treatment)
– rhabdomyolysis (breakdown of muscle resulting in myoglobin release into the bloodstream)
– renal failure
– hepatitis, liver failure
What are some contraindications of statin treatment?
- pregnancy
– impaired fetal myelination - withhold during infection, pre-surgery, post-trauma
Explain the principles behind treatment of serum lipid levels with Bile Acid Sequestrants/Resins
Bile Acid Sequestrants/Resins
(Cholestyramine, colestipol)
- oral route - granular preparations, taken with liquid
- non-absorbable macromolecules
– polymeric cationic exchange resins
- bind bile acid (cholesterol metabolites) preventing gut absorption
– up to 10-fold increase in bile excretion
- increased demand for cholesterol for bile acid synthesis causes upregulation of hepatic LDL receptors, removal of LDL from plasma and more cholesterol metabolism
What are the indication for treatment with Bile Acid Sequestrants/Resins?
- hypercholesterolaemia (high LDL)
- mixed hyperlipidaemia
What are some adverse effects of Bile Acid Sequestrants/Resins?
- common adverse effects
- abdominal discomfort, bloating, constipation, flatulence
- rare adverse effects
- increased TGs, faecal impaction, decreased absorption of fat soluble vitamins, steatthorea
- decreases absorption of other drugs
- not just anions, also drugs with neutral or cationic charge (including glycosides, thiazides, statins, aspirin)
- give other drugs hours before or after resin
Explain the principles behind treatment of serum lipid levels with Ezetimibe
Ezetimibe
- specifically inhibits cholesterol absorption in the intestine by binding to a sterol transporter (NiemannPick C1-like 1 protein)
- does not affect absorption of bile acids, fat soluble vitamins
- lowers LDL
What are some adverse effects of treatment with Ezetimibe?
- diarrhea, headache, tiredness
- allergic reactions, severe joint or stomach pain
What are specific indaction/contraindication facts rearding Ezetimibe?
- can be used alone in statin-intolerant patients, or in combination with all other lipid-lowering agents including statins (to reduce statin dose)
Explain the principles behind treatment of serum lipid levels with Nicotinic Acid/Niacin?
Nicotinic Acid/Niacin
(Nicotinic acid = niacin = vitamin B3)
- mechanism unclear
– decrease secretion of VLDL particles from liver
– reduces plasma LDL and triglycerides (so also for mixed hyperlipidaemia)
– increases HDL
– lowers potentially atherogenic lipoprotein (a) - Lp(a) formed from LDL is found in plaques, inhibits thrombolysis
What are some adverse effects of nicotinic acid/niacin?
- common adverse effects
– vasosodilation, flushing, hypotension
– nausea, vomiting
– tolerance develops to flushing as gastric upsets
- rare adverse effects – itching – glucose intolerance – uric acid retention – may increase hepatic impairment
- not widely used except in combination
Explain the prinicple surrounding treatment of seum lipid levels with fibrates
Fibrates
(Gemfibrozil, fenofibrate)
- agonists at nuclear receptors, so regulate gene expression
– peroxisome proliferator activated receptor
– increased synthesis of lipoprotein lipase (LPL)
- increase lipolysis of lipoprotein triglyceride
- moderate reduction in plasma triglycerides
- moderate increase in HDL
- variable effects on LDL
- generally used as adjunct to dietary changes for high TGs, mixed hyperipidaemia, and second line therapy for hypercholesterolaemia
What are some precautions and adverse effects of treating with fibrates?
Precautions:
- mild elevation of serum aminotransferase
– monitor at 3 month intervals, reduce dose or discontinue if necessary
Adverse Effects:
- common adverse effects
– nausea, dry mouth, headache, rash
- rare adverse effects – arrhythmias – gallstones – photosensitivity – impotence – depression
Explain some features of treatment of serum lipid levels with fish oils.
Fish Oils
- Omega 3 fatty acids (e.g. eicoapentanoic acid (EPA); docosahexanoic acid (DHA); by diet (oily fish) or capsule)
- reduce triglycerides and VLDL
- Plant sources such as flaxseed, canola, walnuts and their derived vegetable oils contain a-linolenic acid (ALA) which can be converted to EPA/DHA, but conversion is variable
What are some adverse effects of treatment with fish oils?
- Adverse Effects:
- aftertaste, fishy burps
- diarrhea, abdominal discomfort
- blood thinning effect
What kind of therapy would be used for someone with severe hypertriglyceridaemia?
- Severe hypertriglyceridemia requires polytherapy
- low fat diet, fibrates, fish oils, statins, niacin, orlistat (used for obesity inhibits fat absorption from gut)
What kind of therapy would be used for someone with severe hypertriglyceridaemia?
Severe hypertriglyceridemia requires polytherapy
-low fat diet, fibrates, fish oils, statins, niacin, orlistat (used for obesity inhibits fat absorption from gut)
