Drug regulation of serum lipids Flashcards
dyslipidaemia
abnormal lipid profile
can lead to atheroscleorsis, increased MI risk, stroke
hypercholestrolaemia
elevated blood cholesterol
high risk: > 7.5mmol/L total cholesterol
treatment target: <4mmol/L
hypertriglyceridemia
elevated blood triglycerides
mixed/combined hyperlipidemia
hypercholesterolemia characterised by elevated LDL and TG, often accompanied by decreased HDL
The normal fasting level and target level for total cholesterol is
0.0-5.5mmol/L; <4.0mmol/L
The normal fasting level and target level for TGs is
0.5-2.0; <2.0
The normal fasting level and target level for HDL is
0.9-2.2; >1.0
The normal fasting level and target level for LDL is
0.0-3.4; <2.5
The normal fasting level cholesterol/HDL ratio is
0.0-5.0
The Mediterranean diet
- high in whole grain breads, cereals, fruits, vegetbles, olive oil, and fish
- can decrease cardiovascular risk
- does not reduce LDL levels
Plant sterol esters
- in margarine
- reduce LDL cholesterol
- no evidence of -CV risk
fish oiles
- reduce TGs
- increase HDL
Cholesterol is derived from
- diet: animal (saturated) fat, eggs
- de novo synthesis in liver
cholesterol is used in the synthesis of
- membranes
- bile acids
- steroid hormones
Which lipoproteins can deposit cholesterol into arterial walls?
LDL, IDL, VLDL
all contain ApoB-100
Statins
- HMG-CoA reductase inhibitors
- discovered in 1970s, Tokyo, by Kuroda and Endo
- hypothesized that fungi (who require sterol for growth) would produce synthesis inhibitors to kill off competing microbes in their environment
- isolated mevastatin from 6000 microbial strains (Penicillium citrinum)
- never used clinically
- Merck, late 1970s discovered lovastatin (Aspergillus terreus)
- still used today
- approved for clinical use in late 1980s
What is the mechanism of statins?
e.g. lova, atorva, fluva, prava, simvastatin
- orally absorbed
- undergo first-pass metabolism
- partially inhibit HMG-CoA –> -endogenous cholesterol synthesis
- body +hepatic LDL R
- -circulating LDL
- +HDL
- also -TG to a lesser extent
Why is poor adherence common with statins?
- benefit greatest after 1-2 years
- don’t feel different - perceived lack of efficacy
When is cholesterol synthesis greatest?
At night
tf we prescribe statins with shorter half-lives in the evening
When are statins indicated?
hypercholesterolemiea
mixed hyperlipidaemia
What are the precautions in statin use?
- avoid grapefruit juice (p450 cytochrome enzymes)
- common metabolic pathway, can +toxicity because they are not broken down
- altered statin levels
- increased by some antibiotics, antifungals, and fibrates
- decreased by phenytoin (epilepsy), barbituates, glitazones (diabetes)
- liver toxicity
- elevation of serum aminotransferase/transaminase (indicator)
- monitored every 2-4mo
- increased creatine kinase
- breaks down muscle, can cause pain and tenderness
- resolved on discontinuation
What are the common adverse effects of statins?
Mild GI symptoms, headache, insomnia, dizziness
no clear mechanisms of explanation
What are the rare, serious adverse effects of statins?
- myopathy (+CK, -Q10): tx w/UQ10 supplement
- rhabdomyolysis - breakdown of muscle, myoglobin into bloodstream
- renal failure
- hepatitis, liver failure
What are the contraindications for statins?
Pregnancy
- statins impair fetal myelination essential for foetal nerve growth and development
Drug-drug interaction potential (e.g. w/antibiotics)
- infection, pre-surgery, post-trauma
What is the mechanism of bile acid sequesterants/resins in the treatment of hypercholesterolemia?
e.g. cholestyramine, colestipol
- granular preparation taken orally w/liquid
- not absorbed; excreted from the GIT
- bind to bile acids, preventing them from emulsifying fat
- tf -cholesterol absorption
- ++bile acid secretion (up to 10x) and tf excretion
- to replace it, body +hepatic LDL R
- tf -LDL in circulation/plasma
What are the indications for bile acid sequestrants/resins?
hypercholesterolaemia
mixed hyperlipidaemia
What are the common adverse effects of bile acid sequestrants/resins?
- abdominal discomfort
- bloating
- constipation (need to be taken with a lot of water)
- flatulence
What are the rare adverse effects of bile acid sequestrants/resins?
- increased TGs
- faecal impaction
- decreased absorption of fat soluble vitamins
- steatthorea (fatty stool)
need to drink lots of water!
Why must bile acid sequestrants/resins be taken several hours before other drugs?
- non-speciifc, tf decrease absorption of other drugs by binding to them
- e.g. glycosides, thiazides, statins, aspirin
