Atherosclerosis + lipid-lowering drugs Flashcards
What is hypercholesterolaemia?
What does it lead to?
Elevated plasma cholesterol
Leads to atherosclerosis
Atherosclerosis is when plaques on the inner surface of an artery
What does atherosclerosis cause/lead to?
Ischaemic heart disease
Peripheral vascular disease
Cerebrovascular disease
State the risk factors for atherogenesis (formation of plaque in arteries) + CVD in general
Genetic
Hypercholesterolaemia (raised LDL or lowered HDL)
Hypertension
Smoking
Obesity
Hyperglycaemia
Reduced physical activity
Infection
What drugs can induce dyslipidaemia?
Abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood
Beta-blockers
Thiazides
Corticosteroids
Retinoids - monitor
Oral Contraceptives
Anti-HIV - monitor lipid levels
What are lipoproteins?
What are the 4 major types?
Central core of hydrophobic lipid, encased in phospholipid, cholesterol and apolipoproteins
The 4 major types types:
- HDL
- LDL
- VLDL
- Chylomicrons
Function of chylomicrons
Transport triglycerides and cholesterol from GI tract to liver.
Free FA released and cholesterol is stored, oxidised to bile salts
Function of VLDL
Transports cholesterol + triglycerides to the tissues
Function of LDL
Large component of cholesterol
Delivers cholesterol to liver and tissues, via endocytosis via an LDL receptor.
Function of HDL
Absorbs cholesterol from cell breakdown and transfers it to VLDL & LDL
What should the ideal cholesterol levels be?
<5.0mmol/l
25 - 30% middle aged population have hypercholesterolaemia (.6.5mmol/l)
Important to know if it is high LDL or low HDL
Hypercholesterolaemia can cause Xanthomata - deposition of yellowish cholesterol-rich material that can appear anywhere in the body
Describe the process of atherogenesis + how this is affected by lifestyle
Summary
- damage to the blood vessel
- inflammatory response
- cholesterol-rich deposits form
- inflammatory mediators may lead to growth of VSM/connective tissue
- plaques form
How do you manage atherogenesis?
Modify risk factors
- Stop smoking
- Exercise
- Treat HT/DM
- Drug-induced
Low cholesterol diet
- only 25-30% cholesterol comes from diet (rest from liver)
Describe the mode of action of statins
HMG-CoA reductase inhibitors
Competitively inhibit the activity of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis
Inhibition of this enzyme results in a decrease in cellular cholesterol concentration
Example of statins
Simvastatin
Pravastatin
Atorvastatin
Fluvastatin
Describe the clinical pharmacology of statins
Reduce plasma cholesterol
Reduction in hepatic cholesterol synthesis leads to an upregulation of hepatic LDL receptors, promoting LDL uptake
Less effective in homozygous familial hypercholesterolaemia
- They cannot make LDL receptor
- Atorvastatin may be effective
- Statins effective in heterozygous disease
Statins are hepatoselective
- liver is the main site of cholesterol synthesis, extrahepatic sites synthesise essential cholesterol
- 1st pass metabolism: 5% reaches systemic circulation
When should statins be taken?
At night
Offsets a nocturnal increase in cholesterol synthesis
Except atrovastatin
What are the drug interactions + contraindications of simvastatin?
Contraindicated with macrolides
Interaction with amlodipine, verapamil, diltiazem
If amlodipine needs to be taken with a statin:
- pravastatin should be used instead (does not interact)
- 20mg simvastatin as maximum dose
Name the uses and limitations of statins as OTC medicines.
10mg simvastatin without cholesterol test
For patients at high risk:
- All males > 55
-
Males 45-55 + females > 55 with…
- family history of IHD
- smokers
- overweight
- S Asians Indian sub-continent ethnicity
Refer angina to GP
Monitoring - signs of hepatoxicity (jaundice, dark urine, itching)
Counsel re muscle pains
Interactions - HIV protease inhibitors, ciclosporin, azoles, fibrates, anticoagulants, macrolides
Treatment might not be documented with GP
Patients may buy a packet for christmas
Briefly describe the mode of action of fibrates
Activate PPAR-alpha = alters lipoprotein metabolism
Promote breakdown in VLDL (w/ small reduction in LDL + increase in HDL)
Reduce triglycerides - used w/ statins when TGs (+cholesterol) raised
Decrease glucose, use in DM
Reduce IHD but not mortality
Adverse effects = rhabdomyolysis
Example of a cholesterol absorption inhibitor
Ezetimibe
Prevents cholesterol absorption
Use on top of a statin
Fill in the gaps
