Cholesterol Pharmacology Flashcards
If we reduce total cholesterol by 10%, what happens to CHD risk?
15% decrease in CHD mortality
What is the primary target in preventing CHD?
LDL cholesterol
What does LDL do to vessels?
It infiltrates arterial walls and is trapped in the intima where it undergoes oxidation
Why is oxidised LDL bad?
It is pro-atherogenic - inhibits macrophage motility, induces T cell activation, is toxic to endothelial cells, and causes platelet aggregation.
What is the most commonly used class of lipid lowering drug?
Statins
What effect can statins have on LDL, TAG and HDL?
LDLs fall by 5-35%
TAG falls by 10-35%
HDLs increase by 5%
How do statins work?
Inhibit HMG co-a reductase which is integral in cholesterol synthesis
What is the result of the action of statins?
Increased LDL and IDL clearance due to increased LDL receptor expression
Decrease VLDL and LDL production
What are the indications for statins?
CV risk prevention (Q risk score)
Familial hypercholesterolaemia
What is the most common adverse effect of statins?
Myopathy i.e. muscle aches
Which enzyme is affected by statins, and in who? (Not HMG co-a reductase, more of an ADR)
Aminotransferase levels are increased in 0.1-2.5% of pts treated. Transient and no long lasting liver damage.
When is it most common for myopathy to be experienced with statins?
At higher doses, and if given at the same time as certain other drugs (cyclosporin, gemfibrozil, erythromycin, niacin).
Aside from lowering LDL and TAG, what other beneficial affects do statins have?
Anti-inflammatory
Plaque reduction
Improved endothelial function
Reduced thrombotic risk
What is the intestinal absorption of statins like?
Variable - 30-85% absorption
Why is bioavailability of statins only 5-30% of administered dose?
Variable intestinal absorption as well as extensive 1st pass metabolism
When is the peak of cholesterol production in the day/night?
Early in the morning
When do pts take short acting statins like simvastatin and why?
Just before bed/at night to coincide with cholesterol produciton peak
What is the benefit of long acting statins?
Superior efficacy
Aside from statins, what are the other main drugs can we give to lower lipids?
Fibrates/Fibric acid derivatives
Nicotinic acid/niacin
Cholesterol lipase inhibitors
How do fibric acid derivatives work?
Peroxisome proliferator-activated receptor agonist
Production of lipoprotein lipase so TAG reduced by a lot
What effect do fibric acid derivatives have on LDL?
Modest reduction that depends on which drug is used
What are the indications for fibric acid derivatives?
Adjunct with diet modification
Hypertriglyceridaemia
Combined hyperlipidaemia with low HDL
What are the ADRs associated with fibric acid derivatives?
GI upset
Gallstones
Myositis
Abnormal LFTs
When are fibric acid derivatives contraindicated?
Hepatic or renal dysfunction
Pre-existing gall bladder disease
What are the fibirc acid derivatives that can be prescribed?
Clofibrate
Gemfibrozil
Which drug is the best at bringing up HDL levels?
Nicotinic acid
How does nicotinic acid lower lipids?
Inhibits lipoprotein (a) synthesis
What adverse effects can nicotinic acid have?
Flushing Itching Headaches Hepatotoxicity Peptic ulcers Hyperglycaemia
When is nicotinic acid contraindicated?
Active liver disease
Abnormal LFTs that are unexplained
Peptic ulcer disease
How does ezetimide work?
Inhibits intestinal cholesterol absorption and cholesterol lipase enzyme
What effects does ezetimide have in the body?
- Decreases cholesterol delivery to the liver
- Increases LDL receptor expression in the liver
- Decreases cholesterol content in atherogenic particles
What are the ADRs associated with ezetimide?
Headaches
Nausea
Abdo pain
Diarrhoea
What can we combine for the most effective lowering of lipids?
Statin plus another therapy
What therpies can we combine with statins?
Fibrate, not gemfibrozil Nicotinic acid Ezetimibe Omega-3 Fatty acids Resins
How do we decide which therapy to comine with statins?
3 factors - cost, benefit, and ADRs.
Why is statin combined with a fibrate potentially contraindicated?
Increased risk for myopathy and rhabdomyolysis
What dietary factors can lower lipids?
Fish oils
Fibre
Vitamin C/E
Alcohol (HDL)
What dietary elements should we cut down/out to lower lipids?
Fat
Dairy
Cake/biscuits
Alcohol (TAG)
