Pharmacology: Cholesterol Flashcards
Why is it important to manage cholesterol levels?
Risk factor for coronary heart disease - LDL is the main factor
A 10% reduction in cholesterol results in a 15% reduction in CHD mortality.
What is the mechanism of action of statins?
Inhibits cholesterol synthesis in hepatocytes - decreases production of VLDL and LDL and increases clearance of LDL by increasing receptors so more are taken up. Works by inhibiting HMG-CoA reductase which is the enzyme for cholesterol synthesis from acetyl-CoA
NB primary and secondary prevention of CVD
What are the indications for statins?
- cardiovascular risk prevention (cardiovascular disease and diabetes mellitis at increased risk) (20% 10yr risk)
- Familial hypercholesterolaemia
What are some of the adverse drug reactions of statins?
- increased transaminase levels (rapidly reversible if statin is stopped) asymptomatic so needs monitoring
- myopathy (diffuse muscle pain)
- GI complaints
- headaches
What are some secondary benefits of statins other than reduced cholesterol?
- anti-inflammatory
- plaque reduction
- improved endothelial cell function
- reduced thrombotic risk
What are the atherogenic effects of oxidated LDL?
- inhibits macrophage motility
- induces T cell activation and vascular smooth muscle cell division and therefore they move into the lumen
- toxic to endothelial cells
- enhances platelet aggregation
(can lead to rupture and therefore MI)
What is the effect of obesity on lipid profile?
Cholesterol increases as weight increases (even within the normal range)
Triglycerides increase
HDL does not increase and even tapers off slightly in morbid obesity
What is the effect of fibric acid derivatives?
- reduce triglyceride production
- some reduction in LDL but this is variable (wherease statins are more consistent)
What is the mechanism of action of fibric acid derivatives?
Acts outside the liver on lipoprotein lipases. Therefore increases fatty acid uptake, reduces triglycerides, increases LDL particle size and also has direct vascular effects.
How effective are fibric acid derivatives?
Work best as an adjunctive therapy to diet
Reduce hypertriglyceridaemia by 50%
Reduce LDL but not as much as statins
Raise HDL more than statins
What are the side effects and contraindications of fibric acid derivatives?
Side effects: GI upset, cholelithiasis (gallstones), myositis (muscle inflammation), abnormal LFTs
Contraindications: renal dysfunction, pre-existing gallbladder disease
What does nicotinic acid do and how?
Reduces VLDL and increases HDL (best agent to raise HDL)
Works by inhibiting lipoprotein A synthesis
(not used regularly but when it does reduces coronary events)
What are the adverse effects of nicotinic acid?
- flushing
- itching
- headaches (has to be given with low dose aspirin)
- hepatotoxicity
- activation of peptic ulcers
- reduced insulin sensitivity
What is the mechanism of action of ezetimibe?
Relatively new agent.
Works in the intestinal brush border so inhibits cholesterol absorption.
Also increases expression of hepatic LDL receptor so more LDL taken up by liver.
The activate metabolite circulates enterohepatically so is delivered back to site of action and limtis systemic exposure.
What are the adverse drug reactions of ezetimibe?
Relatively few side effects due to limited systemic exposure (enterohepatic circulation)
May get headache, abdo pain or diarrhoea
