Lipid and Cholesterol Flashcards
What is atherosclerosis and what is the mechanism?
Atheromatous disease is a chronic inflammatory disorder which can manifest as early as adolescence, and is found in the majority of the population at age 50-60, albeit in varying degrees
• Endothelial dysfunction, which allows LDLs to infiltrate the arterial wall and become entrapped
• The LDL is oxidised which can lead to pro-inflammatory changes
o Inhibits motility of macrophages
o Induces T-cell activation and vascular smooth muscle cell division and differentiation
o Toxic to endothelial cells
o Enhances platelet aggregation
• Lipids are phagocytosed and the macrophages become foam cells.
• Over time connective tissue is deposited and fibrous cap forms over the lipid rich core
• Rupture of this plaque can lead to thrombosis
What are the main drug groups used in reducing LDL cholesterol?
Statins
Cholesterol absorption inhibitors
Fibrates
Nicotinic acid
What are examples of statins? What is their MOA?
Simvastatin
Atorvastatin
Rosuvastatin
Inhibit HMG-CoA reductase which inhibits cholesterol synthesis. Lower hepatic cholesterol levels leads to increased production of LDL receptors and a higher rate of removal from plasma
Lower LDL, raise HDL, lower triglycerides.
(cholesterol is synthesised form acetyl CoA)
What are ADRs and DDIs of statins?
ADRs Myopathy Rhabdomyolysis Elevation of hepatic enzymes GI upset
DDIs:
CYP inhibitors increase the risk of myopathy (grapefruit juice, verapamil)
CYP inducers decrease efficacy (St John’s Wort, Rifampicin)
OAT (organic anion transporter) inhibitors can reduce the efficacy, but if it reduces excretion this can act synergistically by augmenting the lipid lowering effect (for example given with ezetimibe or fibrate)
How are statins monitored?
LFT at baseline
Monitor LDLs
Give an exmamples of cholesterol absorption inhibitors and what is the MOA?
Ezetimibe
Inhibit intestinal cholesterol uptake by blocking the cholesterol transport protein (PNPC1L1). This induces the liver to express more LDL receptors which reduces circulating levels of LDL.
What are ADRs of Ezetemibe?
Headache
Abdominal pain
Diarrhoea
Example of fibre and MOA
Bezafibrate
Act on the Peroxisome proliferator-activated receptor-α (PPAR-α) – complex mechanism of action including increasing production of lipoprotein lipase, reduced triglyceride production. Some effect on HDL and LDL, significantly lowers triglyceride
What are ADRs and DDIs of fibres
GI upset Cholelithiasis Myositis Abnormal LFTs Contraindicated in hepatic and renal dysfunction as well as gallbladder disease
DDI
Fibrates and statins – significant improvement of lipid levels, but increased risk of myopathy and rhabdomyolysis. Mechanism unknown – not CYP450
Gemfibrozil may impair glucuronidation of statins (cerivastatin is the most susceptible)
What is the MOA of nicotinic acid?
Inhibits lipoprotein a synthesis: reduces VLDL and increases HDL if given at high doses, raises HDL
What are SE of nicotinic acid?
Flushing Itching Headache (give with aspirin) Hepatotoxicity GI disturbance Activation of peptic ulcers Hyperglycaemia and reduces insulin sensitivity Contraindicated in: liver disease or LFT elevations, peptic ulcer disease
What dietary factors can improve lipid levels?
Fish oils, fibre, vitamin C & E, and alcohol (which raises HDLs, but also unfortunately, cholesterol)
What is combination therapy?
usually a statin, plus: • A fibrate that isnt gemfibrozil • Nicotinic acid • Ezetimibe • Omega-3 fatty acids • Resins
Differences between dynamics and kinetics of different statins
There are variations in intestinal absorption from 30-85%
First pass metabolism is high
Some statins need to be activated
Therefore oral bioavailability can be as low as 5%
Some statins are metabolised by CYP450 enzymes including CYP3A4, some are metabolised only by phase two pathways.
Simvastatin has a short half-life of 1-4 hours and should be given before bed to ensure its activity coincides with cholesterol synthesis. Atorvastatin has a longer half life and so can be given at any time of day and has greater efficacy
They exhibit non-linear pharmacodynamics – a doubling of dose yields a 6% reduction in LDLs.
What is first pass metabolism
The peak plasma concentration of the drug and the time it spends in the body are affected by both the rate of uptake and first pass metabolism.
First pass metabolism is the metabolism carried out by the gut and liver. It can significantly reduce the available drug – depends on the drug (extraction ratio)
