L21 Lipid lowering therapy Flashcards
What are the 4 types of plasma lipids and what are the possible ways of lipid transport
Plasma lipids: Cholesterol, Triglycerides, Fatty acids, Phospholipids
Lipid transport via lipoproteins
- In the gut triglycerides are transported to the liver via Chylomicron
- From the liver cholesterol is delivered to the periphery via LDL (adverse effects on vessels,
- HDL takes up cholesterol from the periphery (good) and returns it to the liver.
Why is lowering cholesterol a good thing (as 1 or 2’ prevention as well)
Large beneficial effects for 2ndary prevention as starting at higher risk.
- decrease CVS mortality and morbidity with linear 25% reduction in vascular event risk with every 1 mmol/L of total cholesterol reduction
1’ prevention there is limited benefit/small effect on mortality because its already low risk. Some reduction in vascular events.
- Make sure to also do lifestyle changes, base decision to prescribe based on patient 10yr risk and patient preference
Total cholesterol can synergise with other risk factors to increase risk for CHD so good to reduce
What things are looked at in clinical assessment for finding CVS risk
- Risk scoring system
- End organ damage
- BP, Xanthoma, Xanthelasmata on examination
- Urea + electrolytes, Glucose
- Fasting cholesterol, LDL: HDL, Trigylcerides
- ECG
Who is treated with lipid lowering drugs (STATIN). What factors go into choosing those for 1’ prevention
in 2ndary prevention
- Angina, MI
- Cerebrovascular accident
- PVD
- Those with diabetes (surrogate marker for vascular risk
1’ prevention: guidelines vary between countries
- CVS risk >30% over 10 yrs in NZ.
There must be a balance of population at risk vs benefit (how many needed to treat to get beneficial outcome vs resources)
What is mechanism of action of Statins
- Competitively inhibit HMG CoA reductase at proximal cholesterol synthetic pathway
2a) –> decrease intracellular hepatic cholesterol
b) inhibits isoprenoid production
3: in response to reduced cholesterol, hepatocytes increase expression of LDL receptors to take up cholesterol from the circulation to be reused in the liver
Therefore reduce total cholesterol and LDL. (mild increase of HDL, decrease of trig)
Give examples of statins in NZ, and which one has drug interactions, what are these for
Atorvastatin,
- Simvastatin: drug interactions due to mostly metabolised by CYP3A4 so drugs that inhibit/activate it
eg. Amiodarone, verapamil, diltiazem, erythromycin
What are the 6 side effects of statin use/ cautions and when to stop for two of them
Muscle disorders : increased risk with higher statin conc, damaged organic anion transporting polypeptide.
- Myalgia
- Myositis: inflammation of muscle leading to increase serum creatinine kinase so stop statin if CKx10
- Rhabdomyolysis (rarely) –> myoglobin in circulation causes renal failure
- Synergistic for muscle disorders if given with Fibrates (though not unreasonable)
- Deranged LFTS (stop if ALT x 3)
- Teratogenic
What are the two beneficial effects of statins
- Every mmol/L reduction in LDL there is linear reduction in total mortality (12%) and major vascular event (21%)
- Decreasing isoprenoid synthesis has
- antithrombotic
- anti inflammatory
- immune modulation benefits
Give an example of a Fibrate, what patient do we treat with fibrate, and what other treatments given along side
Bezafibrate
- Isolated hypertriglyceridaemia (risk for pancreatitis)
- Combined therapy with statins for resistant hypercholesterolaemia problems
Also given with lifestyles
- diet, exercise, weight loss, reduction in alcohol, diabetes control
What is the mechanism of fibrate
- Agonist of the PPARa nuclear receptor which mediates changes in protein synthesis
- Leads to
- reduced hepatic VLDL production
- increased VLDL clearance (take up back to liver) - Also activates lipoprotein lipase peripherally to break down TGs and enable FA to be taken up by skeletal muscle
- increased skeletal muscle fat storage - Also antiproliferative/inflammatory effects
Mainly decrease TG, mild decrease LDL, increase HDL.
What are the side effects of fibrates
- GI upset: nausea, diarrhoea, illness
- Deranged LFTs
- Myositis (increased risk with concurrent statin)
What is Ezetimibe mechanism, how is it prescribed and what is side effects
Mech
- Inhibits cholesterol absorption by blocking the NPC1L channel in intestinal wall
- Inhibits intestinal delivery of cholesterol to the liver
- Increases expression of hepatic LDL receptors to help mop up circulating LDL
Used with statin (low efficacy as monotherapy), good for resistant hypercholesterolaemia
SE: abdo pain, diarrhoea
What is Nicotinic acid/ Vit B3 mechanism, how is it prescribed and what is side effects (rarely used)
Mech Reduces 1. Mobilisation of FA from the periphery into circulation 2. Hepatic triglyceride/ VLDL production 3. HDL degradation
Used in combo with statin or fibrate, if despite treatment TG is high.
SE: GI intolerance, dry skin
Flushing due to increased PG synthesis (vasodilator).
What is Bile acid binding resin, eg, mechanism, and what is side effects (uncommonly used now)
Cholestyramine: oral satchet
Mech:
1. Bind bile acids and stop enterohepatic circulation
2. Reduce absorption of exogenous cholesterol
3. Increase conversion of endogenous cholesterol to bile acids
4. Increase hepatic LDL expression
SE: not systemically absorbed.
- GI : nausea, bloating , constipation/diarrhoea
- impair vit ADEK absorption
- Interfere with drug absorption eg. digoxin, warfarin, thiazide, T4
