Dawes: Lipid Lowering Therapy Flashcards
(34 cards)
What are the different plasma lipids?
- Cholesterol
- Triglycerides
- Fatty Acids
- Phospholipids
What are the cholesterol subfractions?
- Total Cholesterol (mmol/L)
-
LDL cholesterol - transport from liver to peripheries
- Adverse effects
-
HDL Cholesterol - From the periphery to the liver
- Beneficial effects
-
Triglycerides (mmol/L)
- Adverse Vascular Effects
- Pancreatitis
What is the pathway of lipid transport?
- Dietary cholesterol absorbed in the gut is transported to the liver in chylomicrons which are rich in triglycerides.
- Cholesterol is also synthesised de novo in the liver, gut and CNS.
- Cholesterol in the liver is packaged with triglycerides and converted to VLDL.
- VLDL is converted to LDL in the circulation.
- LDL delivers cholesterol to most tissues and its uptake is facilitated by LDL receptors.
- Excess cholesterol is removed by HDL and then reconverted to LDL and VLDL where it is reuptaken by the liver.
- Some of the cholesterol is then excreted in the bile as either free cholesterol or bile acids.
What does total plasma cholesterol mainly reflect?
LDL cholesterol.
In a fasting state, what does plasma triglyceride levels reflect?
VLDL Concentration
Why do you want to lower cholesterol?
- Primary Prevention
- Reduction in vascular events with a small effect on mortality.
- Secondary Prevention
- Large beneficial effects with reduced CVS mortality and morbidity.
- 1mmol/L reduction in total cholesterol reduces the risk of a vascular event by 25%.
What are the effects of increasing TC levels on the risk for coronary heart disease in the presence of other risk factors?
We must treat all the other risk factors as well - they synergise
What is the clinical assessment for hyperlipidaemia?
- A history of end organ damage
- Primary Prevention or Secondary Prevention?
- Examination
- Increased Blood Pressure
- Xanthoma - Fatty Growths underneath the skin.
- Xanthelasma - Fatty Deposits underneath the skin.
- Investigations
- U + Es
- Fasting Cholesterol/ LDL/ HDL/ Trigylcerides
- Glucose
- ECG
What patients should be treated for a high lipid count?
- Primary Prevention
- Those with CVS risk >30% over next 10 years (NZ) - 10-30% should be discussed about pros/cons
- Those with CVS risk >7.5% over next team years (US) - this is literally almost everyone over 60
- Secondary Prevention
- Angina/MI
- Cerebrovascular Attack
- Peripheral Vascular Disease
- Diabetics
What should be peoples target LDL concentrations?
,<1.8 mmol/L
This should be achieved through both lifestyle changes and drugs.
Which drugs should be used to treat high lipid concentrations?
- Statins - Act to reduce TC, LDL, Triglyceride and increase HDL.
- Simvastatin 10 - 40mg
- Atorvastatin
- Fibrates - Massive reduction in triglyceride count and increase in HDL.
- Bezafibrate 200-400mg od
- Ezetimibe - Decrease TC and LDL
- Nicotinic Acid - Reduce Triglycerides
When are statins presecribed?
- Primary Prevention
- Diabetics
- High CVS risk patients
- Familial Hypercholesterolaemia
- Secondary Prevention
- Previous MI
- Angina
- CVS
- TIA
- PVD
What is the mechanism of action for statins?
Competitively inhibit 3-Hydroxy-3-Methylglutaryl CoA reductase (HMG CoA reductase) resulting in a reduction in cholesterol synthesis with a secondary upregulation of LDL receptor expression on hepatocytes ‘mops’ up the circulating LDl for synthetic functions. As a result, should be given at night.
Also some evidence in vitro to suggest they also cause a reduction of isopredoids that are involved in inflammation, cell signalling, cell diff and prolif, apoptosis and oxidation. (so some trials look to use them for tumour treatment etc.)
What are the pharmacokinetics of simvastatin?
- Tmax = 1.3 - 2.4 hours
- Cmax = 10 - 34 ng/mL
- Low bioavaliability (5%)
- High protein binding (94 - 98%)
- Metabolised by CYP3A4 in the liver. -open to interactions
- Half-life of 2-3 hours.
- Urinary and Faecal excretion.
What are the side effects of statins?
- Myalgia
- Myositis
- Stop if CK x 10 (creatine kinase)
- Rhabdomyolysis
- Deranged LFTs
- Stop if ALT x 3
- Teratogenic - not to be used in pregnancy or breastfeeding
What does simvastatin interact with?
Drugs that are also metabolised by CYP3A4 such as amiodarone, verapamil, diltiazem and erythromycin.
What is the risk of myopathy in patients taking statins?
There is 1 case per 10,000 patients per year. This is related to the statin concentration and there is increased incidence with SLC01B1 (chromosome 12) with encodes for an organic anion-transporting polypeptide OATP1B1. This anion-transporting polypeptide acts to mediate hepatic uptake of drugs.
What is the effects of statins on CV endpoints?
- Total Mortality decreased by 12%
- Major Vascular Event risk decreased by 21%
What is the pleiotropic effect of statins?
Statins also appear to have anti-thrombotic, anti-inflammatory and immune modulatory effects before lowering cholesterol.
When should you use a fibrate such as bezafibrate?
High TG in vitro is linked to many CV issues like endothelial dysfunction but thuis hasn’t been as well linked in human trials. High TG also increase risk of burden and so can be decreased using fibrates for this reason
- Isolated Hypertriglyceridaemia - Also treated with diet, exercise, weight loss and reduced alcohol consumption.
- Combine therapy with statins for resistant hyperlipidaemia
What is the mechanism behind fibrates?
PPAR-alpha (Peroxisome Proliferator-Activated Receptor Alpha) agonist of receptor in the nucles of cells.
- Liver and Skeletal Muscle Lipid Metabolism
- Reduced Hepatic VLDL production
- Increased Hepatic VLDL clearance
- Increased Skeletal Muscle FA storage.
- Activate Lipoprotein Lipase
- Breaks down TG
What are the side effects of fibrates?
- GI upset
- Deranged LFTs
- Myositis - (Increased risk with concurrent statins)
What is the mechanism for ezetimibe?
- Reduce Cholesterol Absorption -through blocking channel
- Reduce Intestinal Delivery of Cholesterol to Liver
- Increase Expression of Hepatic LDL receptors -reducing circulating levels
Low efficacy as monotherapy so used with statins.
What are the side effects of ezetimibe?
- Abdominal Pain
- Diarrhoea
Both due to high levels of cholersterol in the gut that isn’t absorbed
