Dyslipidaemia Flashcards
Discuss hyperlipidaemia and the role of pharmacological therapies
Dyslipidaemia
is defined as high cholesterol plasma concentration with or without high triglyceride plasma concentration, in lipoproteins. It predisposes atherosclerosis and CHD.
Lipid-lowering medications
are used to decrease LDL plasma concentration, in addition to dietary measures,, and correction of other modifiable cardiovascular risk factors.
Treatment with lipid-modifying drugs should reflect the future risk of cardiovascular events.
List the different classes of drugs
- statins
- bile acid resins
- nicotinic acid
- fish oil derivatives
- PCSK9 inhibitors
- fibrates
- ## ezetimbe
Describe statins
HMG-CoA reductase is the rate-limiting enzyme in cholesterol synthesis.
Statins **inhibit HMG-CoA reductase.
Decreased hepatic cholesterol synthesis results in upregulation of LDL receptor synthesis.
- increased LDL clearance from plasma into liver cells
- main outcome is the reduction of plasma LDL with some reduction in plasma TGs (and some HDL increase)
- overall outcome: significantly reduced risk of CHD, stroke and death
Adverse events:
- Stomach cramps, pains
- Constipation
- Headache
- Sleep disturbances (nightmares, insomnia)
- Increased hepatic enzyme activity
- Myalgia,Myopathy (rare),Rhabdomyolysis (rare)
- Predisposing factors
- Older age
- Female
- Certain medications (including hepatic enzyme inhibitors)
- Concomitant admin of fibrates
- Excessive alcohol intake
- Treatment should be ceased
Eg. Atorvastatin, rosuvastatin, simvastatin etc
Describe bile acid resins
- **Sequester bile acids in the intestine and prevent reabsorption and enterohepatic recirculation
- Do no affect HDL concentrations
- **Can cause unwanted increase in triglycerides
- **Interfere with absorption of fat soluble vitamins and other medications
Colestyramine:
Indications: Hypercholesterolaemia,Itch associated with partial biliary tract obstruction,Diarrhoea followingileal resection or disease.
e.g. colestyramine
Describe nicotinic acid
- Water soluble vitamin
- **Inhibits mobilisation of free fatty acids from peripheral tissue
- **↓ transport of free fatty acids to the liver
- **↓ hepatic synthesis of triglycerides and secretion on VLDL
- **↑ HDL (20-30%)
Used as an *adjunct to other therapies
Indications:
- Hypercholesterolaemia
- mixed hyperlipidaemia or severe hypertriglyceridaemia
- Pellagra
Adverse Effects:
- Warmth/flushing of face and neck
- Hypotension
- Dyspepsia
- Pruritus
- Liver toxicity at high doses
Contraindications:
- Co admin with statins can result in myopathy and rhabdomyolysis
Describe fish oil derivatives
- Omega-3 decrease plasma triglycerides but increase cholesterol
- Thought to reduce VLDL formation and accelerate VLDL metabolism to LDL
- High affinity to PPAR⍺ and may upregulate metabolism of fatty acids in the liver
Considered to be relatively safe but may increase bleeding times in high doses
Heart foundation recommends consuming 500mg of DHA and EPA through a combination of 2-3 serves (150g) of oily fish per week
Describe PCSK9 inhibitors
PCSK9 **binds to the LDL receptor and causes degradation of the receptor.
PCSK9 inhibitors are **monoclonal antibodies that bind to circulating PCSK9 rendering them unable to bind to the LDL receptor
- stops binding to hepatocyte LDL receptor
- promotes continued clearance of cholesterol
- currently expensive and only approved for specific indications (including familial hypercholesterolaemia uncontrolled despite maximal HMG-COA reductase inhibitor therapy)
Given via subcutaneous injection
Adverse Effects:
- Injection site reactions
- myalgia
- neurocognitive effects ^[why? how? what?]
Describe fibrates
- Reduce circulating VLDL ->decreased triglycerides ->
- 10% decreased LDL
- 10% increased HDL
- Mechanism of action complex and not completely understood but is thought to work at thePPAR⍺ (nuclear receptor)
- increased transcription of genes for lipoprotein lipase (increasing removal of TG’s fromthe small intestine
- Not been shown to improve survival
- Only indicated for isolated hypercholesterolaemia***if statins are not tolerated
Adverse effects
- GI disturbances, increased creatinine concentration (reversible), rarely: cholestatic jaundice, anaemia, leucopenia, myopathy, rhabdomyolysis, hypersensitivity reactions (eg angioedema, anaphylaxis, exfoliative dermatitis)
E.g. fenofibrate
Describe ezetimbe
is a **Cholesterol absorption inhibitor
- **Reduces absorption of dietary and biliary cholesterol by inhibiting cholesterol transport (via blockade of NPC1L1) across the intestinal wall
- This leads to an increased demand for cholesterol, an increase in LDL receptor expression and LDL uptake and andremoval from the plasma
- Does not affect the absorption of fat soluble vitamins, triglycerides or bile acids
It is an *adjunct to diet and statins
Indications:
- Hypercholesterolaemia
- Homozygous sitosterolaemia (phytosterolaemia)
Adverse Effects:
- Diarrhoea
- Abdominal pain
- Headache
- Rash
The main effect of HMGCoA-reductase inhibitors (statins) is
A: ↓ LDL clearance from plasma into liver cells
B: No change to plasma triglycerides
C: Slight decrease or no change to HDL
D: ↓ LDL
E: Significantly reduce the risk of coronary heart disease, stroke but no change to mortality
D
New lipid lowering monoclonal antibodies that bind to circulating PCSK9 lower LDL by which mechanism?
A. stops PCSK9 from binding to hepatocyte LDL receptor allowing LDL binding and promoting clearance of cholesterol
B. stops PCSK9 binding to hepatocyte LDL receptor increasing PCSK9 concentrations and decreased cholesterol production
C. stops PCSK9 binding to plasma LDL receptor allowing LDL binding and promoting clearance of cholesterol
D. stops PCSK9 from binding to plasma LDL receptor increasing PCSK9 concentrations and decreased cholesterol production
E. Inhibits PCSK9 from binding to LDL reducing VLDL production
A
Ezetimibe is thought to lower cholesterol via which mechanism?
A. Inhibiting HMGCoA reductase
B. Binding to bile acids
C. Reduced gastric absorption
D. Inhibiting mobilisation of free fatty acids from the peripheral tissues
E. Inhibiting PCSK9
C
