L7 L8 L9 Dyslipidemia and Coronary Heart Disease Flashcards
1
Q
What are the 4 essential functions of cholesterol?
A
- structural component of all cell membranes
- precursor of bile acids in liver
- Precursor of vitamin D
- Precursor of steroid hormones.
2
Q
Where does the synthesis of aldosterone, cortisol and androgens from cholesterol occur?
A
In the adrenal cortex.
3
Q
Name the 2 systems in which cholesterol is derived.
A
- Endogenous system: intracellular synthesis of cholesterol
2. Exogenous system: cholesterol is derived from dietary sources.
4
Q
Briefly describe the process of cholesterol synthesis.
A
Acetyl CoA is converted to HMG CoA. HMG CoA reductase converts HMG CoA to mevalonic acid, which is converted to cholesterol.
HMG CoA reductase regulates cholesterol synthesis in the adrenal cortex.
Enzyme regulation is controlled by gene expression, degradation, hormones and drugs.
5
Q
List the 4 plasma lipoproteins.
A
Chylomicrons
VLDL
LDL
HDL
6
Q
Describe HDL
A
Synthesised in the liver and intestine.
Has lowest triglyceride concentration of all lipoproteins, and high cholesterol content.
Delivers cholesterol to the liver for elimination.
7
Q
Describe LDL.
A
Synthesised from VLDL.
Has low TG content and highest cholesterol content.
Delivers cholesterol to the peripheral tissues and the liver.
8
Q
Describe VLDL.
A
Synthesised in the liver.
Has high TG content and low cholesterol content.
Delivers de novo TG to peripheral tissues
9
Q
Describe chylomicrons.
A
Generated in the intestine. Has highest TG content and lowest cholesterol content.
Delivers dietary TG to peripheral tissues.
10
Q
How do plasma HDL levels relate to atherosclerosis?
A
Plasma HDL levels are inversely related to atherosclerotic risk.
HDL removes cholesterol from plaque, thus decreasing cardiovascular risk.
11
Q
In what ways does HDL protect against atherosclerosis?
A
Reverse cholesterol transport Inhibition of LDL oxidation Modulation of pro-atherogenic properties of oxidised LDL Anti-inflammatory anti-apoptotic antithrombotic vasodilation
12
Q
Why is it necessary to fast before a lipoprotein blood test?
A
If a patient does not fast before the sample is drawn, only total cholesterol and HDL cholesterol levels will be valid. This is because the concentration of LDL and triglycerides is affected by recent consumption of food.
13
Q
Describe the process of development of atherosclerosis.
A
- leukocytes adhere to endothelial monolayer (innermost layer of the blood vessel).
- Bound leukocytes migrate into the intima (middle layer of vessel wall)
- Monocytes (major leukocyte recruited) mature into macrophages
- Macrophages uptake lipids, yielding foam cells.
- SMCs migrate from the media to the intima and proliferate. Synthesis of collagen, elastin and proteoglycans is heightened. Extracellular lipids derived from dead and dying cells accumulate in the central region of the plaque. advancing plaques also contain cholesterol crystals and micro vessels.
- plaque ruptures and forms a thrombus, reducing blood flow. occurs when plaques fibrous cap ruptures.
14
Q
What are the 4 ways in which lowering cholesterol can reduce the risk of coronary artery disease?
A
- Prevents progression of existing lesions
- changes composition of atherosclerotic plaques
- restores endothelial function
- combats inflammation associated with atherogenesis
15
Q
List 6 lifestyle interventions for lowering cholesterol.
A
- healthy eating recommendations
- smoking cessation
- physical activity
- weight reduction
- limit alcohol intake
- reduce salt intake
16
Q
What is the mechanism of action of statins?
A
Competitively inhibit HMG-CoA reductase, thus preventing the conversion of HMG-CoA to mevalonic acid in an early, rate limiting step in cholesterol synthesis.
Mevalonic acid is a cholesterol precursor.
17
Q
What are 3 indications for use of statins?
A
Hypercholesterolemia
Mixed hyperlipidemia
High risk of CHD, with or without raised cholesterol
18
Q
What are 3 precautions for use of statins?
A
- Severe intercurrent illness such as infection, trauma or metabolic disorder increases risk of adverse effects.
- Avoid stopping statins during acute coronary syndromes (MI, unstable angina), as this is associated with increased cardiovascular events, especially during first week.
- Myopathy with lipid lowering agent
19
Q
Describe dosing advice for statins?
A
Dose should be titrated according to lipid concentration and CV risk.
Dose should be increased at 4 week intervals for maximum effect.
Fluvastatin, Simvastatin and pravastatin are slightly more effective when taken as an evening dose, but this is irrelevant if compliance will be compromised.
20
Q
Compare the LDL-lowering potency of rosuvastatin, fluvastatin, atorvastatin, pravastatin and simvastatin.
A
R > A > S > P = F
21
Q
Describe the general dose response of statins (i.e. lipid lowering effectiveness).
A
Statins lower LDL by 20-40% with initial doses, and then by 35-60% with maximal doses.
Decrease triglycerides by 10-45%, and increase HDL by 5-15%.
22
Q
list 5 mild and more common adverse effects of statins.
A
Statins are generally well tolerated, however may have the following side effects:
headache
dizziness
insomnia
myalgias
GI symptoms (flatus, constipation, pain) which usually disappear with continued treatment.
23
Q
Describe potentially harmful adverse effects of stains.
A
Dose-related risk of myopathy (muscle ache, pain and weakness associated with increased serum creatine kinase) and rhabdomyolosis. Risk is increased by illness and drug interactions.
24
Q
Describe drug interactions of statins.
A
Simvastatin and atorvastatin are metabolised by CYP450 3A4, and so plasma concentrations are effected by enzyme inducers or inhibitors.
Fluvastatin is significantly metabolised by CYP450 2C9, and is effected by inducers or inhibitors of this enzyme. rosuvastatin is metabolised 10% by this enzyme.
Grapefruit juice increases plasma concentrations of atorvastatin and simvastatin.
Gemfibrozol is a potent CYP2C8 inhibitor. this enzyme extensively metabolises simvastatin.
25
give 5 examples of CYP3A4 inhibitors.
```
Clarithromycin (strong)
Erythromycin (moderate)
calcium channel blockers used for hypertension
grapefruit juice
itraconazole
```
26
list practice points of statin therapy.
monitor baseline AST and ALT as these may become elevated on statins. Also monitor CK.
cease statin if CK is 10x upper normal limit
cease statin if aminotransferases are persistently 3x more than upper limit of normal
cease statin if patient has persistent, unexplained muscle pain even if CK is normal.
27
list 2 bile acid binding resins.
Cholestyramine (powder form) and colestipol (granules).
28
What is the mechanism of action of bile acid binding resins?
anion exchanging agents that bind bile acids in intestinal lumen, causing them to be eliminated in the stool. (i.e. they disrupt enterohepatic recirculation of bile acids).
This increases the demand for cholesterol for new bile acid synthesis, --> increased LDL uptake and removal from plasma.
29
What are the indications for use of bile acid-binding resins.
Hypercholesterolaemia
| Mixed hyperlipidaemia
30
What are the precautions for use of bile acid-binding resins?
Bile acid binding resins may worsen hypertriglyceridaemia (when triglycerides > 3mmol/L)
Resins are ineffective in complete billiard obstruction
May worsen constipation, divertiular disease and severe haemorrhoids
31
What are the usual doses of cholestyramine and colestipol?
Cholestyramine: 12-16g daily in 2-3 divided doses
Colestipol: 10-30g daily in 2-4 doses (increase every 1-2 months).
32
Describe the administration of bile acid binding resins.
Take dose before main meals.
Mix with water, juice or highly fluid foods.
Cholestyramine: can mix and stand in fridge for at least 4 hours or overnight to reduce grittiness.
To reduce bloating - avoid mixing in carbonated fluids and use a straw
maintain adequate intake of fluids and fibre
33
Describe the dose response of bile acid binding resins.
decrease LDL by 15-30%
Increase TG by 3-10%
increase/decrease HDL by 3%
34
What are the adverse effects of bile acid binding resins?
Often cause GI symptoms such as constipation, diarrhoea, indigestion, dyspepsia, nausea, flatulence, abdominal pain
can raise TG levels
reduce the absorption of fat-soluble vitamins and folic acid
35
Describe drug interactions of bile acid binding resins.
result in GI binding and reduced absorption of anionic drugs (such as warfarin, beta-blockers, digitoxin, thyroxine).
Take other medicines at least 1 hour before or 4-6 hours after resin.
36
What is the mechanism of action of ezetimibe?
reduces absorption of dietary and billiard cholesterol by inhibiting its active transport across the intestinal wall.
Also inhibits the absorption of the plant sterol sitosterol from the gut, resulting in 40% decrease in blood sitosterol levels. Provides effective treatment for sitosterolemia.
37
What are the indications for use of ezetimibe.
hypercholesterolaemia and homozygous sitosterolaemia.
38
What are the precautions for use of ezetimibe?
treatment with fenofibrate may increase risk of gallbladder disease
reports of depression in the elderly, particularly in the first weeks of treatment.
39
describe dose and dosage response to ezetimibe.
10mg once daily.
decreases LDL by 18-22%
little effect on TG or HDL
additive effect with statins
40
What are the adverse effects of ezetimibe?
Generally well tolerated.
| headache, diarrhoea, myalgia, rarely causes myopathy, gall stones.
41
Describe drug interactions with ezetimibe.
Bile acid binding resins may reduce ezetimibes effect on LDL concentration. If combines, should take ezetimibe at least 2 hours before or 4 hours after resin.
Rifampicin decreases the concentration of ezetimibe. For long causes of rifampicin, use an alternative.
42
What is the mechanism of action of nicotinic acid? (niacin/vit B3)
Inhibits the mobilisation of free fatty acids from peripheral adipose tissue to the liver, resulting in decreased TG and LDL levels.
Increases HDL.
Decreases lipoprotein a which is atherogenic.
43
What are the indications for use of nicotinic acid?
Hypercholesterolaemia
mixed hyperlipidaemia
severe hypertriglyceridaemia
44
What are the precautions for use of nicotinic acid?
may exacerbate peptic ulcer disease
may cause gout
may increase blood glucose
contraindicated after recent MI
caution in CAD: may cause AF and other arrhythmias)
may potentiate hypotensive effects of antihypertensive drugs
contraindicated in symptomatic hypotension.
45
describe dosing and dose response of nicotinic acid.
start at low dose (e.g. 250mg tds) and slowly titrate as tolerated.
Can improve levels of all serum lipids.
decrease LDL by 15-30%, TG by 30-60% and increase HDL by 20-35%
46
What are the adverse effects of nicotinic acid?
vasodilation --> flushing, itching, headaches, hypotension. Occur within 20 minutes and persists for 20-60 minutes.
Dyspepsia, nausea, vomiting and diarrhoea.
Infrequent or rare effects include hyperglycaemia, hyperuricaemia, impaired liver function and myopathy
47
What are some practice points for the use of nicotinic acid?
Can reduce or prevent flushing by taking aspirin 30 minutes before dose.
Take with food to minimise GI upset
Take antacids to minimise dyspepsia.
monitor liver function and blood glucose periodically, particularly at the start of treatment.
48
What are the potential drug interactions for nicotinic acid?
May cause hypotension with BP-lowering drugs
Increases blood glucose, so need to adjust dosage of diabetic medications
When used with statins, there is an increased risk of myopathy and rhabdo, so must monitor for adverse reactions and creatine kinase levels
49
What are the 2 fibrate drugs used in dyslipidemia? Why are they 2nd line drugs?
Fenofibrate and gemfibril.
| Clinical evidence for their efficacy is not as robust as with statins.
50
What is the mechanism of action of fibrates?
Activate peroxisome proliferator-activated receptors, which affect genes modulating lipoprotein synthesis and catabolism.
51
Describe the dose response to fibrates?
has variable effect on LDL
decrease TG in liver by increased FA oxidation
Increase HDL
52
What are the indications for use of fibrates?
severe hypertriglyceridaemia with risk of pancreatitis
mixed hyperlipidaemia and dyslipidaemia associated with diabetes
hypercholesterolaemia
53
What are the precautions for use of fibrates?
increased risk of gall bladder disease when combined with ezetimibe
Contraindicated in hepatic impairment, gallstones, gall bladder disease and primary billiard cirrhosis
contraindicated in those that have developed photosensitivity from previous use of a fibrate drug
54
What are the recommended doses of fenofibrate and gemfibrozil?
Fenofibrate: 145mg once daily.
Gemfibrozil: 600mg bd
55
Describe the dose response to fibrates.
change LDL by 10-25%
decrease TG by 30-60%
increase HDL by 10-30%
56
What are the adverse effects of fibrates?
```
Usually well tolerated.
GI upset
photosensitivity
rarely increases billiard secretion of cholesterol leading to gallstones and cholestatic jaundice
rarely causes myopathy and rhabdo
```
57
Give 2 counselling points for fibrates.
Seek medical advice promptly if urine is dark brown, or if you have any muscle pain, tenderness or weakness.
Avoid exposure of skin to sun
58
Give 3 practice points for use of fibrates.
Fibrates combined with a statin may cause muscle toxicity.
Monitor full blood count, LFT and CK at baseline and repeat during treatment.
Monitor for signs of unexplained muscle toxicity, monitor CK levels.
59
Give 5 drug interactions of fibrates.
Combination of gemfibrozil and statins causes 2-4 fold increase in systemic statin levels. gemfibrozil is strong CYP2C8 inhibitor.
Gemfibrozil increases concentration of thiazolidinediones (anti-diabetics) which are CYP2C8 substrates.
both fibrates increase concentration of warfarin, and decrease concentration of cyclosporin.
Gemfibrozil increases concentration of tiagabine.
60
Give 5 complimentary treatments for dyslipidemia.
```
Fish oil/fish
Plant sterol esters
Fibre
HRT
Antioxidant therapy
```
61
Describe the use of fish oil and fish for the treatment of dyslipidemia?
decrease TG by 30-60%
variable effect on TC and little effect on LDL
High doses may increase bleeding time
62
Describe the use of plant sterol esters for the treatment of dyslipidemia?
Decrease cholesterol concentration, and are used as additional risk reduction strategy.
Available in plant sterol-enriched spreads.
63
Describe the use of fibre in the treatment of dyslipidaemia?
Increased intake of fibre in diet, or adding supplementary fibre to a low-fat diet.
modest reduction in LDL (about 5%)
causes GI upset such as bloating and flatulence.
64
Describe the use of HRT in the treatment of dyslipidaemia?
Estrogen and progestin replacement study resulted in significant increase in CHD events, increased breast cancer, increased stroke and increased pulmonary embolism.
IE has negative cardioprotective effects.
65
Describe the use of antioxidant therapy in the treatment of dyslipidemia?
Vitamin E, C and beta-carotene
| no benefit to CHD
66
Define primary and secondary prevention.
Primary: treatment of patients who have not yet developed disease. Includes the treatment of patients with multiple risk factors who are likely to develop CVD.
Secondary: aims to prevent further deterioration in those diagnosed with CVD.
67
What are the three rationale for treating dyslipidaemia?
1. reduce disease progression, improve survival and reduce risk of MI and stroke in patients with CVD
2. Reduce premature CV morbidity and mortality in people at high risk of CV events
3. prevent pancreatitis due to hypertriglyceridaemia.
68
Why is it important to evaluate blood lipids and blood pressure?
Both are risk factors for cardiovascular events.
69
Name the three risk groups indicating an initial blood lipid test.
Group A: definite high risk
| Group B: Potentially at high risk, depending on lipid study results
70
What are the characteristics of risk group A?
Patient known to have CHD, ischaemic or cerebrovascular disease.
diabetes
renal failure or transplantation
Indigenous
family history of dyslipidaemia
known lower limb atherosclerosis or aortic aneurism.
71
What are the characteristics of risk group B?
```
At least one of the following:
smoker
significant family history of CHD
overweight
hypertension
impaired fasting glucose or glucose intollerance
renal impairment
over 45 years of age
```
72
Describe an aneurism.
Inner and middle muscle layers of the artery become damage, and blood flow is only contained by the thin outer coat of the artery.
This causes a bulge, which can be fatal if it ruptures. Increase in blood pressure may cause an aneurysm to rupture.
73
What are the normal, or healthy levels of lipids?
HDL: >1
TG: <4
74
What are some secondary causes of dyslipidaemia?
```
Sedentary lifestyle with excessive intake of saturated fat, cholesterol and trans fats
Diabetes
excess alcohol consumption
chronic kidney disease
hypothyroidism
liver disease
drugs
```
75
What is the treatment for atherogenic dyslipidaemia?
increase physical activity for weight reduction
| drugs to increase removal of VLDL and small dense LDL particles, and decrease TG
76
Describe metabolic syndrome
Central obesity combined with any 2 of the following:
elevated TG
Decreased HDL
Increased BP, or treatment for hypertension
Increased fasting plasma glucose or treatment for diabetes (T2)
77
Which drugs can induce dyslipidemia?
Some antihypertensives such as thiazide diuretics and beta blockers.
Oral contraceptives, mainly the progesterone component
Glucocorticoids
Testosterone
Ethanol
retinoids
cyclosporin
78
Describe the most common cause of dyslipidemia in children.
Primary causes of dyslipidaemia are single or multiple gene mutations that result in either:
overproduction or defective clearance of TG and LDL, or,
Underproduction or excessive clearance of HDL
79
Describe familial hypercholesterolaemia.
Autosomal dominant disorder.
Strongly associated with premature CHD.
Heterozygotes have increased LDL of 6.5-11.7mmol/L. Homozygotes have LDL above 12.5mmol/L.
Mean age of death in untreated individuals is mid 50s for males and mid 60s for females.
Diagnosed by very high LDL, strong family history of premature CHD events and presence of tendon xanthomas.
Treat with high dose statins.
80
What are tendon xanthomas?
Cholesterol deposits around tendons such as the achilles tendon, and extensor tendons of the hand.
81
Describe apheresis.
Blood of the patient is passed through a machine that filters LDL from the blood. Used as treatment for homozygotes with FH.
82
What is hypoalphalipoproteinemia?
HDL cholesterol below 1mmol/L.
Concentrations of alpha lipoproteins (or HDL) are reduced. Assosciated with increased risk of CHD.
Not clear on the influence of genetics or environment.
Evidence shows that lowering LDL cholesterol in patients with low HDL reduces risk of CHD.
treat with statins or nicotinic acid.
83
What is a CHD risk equivalent?
Condition that places you at high risk for experiencing a cardiac event. Having one or more of these conditions may place you at the same risk of having an event as someone who has already experienced one.
Such conditions include carotid artery disease, abdominal aortic aneurism, diabetes, and peripheral artery disease.
84
What does it mean for the patient if they have a CHD risk equivalent?
Do not require further assessment using the Framingham Risk Equation, and are at very high risk (>15%) of CVD within next 5 years.
85
Why is it important to identify ALL cardiovascular risk factors?
Enables intensive management by lifestyle and pharmacological interventions.
86
Define absolute risk and relative risk?
Absolute: numerical probability of an event occurring within a specified period.
Relative: ratio of the rate of events in the population exposed to a risk factor compared with the rate among the population not exposed to this risk factor.
87
Who should have their absolute CV risk assessed?
```
All adults aged 45-74 without existing CVD, or not already known to be at risk.
Indigenous adults over 35
diabetics 45-60 years
adults who are overweight/obese
adults with AF
```
88
Describe the classification of CVD absolute risk level.
HIGH: >15%. need frequent review.
MOD: 10-15% need 6-12 month review
LOW: <10%. 2 year review.
89
What are the National Heart Foundation treatment guidelines for dyslipidemia?
1. Treat secondary causes of dyslipidemia (i.e. not primary/genetic causes).
2. Provide management and/or treatment for modifiable CV risk factors.
3. Institute other secondary prevention strategies
4. provide treatment for dyslipidemia.
90
How long should lifestyle interventions last for? What should be done after this time? How effective are lifestyle interventions?
6-12 weeks then repeat lipid studies. Reassess absolute CHD risk with implemented lifestyle changes.
Most patients can obtain a 5% or more decrease in total cholesterol.
91
When should lipid-modifying drugs be prescribed?
Should be prescribed to patients at greatest risk of CVD, rather than considering lipid levels alone.
Indicated for use in those at high risk.
92
Which drugs are appropriate for use in hypercholesterolaemia?
```
Statins
Bile acid binding resins
nicotinic acid
ezetimibe
fibrates (second line)
```
93
Which are the drugs of choice or treatment options for hypertriglyceridaemia?
Lifestyle therapy
Treatment with a statin in presence of vascular disease, and with other drugs to lower TG (e.g. fibrates, nicotinic acid and fish oils)
Use fibrates and nicotinic acid in patients with TG > 11.3mmol/L due to risk of pancreatitis.
94
What are the drugs of choice for mixed hyperlipideamia?
Innitial choice of drug is guided by predominant disorder.
Increased TC = statin
increased TG = fibrate. Consider statin if pt has CVD
Nicotinic acid is often poorly tolerated, however is able to decrease TC and TG
