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semester 4 - CPT & Prescribing > 7. Hyperlipidaemia > Flashcards

7. Hyperlipidaemia Flashcards

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1
Q

where does most of cholesterol in body come from?

A

Most cholesterol synthesised in body with contribution (~25%) from diet

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2
Q

role of cholesterol?

A

Essential for membrane integrity, precursor in production of steroid hormones, bile acids and
vitamin D

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3
Q

association of LDL with atheromatous plaques?

A

LDL susceptible to oxidation at damaged endothelium, ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed – precursor to atheromatous plaques

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4
Q

function of HDL?

A

HDL carrier of cholesterol away from circulation to tissues that require it and the liver for
disposal in bile – so called “good cholesterol”

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5
Q

what does cholesterol increase risk of?

A

Risk of suffering from a significant cardiovascular event

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6
Q

What drugs are used to treat hyperlipidaemia?

A
  • Statins
  • Fibrates (PPAR activators - increase LDL transcription)
  • Cholesterol absorption inhibitors
  • PCSK9 inhibitors
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7
Q

What are 2 statins?

A

Atorvastatin, simvastatin

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8
Q

How do statins work?

A
  • Competitive inhibition of HMG-CoA reductase(rate controlling enzyme in HMGCoA to mevalonate pathway) leading to reduced conc of cholesterol within cell
  • low conc of cholesterol stimulates upregulation of hepatic LDL receptors - increased clearance of circulating LDL
  • low intracellular cholesterol also decreases secretion of VLDL
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9
Q

What are the additional effects of statins?

A
  • Improved vascular endothelial function - ↑NO, VEGF, ↓endothelin
  • Stabilisation of atherosclerotic plaque - ↓SMC proliferation ↑collagen
  • Improved haemostasis - ↓plasma fibrinogen, platelet aggregation, ↑fibrinolysis
  • Anti-inflammatory - ↓proliferation of inflammatory cells into plaque, plasma CRP, adhesion molecules and cytokines
  • Antioxidant - ↓superoxide formation
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10
Q

Describe activity of the statins and their derivatives.

A
  • Simvastatin is a pro-drug activated by first pass metabolism t1/2 2hrs
  • Atrovastatin is active and also has active metabolites after first pass metabolism t1/2 >30hrs
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11
Q

What are the adverse affects of statins?

A
  • GI disruption, nausea and headache
  • myalgia - diffuse muscle pain (↑CPK >10 X normal limit) dose related
  • Rarely - rhabdomyolysis - OAT differences?
    Increased liver enzymes
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12
Q

What are the warnings, contraindications for statins?

A
  • Renal or hepatic impairment,

- pregnancy and breastfeeding

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13
Q

Δ important drug interactions for statins?

A
  • CYP 3A4 inhibitors- increases [plasma] statin

- Remember amlodipine (CCB) also increases [plasma] statin

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14
Q

Give examples of drugs that inhibit CYP 3A4.

A

amiodarone, diltiazem, macrolides

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15
Q

What must be done before prescribing statins?

A

Full lipid profile inc. HDL, and non-HDL + TGs before prescribing

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16
Q

What are the nice guidelines for prescribing statins for primary and secondary prevention?

A
  • Primary prevention 20 mg atorvastatin once daily (10 year CVD risk of >10% using QRISK) inc. patient considerations and risk/benefit
  • Secondary prevention 80 mg atorvastatin once daily (amended according to adverse reactions/drug interactions, CKD - 20 mg)
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17
Q

What is the target reduction when prescribing statins?

A

> 40% reduction in non HDL-C at three months

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18
Q

When is it better to take statins?

A

q. h.s (every night at bedtime)
- due to circadian rhythms, increased LDL synthesis/activity at night
- especially for simvastatin, short half life

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19
Q

which fruit should be avoided when taking statins?

A

grapefruit juice or (whole grapefruit) – CYP3A4!

20
Q

What do Fibric acid derivatives (Fibrates) do?

A

Activation of nuclear transcription factor - PPARα (peroxisome proliferation-activated receptor)

21
Q

What does the PPARα regulate?

A

expression of genes that control lipoprotein metabolism - increase production of lipoprotein lipase

22
Q

Give an example of a fibrate.

A

Fenofibrate

23
Q

What are the effects of fibrates?

A 
↑expression of LPL 
↑triglycerides from lipoprotein in plasma 
↑fatty acid uptake by the liver 
↑levels of HDL 
↑LDL affinity for receptor
24
Q

are fenofibrate prescribed alone?

A

rarely now used alone, co-prescribed in mixed hyperlipidaemias

25
Q

adverse effects of fenofibrate

A

cholelithiasis (gall stones), GI upset, myositis

26
Q

warnings, contraindications of fenofibrates

A

photosensitivity, gall bladder disease

27
Q

important drug interactions of fenofibrates

A

warfarin – increase anticoagulation

28
Q

How do cholesterol absorption inhibitors work and what are the effects?

A
  • Inhibit NPC1L1 transporter
  • Reduces absorption of cholesterol by the gut ~50%
  • Hepatic LDL receptor expression increases
  • ↓total cholesterol ~ 15%, LDL ~ 20%
29
Q

Give an example of a cholesterol absorption inhibitor.

A

ezetimibe

30
Q

Describe activity/metabolism/clearance of cholesterol absorption inhibitors.

A
  • is a prodrug
  • metabolised by liver (consider liver failure)
  • remains mostly in the enterohepatic circulation and doesn’t enter system circulation
  • secreted by bile
31
Q

What are the adverse effects for cholesterol absorption inhibitors?

A

Abdominal pain, GI upset

32
Q

What are the warnings, contraindication for cholesterol absorption inhibitors?

A

hepatic failure

33
Q

What are important drug interactions for cholesterol absorption inhibitors?

A

mindful if prescribed with statin – theoretical increased risk of rhabdomyolysis, ciclosporin

34
Q

how is ezetimibe prescribed and what specifically for?

A

• Adjunct to statin (or if not tolerated?) for homozygous familial hypercholesterolemia

35
Q

discuss Multiple target therapy for hyperlipaedemia

A
  • Combination of ezetimibe with statin benefit in CKD and in some for secondary CVD prevention
  • Those that can only tolerate a low dose statin – addition of ezetimibe maybe additive or synergistic?
  • Addition of fibrates or nicotinic acid - specialist advice in familial hypercholesterolemia – but not primary or secondary prevention of CVD in general populations
36
Q

What should be the target LDL and total cholesterol for secondary prevention?

A
  • LDL less than 2mmol/L

- total less than 4mmol/L

37
Q

What is PCSK9?

A

protein that binds internalised LDL-R – directing for degradation

38
Q

how do PCSK9 inhibitors act?

A
  • When LDL attaches to LDL-R , receptor is internalised, LDL catabolised and receptor degraded or recycled in cell
  • PCSK9 – protein that binds internalised LDL-R – directing for degradation
  • inhibiting PCSK9 by monoclonal antibody binding to PCSK9 so less bind to receptors could reduce the degradation of the LDL receptor in hepatocytes so more receptors available for uptake of LDL and thus reduce circulating LDL
  • PCSK9 inhibitors demonstrated highly significant reduction in LDL cholesterol over placebo (statin +/- ezetimibe)
39
Q

Give 2 examples of PCSK9 inhibitors.

A

alirocumab, evolocumab

40
Q

advantages of PCSK9 inhibitors?

A

• Long term effects on cholesterol lowering and CVD risk remain to be determined

41
Q

Disadvantages of PCSK9 inhibitors?

A

• Requires lifetime injections – current cost 100 x statin

42
Q

What are the nice guidelines for use of PCSK9 inhibitors

A

Resistant familial hypercholesterolemia and some high risk secondary prevention patients (CVS risk, with high LDL)

43
Q

what is primary prevention of hyperlidaemia?

A

treating a patient with elevated cholesterol levels but have not experienced cardiovascular event or disease

44
Q

what is secondary prevention of hyperlidaemia?

A

have had a major cardiovascular event

45
Q

What are other options for treating cholesterol?

A
  • Plant sterols provide LDL cholesterol lowering effects - Naturally occurring in grains, legumes etc. structurally similar to cholesterol – competing for absorption
  • Fish oils/oily fish Fibre, whole grains Vitamin C/E
    • Alcohol – increases HDL cholesterol BUT also increases triglycerides

semester 4 - CPT & Prescribing (25 decks)

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