4 - Hyperlipidaemia Drugs Flashcards

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1
Q

What are the pro-atherogenic effects of oxidised LDL?

A
  • Inhibits macrophage motility
  • Induces T-cell activation and VSMC division / differentiation
  • Toxic to endothelial cells
  • Enhances platelet aggregation
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2
Q

How do atheromas form?

A
  • Endothelial injury e.g hypertension, smoking, hyperlipidaemia
  • LDL deposits in the intima of blood vessels
  • LDL gets oxidised and then phagocytosed by macrophages forming foam cells
  • Smooth muscle cells start to proliferate forming a fatty streak
  • Fibrous cap forms of the top
  • Centre of the plaque dies and necrosis develops, dead cells release cholesterol so cholesterol clefts are seen
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3
Q

What is the mechanism of action of statins and what are the two main ones prescribed?

A

- Atorvastatin and Simvastatin

  • Inhibit HMG CoA Reductase in the rate limiting pathway so inhibits cholesterol synthesis in hepatocytes

- Upregulates hepatic LDL receptors so increased clearance of circulating LDL

  • Decreased LDL and VLDL production so less cholesterol
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4
Q

What other actions do statins have to lower CVD risk, apart from lowering cholesterol?

A
  • Anti-inflammatory
  • Plaque reduction/stabilisation
  • Improved endothelial cell function e.g increased NO production
  • Reduced thrombotic risk due to improved haemostasis
  • Antioxidant
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5
Q

What are some adverse effects of statins?

A
  • GI disruption
  • Nausea
  • Headaches
  • Myalgia (raised CPK>10x normal limit)
  • Rhabdomyolysis (rare and in high doses for long period of time)
  • Renal impairment from muscle breakdown
  • Hepatocyte injury so raised ALT
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6
Q

What are some contraindications for statin use (should not be used)?

A

- Renal impairment

- Pregnancy and breastfeeding as cholesterol needed for fetus

- Drugs that inhibit CYP3A4: amiodarone, diltiazem, macrolides, amlodipine (stop statins shortly when taking antibiotics)

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7
Q

How are statins administered?

A
  • Orally and they are prodrugs until first pass metabolism
  • Simvastatin has short half life of 2 hours so take at night
  • Atorvastatin has long half life of 30 hours
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8
Q

When are statins prescribed ?

A

- 10 year CVD risk >10% using QRISK

- Familial Hypercholesterolaemia

- Post MI

Primary prevention: Low dose 20mg atorvastatin OD

Secondary prevention: High dose 80mg if tolerated and no drug interactions. Done as low NNT

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9
Q

What advice should be given to a patient taking statins and what is the aim when prescribing these?

A
  • Do not eat/drink grapefruit
  • Take at night as LDL receptor synthesis follows circadian rhythm and short half life of simvastatin
  • Take full lipid profile before inc HDL and TG
  • Want >40% reduction in non-HDL-C at three months
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10
Q

What is the mechanism of action of fibric acid derivatives (fibrates) and what is the name of the drug from this class prescribed?

A

- PPARα (transcription factor) agonist – increases production of lipoprotein lipase which allows chylomicrons to release their TAG into muscle and liver cells lowering TAG in blood

- Reduces triglyceride production

- Increase HDL levels

- Fenofibrate: usually co-prescribed with a statin and good diet

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11
Q

What are the possible adverse effects of fibric acid derivatives?

A
  • Cholelithiasis
  • GI upset
  • Myositis/Rhabdo when given with statins
  • Hepatic, renal and gall bladder issues
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12
Q

What are the contraindications for fibric acid derivatives?

A
  • Patient taking warfarin as high risk of bleeding
  • Hepatic or renal dysfunction
  • Pre-existing gallbladder disease
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13
Q

When are fibrates used?

A
  • Adjunctive therapy to diet if statin not tolerated or contraindicated

- Hypertriglyceridemia (high TAG)

  • Combined hyperlipidemia with low HDL
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14
Q

How does ezetimibe work as a lipid lowering drug?

A

- Cholesterol absorption inhibitor (lowers cholesterol+LDL)

    • ↓ intestinal absorption* by inhibiting NPC1L1 transporter
  • ↑ expression of hepatic LDL receptors
  • ↓ cholesterol content of atherogenic particles
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15
Q

What are the possible adverse effects of ezetimibe and what are some contraindications for its use?

A
  • Headache
  • Abdominal pain
  • Diarrhoea
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16
Q

When is ezetimibe prescribed?

A
  • Adjunct to statin instead of resins and bile salt sequesterants as better tolerability/less side effects
  • Used if statins not tolerated
  • Familial hypercholesterolaemia
  • No dose escalation, always 10mg
17
Q

What is the target cholesterol for those undergoing secondary prevention?

A

- <2mmol/L LDL and <4mmol/L total cholesterol

  • Often use multiple target therapy, e.g ezetimibe itself gets stuck in enterohepatic circulation so no systemic exposure
18
Q

Describe how lipid lowering drugs can be used in combination therapy and what should one consider when assessing the use combination therapy of lipid lowering drugs?

A
  • Benefit (CV risk reduction)
  • Cost
  • ADRs
19
Q

Complete the table by indicating whether the drug increases/decreases or does not affect the listed lipid parameter

A
20
Q

How does alirocumab work as a lipid lowering drug?

A

- Monoclonal antibody that inhibts PCSK9 enzyme

  • PCSK9 normal degrades LDL receptors so less internalised but this drug stops this so increased expression of LDL receptors with this drug
  • Big reduction in LDL but very expensive!!!
21
Q

How is alirocumab administered and why is it not used much in practice?

A
  • Biweekly subcut injections

- Too expensive: weekly cost of £100 over £1 with statins

  • Given when primary hypercholesterolaemia has not responded to anything else
22
Q

Apart from lipid lowering drugs, what can be done by a patient to lower their cholesterol?

A

- Eat plant sterols as they compete with cholesterol for absorption, found in grains and legumes. (not as helpful with ezetimibe as this is inhibiting cholesterol absorption too)

- Eat fish oils, fibre, vitamin C and E

  • Alcohol increases HDL but also increases TAG so be careful

USE THIS METHOD IF STATINS NOT TOLERATED

23
Q

Why are statins the first line therapy for high cholesterol?

A
  • Very low NNTT
  • Cheap as off patent
24
Q

How is a persons 10 year CVD risk calculated?

A

- QRISK score

  • Takes into account age, smoke, diabetes etc and helps to decide how to manage, e.g change diet or statins
25
Q

How do bile acid sequesterants work and why are they not used so much anymore?

A
26
Q

Which statin is the best at lowering the lipid profiles?

A

NOT ALL THE SAME

27
Q

What are some of the factors taken into consideration on the QRISK score?

A
28
Q

What are some factors that affect your QRISK score?

A
  • Smoking
  • Weight
  • Age

CVD risk >10% start 20mg atorvastatin for primary prevention or 80mg or secondary

29
Q

What is inclisiran?

A