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Semester 4 - Clinical Pharmacology And Therapeutics > Hyperlipidaemias > Flashcards

Hyperlipidaemias Flashcards

1
Q

What is cholestrol used for?

A

Cell membrane integrity and precursor in production of steroid hormones, bile acids and vitamin D production.

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2
Q

Why is LDL bad?

A

Susceptible to oxidation at damaged endothelium initiated by necrotic tissue and ROS, adhere to proteoglycans and cause atherosclerosis

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3
Q

Why is HDL good?

A

Carrier of cholestrol away from circulation to liver for recycling.

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4
Q

How is serum cholestrol related to CHD?

A

Higher serum cholestrol, higher incidence of CHD

But, link not as clear when look at world picture as other things have an effects too.

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5
Q

What things increase the risk of CVD?

A 
High BP
Low HDL-cholesterol 
Smoking 
Diabetes 
Echo LVH (heart failure)
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6
Q

How does LDL cause fatty streaks (atherosclerosis)?

A

Accumulation of LDL at the intima

Oxidation by local endothelial cell products

Modified LDL and additional oxidation - oxidised LDL

Recruited monocytes uptake oxidised LDL via scavenger receptors (SR-A)

Foam cells formed building up in intima / endothelial space

Proliferation of smooth muscle cells

Fatty streaks develop.

Chronic inflammation and accumulation of disrupted VSMC

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7
Q

When do fatty streaks develop?

A

The age in which they develop is variable and is influenced by lifestyle and congenital factors.

1/3 - 20-29yr olds
2/3 - 30-39yr olds
3/4 - 49yr olds
4/5 - 50 year olds

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8
Q

How do statins work?

A

Competitive inhibition of HMG-CoA reductase -rate controlling enzyme in mevalonate pathway.

Upregulation of hepatic LDL receptors

Increased clearance of circulating LDL and decrease secretion of VLDL

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9
Q

What are the most commonly prescribed statin?

A

Atorvastatin

Simvastatin

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10
Q

What are the additional benefits of statin therapy?

A

Deceased CVD risk

Improved vascular endothelial function

Stabilisation of atherosclerotic plaques (deceased SMC proliferation and increased collagen)

Improved haemostasis

Anti inflammatory

Antioxidant (decrease superoxide formation)

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11
Q

How does simvastatin work?

A

Prodrug activated by first pass metabolism -half life is 2hours

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12
Q

How does atorvastatin work?

A

First pass metabolism - active derivative

Half life is 30hours

Now prescribed more as cheap and long half life.

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13
Q

What are the ADRs of statins?

A

Transient serum transaminase elevation

Myalgia - diffuse muscle pain (dose related and more likely if taken in combination with other cholesterol lowering agents)

Rhabdomyoloysis (rare)

GI disruption, nausea, headache

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14
Q

Which statins are best?

A

All cause a dose dependant reduction in LDL cholestrol and specific side effect severity appears to drive choice.

In UK- atorvastatin and simvastatin

USA - Rauvostatin as it has he greatest efficacy (works at lower dose) but, concerns about side effects (diabetes?)

Cerivastatin was withdrawn from sale as drug interactions caused deaths (rhabdo, renal failure)

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15
Q

What are the NICE guidelines regarding statins?

A

Primary prevention 20mg Atorvostatin once daily. - if 10 yr CVS risk is over 10% (used to be 20%)

Secondary prevention (if already had MI stroke ect.) 80mg Atorvostatin once daily.

Full lipid profile inc. HDL, non-LDH and TGs

Should have over 40% reduction in non HDL-C at three months

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16
Q

How do fibrin acid derivates (fibrates) work?

A

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

PPARs regulate expression of genes that control lipoprotein metabolism - increase production of lipoprotein lipase.

The enhance the clearance of triglycerides from lipoprotein in plasma,
Increase fatty acid uptake by the liver,
Increase LDL affinity for its receptor (larger, more buoyant LDL, elevated levels of HDL)

They act at different sites to statins so, in very special circumstances they can be co-pescribed.

17
Q

Examples of fibrates

A

Fenofibrate
Ciprofribrate
Genfibrozil

18
Q

What are the indications of fibrates?

A

Adjunctive therapy to diet in hypertriglyceridaemia

Combined hyperlipidaemia with low HDL who do not respond to NA

Fenofibrate widely distributed and albumin bound.

19
Q

What are the side effects of fibrates?

A

GI upset, cholelothiasis (gall stones), myositis, abnormal LFTs, Warfarin potentiation

20
Q

When are fibrates contraindicated?

A

Hepatic or renal dysfunction

Pre-existing gall bladder disease

21
Q

How do nicotinic acid work?

A

B vitamin has effects on lipids at pharmacological doses.

Antilopolytic - reduced fatty acid supply and decrease triglyceride synthesis.

It decreases VDL and LDL but increases HDL greatly. It is the best agent for increasing HDL.

22
Q

Give an example of a nicotinic acid

A

Niacin

23
Q

ADRs of niacin

A

Flushing (NIAC receptors in skin), headache, itching -reduced by immediate release preparations or low dose aspirin 30mins before (decrease prostaglandin release), hepatotoxicity, GI disturbance

Often poorly tolerated by can be overcome by slow dose increase.

24
Q

When is Nicotinid acid prescribed?

A

Rarely

25
Q

How doe cholestrol absorption inhibitors work?

A

Acts at the brush border of the SI mucosa inhibition NCPC1L1 transporter.

This reduces absorption of cholesterol into the gut by 50%.

It increases hepatic LDL receptor expression.

It decreases total cholestrol by 15% and LDL by 20%.

It is a prodrug - if is more efficacious once the liver turns it into ezetimibe glucuronide and then enters enterohepatic circulation.

26
Q

Give an example of a cholestrol absorption inhibitor

A

Ezetimibe

27
Q

When is multiple target therapy used?

A

Ezetimibe is used in combination with statins in CKD and CVD prevention.
Also used in those that can only tolerate a low statin.
Add fibrates or nicotinic acid when specialist advice in familial hypercholetrolaemia.

28
Q

What cholestrol level do you aim for?

A

2mmol/L LDL cholestrol

4 mmol/L total cholesterol

29
Q

What does it mean if a drug name ends in …Mab?

A

It is a monoclonal antibody

30
Q

What are alirocumab and evolocumab?

A

PCSK9 inhibitor.

Monoclonal antibody

31
Q

Will PCSK9 inhibitors replace statins eventually?

A

Maybe, but do not know long term effects.

Also, given as depot injection under skin every two weeks.

Cost is expensive as under patent.

Currently recommended for primary and secondary prevention in resistant familial hypercholesterolaemia and in some high risk secondary prevention patients.

32
Q

What are thee non POM options to reduce cholestrol?

A

Plant sterols provide LDL cholestrol lowering effects.

Naturally occurring in grains, legumes ect. Structurally similar to cholestrol - competing for absorption.

Work with statin but not ezetimide (as ezetimide inhibit channels go through)

Fish oils

Fibre

Vitamins C and E

Alcohol - increases HDL cholestrol BUT increase triglycerides.

33
Q

What is the cost effectiveness of treating hypercholestrolaemia?

A

Number needed to treat is relatively small (17-20)

Currently statins recommended in the UK are off patent so anybody can make it.

10 years age, the economical considerations with lowering the 10 year CVD risk to 10% but, now they are cheaper it can be done.

34
Q

How do doctors assess CVD risk?

A

QRISK 3rd version

(used to be “Manchester” tables

Semester 4 - Clinical Pharmacology And Therapeutics (26 decks)

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