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Pharmacology > Cholesterol > Flashcards

Cholesterol Flashcards

1
Q

What does oxidation of LDLs cause?

A

Inhibition of macrophage motility
T cell activation and vascular smooth muscle cell division and differentiation
Enhanced platelet aggregation

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2
Q

What are the main drug classes used for lowering lipids?

A 
Statins
Cholesterol lipase inhibitors 
Nicotinic acid/niacin 
Fibrates 
Resins
Omega-3 fatty acids 
Plant sterols
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3
Q

How do statins work?

A

Inhibit HMG-reductase, inhibiting synthesis of cholesterol in hepatocytes

Increased clearance of IDL and LDL

Decrease production of VLDL and LDL

Increase LDL receptors/expression of lipoprotein lipase

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4
Q

How is cholesterol produced?

A

From acetyl CoA
Requires enzymes
-HMG-CoA reductase
-HMG-CoA synthetase

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5
Q

Function of LDLs and VLDLs?

A

LDLs transport cholesterol from the liver to tissues

VLDLs transport TAGs synthesised in the liver to adipose tissue

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6
Q

Indications for statins?

A
  • People with a 10% or greater 10 year risk of developing CVD
  • Familial hypercholesteroaemia
  • Diabetes mellitus
  • Chronic kidney disease
  • Over 85 years
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7
Q

What are some adverse drug reactions to statins?

A

Increased transaminase levels - reversible
Myopathy - diffuse muscle pain and raised creatinine phosphokinase
GI complaints
Arthralgias
Headaches

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8
Q

What can increase myopathy in statin use?

A

When higher doses are used in combination with

  • cyclosporine
  • gemfibrozil
  • erythromycin
  • niacin
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9
Q

Name some secondary benefits of statins

A

Anti-inflammatory
Plaque reduction
Improved endothelial cell function
Reduced thrombotic risk

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10
Q

What are fibric acid derivatives?

A

They are carboxylic acids which are PPARα agonists

-increase the production of lipoprotein lipase

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11
Q

How does atherosclerosis develop?

A

Endothelial injury
Platelet adhesion and PDGF released affecting smooth muscle cells
Macrophages, lymphocytes, smooth muscle cells and LDLs accumulate
Macrophages phagocytose LDLs and become foam cells
Foam cells die and release contents, producing a lipid core
Macrophages release cytokines and growth factors, leading to proliferation of of smooth muscle towards the lipid core and into the media
Inflammatory response causes fibrosis
Small blood vessels grow into the plaque

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12
Q

Actions of fibric acid derivatives?

A

Increase lipoprotein lipase

  • increased fatty acid uptake and oxidation
  • reduced triglyceride levels
  • increased LDL particle side and HDL-C levels
  • direct vascular effects
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13
Q

What are some indications for fibric acid derivatives?

A

Adjunctive therapy to diet
Hypertriglycerdemia
Combined hyperlipidaemia with low HDL who do not response to nicotinic acid

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14
Q

What is the efficacy of fibric acid derivatives?

A

Decreases TG by 25-50%
LDL decreases are variable
Increased HDL by 15-25% in hypertriglyceridemia

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15
Q

Side effects of fibric acids?

A

GI upset
Cholelithiasis (gall stones)
Myositis (muscle ache)

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16
Q

Contraindications for fibric acid derivatives?

A

Hepatic or renal dysfunction

Pre-existing gall bladder disease

17
Q

Action of nicotinic acid?

A

Reduces VLDL and increases HDL at higher doses
-by inhibiting lipoprotein synthesis

Shown to reduce coronary events

18
Q

Adverse effects of nicotinic acid?

A 
Flushing 
Itching 
Headache 
Hepatotoxicity 
GI
Activation of peptic ulcer
Hyperglycaemia and reduced insulin sensitivity
19
Q

Contraindications for nicotinic acid?

A

Active liver disease or unexplained LFT elevations

Peptic ulcer disease

20
Q

Give an example of a cholesterol lipase inhibitor

A

Ezetimibe

21
Q

Mechanism of action of cholesterol lipase inhibitors (Ezetimibe)

A

Selectively inhibit intestinal cholesterol absorption
Decrease intestinal delivery of cholesterol to the liver
Increase expression of hepatic LDL receptors
Decrease cholesterol content in atherogenic particles

22
Q

Adverse drug reactions of Ezetimibe?

A

Headache
Abdominal pain
Diarrhoea

23
Q

What can statins be combined with?

A 
Fibrates (not gemfibrozil)
Nicotinic acid
Ezetimibe 
Omega-3 FAs
Resins
24
Q

How can pharmacodynamics between statins vary?

A

Intestinal absorption varies between 30-85%
Hepatic first pass uptake may occur via diffusion of active transport (by OATP2)
Some require activation
Therefore systemic availability can fall to 5-30% of administered dose

25
Q

How are statins eliminated?

A

Undergo hepatic elimination

Either by CYP3A4 or phase II pathways

26
Q

Why is simvastatin given at night?

A

Has a short half life of 1-4 hours

Given to coincide with peak cholesterol production in early morning

27
Q

Why can atorvastatin and rosuvastatin be given at any time?

A

Have half-lives of around 20 hours

28
Q

What kind of pharmacokinetics (linear or non-linear) do statins exhibit?

A

Non-linear

29
Q

Which drug is best for raising HDL-C?

A

Nicotinic acid

30
Q

What are the effects of HDL and LDL levels on CVS risks?

A

HDL reduce CHD risk

LDL increase risk

31
Q

What are target levels of

  • total cholesterol
  • LDL
  • HDL
A

Total - 5 mmol/L
LDL - 3 mmol/L
HDL - above 1.2 mmol/L

32
Q

What are the other two main factors increasing CHD risk?

A

Smoking

Hypertension

33
Q

DDIs of statins?

A

Those metabolised by phase I are affected by CYP inducers and inhibitors - inhibitors increase risk of myopathy and other effects
Inducers decrease levels

34
Q

What monitoring should be done on patients on high levels of statins

A

Regular LFTs

Constant LDL level monitoring

35
Q

How do cholesterol absorption inhibitors work?

A

Block the cholesterol transport protein NPC1L1 in the brush border
Reduces cholesterol absorption and that reaching the liver
Causes a secondary upregulation of LDL transporter expression
Lowers circulating cholesterol level

36
Q

Why is there low systemic exposure with ezetimibe?

A

Ezetimibe and its active glucuronide metabolite circulate enterohepatically so delivers agent back to the site of action

Pharmacology (23 decks)

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