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PHAR 152* > Dyslipidemia > Flashcards

Dyslipidemia Flashcards

1
Q

What is the pathogenesis of atherosclerosis?

A

The initial event in atherosclerosis is infiltration of low-density lipoproteins (LDLs) into the sub endothelial region.

The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood.

This is most marked at points where the arteries branch, and this is where the lipids accumulate to the greatest degree

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2
Q

What is structural and chemical qualities of cholesterol?

A

It is a sterol (a modified steroid molecule)

A type of lipid molecule synthesized by all animal cells, and it serves as a structural component of all animal cell membranes

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3
Q

What are some molecules that use cholesterol as a precursor?

A

Bile acids

Vitamin D

Steroid hormones (corticosteroids and sex steroids)

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4
Q

What are triglycerides?

A

Composed of three fatty acids connected by a glycerol backbone

They are fatty acids that can be oxidized for energy by many tissues

The glycerol backbone can be used for gluconeogenesis

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5
Q

How are lipid-soluble particles like cholesterol and triglycerides transported across the body?

A

Specialized vehicles called apolipoproteins can help shuttle lipid soluble molecules around the body

Lipoproteins have varying density based on the relative amount of protein vs. Liquid

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6
Q

What are the components of a plasma lipoprotein?

A

Proteins and lipids; the proteins are located on the periphery while the lipids are concentrated in the middle

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7
Q

What are the major types of plasma lipoproteins?

A

Chylomicrons

Very Low Density Lipoprotein (VLDL)

Low Density Lipoprotein (LDL)

High Density Lipoprotein (HDL)

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8
Q

What are chylomicrons?

A

They are large lipoproteins containing lots of triglycerides

They are a major vehicle to carry dietary fat following absorption from the gut

They break down in 3-6h (short half-life)

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9
Q

What is the role of chylomicrons?

A
  1. They are a source of triglycerides for tissue and muscle (cardiac and skeletal)
  2. Source of triglycerides and cholesterols for liver to produce VLDL
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10
Q

What happens to LDL levels in a high fat and cholesterol diet?

A

There is an excess supply oof chylomicrons, and when these particles enter the liver, the organ down regulates LDL-receptors (to prevent further uptake of LDL)

This means that LDL begins to build up in the blood

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11
Q

What are VLDLs?

A

Very similar to a chylomicrons molecule

Synthesized in liver

They are the main source of fatty acids in the fasting state (between meals)

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12
Q

What is the fate of VLDLs?

A

Tissues will strip the VLDL of its lipids, and it will become an LDL particle (

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13
Q

What is intermediate density lipoprotein (IDLs)?

A

Additional loss of triglycerides from VLDL, will turn them into IDL. IDL will be converted into LDLs in a similar process

This conversion occurs most often in the liver and in tissues that use triglycerides

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14
Q

What is LDL?

A

It is the main carrier of cholesterol in blood (60-70%)

Many tissues can synthesize their own cholesterol

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15
Q

What happens to cells that have low cholesterol, but need more to continue cell growth and division?

A

The cell will build an LDL receptor to pull triglycerides and cholesterol from LDLs in the blood stream

Liver cells always express LDL receptors

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16
Q

What is the disease causing factor in familial hypercholesterolemia ?

A

These individuals do not produce enough, or do not produce LDL receptors in their cells

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17
Q

What happens when intracellular cholesterol levels are elevated?

A

Inhibits intracellular production

Decreases synthesis of LDL receptors

Increases cholesterol storage within the cells

LDL is excreted in bile

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18
Q

What is HDL?

A

It is derived mainly in the gut and liver. HDLs are formed in by remodelling chylomicrons or by VLDL catabolism

Its main role is a “reverse cholesterol transporter” (pulls excess cholesterol from tissues and transports them to liver for excretion)

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19
Q

Are HDL increasing drugs effective in reducing the incidence of major events?

A

No, these drugs are able to increase HDL levels, but they do not have the same protective qualities as endogenous HDL

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20
Q

What is the pathophysiology of atherosclerosis?

A

Thought to arise form transport and retention of LDL through the endothelial layer into the sub endothelial space

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21
Q

What is the significance of LDL particle oxidation?

A

Oxidized LDL appears to elicit an immune response.

Studies of atherosclerotic plaques, almost always show oxidized LDLs. Oxidized LDLs in the sub-endothelial space triggers signals to recruit monocytes into the artery wall. This recruitment of immune cells is bound to cause inflammation

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22
Q

Can oxidized LDL be broken down?

A

No, macrophages instead will engulf enormous volumes of oxidized LDL and become “foam cells”

The buildup of foam cells under the lining of a vessel, effectively reducing vessel diameter.

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23
Q

How do plaques get bigger and more involved ?

A

VAscular smooth muscles proliferate and lay down collage and other matrix molecules, and further contribute to the bulk of the lesions. Repeated injury and repair eventually leads to a fibrous cap protecting the plaque below

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24
Q

Does PCI provide 100% against heart attacks?

A

No, in PCI the largest and most accessible plaques are scented. A smaller or more distal plaque could still burst and cause a platelet response that causes myocardial infarction.

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25
Q

What are antioxidants?

A

HIghly marketed supplements aimed at interacting with oxidizing compounds (free radicals)

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26
Q

Can antioxidants reduce major CV events attributed to the buildup of oxidized LDL?

A

No, there is no appreciable difference in the incidence of major CV events between placebo and antioxidants

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27
Q

Should we discourage antioxidants for major CV event incidence reduction?

A

No need, they are safe and the theory is sound. The trials though do not show any added benefit of antioxidants

28
Q

When does atherosclerosis develop?

A

Low levels of atherosclerosis appear as “fatty streaks’ in blood vessels that can be seen in the first 10 years of life

Atherosclerosis starts early, and can progress faster in some individuals

29
Q

What are some outcomes of atherosclerosis?

A

Cerebral circulation:
Ischemic stroke, vascular dementia

Abdominal aorta:
Aneurysmal dilation and rupture of the vessel

Renal vessels:
Renovascular hypertension

Periphery:
Vascular insufficiency, intermittent claudication, and gangrene

Coronary arteries:
Coronary artery disease and atherosclerotic cardiovascular disease

30
Q

Do we give people with low risk for cardiovascular disease (Framingham risk score below 10) LDL lowering drugs?

A

In general, we do not give LDL lowering drugs to patients with low Framingham risk scores.

The exception are individuals who have low Framingham risk scores, but have an LDL level of more than 5.0mmol/L

31
Q

What is the general target for LDL therapy?

A

LDL levels to 2mmol/L or lower

32
Q

What are some risk factors that further elevate an individual’s risk factor for major CV events due to elevated LDL levels?

A

Family history:
(1st degree relative with established ASVD at earlier age (under 55 for males, and under 65 for women)

Lp(a):
An LDL molecule covalently bonds to an Apo A. Highly genetic predisposition that is associated with higher risk

Coronary Artery Calcium:
This test can reveal the extent of disease activity in the coronary arteries. High CAC indicated higher risk

33
Q

What are statin indicated conditions?

A

The following are three conditions that are considered statin indicated conditions:

An LDL level of above 5.0moles/L, usually this high due to a genetic condition

Most diabetes patients (see details in the guideline)

Atherosclerotic Cardiovascular Disease

34
Q

What is the LDL target for patients that have a current LDL score of more than 5.0moles/L?

A

2.5mmol/L (or 50% reduction)

35
Q

What is a more technical term for statins?

A

HMG-CoA reductive inhibitors

All of the drugs in this class end in -statin

36
Q

What is the mechanism of action for statins?

A

Inhibits an enzyme that is responsible for intracellular synthesis of cholesterol.

These drugs effectively decrease cellular supply of cholesterol, making tissues more reliant on LDLs in the bloodstream (via the up regulation of LDL receptors)

37
Q

Are LDL reductions of over 50% seen in statin use?

A

Yes, Atorvastatin 80mg, and Rosuvastatin 20mg and 40mg are all drug strengths that cut LDL levels by more than half

38
Q

Does LDL reduction prevent major CV events?

A

No, like BP drugs they can only reduce risk.

Patients that have the highest unmediated LDL levels will see the greatest benefit in absolute terms

39
Q

Do statins have good evidence for reducing major CV events?

A

Yes, statins perform better than placebo and high dose statins outperform low dose statins

40
Q

What is the current statin dosing recommendation?

A

Highest intensity of statin drugs that can be tolerated by the patient should be used regardless of the start LDL levels

(The stronger the drug, the greater risk reduction)

41
Q

Can only a few people tolerate high doses of statins?

A

No, most people can tolerate high statin doses

42
Q

What are some potential non-LDL reduction benefits of statin use?

A

Increase in HDL levels (5-10% increase)

Reduction in triglycerides (up to 30% decline)

43
Q

Are statins effective in patients who have no risk factors?

A

This is a trick question, in patients with low risk likely have lower LDL levels. Lower LDL levels can only be reduced only so much in absolute terms.

LDL reduction may not reduce incidence of major CV events in low or no risk factor patients, it should give them the benefit of having lower LDL

44
Q

What is the NNT for statin use?

A

If the NNT is less than 50 to prevent a CV event over the next 5 years, it is generally accepted as reasonable for statins

45
Q

Are dietary changes in people who need LDL reduction have the same effects as statins?

A

Dietary changes are harder to make and for many older patients it is too late to make an appreciable change in LDL levels and improve health

46
Q

If given reference ranges for LDL levels that differ from the Canadian guidelines, what should I do?

A

Ignore the provided reference frame, go with current Canadian guidelines

47
Q

Do we have to tritrate up statin doses?

A

No, in most cases a high dose statin can be started immediately

Patients may not feel comfortable or have potential drug interactions, then we can go slower

48
Q

When are patients given LDL reducing treatment under secondary prevention?

A

Usually initiated in patients with clinically relevant atherosclerotic disease (heart attack, PCI, etc.)

49
Q

When are Apo B and non-HDL values used in determining risk in patients with dyslipidemia?

A

In patients with high triglycerides, we use non-HDL or ApoB values to accurately determine risk

50
Q

Are high LDL levels usually due to a genetic predisposition?

A

Yes, especially when LDL is close to 4 or above

51
Q

For patients with atherosclerotic cardiovascular disease and high LDL, but not meeting the target of 1.8mmol/L?

A

We can prescribe PCSK9 inhibitors or ezetimibe

52
Q

What are PCSK9 inhibitors?

A

A relative new class of cholesterol-lowering agents (monoclonal antibodies). They prevent the degradation of the LDL receptor on hepatocytes. These drugs only come as subcutaneous injections

ex. Evolocumab and Alirocumab

53
Q

Is Ezetimibe a better cholesterol-reducing agent than PCSK9 inhibitors?

A

No, PCSK9 inhibitors are more efficacious (54% decrease in LDL) vs. Ezetimibe (16.7% decrease)

54
Q

Can PCSK9 inhibitors be used in patients that are intolerant to stains?

A

Yes, can be really useful in patients that have a hard time tolerating high dose statins.

55
Q

Do PCSK9 inhibitors have a lot of side effects compared to statins?

A

They surprisingly have similar levels of side effects despite increased utility and effficacy

56
Q

What is ezetimibe?

A

It inhibits luminal cholesterol absorption in the small intestine.

This results in reduce input of cholesterol, which leads to the consumption of existing cholesterol from pre-existing LDL (5-20% reduction in LDL mono therapy)

Often combined with statin drugs when their doses are maxed out

57
Q

What are some general statin side effects?

A

GI discomfort

Fatigue

These effects are transient and are reported at the same rates as placebo

58
Q

What are some particularly concerning side effects seen in statin use?

A

Rhabdomyolysis (muscle break down, increased creatine kinase CK)

Slightly increased rate of diabetes

Concern for cognitive impairment/memory loss, likely compensated by therapy preventing other brain conditons

59
Q

What is the incidence of muscle pains in patients on statins?

A

5.1% experience general muscle aches, not rhabodmyolysis

RHabdomyolysis incidence: 1.6 cases per 100,000 man years (very rare)

60
Q

What causes the variability in muscle pain in patients on statins?

A

The level of serum creatinine kinase (CK) determine the severity of the muscle pain

61
Q

What are the three types of muscle pain experienced by patients on statins?

A

Myalgia (not associated with damage)

Myositis (inflamed muscle)

RHabdomyolysis (big time damage to muscle, release of myoglobins)

62
Q

What should a pharmacist do if a serum creatinine kinase (CK) levels falls under myosistis?

A

Pharmacists should be concerned and suggest to discontinue the drug and try it again with a different dose

63
Q

How can we be sure if a pain is due to statin therapy?

A

Symptoms resolve when statin is D/c

Symptoms recur when statin restarted

Symptoms recur when another statin tried

64
Q

What is the basic ADME for statins?

A

All statins are metabolized by the liver (70% of metabolites are excreted by the liver).

Overwhelming liver metabolism enzyme systems is the likely source for drug interactions with statins

65
Q

Is atorvastatin eliminated more preferentially by the kidneys vs. Rosuvaststin?

A

No, atorvastatin is better in CKD patients because it is more hepatically cleared

PHAR 152* (16 decks)

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