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Cardiovascular System > Atherosclerosis and Lipid-lowering pharm > Flashcards

Atherosclerosis and Lipid-lowering pharm Flashcards

1
Q

Atherosclerosis is a degenerative and inflammatory disease that causes the ________ and ________ of vessels.

A

Thickening and loss of elasticity

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2
Q

In which part of vessels does atherosclerosis most commonly occur?

A

Medium and large arteries, most commonly where they bifurcate/branch

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3
Q

What are 4 constitutional risk factors for atherosclerosis?

A

1) Age
2) Male gender
3) FHx
4) Genetics

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4
Q

What are 4 modifiable risk factors for atherosclerosis?

A

1) HLD
2) HTN
3) DM
4) Smoking

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5
Q

In which layer of vessels do atheroma form?

A

Tunica intima

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6
Q

What are the 3 principal components of atheromas?

A

1) Fibrous cap: Smooth muscle cells, macrophages, T cells
2) ECM (collagen, elastic fibers, proteoglycans)
3) Necrotic center: Intra and extracellular lipids, cell debris, cholesterol

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7
Q

What are 3 complications of atherosclerosis?

A

1) Vessel wall thickening → ↓ tissue perfusion → ischemia
2) Loss of elasticity → aneurysm, rupture, hemorrhage
3) Endothelial change → thrombosis

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8
Q

What are the different types of atherosclerotic lesions?

A

Early: fatty streak
Established: Atheromatous plaque (friable, prone to complications)
Complicated

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9
Q

What are 3 forms of chronic atherosclerotic stenosis?

A

1) Stable angina
2) Chronic IHD
3) Bowel Ischemia
4) Ischemic encephalopathy
5) Intermittent claudication

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10
Q

What are the 5 forms of acute plaque change?

A

1) Rupture
2) Fissure
3) Erosion
4) Ulceration
5) Hemorrhage

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11
Q

How do px with acute plaque changes normally present?

A

Intermittent claudication:
- pain in calf, thigh, butt, induced by exercise, relieved by rest
- progressive worsening

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12
Q

Unstable plaques are often (smaller/larger) and have (more/less) fibrous tissue than stable plaques.

A

Smaller and less fibrous tissue

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13
Q

What are the factors that determine the stability of a plaque?

A

1) Intrinsic:
- structure and composition (<fibrous → ↑unstable)
- ↑ MMP by macrophages → ↑ collagen and ECM degradation → ↑unstable
- ↓ TIMP by macrophage/endothelial/smooth muscle → ↓ MMP inhibition → ↑unstable

2) Extrinsic:
- ↑BP → ↑unstable
- Platelet reactivity → ↑prothrombotic → ↑unstable

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14
Q

What is the pathogenesis of atherosclerosis?

A

1) Chronic endothelial injury (by hemodynamic factors, HLD, Smoking, etc.)
2) Lipids accumulate in tunica intima + endothelial dysfunction
3) Macrophage adhesion/activation by VCAM-1 → Inflammation
4) Smooth muscle recruitment by inflammation (by cytokines/growth factors)
5) Macrophages engulf but cannot digest excess oxidised LDL → foam cells
6) Smooth muscle secrete ECM and engulf lipids → fibrous cap
7) Structural change of vessel wall

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15
Q

How do foam cells form in artheromas?

A

Circulating monocytes adhere to dysfunctional vessel wall by VCAM-1 → activated
→ recruit inflammatory cells → recruit more macrophages (+ve feedback)
→ macrophages engulf but cannot digest excess LDLs that have been oxidised by free radicals
→ foam cells

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16
Q

How does hyperlipidaemia lead to atherosclerotic plaque?

A

↑LDLs → ↑circulating apoproteins
+ endothelial injury → ↑ lipids accumulate in tunica intima

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17
Q

The greater the triglyceride content in lipoproteins, the (higher/lower) the density of lipoproteins.

A

↑ triglyceride → ↓ density

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18
Q

The greater the protein content in lipoproteins, the (higher/lower) the density of lipoproteins.

A

↑ protein → ↑ density

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19
Q

What are chylomicrons?

A

From in mucosal epithelia of small intestine and contain mainly dietary lipids
- transported to adipose tissue for storage

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20
Q

What are VLDLs?

A

Very low density lipoproteins
- synthesised in hepatocytes
- contain mainly endogenous lipids
- FA used for storage by adipocytes and muscle cells for ATP

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21
Q

What are ILDLs?

A

Intermediate low density lipoproteins
- triglyceride depletion of VLDLs
- taken up my liver for reprocessing
- form LDL after further triglyceride depletion

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22
Q

What are LDLs?

A

Low density lipoproteins
- deposit cholesterol in and around smooth muscle fibers in arteries → fatty plaque → ↑CAD risk

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23
Q

What are HDLs?

A

High density lipoproteins
- made in liver
- removes excess cholesterol from cell and transport to liver for elimination → ↓CAD risk

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24
Q

How is exogenous triglycerides/cholesterol transported in tissues?

A

1) core triglycerides in chylomicrons (from small intestine) hydrolysed by lipoprotein lipase
2) tissues take up free FAs
3) chylomicron remnants bind to hepatocyte receptors and get endocytosed
4) cholesterol is stored, oxidised to bile acids, or secreted in bile unaltered
5) can also enter endogenous pathway in VLDL

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25
Q

How is endogenous triglycerides/cholesterol transported in tissues?

A

1) cholesterol/synthesised triglycerides transported from liver as VLDL to muscle and adipose tissue
2) triglycerides hydrolysed → FA enter tissues
3) VLDL → ILDL → LDL
4) Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins
5) cholesterol can return to plasma from tissues in HDLs

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26
Q

What are the 6 types of dyslipidaemias?

A

Type 1: ↑ Chylomicrons
Type 2a: ↑ LDL
Type 2b: ↑ LDL, ↑ VLDL
Type 3: ↑ ILDL
Type 4: ↑VLDL
Type 5: Chylomicrons
(decreasing risk of Cholesterol, except type 1)

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27
Q

What are statins?

A

HMG-CoA reductase inhibitors

28
Q

What is the moa of statins?

A

1) inhibit HMG-CoA reductase → inhibit rate-limiting step in cholesterol synthesis
2) Upregulate LDL receptors → ↑uptake of circulating LDLs

29
Q

What are the clinical indications for statins?

A

1) All types of hyperlipidaemias
2) ↓risk of CAD and mortality of px w IHD

30
Q

When and why are statins given?

A

In the evening
- px dont eat in the evening (↓dietary cholesterol) → HMG-CoA most active (to ↑cholesterol synthesis)

31
Q

How are statins administered?

A

Oral (with first pass extraction)

32
Q

What are 2 AEs of statins?

A

1) Liver: biomedical abnormalities in liver function
2) Myopathy and rhabdomyolysis (tea-coloured urine)

33
Q

Why would a dyslipidemia px have tea-coloured urine?

A

They are taking statins and are experiencing rhabdomyolysis as an AE
OR
They are taking ezetimibe (w or w/o simvastatin)

34
Q

What are 4 examples of statins?

A

1) Lovastatin
2) Simvastatin
3) Pravastatin
4) Fluvastatin

35
Q

In what px are statins contraindicated?

A

Affects neurodevelopment (brain need fat)
1) Pregnant
2) Nursing
3) Children/teens

36
Q

What are 6 drug classes used in hyperlipidemias?

A

1) Statins (HMC-CoA reductase inhibitors)
2) PCSK9 Inhibitors
3) Omega 3 Acid Ethyl Esters
4) Fibrates
5) Resins
6) Ezetimide

37
Q

What are 2 examples of PCSK9 inhibitors ?

A

(-cumab)
1) Evolocumab
2) Alirocumab

38
Q

What is the moa of PCSK9 inhibitors?

A

Inhibition of PCSK9 (targets LDL receptors for degradation in lysosomes)
→ ↓ LDL receptor degradation → ↑LDL uptake/degradation

39
Q

When are PCSK9 inhibitors (eg. evolocumab, alirocumab) indicated?

A

1) Familial hypercholesterolaemias (type 2a), esp those intolerant to statins
2) px with significant atherosclerotic CVD that need additional LDL lowering AFTER diet control and max tolerated statin therapy

40
Q

What lipid lowering medication is commonly given concurrently with PCSK9 inhibitors?

A

Statins (eg. Simvastatin, Lovastatin, Pravastatin, Fluvastatin)

For:
1) Familial hypercholesterolaemias (type 2a), esp those intolerant to statins
2) px with significant atherosclerotic CVD that need additional LDL lowering AFTER diet control and max tolerated statin therapy

41
Q

How are PCSK9 inhibitors adminitered?

A

Injection

42
Q

PCSK9 inhibitors reach max serum conc after ___ days, have a T1/2 of _______ and are dosed every 2/4 weeks.

A

Max serum conc. after 3 days
T1/2: 10-20 days
dosed every 2-4 weeks

43
Q

What are 2 AEs of PCSK9 inhibitors?

A

1) Injected site inflammatory reactions (eg. erythema, itchiness, swelling, pain)
2) ↑ incidence of nasopharyngitis and sinusitis

44
Q

What are 2 examples of Fibrates/Fibric acid derivates?

A

(-fib-)
1) Gemfibrozil
2) Fenofibrate

45
Q

What is the moa of fibrates?

A

Ligands for PPAR-α protein → ↑ activity of lipoprotein lipase
→ ↓plasma triacylglycerol levels
→ ↓VLDLs (by ↓liver secretion)
→ ↑HDL (moderately)

46
Q

What are the clinical indications for Fibrates/Fibric acid derivates?

A

Hypertriglyceridemia with VLDL elevation (especially dysbetalipoproteinemia)
(Type 3 dyslipidemia)

47
Q

What are 3 AEs of Fibrates/Fibric acid derivates?

A

1) GI effects (eg. nausea)
2) Rashes
3) Gallstones
4) Myositis

48
Q

What is Omacor?

A

An Omega-3 acid ethyl ester
(EPA + DHA ethyl esters)

49
Q

What is the moa of Omacor?

A

1) ↓Hepatic TG prod.
2) ↑TG clearance from VLDLs
3) ↑ FA breakdown (via ß-oxidation)
4) ↑lipoprotein lipase activity

50
Q

What lipid lowering medication is commonly given concurrently with Omacor?

A

Statins (eg. Simvastatin, Lovastatin, Pravastatin, Fluvastatin)

For Familial Combined Hyperlipidemia (Type 2b) when TG control is insufficient

51
Q

What are the clinical indications for Omacor?

A

1) For Hypertriglyceridemia (Type 4) monotherapy with dietary measures
2) For Familial Combined Hyperlipidemia (Type 2b) when TG control is insufficient

52
Q

Where is omacor metabolised?

A

in the liver (as with all lipids)

53
Q

How is Omacor administered?

A

oral with food

54
Q

In which px is omacor contraindicated?

A

those allergic to fish

need to monitor px who:
1) have fimilal hypercholesterolemia (DHA may ↑LDL)
2) are on anticoagulants (eg. aspirin, warfarin) (↓prod of TXA2 → ↑ bleeding time)

55
Q

What are 3 AEs of Omacor?

A

1) GI symptoms (abdominal distension, pain, diarrhoea, etc.)
2) ↑ bleeding time (↓ TXA2 prod.)
3) ↑LDL (from DHA)
4) Allergic rxn in those allergic to fish

56
Q

What is cholestyramine?

A

A bile acid binding resin

57
Q

What is the moa of cholestyramine?

A

Bind negatively charged bile acids and salts in small intestine → ↓bile acid conc.
→ ↑ conversion of cholesterol to bile by hepatocytes → ↓intracellular cholesterol
→ ↑ LDL uptake to replenish → ↓LDL
(may ↑VLDL but no effect on HDL)

58
Q

What are the clinical indications for cholestyramine?

A

1) px with primary hypercholesterolemia (type 2a)
2) px with combined hyperlipidemia (type 2b) (with niacin)

59
Q

What lipid lowering medication is commonly given concurrently with Cholestyramine?

A

Niacin
(for px with combined hyperlipidemia (type 2b))

60
Q

How is Cholestyramine administered?

A

Orally

61
Q

What are 2 AEs of Cholestyramine?

A

1) GI effects: constipation, nausea, flatulence
2) Impaired absorption of fat soluble vitamins (A, D, E, K)

62
Q

What is ezetimibe (Zetia)?

A

Intestinal sterol absorption inhibitor

63
Q

What is the moa of ezetimibe?

A

Inhibit sterol transporter (NPC1L1)
→ ↓cholesterol absorption at small intestine

64
Q

What lipid lowering medication is commonly given concurrently with ezetimibe?

A

Simvastatin
Vytorin: ezetimibe + simvastatin

65
Q

When is ezetimibe indicated?

A

Whenever need ↓LDL

66
Q

Ezetimibe is readily absorbed and conjugated in the _______ to a _______.

A

Intestinal wall to an active glucuronide

67
Q

What are 3 AEs of Ezetimibe?

A

1) GI effects (eg. diarrhoea, flatulence)
2) Rhabdomyolysis (more common when w statins)
3) Reversible hepatotoxicity

Cardiovascular System (12 decks)

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