L40 – Lipid-Lowering Drugs Flashcards Preview

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Flashcards in L40 – Lipid-Lowering Drugs Deck (88):
1

Conditions caused by atherosclerosis in coronary artery and cerebral artery?

Coronary artery > angina, MI
Cerebral artery > Stroke

2

What are some general risk factors of atherosclerosis?

Lifestyle- smoking, diet
Diabetes mellitus
Hypertension
Age & arterial age

3

What are some biochemical disorders that are risk factors of atherosclerosis?

Increase vascular inflammation

Increase coagulation factors

Lipoprotein disorders

4

What lipoprotein disorders are risk factors for atherosclerosis?

High LDL
Low HDL
High triglycerides

5

Lipid components of liproprotein? Protein components?

Lipid components = cholesteryl esters, triglycerides (TG)

Protein components = apolipoproteins

6

List 3 roles of protein components of lipoproteins?

 Provide structural stability
 For lipoprotein-receptor interactions
 As co-factors in enzymatic processes

7

Which liporproteins are high in Molecular weight?

LDL VLDL Chylomicrons

8

HDL relay cholesterol esters to what?

To liver
Mostly to VLDL and LDL

9

What enzyme is used for HDL to transfer cholesterol to VLDL?

cholesteryl ester transfer protein (CETP)

10

What levels of LDL is desirable and what is high?

Normal = <3.4 (130) mmol/L (mg/dL)


High = >4.1 (160) mmol/L (mg/dL)

11

What levels of Total cholesterol is desirable and what is high?

Normal = <5.2 (200) mmol/L (mg/dL)


High = >6.2 (240) mmol/L (mg/dL)

12

What risk is assessed to determine need for drug therapy for lipid lowering?

10- year Coronary Heart Disease risk

13

The higher the CHD risk, the higher or lower the drug therapy threshold and LDL target?

Higher CHD risk, lower LDL target and lower drug therapy threshold

14

What 10 years CHD risk is low risk, moderate risk and High risk?

Low risk = CHD risk lower than 10%

Moderate risk = CHD risk 10-20%

High risk = CHD risk > 20%

15

How to reduce intake of cholesterol in managing lipoprotein disorder?

 Dietary restriction
 Cholesterol absorption inhibitors (drugs)

16

What drugs can lower plasma level of LDL?
Snrp

Statins (HMG-CoA reductase inhibitor)

Niacin (nicotinic acid)

Resins (bile acid sequestrants)

PCSK9 inhibitors

17

What drugs can lower plasma VLDL?

Niacin

Fibrates (fibric acid derivatives)

omega- 3 fatty acid

18

What drug raises plasma HDL?

Niacin

19

Name 3 most common Statins
LSA

LOVAstatin

SIMVAstatin

ATORVAstatin

20

Explain the action of statin on cholesterol, LDL and triglycerides.

1) Decrease synthesis of cholesterol in liver by inhibiting HMG-CoA reductase

2) + Increase clearance of plasma LDL by increase synthesis of LDL receptor in liver

>> Decrease plasma triglycerides

21

How do statins change plasma HDL levels?

Statins lower plasma LDL levels

Lower LDL = Less HDL able relay choelsterol to LDL

Increase in plasma HDL

22

Under what circumstances is statins used and when is it not?

Used: Prevention of atherosclerosis in patients with elevated LDL

Not used: pregnant women or children

23

Why is statins not used in pregnant women and children?

Pregnant women: Lower cholesterol synthesis > insufficient for fetus

Children> statins cause some genetic defect with high risk of CHD

24

What is different between types of statins?

Duration of action

Different efficacy and potency

25

How is the response in patients with homozygous familial hypercholesterolemia to statins?

Attenuated response

26

Difference in half-life between different statins? Difference in time of taking drugs?

Short = 1-4 hours, take at night

Intermediate = 12 hours, take at night

Long = 20 hours, take anytime

27

Give examples of different half-life statins?

Short= LOVAstatin, (PARAVAstatin, FLUVAstatin)

Intermediate = SIMVAstatin

Long = ATROVAstatin, (ROSUVAstatin)

28

Why are short and intermediate half life statins taken at night before sleep?

Hepatic cholesterol synthesis is at maximal between midnight and 2:00am

29

What are the 3 main adverse effects of statins?

Mild GI disturbances

Risk of Hepatotoxicity

Risk of Myopathy

30

How do Statins increase risk of hepatotoxicity? Symptoms?

Increase plasma level of liver enzymes

Malaise, anorexia

31

How is hepatotoxicity measured?

Measure serum alanine aminotransferase level (ALT)

32

What symptoms and complications arise from high statin level induced myopathy?

Muscle pain (myalgia), weakness & fatigue

complications : renal failure, death

33

How is myopathy measured?

plasma creatine kinase (CK) level

34

Factors that affect plasma levels of statins?

High age
Hepatic or renal dysfunction
Small body size (female)
Other drug intake

All increase plasma level of statins

35

What drugs can lead to increased plasma levels of statins?

drugs that decrease uptake of statins or decrease metabolism of statins

36

What enzymes metabolize statins and are subject to drug action that leads to increased plasma statin levels?

Cytochrome P450 metabolize statins

Subject to Glucuronidases (e.g. warfarin, macrolides, azole antifungal)

37

What is niacin?

Nicotinic acid /Vitamin B3

38

How does Niacin change plasma lipoprotein levels?

In Plasma:
Decrease LDL, VLDL
Increase HDL

Reduce TAG level

39

How does Niacin decrease VLDL, LDL?

1) Inhibit hormone-sensitive lipase in adipose tissue

> decrease flux of free fatty acids to liver

> Less hepatic TAG synthesis > less TAG end up in VLDL, LDL

2) Enhance Lipoproteinlipase activity > clearance of VLDL into LDL (LPL turn VLDL to LDL)


40

How does niacin raise HDL level?

Niacin decreases clearance of HDL apo A-1 in liver

41

What are 2 distinct advantages of niacin?

Most effective in raising HDL level

Can normalise LDL in patients with LDLR genetic defects

42

What are some adverse effects on skin by niacin?

Flushing

Skin rashes and acanthosis nigricans (dark skin folds)

43

What adverse effects do niacin and statins share?

GI disturbances

Risk of hepatotoxicity

Not suitable for pregnant women - risk of birth defect

44

Niacin is not used in which patients?

Pregnant

Severe peptic disease (GI ulcers caused by H. pylori and long term use of aspirin, NSAIDS)

45

What drug is used to counter niacin for flushing?

Aspirin

46

Is niacin short or long acting?

Short
Tachyphylaxis (sudden unresponsiveness) occurs within days

47

What are 2 rare adverse effects of niacin?

Maculopathy (damage to eye)

Atrial arrhythmias

48

What are fibrates?

Fibric acid derivatives

PPAR alpha activators

49

Name 3 most common fibrates. CFG

CLOfibrate

FENOfibrate

Gemfibrozil

50

How does fibrate change plasma lipoprotein levels?

Lower VLDL
Increase OR lower LDL (not very effective against LDL)
Increase HDL

51

How does fibrate lower VLDL?

1) Increase LPL synthesis > lower TG and increase VLDL break down

2) Increase FA oxidation in liver > decrease VLDL secretion

52

How does fibrate increase HDL level?

Increase HDL, apo A-I and apo A-II production

53

How come fibrate is ineffective against LDL regulation?

Fibrate can lower level of VLDL and so lower LDL

But also increases conversion of TAG to FA by increasing LPL activity

54

Fibrate is used for which patients and not for which?

Used: Hypertriglyceridemia

Not used: Combined hyperlipidemia (high LDL), pregnant women, children, patients with hepatic or renal dysfunction, biliary tract disease

55

What are some uncommon adverse effects of fibrates?

GI disturbances, rashes

56

What adverse effect do statins and fibrates share?

Risk of myopathy

57

Which statin can be safely used with fibrate? Why?

Fenofibrate

limits statin uptake and metabolism, no need to take extreme caution with statin dosage

Lowest RISK in all statin- fibrate combos

58

Why is niacin administered with great care for diabetics and gout patients?

Diabetics: Niacin decreases glucose tolerance

Gout patient: Niacin increase uric acid levels

59

How does fibrate affect plasma level of liver enzymes, action of warfarin?

Increase plasma level of liver enzymes

Increase action of warfarin

60

How come fibrates are not used in patients with biliary tract disease?

Increases risk of cholesterol gallstones

61

What are Resins?

Bile acid sequestrants

62

Name 3 most common resins

CCC

Cholestyramine

Colestipol

Colesevelam

63

How does Resin alter cholesterol levels?

Bind to bile acids > Increase secretion of bile acids in jejunum and ileum

Increase conversion of cholesterol to bile acid in liver > to be excreted

64

How does Resin change plasma LDL levels?

Promote LDLR synthesis in liver > increase LDL uptake

65

How come the body naturally offsets the effect Resins have on LDL?

Increased LDLR synthesis, more uptake of LDL from plasma > LDL converted to bile acid and excreted > overall lower LDL conc. in liver

Natural compensation for low LDL conc. in liver by promoting LDLR production & enhance cholesterol synthesis > offset resin action

66

Resin is used and not used in which patients?

Used: High LDL patients (e.g. mixed hyperlipidemia)

Not used: Hyperglyceridemia patients (may cause increase hepatic TAG synthesis), patients with diverticulitis (intestinal inflammation/ infection)

67

What alternative effects/ advantages does Resin have apart from lipid lowering?

Counteract Digoxin toxicity

Relieve Pruritus due to cholestasis and bile acid accumulation

No systemic toxicity

68

Are resins absorbed in GI?

No

69

What common adverse effects on the GI does resin cause?

Bloating, Dyspepsia, constipation

Decrease absorption in GI of fat-soluble vitamins and other drugs

70

How can GI disturbances caused by Resin be reduced?

suspend drug in liquid before ingestion

increase dietary fiber intake

71

What is Ezetimibe?

Cholesterol Absorption inhibitor

72

How does ezetimibe change cholesterol levels?

Decrease cholesterol absorption in intestines:
1) binding to NPC1L1
2) inhibiting ACAT

Both lowering LDL level in plasma and liver

73

How does ezitimibe change plasma LDL level?

promote synthesis of LDLR in liver

74

Ezetimibe conc. in plasma is changed by which other lipid lowering drugs?

Increased by fibrates
Reduced by Resins

75

What are some adverse effects of Ezetimibe?

mild (e.g. headache, diarrhea)

Relatively safe

76

What are PCSK9 inhibitors?

Human monoclonal antibodies against PCSK9

77

Name 2 common PCSK9 inhibitors?

Alirocumab and Evolocumab

78

How does PCSK9 inhibitor change plasma LDL level?

Bind to PCSK9 > inhibit PCSK9 from binding to LDLR and cause LDLR degradation

> decrease LDLR degradation = more LDL absorption into liver, less plasma LDL

79

PCSK9 inhibitors are used in what patients?

Used as second line treatment in:

patients with heterozygous or homozygous familial hypercholesterolemia,

Adults with cardiovascular diseases and hypercholesterolemia (prevent MI, stroke... etc)

80

What are some adverse effects of PCSK9 inhibitors?

Relatively safe

Mild muscle ache, injection site reaction, nasopharyngitis

81

Are Resins effective against TG?

No

82

What 2 precautions are taken when giving combo therapy?

Use lowest effective dose

Closely monitor for potential toxicity

83

Which combos are synergistic with statins?

Statin + Ezetimibe or Resins or PCSK9 inhibitors

84

Which combos are synergistic with PCSK9 inhibitor?

PCSK9 inhibitor + Statins or Ezetimibe

85

Which 2 combos are used for combined hypercholesterolemia?

Statin + niacin

Niacin + resin

86

What are the 2 combs that may cause myopathy?

Statin + Fenofibrate

Statin + Niacin

87

Statin + Fenofibrate, although lowest risk of all statin- fibrate combos, may still cause which two disorders?

myopathy and hepatotoxicity

88

What triple therapy is given for high risk patients?

Statins, Resins, Niacin

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