L40 – Lipid-Lowering Drugs

Question 1

Conditions caused by atherosclerosis in coronary artery and cerebral artery?

Answer 1

Coronary artery > angina, MI

Cerebral artery > Stroke

Question 2

What are some general risk factors of atherosclerosis?

Answer 2

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

Question 3

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

Answer 3

Increase vascular inflammation

Increase coagulation factors

Lipoprotein disorders

Question 4

What lipoprotein disorders are risk factors for atherosclerosis?

Answer 4

High LDL
Low HDL
High triglycerides

Question 5

Lipid components of liproprotein? Protein components?

Answer 5

Lipid components = cholesteryl esters, triglycerides (TG)

Protein components = apolipoproteins

Question 6

List 3 roles of protein components of lipoproteins?

Answer 6

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

Question 7

Which liporproteins are high in Molecular weight?

Answer 7

LDL VLDL Chylomicrons

Question 8

HDL relay cholesterol esters to what?

Answer 8

To liver

Mostly to VLDL and LDL

Question 9

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

Answer 9

cholesteryl ester transfer protein (CETP)

Question 10

What levels of LDL is desirable and what is high?

Answer 10

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

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

Question 11

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

Answer 11

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

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

Question 12

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

Answer 12

10- year Coronary Heart Disease risk

Question 13

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

Answer 13

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

Question 14

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

Answer 14

Low risk = CHD risk lower than 10%

Moderate risk = CHD risk 10-20%

High risk = CHD risk > 20%

Question 15

How to reduce intake of cholesterol in managing lipoprotein disorder?

Answer 15

 Dietary restriction

 Cholesterol absorption inhibitors (drugs)

Question 16

What drugs can lower plasma level of LDL?

Snrp

Answer 16

Statins (HMG-CoA reductase inhibitor)

Niacin (nicotinic acid)

Resins (bile acid sequestrants)

PCSK9 inhibitors

Question 17

What drugs can lower plasma VLDL?

Answer 17

Niacin

Fibrates (fibric acid derivatives)

omega- 3 fatty acid

Question 18

What drug raises plasma HDL?

Answer 18

Niacin

Question 19

Name 3 most common Statins

LSA

Answer 19

LOVAstatin

SIMVAstatin

ATORVAstatin

Question 20

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

Answer 20

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

Question 21

How do statins change plasma HDL levels?

Answer 21

Statins lower plasma LDL levels

Lower LDL = Less HDL able relay choelsterol to LDL

Increase in plasma HDL

Question 22

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

Answer 22

Used: Prevention of atherosclerosis in patients with elevated LDL

Not used: pregnant women or children

Question 23

Why is statins not used in pregnant women and children?

Answer 23

Pregnant women: Lower cholesterol synthesis > insufficient for fetus

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

Question 24

What is different between types of statins?

Answer 24

Duration of action

Different efficacy and potency

Question 25

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

Answer 25

Attenuated response

Question 26

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

Answer 26

Short = 1-4 hours, take at night Intermediate = 12 hours, take at night Long = 20 hours, take anytime

Question 27

Give examples of different half-life statins?

Answer 27

Short= LOVAstatin, (PARAVAstatin, FLUVAstatin) Intermediate = SIMVAstatin Long = ATROVAstatin, (ROSUVAstatin)

Question 28

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

Answer 28

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

Question 29

What are the 3 main adverse effects of statins?

Answer 29

Mild GI disturbances Risk of Hepatotoxicity Risk of Myopathy

Question 30

How do Statins increase risk of hepatotoxicity? Symptoms?

Answer 30

Increase plasma level of liver enzymes Malaise, anorexia

Question 31

How is hepatotoxicity measured?

Answer 31

Measure serum alanine aminotransferase level (ALT)

Question 32

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

Answer 32

Muscle pain (myalgia), weakness & fatigue complications : renal failure, death

Question 33

How is myopathy measured?

Answer 33

plasma creatine kinase (CK) level

Question 34

Factors that affect plasma levels of statins?

Answer 34

High age Hepatic or renal dysfunction Small body size (female) Other drug intake All increase plasma level of statins

Question 35

What drugs can lead to increased plasma levels of statins?

Answer 35

drugs that decrease uptake of statins or decrease metabolism of statins

Question 36

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

Answer 36

Cytochrome P450 metabolize statins Subject to Glucuronidases (e.g. warfarin, macrolides, azole antifungal)

Question 37

What is niacin?

Answer 37

Nicotinic acid /Vitamin B3

Question 38

How does Niacin change plasma lipoprotein levels?

Answer 38

In Plasma: Decrease LDL, VLDL Increase HDL Reduce TAG level

Question 39

How does Niacin decrease VLDL, LDL?

Answer 39

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)

Question 40

How does niacin raise HDL level?

Answer 40

Niacin decreases clearance of HDL apo A-1 in liver

Question 41

What are 2 distinct advantages of niacin?

Answer 41

Most effective in raising HDL level Can normalise LDL in patients with LDLR genetic defects

Question 42

What are some adverse effects on skin by niacin?

Answer 42

Flushing Skin rashes and acanthosis nigricans (dark skin folds)

Question 43

What adverse effects do niacin and statins share?

Answer 43

GI disturbances Risk of hepatotoxicity Not suitable for pregnant women - risk of birth defect

Question 44

Niacin is not used in which patients?

Answer 44

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

Question 45

What drug is used to counter niacin for flushing?

Answer 45

Aspirin

Question 46

Is niacin short or long acting?

Answer 46

Short | Tachyphylaxis (sudden unresponsiveness) occurs within days

Question 47

What are 2 rare adverse effects of niacin?

Answer 47

Maculopathy (damage to eye) Atrial arrhythmias

Question 48

What are fibrates?

Answer 48

Fibric acid derivatives PPAR alpha activators

Question 49

Name 3 most common fibrates. CFG

Answer 49

CLOfibrate FENOfibrate Gemfibrozil

Question 50

How does fibrate change plasma lipoprotein levels?

Answer 50

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

Question 51

How does fibrate lower VLDL?

Answer 51

1) Increase LPL synthesis > lower TG and increase VLDL break down 2) Increase FA oxidation in liver > decrease VLDL secretion

Question 52

How does fibrate increase HDL level?

Answer 52

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

Question 53

How come fibrate is ineffective against LDL regulation?

Answer 53

Fibrate can lower level of VLDL and so lower LDL But also increases conversion of TAG to FA by increasing LPL activity

Question 54

Fibrate is used for which patients and not for which?

Answer 54

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

Question 55

What are some uncommon adverse effects of fibrates?

Answer 55

GI disturbances, rashes

Question 56

What adverse effect do statins and fibrates share?

Answer 56

Risk of myopathy

Question 57

Which statin can be safely used with fibrate? Why?

Answer 57

Fenofibrate limits statin uptake and metabolism, no need to take extreme caution with statin dosage Lowest RISK in all statin- fibrate combos

Question 58

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

Answer 58

Diabetics: Niacin decreases glucose tolerance Gout patient: Niacin increase uric acid levels

Question 59

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

Answer 59

Increase plasma level of liver enzymes Increase action of warfarin

Question 60

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

Answer 60

Increases risk of cholesterol gallstones

Question 61

What are Resins?

Answer 61

Bile acid sequestrants

Question 62

Name 3 most common resins CCC

Answer 62

Cholestyramine Colestipol Colesevelam

Question 63

How does Resin alter cholesterol levels?

Answer 63

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

Question 64

How does Resin change plasma LDL levels?

Answer 64

Promote LDLR synthesis in liver > increase LDL uptake

Question 65

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

Answer 65

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

Question 66

Resin is used and not used in which patients?

Answer 66

Used: High LDL patients (e.g. mixed hyperlipidemia) Not used: Hyperglyceridemia patients (may cause increase hepatic TAG synthesis), patients with diverticulitis (intestinal inflammation/ infection)

Question 67

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

Answer 67

Counteract Digoxin toxicity Relieve Pruritus due to cholestasis and bile acid accumulation No systemic toxicity

Question 68

Are resins absorbed in GI?

Answer 68

No

Question 69

What common adverse effects on the GI does resin cause?

Answer 69

Bloating, Dyspepsia, constipation Decrease absorption in GI of fat-soluble vitamins and other drugs

Question 70

How can GI disturbances caused by Resin be reduced?

Answer 70

suspend drug in liquid before ingestion increase dietary fiber intake

Question 71

What is Ezetimibe?

Answer 71

Cholesterol Absorption inhibitor

Question 72

How does ezetimibe change cholesterol levels?

Answer 72

Decrease cholesterol absorption in intestines: 1) binding to NPC1L1 2) inhibiting ACAT Both lowering LDL level in plasma and liver

Question 73

How does ezitimibe change plasma LDL level?

Answer 73

promote synthesis of LDLR in liver

Question 74

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

Answer 74

Increased by fibrates | Reduced by Resins

Question 75

What are some adverse effects of Ezetimibe?

Answer 75

mild (e.g. headache, diarrhea) Relatively safe

Question 76

What are PCSK9 inhibitors?

Answer 76

Human monoclonal antibodies against PCSK9

Question 77

Name 2 common PCSK9 inhibitors?

Answer 77

Alirocumab and Evolocumab

Question 78

How does PCSK9 inhibitor change plasma LDL level?

Answer 78

Bind to PCSK9 > inhibit PCSK9 from binding to LDLR and cause LDLR degradation > decrease LDLR degradation = more LDL absorption into liver, less plasma LDL

Question 79

PCSK9 inhibitors are used in what patients?

Answer 79

Used as second line treatment in: patients with heterozygous or homozygous familial hypercholesterolemia, Adults with cardiovascular diseases and hypercholesterolemia (prevent MI, stroke... etc)

Question 80

What are some adverse effects of PCSK9 inhibitors?

Answer 80

Relatively safe Mild muscle ache, injection site reaction, nasopharyngitis

Question 81

Are Resins effective against TG?

Answer 81

No

Question 82

What 2 precautions are taken when giving combo therapy?

Answer 82

Use lowest effective dose Closely monitor for potential toxicity

Question 83

Which combos are synergistic with statins?

Answer 83

Statin + Ezetimibe or Resins or PCSK9 inhibitors

Question 84

Which combos are synergistic with PCSK9 inhibitor?

Answer 84

PCSK9 inhibitor + Statins or Ezetimibe

Question 85

Which 2 combos are used for combined hypercholesterolemia?

Answer 85

Statin + niacin Niacin + resin

Question 86

What are the 2 combs that may cause myopathy?

Answer 86

Statin + Fenofibrate Statin + Niacin

Question 87

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

Answer 87

myopathy and hepatotoxicity

Question 88

What triple therapy is given for high risk patients?

Answer 88

Statins, Resins, Niacin