Pharmacovigilance, Pharmacogenetics & Hyperlipidaemia

Question 1

Compare Type A and Type B Adverse Drug Reactions (ADR)

Answer 1

Type A;

• Dose dependent
• Frequent
• Predictable
• Overdose
• Explained by pharmacological effect

Type B;

• Dose independent
• Rare
• Unpredictable
• Not explained by pharmacological effect

Question 2

2 examples of Type A ADRs

Answer 2

• Bleeding after anticoagulants

- Hypoglycaemia after insulin

Question 3

What are 4 methods of action for an ADR

Answer 3

• Exaggerated response
• Desired pharmacological effect at alternative site
• Additional pharmacological effect
• Triggering immunological effect (anaphylaxis)

Question 4

What scheme is in place to report ADRs

Answer 4

Yellow Card scheme

Question 5

Most cholesterol is made in the body, how much comes from diet?

Suggest some uses of it

Answer 5

25%

• Membrane integrity
• Production of steroid hormones, Bile acids and Vit D

Question 6

Below what level should total cholesterol be?

Answer 6

5.2 mmol/l

>6.2 is high

Question 7

How do Statins work?

Answer 7

• Competing inhibition of HMG-CoA Reductase

- Upregulation of LDL receptors-> Increased clearance of circulating LDL

Question 8

How do Statins improve endothelial function?

Answer 8

Increased NO and Vascular Endothelial Growth Factor

Question 9

How do Statins improve atherosclerotic plaque stabilisation?

Answer 9

Reduced SMC proliferation and increased Collagen

Question 10

How do Statins improve haemostasis?

Answer 10

• Reduced fibrinogen
• Increased platelet aggregation
• Increased fibrinolysis

Question 11

How do Statins improve anti-inflammatory function?

Answer 11

Reduced proliferation of inflammatory cells into plaque

Question 12

How are Statins anti-oxidants?

Answer 12

Reduced Superoxide formation

Question 13

How do Simvastatin and Atorvastatin?

Answer 13

Simvastatin;

• Is a prodrug
• Half life of 2 hours

Atorvastatin;

• Is an active drug
• Half life of 24 hours

Question 14

List some ADRs of Statin therapy

Answer 14

• GI disruption + nausea
• Headaches
• Myalgia (due to Myopathy, check CK levels)
• RARELY Rhabdomyolysis
• Raised Liver enzymes

Question 15

List 4 contraindications of statin therapy

Answer 15

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Question 16

Why is CYP 3A4 important in Statin metabolism?

Answer 16

Drugs such as Amlodipine, Diltiazem and Macrolides inhibit the enzyme, thus increasing [plasma statin]

Question 17

Describe the statin therapy prescription for Primary Prevention

(Elevated cholesterol but no CVS disease/ event)

Answer 17

20mg Atorvastatin once daily

This still counts as high intensity

Question 18

Describe the statin therapy prescription for Secondary Prevention

(Elevated cholesterol WITH CVS disease/ event)

Answer 18

80mg Atorvastatin once daily

Question 19

What’s the target for statin therapy?

Answer 19

> 40% reduction in non-HDL Cholesterol at 3 months

Question 20

How does grapefruit juice affect CYP 3A4?

Answer 20

Inhibits it

Question 21

What is the Nocebo effect?

Answer 21

Patient thinks they’ll have side effects, so they experience them

Question 22

How can Fibrates (Fibric acid derivatives) help in treating hyperlipidaemia?

Answer 22

Activation of a nuclear transcription factor that regulates expression of a gene controlling Lipoprotein metabolism

(PPAR-Alpha)

Thus, increased LPL production

Question 23

What are some ADRs of Fibrates?

Answer 23

• GI Upset
• Myositis (rare)
• Cholelithiasis (Gall stones)

Question 24

What are some contraindications of using Fibrates?

Answer 24

• Photosensitivity

- Gall bladder disease

Question 25

How may Fibrates such as Fenofibrate interact with Warfarin?

Answer 25

May increase anticoagulation

Question 26

How do Cholesterol Aborption Inhibitors work?

Name one example

Answer 26

Inhibit NPC1L1 transporter-> reduced gut cholesterol absorption

Ezetimibe (A prodrug, mostly stays in enterohepatic circulation)

Question 27

List 2 ADRs and 1 contraindication for using Ezetimibe

Answer 27

• GI Upset
• Ab pain
• Hepatic failure

Question 28

What can happen if Ezetimibe is taken alongside Statins and Ciclosporin?

Answer 28

Statins;
- Increased risk of Rhabdomyolysis

Ciclosporin;
- Increased systemic concentration of Ezetimibe

Question 29

How can Ezetimibe be incorporated into a prescription?

Answer 29

• Can be taken on its own or alongside a statin

- No dose escalation (always 10mg)

Question 30

In Secondary Prevention of Hyperlipidaemia suggest targets for;

• LDL Cholesterol
• Total Cholesterol

Answer 30

LDL: 2mmol/L

Total: 4mmol/L

Question 31

How do PCSK9 Inhibitors work?

Give 2 examples

Answer 31

Inhibit the PCKS9 protein, which binds endocytosed LDL-Receptor and directs degradation

• Alirocumab
• Evolocumab (these drugs are Monoclonal AntiBodies)

Question 32

PCSK9 Inhibitors are x100 expensive than statins and need to be taken as injections.

When are they currently recommended for use by NICE?

Answer 32

Primary and Secondary prevention in Resistant Familial Hypercholesterolaemia

Question 33

Describe the effects and use of Plant Sterols

Answer 33

• Some LDL-C lowering effects
• Naturally in grains, legumes etc
• Work with statins but not Ezetimibe (PSs and E compete)