S4: pharmacovigilance, pharmacogenetics & hyperlipidaemia

Question 1

Define pharmacovigilance

Answer 1

The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem

Question 2

Explain the classification of adverse drug reactions

Answer 2

Type A – augmented (explained by pharmacologic drug effect)
Type B – bizarre (rare, unpredictable, not explained by pharmacologic drug effect)
Type C – chronic (rare, long-term exposure)
Type D – delayed (time-dependent, rare)
Type E – end of treatment (relapse after stopping a therapy)

Question 3

Give examples of type A and type B adverse drug reactions

Answer 3

Type A: bleeding after anticoagulants, hypoglycaemia from insulin
Type B: urticaria from aspirin, exanthem from antibiotics

Question 4

Define adverse drug reactions

Answer 4

Response to a drug which is noxious and unintended, and which occurs at doses normally used in man – causal link

Question 5

Describe the yellow card scheme

Answer 5

Recently introduced products – all suspected ADRs inc. minor ones, all reactions to vaccines
Established products – serious or unusual suspected reactions

Question 6

Describe the role of lipids in the pathophysiology of atherosclerosis

Answer 6

LDL susceptible to oxidation at damaged endothelium
ROS contributes to endothelial dysfunction increasing adherence of lipid rich deposits and foam cells formed
Precursor to atheromatous plaques

Question 7

Describe the mechanism of action of statins

Answer 7

Competitive inhibition of HMG-CoA reductase – rate controlling enzyme in HMG-CoA to mevalonate pathway
Contributes to upregulation of hepatic LDL receptors
Increased clearance of circulating LDL

Question 8

List additional benefits of statin therapy

Answer 8

Improved vascular endothelial function 
Stabilisation of atherosclerotic plaque 
Improved haemostasis 
Anti-inflammatory 
Antioxidant

Question 9

What are the adverse effects, warnings, contraindications & important drug interactions of statins?

Answer 9

Adverse effects: GI disruption, nausea, headache, myalgia (diffuse muscle pain), rhabdomyolysis, increased liver enzymes
Warnings, contraindications: renal or hepatic impairment, pregnancy and breastfeeding
Important drug interactions: CYP3A4 important (amiodarone, diltiazem, macrolides) – increases [statin], amlodipine also does this (may be appropriate to withhold statin short-term whilst taking other agents)

Question 10

List examples of statins

Answer 10

Atorvastatin – first pass metabolism

Simvastatin – prodrug activated by first pass metabolism

Question 11

Describe the mechanism of action of fibric acid derivatives

Answer 11

Activation of nuclear transcription factor – PPARalpha
PPARa regulate expression of genes that control lipoprotein metabolism – increased production of lipoprotein lipase
Increased triglycerides removal from lipoprotein in plasma, increased fatty acid uptake by the liver

Question 12

What are the adverse effects, warnings, contraindications & important drug interactions of fibric acid derivatives?

Answer 12

Adverse effects: cholelithiasis (gall stones), GI upset, myositis
Warnings, contraindications: photosensitivity, gall bladder disease
Important drug reactions: warfarin – increase anticoagulation

Question 13

List examples of fibric acid derivatives

Answer 13

Fenofibrate

Question 14

Describe the mechanism of action of cholesterol absorption inhibitors

Answer 14

Inhibit NPC1L1 transporter at brush border in small intestines
Reduces absorption of cholesterol by the gut
Hepatic LDL receptor expression increases
Adjunct to statin (or if not tolerated for some patients)

Question 15

What are the adverse effects, warnings, contraindications & important drug interactions of cholesterol absorption inhibitors?

Answer 15

Adverse effects: abdominal pain, GI upset, angioedema
Warnings, contraindications: hepatic failure
Important drug interactions: mindful if prescribed with statin – increased risk of rhabdomyolysis, ciclosporin

Question 16

List examples of cholesterol absorption inhibitors

Answer 16

Ezetimibe

Question 17

Why might it be appropriate to prescribe a statin and ezetimibe together?

Answer 17

No dose escalation with ezetimibe

Combination of ezetimibe with statin benefit in CKD and in some for secondary CVS prevention

Question 18

Describe the mechanism of action of PCSK9 inhibitors

Answer 18

PCSK9 – protein that binds internalised LDL-R – directing for degradation
PCSK9 inhibitors demonstrated highly significant reduction in LDL cholesterol over placebo in primary hypercholesterolaemia

Question 19

List examples of PCSK9 inhibitors

Answer 19

Alirocumab

Evolocumab

Question 20

Describe the mechanism of action of siRNA

Answer 20

Inhibits hepatic translation of PCSK9

Very newly available to some in primary care

Question 21

List examples of siRNA

Answer 21

Inclisiran