NSAIDs, Antiplatelets, Statins and PPIs

Which medications can cause the accumulation of statins via inhibition of CYP450 enzymes?

Amiodarone, Diltiazem, macrolides, protease inhibitors, grapefruit juice

Amlodipine as well but the mechanism is not clear

What are the 3 main indications for statins?

1) Primary prevention of CV events (QRisk% >10)

2) Secondary prevention of CV events in people with IHD, stroke or PAD

3) Dyslipidaemia

What is the MOA of statins?

Competitive HMG-CoA reductase inhibition

Reduces LDL levels, and slightly increases HDL

What are the common adverse effects of statins?

headache, GI upset, muscle aches

What are the more serious adverse effects of statins?

myopathy, rhabdomyolysis, increase in liver enzymes (ALT), drug-induced hepatitis

What should be monitored with statin use? When?

Lipid profile- baseline, 3 and 12 months

When statin be stopped (looking at lipid profile results)?

A rise in ALT x3 the upper limit

Why is Simvastatin advised to be taken at night?

It has a short half-life: Cholesterol synthesis is greatest in the early hours of the morning

What dose of Atorvastatin is indicated for secondary prevention of CVD?

"High-intensity" - 80mg

What action should be taken if a person who regularly takes a statin needs to receive a short course of clarithromycin (macrolide)?

Withhold the statin temporarily

Can pregnant women take statins?

No, it is contraindicated as cholesterol; of essential for foetal development.

Other than lipid profile, what other test should be done before starting a statin? Why?

Thyroid function test (TFTs) as untreated hypothyroidism is a reversible cause of hyperlipidaemia and can increase the risk of adverse effects from statins.

What are the common indications for NSAIDs and COX-2 inhibitors?

1) Mild-moderate pain management (as needed)

2) RA, OA and acute gout (regular)

What is the MOA of NSAIDs?

Inhibit prostaglandin synthesis from arachidonic acid by inhibiting COX enzyme

What are the main adverse effects of NSAIDs?

GI toxicity, renal impairment and major cardiovascular events (MI and stroke).

Which NSAID has the lowest risk of MACE?

Naproxen

COX-2 inhibitors, high dose ibuprofen and diclofenac are associated with which major adverse effect?

Major adverse cardiovascular events

When are NSAIDs contraindicated?

Severe renal impairment, heart failure, liver failure and NSAID hypersensitivity

What NSAID is preferred when CV risk is low and GI toxicity is a greater concern?

Low-dose ibuprofen (200-400mg 8hrly)

NSAID + corticosteroid use increase the risk of...?

Peptic ulcers

NSAID + anticoagulants/SSRIs use increase the risk of...?

GI bleeds

NSAID + ACEi/ARBs/diuretics use increase the risk of...?

renal impairment

What effect do NSAIDs have on the effectiveness of antihypertensives

Impaired effectiveness

What patient risk factors warrant co-prescription of a PPI with NSAID therapy?

> 65 year olds, previous peptic ulcer disease, CVD, diabetes and concurrent therapy with GI side effects e.g. aspirin and prednisolone

What is the MOA of aspirin?

Irreversible inhibitor of COX enzymes to reduced production of thromboxane from arachidonic acid, reducing platelet aggregation and risk of arterial occlusion

What advice is given to a patient taken oral NSAIDs

Take with food to minimise GI upset

What are the common indications for PPIs?

1) Prevention and treatment of peptic ulcer disease

2) Treatment of GORD

3) Eradication of H. Pylori infection

What is the MOA of PPI?

They reduce gastric acid secretion via irreversible inhibition of H+/K+-ATPase in parietal cells.

What are the common side effects of PPIs?

GI upset and headache

PPIs can increase the risk of what infection?

C. difficile colitis

Hypomagnesemia is caused by ___ and can lead to ___ in severe cases?

Long term PPI-use which can lead to neuromuscular symptoms (e.g. tetany) and arrthymias

Which class of drug can increase risk of fracture?

PPIs - cautioned in people with osteoporosis

What is the main interaction with PPIs (particularly omeprazole)?

Interaction with clopidogrel: reduces antiplatelet effect by decreasing activation by cytochrome P450 enzymes.

Why is it important to down titrate the dose/frequency when wihthdrawing a long term PPI?

To avoid a rebound of symptoms

What action should be taken when a person undergoing H. Pylori testing is also on a regular PPI? Why?

Hold PPI for 2 weeks before testing (of all kinds) as this can increase the chance of a false-negative.

When stepping down a PPI, what other aids can be used to help with symptom control?

Antacids or alginates

What is the typical PPI prescription for prevention of NSAID-associated peptic ulcers?

Lansoprazole 30mg OD PO

What are the common indications for antiplatelets and aspirin?

1) Treatment of acute ACS

2) To prevent coronary artery stent occlusion

3) Secondary prevention of MACE

What is the difference in MOA between clopidogrel/prasugrel and ticagrelor?

Clopidogrel and prasugrel are irreversible ADP receptor inhibitors, whereas Ticagrelor acts reversibly.

What are the common side effects of antiplatelets?

Bleeding and GI upset

What is a rare, more serious adverse effect of antiplatelets?

Thrombocytopenia

When are antiplatelets contraindicated?

During an active bleed and should be stopped 7 days before an elective surgery.

When are antiplatelets cautioned?

In renal and hepatic impairment, and where there are risks factors for bleeding.

Given that clopidogrel and prasugrel are prodrugs, explain how can other medications affect their metabolism and give examples?

They are metabolised by cytochrome P450- so CYP inhibitors can reduced their efficacy.

E.g. omeprazole, erythromycin, ciprofloxacin, some antifungal and some SSRIs, aswell as grapefruit juice.

Other than CYP inhibitors, what other drug classes interact with antiplatelets?

Other antiplatelets, anticoagulants and NSAIDs (all increase bleeding risk).

How long does low dose clopidogrel take to have it's full effect? What action is made if a rapid effect is needed?

Low dose clopidogrel takes a week to reach full effect.

A loading dose should be prescribed if a rapid effect is needed.

What is the loading and maintenance dose of clopidogrel when treating ACS?

300mg (once) and then 75mg OD.

How long should DAPT be continued for to reduce risk of stent thrombosis?

12 months

Should clopidogrel/prasugrel/ticagrelor be taken with or without food?

Can be taken with or without food.

Why can ticagrelor be stopped 5 days before an elective surgery but clopidogrel/prasugrel need to be stopped 7 days before?

Clopidogrel/prasugrel act irreversibly s their effect persists lifespan of platelets (7-10 days), whereas ticagrelor acts reversibly so its effects wears off quicker.

When considering a transfusion for reversing the effect of antiplatelet drugs, why do platelet function tests (thromboelastography) need to be done?

There is significant inter-individual variability due to genetic variation in CYP enzymes. People with more than 76% inhibition are 11 times more likely to need a transfusion for bleeding.

What is the most common side effect of aspirin?

GI upset

What are the more serious adverse effects of aspirin?

Peptic ulceration, haemorrhage and hypersensitivity reaction (bronchospasm).

What can regular high-dose aspirin therapy cause?

Tinnitus (perception of sound when no external sound is present)

When is aspirin contraindicated?

Children under 16 (risk of Reyes syndrome), people with aspirin hypersensitivity, in the 3rd trimester of pregnancy.

When is aspirin cautioned?

Peptic ulceration (consider GI protection) and in gout (can trigger an attack).

What is the maximum daily dose of aspirin when treating pain?

4g a day in divided doses

What is the advice given to patients taking oral aspirin?

To take it with food to minimise GI irritation.

When and why would enteric coated aspirin tablets be unsuitable.

In medical emergencies or for rapid pain relief due to slower absorption.

What is the preferred long-term single agent for CAD/PAD?

Aspirin

What is the preferred long-term single agent following a stroke/TIA?

Clopidogrel

Why is aspirin not recommended/licensed for primary prevention of CVD in the UK?

Trials was found that the absolute risk of MACE in this group is low (1/500) and the benefits are outweighed by the increased risks of serious bleeding.