NSAIDs

Question 1

benefit of NSAIDs

Answer 1

inhibiting down stream products of arachidonic acid

Question 2

prostanoids

Answer 2

prostaglandins, prostacyclin and thromboxanes
produced locally on demand
short half lives- fine local control

Question 3

prostaglandin = PGE2 function

Answer 3

protective
regulation of acid secretion in parietal cells
GI mucosal protection
Uterine contraction

Question 4

prostacyclin, PGI2 function

Answer 4

inhibits platelet aggregation, ↑[cAMP] → ↓calcium vasodilator
protective, maintenance of blood flow and mucosal repair

Question 5

TXA2 function

Answer 5

platelet aggregation, ↑calcium and ↓cAMP in platelets vasoconstriction
bad

Question 6

COX1 function

Answer 6

GI protection (acid and mucus) 
Platelet aggregation 
Vascular resistance
Chronic inflammation Chronic pain 
Raised blood pressure

Question 7

COX2 function

Answer 7

Renal homeostasis 
Tissue repair and healing 
Reproduction (uterine contractions)
Inhibition of platelet aggregation
Chronic inflammation  Chronic pain 
Fever 
Blood vessel permeability

Question 8

NSAIDs basic function

Answer 8

inhibition of COX
↓prostaglandin, prostacyclin and thromboxane synthesis
Compete with arachidonic acid

Question 9

NSAIDs - analgesia

Answer 9

• Local peripheral action at site of pain – greater efficacy if inflamed
• Inhibition of COX reduces peripheral pain fibre sensitivity by blocking PGE2
↓PGE2 synthesis in dorsal horn -
↓neurotransmitter release → ↓excitability of neurons in pain relay pathway

Question 10

NSAIDs - anti-inflammatory

Answer 10

reduce production of prostaglandins released at site of injury

Question 11

NSAIDs - antipyretic

Answer 11

Inhibition of hypothalamic COX-2 (where cytokine induced prostaglandin synthesis is elevated)
results in a reduction in temperature

Question 12

COX selectivity

Answer 12

COX1 selective: aspirin
COX2 selective:celecoxib, etoricoxib
in between ibuprofen, naproxen,

Question 13

GI consideration
#,X,^

Answer 13

Dyspepsia, nausea, peptic ulceration, bleeding and perforation, exacerbation of IBD, reduced blood flow

↓mucus and bicarbonate secretion, ↑acid secretion • ↓mucosal blood flow → enhanced cytotoxicity and hypoxia

Xelderly, prolonged use, smoking, alcohol, history of peptic ulceration, helicobacter pylori

Δ aspirin, glucocorticoid steroids, anticoagulants (PPI should be considered)

Question 14

Renal considerations

Answer 14

• # reversible ↓GFR ↓renal blood flow
↑Na, ↑H2O, ↑BP
X More likely in underlying CKD, heart failure
Δ ACEi, ARBs, diuretics
might constrict afferent arterial in kidney,

Question 15

Selective COX2 inh

Answer 15

avoid inhibition of homeostatic
etoricoxib
actions mediated by COX-1 
less GI adverse effects
unopposed platelet aggravation

Question 16

protein binding

Answer 16

Displace other bound drugs → increasing free drug concentration
sulfonylurea – hypoglycaemia
methotrexate - accumulation and hepatotoxicity
warfarin – increased risk of bleeding

Question 17

indication for NSAIDs

Answer 17

• Inflammatory conditions – joint and soft tissue
• Osteoarthritis – topical NSAID and paracetamol should be tried first
• Postoperative pain • Topical use on cornea
• Menorrhagia (moderate reduction in blood loss)
• Low dose aspirin for platelet aggregation inhibition
• Opioid sparing when used in combination

Question 18

X NSAIDs

Answer 18

• Cardiovascular disease – risk
• Renal function - age
• GI disease - previous use of NSAIDs
• DDIs – ACEi and ARBs, steroids, diuretics, methotrexate, warfarin (not exhaustive list)
• Level of pain, pyrexia, level of inflammation
• Third trimester of pregnancy – not sustained use – delayed labour and early closure of ductus arteriosus

Question 19

NSAIDs use

Answer 19

Lowest effective dose for the shortest time necessary taking into account patient specific risk factors

Question 20

paracetamol

indication and mechanism

Answer 20

non-NSAID, non-opiate analgesic with antipyretic action
for analgesia AND fever
COX-2 selective inhibition in CNS (spinal chord) - ↓pain signals to higher centres
inactivated by conjugation in the liver

Question 21

NAPQI

Answer 21

Highly reactive metabolite
normal therapeutic doses - conjugation with glutathione renders NAPQI harmless
Hepatic glutathione is limited
highly nucleophilic-causing cell death – necrosis and apoptosis

Question 22

paracetamol overdose

Answer 22

asymptomatic for many hours
• Nausea, vomiting, abdominal pain – first 24h
• Maximal liver damage occurs at ~ 3-4 days
– i .v. acetylcysteine reduces toxic metabolites, by replacing glutathione