NSAIDs Flashcards
benefit of NSAIDs
inhibiting down stream products of arachidonic acid
prostanoids
prostaglandins, prostacyclin and thromboxanes
produced locally on demand
short half lives- fine local control
prostaglandin = PGE2 function
protective
regulation of acid secretion in parietal cells
GI mucosal protection
Uterine contraction
prostacyclin, PGI2 function
inhibits platelet aggregation, ↑[cAMP] → ↓calcium vasodilator
protective, maintenance of blood flow and mucosal repair
TXA2 function
platelet aggregation, ↑calcium and ↓cAMP in platelets vasoconstriction
bad
COX1 function
GI protection (acid and mucus) Platelet aggregation Vascular resistance Chronic inflammation Chronic pain Raised blood pressure
COX2 function
Renal homeostasis Tissue repair and healing Reproduction (uterine contractions) Inhibition of platelet aggregation Chronic inflammation Chronic pain Fever Blood vessel permeability
NSAIDs basic function
inhibition of COX
↓prostaglandin, prostacyclin and thromboxane synthesis
Compete with arachidonic acid
NSAIDs - analgesia
• 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
NSAIDs - anti-inflammatory
reduce production of prostaglandins released at site of injury
NSAIDs - antipyretic
Inhibition of hypothalamic COX-2 (where cytokine induced prostaglandin synthesis is elevated)
results in a reduction in temperature
COX selectivity
COX1 selective: aspirin
COX2 selective:celecoxib, etoricoxib
in between ibuprofen, naproxen,
GI consideration #,X,^
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)
Renal considerations
• # 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,
Selective COX2 inh
avoid inhibition of homeostatic etoricoxib actions mediated by COX-1 less GI adverse effects unopposed platelet aggravation
protein binding
Displace other bound drugs → increasing free drug concentration
sulfonylurea – hypoglycaemia
methotrexate - accumulation and hepatotoxicity
warfarin – increased risk of bleeding
indication for NSAIDs
- 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
X NSAIDs
- 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
NSAIDs use
Lowest effective dose for the shortest time necessary taking into account patient specific risk factors
paracetamol
indication and mechanism
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
NAPQI
Highly reactive metabolite
normal therapeutic doses - conjugation with glutathione renders NAPQI harmless
Hepatic glutathione is limited
highly nucleophilic-causing cell death – necrosis and apoptosis
paracetamol overdose
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
