14. NSAIDs Flashcards
how is the effect of NSAIDS achieved?
The therapeutic benefit of prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) is a result of inhibiting down stream products of arachidonic acid
how is arachidonic acid produced and where is it found?
- Arachidonic acid derived primarily from dietary linoleic acid – vegetable oils converted hepatically to arachidonic acid and incorporated into phospholipids
- Found throughout the body – particularly in muscle, brain, liver and kidney
what are prostanoids?
prostaglandins, prostacyclin and thromboxanes
when are prostanoids produced?
Prostanoids are produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control
what is the action of prostacyclin?
- Prostacyclin (PGI2) produced and released by endothelial cells – inhibits platelet aggregation
- PGI2 binds to platelet receptors → ↑[cAMP] in platelets
- ↑[cAMP] → ↓calcium - preventing platelet aggregation
- ↓in platelet aggregatory agents
- Stabilises inactive GPIIb/IIIa receptors
what are the 3 types of prostaglandins?
PGE2, PGF2α, PGD2
what is the effect of PGE2 and PGI2 on gastric secretion?
- PGE2 cotributes to regulation of acid secretion in parietal cells - reduced acid secretion by activating GPi receptor so inhibits adenylyl cyclase so decreased cAMP
- Prostacyclin (PGI2) contributes to maintenance of blood flow and mucosal repair
what receptors do prostanoids act on?
Prostanoids signal through many GPCRs
• Many receptors, differential expression in tissues and response
what enhances action of prostanoids?
• Often action is enhanced by local autacoids including bradykinin and histamine
Why is it important to have a balance between TXA2 and PGI2?
- TXA2 and PGI2 have apposing vascular effects - TXA2 is a vasoconstrictor and platelet aggregator, PGI2 is a vasodilator and inhibit platelet aggregation
- fine balance between them crucial – haemodynamic and thrombogenic control
Imbalance/disruption to prostanoids plays significant role in which conditions?
hypertension, MI and stroke risk
what is the advantage of Mediterranean diet?
• Diet rich in fish oils (Ω fatty acids) – “The Mediterranean diet” proposed to lead to conversion to TXA3 and PGI3 – better prostanoids – lower incidence of CVD?
what are the Two functional isoforms of Cyclooxygenase enzymes and where are they found?
COX-1 constitutively active across most tissues
COX-2 inducible – mostly – in chronic inflammation
constitutively in brain, kidney and bone
What are the homeostatic functions of COX1 and 2?§
COX1: - GI protection - platelet aggregation - vascular resistance COX2: - renal homeostasis - tissue repair and healing - uterine contractions - inhibition of platelet aggregation
What are the pathological functions of COX1 and 2?
COX1: - chronic inflammation - chronic pain - raise BP COX2: - Chronic inflammtion - chronic pain - fever - blood vessel permeability - tumour cell growth
what are NSAIDs given for?
varying antipyretic, analgesic and anti-inflammatory properties
what is the single common mode of action of NSAIDs?
inhibition of COX ↓prostaglandin, prostacyclin and thromboxane synthesis
• Compete with arachidonic acid for hydrophobic site of COX
How do NSAIDs provide analgesia?
- Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2
- centrally: ↓PGE2 synthesis in dorsal horn - ↓neurotransmitter release → ↓excitability of neurons in pain relay pathway
When is full analgesic effects of NSAIDs achieved?
- efficacious after first dose
- but full analgesia after several days dosing
How do NSAIDs provide anti-inflammatory effects?
- ↑COX activity → prostaglandin mediated increase in vasodilatation and oedema
- NSAIDs reduce production of prostaglandins released at site of injury
- Vasodilation in post capillary venules contributes to increased permeability and local swelling NSAIDs inhibit this
- possible COX independent pathway, some effects ↓ROS by oxygen scavenging properties?
do NSAIDs treat the inflammatory condition ?
Symptomatic relief with COX inhibition – little effect on underlying chronic condition
How do NSAIDs provide anti-pyretic effects?
- Pyrogens (e.g. IL1, 6) induce prostaglandin (PGE2) synthesis in the theromoregulatory centre in the hypothalamus leading to increase in set point temperature and fever
- Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature
how are NSAIDs differentiated?
- NSAIDs are differentiated by their selectivity
* High prevalence of ADRs attributable to COX-1 led to selective COX-2 inhibitors (coxibs)
list the COX1 selective NSAIDs
aspirin(low dose)
list the NSAIDs with increasing COX 2 selectivity
ibuprofen, naproxen, diclofenac, celecoxib, etoricoxib
What are some GI ADRs with COX inhibitors?
- Dyspepsia, nausea, peptic ulceration, bleeding and perforation
- Exacerbation of inflammatory bowel disease
why do NSAIDs cause GI ADRs?
- ↓mucus and bicarbonate secretion, ↑acid secretion
* ↓mucosal blood flow → enhanced cytotoxicity and hypoxia
what are the GI warnings, contraindications of NSAIDs?
elderly, prolonged use, smoking, alcohol, history of peptic ulceration, helicobacter pylori
what are some important GI drug interactions of NSAIDs?
aspirin, glucocorticoid steroids, anticoagulants (PPI should be considered)
What are some renal ADRs with COX inhibitors?
- NSAIDs produce reversible ↓GFR ↓renal blood flow Therapeutic dose in healthy person – less issues
- Prostaglandins inhibit sodium absorption in the collecting duct – natriuresis – NSAIDs inhibit this action therefore ↑Na, ↑H2O, ↑BP ~5mmHg
what are the renal warnings, contraindications of COX inhibitors?
More likely in underlying CKD, heart failure
where there is greater reliance on prostaglandins and prostacyclin for vasodilatation of afferent arteriole and renal perfusion
what are some important renal drug interactions of NSAIDs?
ACEi,ARBs, diuretics
why should NSAIDs and ACEi/ARBs not be used together?
when there is a decrease in renal blood flow, there is an increase in vasodilating prostaglandins to increase blood flow however using NSAIDs inhibit prostaglandins production so blunts this response
when there is a decrease in renal blood flow, renin is released which causes efferent arteriole constriction by angiotensin II to increase GFR however this response is blunted by ACEi/ARBs which inhibit angiotensin II production.
therefore, the combined used of NSAIDs and ACEi/ARBs restricts both dilation of afferent arteriole and constriction of efferent arteriole resulting in reduced GFR.
Give 2 examples of selective COX-2 inhibitors.
celecoxib, etoricoxib
what is the advantage of COX-2 selective inhibitors?
- The intention of COX-2 inhibitors was to avoid inhibition of homeostatic actions mediated by COX-1
- Less inhibitory action on COX-1 but selectivity for COX-2 varies among drugs X
- Less GI ADRs, renal ADRs similar to non-selective
what is the disadvantage of COX-2 selective inhibitors?
• COX-1 is used for thromboxane A2 pathway and COX-2 for prostacyclin pathway
COX-2 selective inhibitors do not share antiplatelet action but inhibit PGI2 - potentially leading to unopposed aggregatory effects of thromboxane A2 which is bad for CVS
• Some evidence of less analgesic effect
can COX-2 inhibitors be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment?
yes
what does all NSAIDs have an increased risk of?
risk of MI including in low risk people
what is the association between NSAIDs and protein binding?
• NSAIDs Displace other bound drugs → increasing free drug concentration
• Particularly high protein bound drugs e.g.
- sulfonylurea –> hypoglycaemia
- methotrexate -> accumulation and hepatotoxicity
- warfarin –> increased risk of bleeding
What are some indications for use of 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
What are some contraindications for use of 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
what is the advice when prescribing NSAIDs?
Lowest effective dose for the shortest time necessary taking into account patient specific risk factors
What should paracetamol be used for?
Mild to moderate analgesia and fever
what is the mechanism of paracetamol?
• mechanism still not completely elucidated – 150+ years after discovery! COX-2 selective inhibition in CNS (spinal chord) - ↓pain signals to higher centres
peroxidases in peripheral inflammation so very little anti-inflammatory action
What is the half life of paracetamol?
2 hrs
