2017B12 Describe the clinical effects of non-steroidal anti-inflammatory drugs
including mechanisms through which they exert these effects.

 

List:

·      Classification and examples

·      Arachidonic acid pathway

·      Prostaglanding receptors

·      The big 3 effects

·      Organ system effects

·      COX-2 selective

 

NSAID classification: (examiner request)

Non-selective irreversible

·  Salicylates: aspirin

Non-selective reversible

·  Propioinic acids (e.g. ibuprofen, naproxen)

·  Phenylacetic acid derivative (e.g. diclofenac)

·  Indoles (e.g. indomethacin)

·  Enolic acid derivatives (e.g. meloxicam)

·  (many others)

COX-2 selective

·  Celecoxib

·  Parecoxib (pro-drug for valdecoxib)

·  Rofecoxib (no longer in use)

 

Arachidonic acid pathway:

 

Prostaglandin receptors:

G protein coupled receptor subtypes

·  Gs: ↑cAMP

·  Gi: ↓cAMP

·  Gq: ↑IP3 -> ↑ICF [Ca2+], ↑DAG

Prostaglandin receptor subtypes

·  PGD2: Gs, Gi

·  PGE2: Gq, Gs

·  PGF2α: Gq

·  PGI2: Gi

·  TXA2: Gq, Gs

 

The big three:

Anti-pyretic

·  ↓PGE2 in hypothalamus

Analgesic

·  ↓PG (especially E2) production at inflamed tissue

·  ↓Nociceptive receptor activation and expression

·  ↓Hyperalgaesia and allodynia

Anti-inflammatory

·  ↓PG (especially E2) production by inflamed tissues

·  ↓Vasodilatation, ↓capillary leak, ↓oedema, ↓WBC chemotaxis

·  ↓Healing: bone (post fracture), pleura (post pleurodesis)

 

Organ systems:

Cardiovascular

·  ↓PGI2 -> vasoconstriction, ↑platelet aggregation -> thrombosis e.g. AMI
(especially COX-2 inhibitors; rofecoxib withdrawn for this reason)

·  ↓TXA2 -> vasodilatation, ↓platelet aggregation -> bleeding, bruising

·  Risk of systemic vasculitis

Respiratory

·  ↓PGD2 -> bronchodilatation

·  ↓PGE2 -> bronchoconstriction

·  ↓PGF2α -> bronchodilatation

·  ↑Shunt of arachidonic acid to leukotrienes -> bronchoconstriction

·  (overall: bronchoconstriction, ↑in 20% asthmatics)

Gastro-intestinal

·  ↓PGE2 -> ↑parietal cell activity -> ↑HCl secretion

·  Deranged LFT

Renal

·  ↓PGE2, ↓PGI2 -> ↓tubuloglomerular feedback, ↓renin release

o Risk of renal failure, hyperkalaemia

o Important if hypovolaemic or also taking ACE inhibitor

·  ↓Ureteric contraction -> pass kidney stone (indomethacin)

·  Risk interstitial nephritis

Obstetric

·  ↓PGE2 -> myometrial relaxation

·  ↓PGF2α -> myometrial relaxation

·  ↓PGE2 -> closure of ductus arteriosus -> asphyxia

Other

·  Displace other drugs from protein-binding sites, e.g. warfarin on albumin

·  Metabolic acidosis in overdose

 

COX-2 inhibitors:

Pros

·  Selective for inflamed tissue (enzyme is inducible cf. constitutive)

·  ↓Peptic ulceration

·  ↓Bronchoconstriction

·  ↓Renal impairment (examiner 2013)

·  ↓Bleeding risk

Cons

·  ↑Thrombosis risk, AMI (rofecoxib)

·  ↑Fluid retention

·  Expensive

·  Sulfur allergy

·  Parecoxib is a prodrug with very slow onset of effect

 

 

 

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