S8) NSAIDs Flashcards
What is the principal action of non-steroidal anti-inflammatory drugs?
Principle action – key enzymes in prostaglandin synthesis
What are the three primary therapeutic effects of NSAIDs?
- Analgesia
- Anti-Inflammatory
- Antipyretic
Why do NSAIDs commonly have short half lives?
Short half lives allows fine control of the signalling response
How are prostaglandins synthesised?
Prostaglandins are synthesised from arachidonic acid
Identify two types of prostaglandins
- Prostacyclins
- Thromboxanes
Describe the prostaglandin synthesis pathway
Prostaglandins are synthesised from cell membrane phospholipids and arachidonic acid and thereafter catalysed by COX-1/2 to produce specific PG enzymes
PG ‘E’ is the most important in mediating the inflammatory response.
Identify four of its functions
- Vasodilation
- Hyperalgesia
- Fever
- Immunomodulation
PG synthesis by COX -1 has major cytoprotective role in three locations.
Identify them
- Gastric mucosa
- Myocardium
- Renal parenchyma
What is the half life of PG and what is the significance of this for NSAIDs?
- PG t1/2 short (10 mins) – need constant synthesis
- Due to its constitutive expression, most ADRs caused by NSAIDs are due to COX-1 inhibition
What induces COX-2 expression and where is it expressed?
- COX-2 expression induced by inflammatory mediators such as bradykinin
- COX-2 appears to be constitutively expressed in parts of the brain and kidney
How do the main therapeutic effects of NSAIDs occur?
Main therapeutic effects of NSAIDs occur via COX-2 inhibition
Illustrate how differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs
Explain prostaglandin binding with receptors
- Prostaglandins bind with GPCRs
- Specific actions depend on PG receptor types
For PG E, at least four main types: EP 1-4
In four steps, describe how prostaglandins act as inflammatory response mediators
⇒ Range of autacoids and prostanoids released from local tissues/blood vessels post injury
⇒ Autacoid release also induces expression of COX-2
⇒ Synergise with other autacoids (bradykinin/histamine)
⇒ PGs act as potent vasodilators & synergise permeating effects of bradykinin/histamine
State the effect of prostaglandin release post injury at the following receptors:
- EP2 receptor Gs
- EP1 receptor Gq
- EP2 receptor Gs – ↑ vasodilation
- EP1 receptor Gq – ↑ peripheral nociception
With regards to sensitising peripheral nociception, describe the three effects of GPCR activation by EP1
- Increased neuronal sensitivity to bradykinin
- Inhibition of K+ channels
- Increased Na+ channels sensitivity
All act to increase afferent ‘C’ fibre activity (carry pain stimuli)
In four steps, expain how peripheral sensitisation occurs
⇒ EP 1 binding leads to ↑ ‘C’ fibre activity
⇒ ↑ intracellular [Ca2+]
⇒ Neurotransmitter release
⇒ Other autacoids involved to ↑ sensitivity
In terms of nociception, illustrate the relationship between allodynia and hyperalgesia
- Allodynia is pain due to a stimulus that does not usually provoke pain
- Hyperalgesia is increased pain from a stimulus that usually provokes pain
In four steps, explain how sensitising central nociception occurs
⇒ Increased sustained nociceptive signalling peripherally ↑ cytokine levels in dorsal horn cell body
⇒ ↑ COX-2 synthesis and ↑ PGE<strong>2</strong> synthesis
⇒ PGE2 acts via local EP2 receptor (Gs type)
⇒ ↑ sensitivity and discharge rate of secondary interneurones
In four steps, explain how prostaglandins lead to a state of pyrexia
⇒ Bacterial endotoxins stimulate macrophage release of IL-1
⇒ IL-1 stimulates PGE2 synthesis within hypothalamus
⇒ PGE2 acts via EP3 receptor (Gi type)
⇒ ↑ heat production and ↓ heat loss
The main therapeutic effects achieved via COX-2 inhibition.
Briefly, explain how this occurs
- Pharmacological action for nearly all NSAIDs via competitive inhibition of COX-1 and COX-2
- Occupation of COX-1 /2 hydrophobic channel by NSAID competes with AA site occupation
How are NSAIDs administered?
Typically given orally but many topical preparations for soft tissue injury
Which pharmacokinetics pattern do NSAIDs illustrate?
Linear pharmacokinetics within therapeutic dose range
There are two groups of NSAIDs according to half lives.
Identify them
- T1⁄2 < 6hrs
- T1⁄2 >10 hrs
How are NSAIDs transported in the blood?
Many heavily bound to plasma protein (90-99%)
Describe the therapeutic use of NSAIDs as an anti-inflammatory
Very wide use in musculoskeletal disorders – rheumatoid / osteoarthritis
Describe the therapeutic use of NSAIDs as an analgesic
- Used for mild to moderate pain accompanying many disease states
- Universal use in Hospitals / OTC
Inhibition of COX-1 constitutive PG synthesis leads to many side effects.
Indicate which patient group this usually affects
Long term use in elderly – particularly associated with iatrogenic morbidity and mortality
Renal ADRs occur in compromised individuals with HRH or hypovolaemia.
What is HRH?
- Heart failure
- Renal disease
- Hepatic cirrhosis
The major ADRs are seen in stomach /GI tract.
Identify some
- Stomach pain
- Nausea
- Heartburn
- Gastric bleeding
- Ulceration
Explain why a gastric ADR can occur by the selective inhibition of COX-1
Gastric COX-1 PGE2 stimulates cytoprotective mucus secretion throughout GI tract, reduce acid secretion and promote mucosal blood flow
Explain why a renal ADR can occur due to NSAIDs
- PGE2 and PGI2 maintain renal blood flow
- If reduced by NSAIDs then GFR decreases – further risk of renal compromise (especially neonates/elderly)
Apart from GI and renal symptoms, identify some other NSAID ADRs
- Vascular – decreased bleeding time, bruising haemorrhage
- Hypersensitivity – skin rashes, bronchial asthma
- Rare serious brain/liver injury – usually in viral infections treated with aspirin risk of damage
What are the therapeutic benefits from combining NSAIDs with low dose opiates?
- Extends therapeutic range for treating pain
- Reduces ADRs seen with opiates alone
Identify three highly protein bound drugs affected by NSAIDs
- Sulphonylurea
- Warfarin
- Methotrexate
What is the effect of NSAIDs given in combination with aspirin?
NSAIDs + low dose Aspirin – compete for COX-1 binding sites and may interfere with cardioprotective action of Aspirin
What is the result of multiple NSAIDS given in combination?
- Increase risk of ADRs – often occurs due to self medication with NSAIDs
- Affect each others PK/PDs due to competition for plasma protein binding sites
Describe how aspirin acts uniquely in the body
- Only NSAID to irreversibly inhibit COX enzymes by acetylation
- T1⁄2 < 30 minutes rapidly hydrolysed in plasma to salicylate
Why is paracetamol a unique non NSAID?
Paracetamol is a unique ‘non NSAID’ as it has virtually no anti-inflammatory action – more of a NOAD (non-opiate anagelsic drug)
When is paracetamol used?
Paracetamol is very effective for mild/moderate analgesia and fever
What is the therapeutic dose for paracetamol?
Therapeutic dose: 8 x 500 mg tablets/day
In normal doses, paracetamol displays linear pharmacokinetics.
How is it metabolised?
- Mainly Phase II Conjugation – Glucoronide 60%, Sulphate 30%
- Some Phase 1 Oxidation – NAPQI 10%
NAPQI is very reactive and toxic.
How is it detoxified?
- At normal doses, NAPQI is detoxified by Phase II conjugation with Glutathione
- Linear detoxification step limited by availability of Glutathione
What is a toxic dose of paracetamol?
Single doses > 10 g (20 tablets) potentially fatal
At high doses, paracetamol pharmacokinetics become zero order.
Describe paracetamol metabolism at high doses
- First step Phase II metabolism saturated
- ↑ Phase I production of NAPQI
- Phase II conjugation of NAPQI with glutathione rate limited – also saturated
Paracetamol overdoses are time dependent – delayed hepatoxic effects peak 72 - 96 hrs post ingestion.
How can this be treated?
- 0-4hrs – activated charcoal orally reduce uptake by 50-90%
- 0-36 hrs – start N-Acetylcysteine IV
- Methionine orally (if NAC cannot be given promptly)
