Lecture 34: Analgesia 2 Flashcards
What is the mechanism of action for NSAIDs?
Inhibits the cyclo-oxygenase enzyme (cox1 and COX2), leading to suppression of prostanoids production in the cells.
Traditional NSAIDS inhibit COX1 and COX2. Newer agents are selective for COX2.
Most inhibitions are reversible and incomplete.
Aspirin selectively acetylates a single serine residue of the enzyme and inactivates it irreversibly
What are the effects of NSAIDS?
- Decreasing PGs = decreased inflammation, relieve mild pain
- Decrease PG E2 = Anti pyretic
- Anticoagulation - Inhibiting platelets aggregation by decrease TXA2
What are prostaglandins?
- lipid compounds derived from FA
- Highly potent with widespred biological action
- Produced by all cells except RBC
- Very short t1/2
- Function locally
What do prostaglandins do?
- Cell growth
- Sensitize neurons to pain
- Aggregation or disaggregation of platelets
- Induced labour
- Thermoregulation
Whats the role of arachidonic acid in prostaglandins?
A substrate for eicosanoids (Leukotrienes (inflammatory) and prostanoids)
What are prostanoids?
Prostanoids are created from arachidonic acid via COX1,2
- Prostaglandins
- Prostacycline
- Thromboxine
i.e if you inhibit prostanoid production you inhibit all prostanoids.
Eicosanoids refers to:
Cyclooxygenase pathway (COX1 and COX2) and lipoxygenase pathway (luekotrienes // inflammation) from Arachidonic acid, products
When are COX1&2 active? What are the implications of this?
COX1 is constitutively active, whilst COX2 is induced
This means COX1 is always inhibited by non-selective NSAIDS and thus its products. Long term use means it can cause bleeding and renal failure
What are the newer COX2 selective NSAIDS?
Celecoxib
Valdecoxib
Parecoxib
Are COX2 selective NSAIDS safer?
- Associated with gastric side effects
- Increase in serious adverse events - Heart Attacks and Strokes
What is the pharmacokinetics of NSAIDS?
- All highly lipophilic
- Rapid and complete absorption (oral) and very little first past metabolism (95% bioavail)
- High degree of protein binding, small VoD
- SLOW ONSET
- Differences in clearance = variability in t1/2
- Liver metabolism, inactive metabolites
What is the drug interactions of NSAIDS?
Protein-binding displacement interactions
i.e will displace drugs from proteins and increase the free portion aka active protion, increasing plasma levels. possibly OD
Interactions:
- Oral anti-coagulatnts
- Anti cancer methotrextate
- Oral anti-diabetic
- Thyroid hormones
- Digoxin
Competes for active tubular secretion with other organic acids i.e uric acid
What can influence the anti-inflammatory properties of NSAIDS?
Enzyme inhibitors i.e Cimetidine, enhances anti inflam
Enzyme activators i.e carbamazepine, decrease anti-inflam
How are NSAIDS excreted in the urine?
- Phase 2 glucuronides
- Sulphate conjugates
- Small percentage is excreted unchanged
What are some traditional NSAID examples:
ASPIRIN
Diclofenac
Indomethacin
What exactly do NSAIDS do to the COX enzymes?
COX1 enzyme is inhibited
COX2 enzyme changes it catalytic activity in response to NSAID
Describe the impact of low dose Aspirin on the body:
Irreversibly acetylates platelets COX1
- > Inhibit formation of TXA2
- > Decreased platelets adhesions
- > Reduces risk of MI and Stroke
-> Partial sparing of endothelial PGI2 (Vasodilator)
(At low dose)
= Decrease thrombosis and thus decrease Coronary thrombosis
= Increase Vasodilation
= Decrease toxicity to the kidney and gastric mucosae
(in low dose)
Describe the impact of HIGH dose Aspirin on the body:
High dose aspirin and clinical doses of other NSAIDS:
- Additionally inhibit prostacyclins which are vasodilators
- More side effects
How can aspirin cause asthma?
Aspirin induced asthma, cross sensitivity with other NSAIDS
- Can be severe and life threatening
- Triggered 1-3hrs post ingestion
Inhibition of COX1&2 leads to:
- Decrease PGE2 (bronchodilator)
- Activation of lipoxygenase pathway -> Increase inflammatory mediators, leukotrienes and thus bronchospasm
Describe aspirin samters triad:
- Aspirin intolerance:
- Rhinitis
- Facial flushing
Can progress to
- Severe asthma
- Nasal polyps
What is aspirins reyes syndrome?
An acute metabolic encephalopathy following aspirin administration in children
- Brain (encephalopathy)
- Liver (fatty, increased ammonia, enzyme induced)
Children are more prone post viral illness
How is NSAID use linked to bleeds?
NSAIDS block TXA2 production and thus hinders clotting.
Important consideration in surgical patients as could increase operative blood loss and epidurals may develop into haematomas.
How do NSAIDS cause GI issues?
- Block gastric cryoprotective prostanoid (PG) production from gastric epithelium. which normally protects against acid.
Normally this prostanoid:
- Decreases acid secretion
- Increased HCO3
- Increases mucous
- Increases mucosal thickness and blood flow
Do injectable NSAIDS protect the GI mucosa?
Nope
How do NSAIDS impact the kidneys?
Effects are relatively mild and rare in healthy adults but can in compromised pts cause renal failure
- Papillary necrosis
- Interstitial nephritis
- Acute tubular necrosis
So called analgesic nephropathy
Are NSAIDS safe for pregnancy and lactation?
They cross the placenta and are excreted in the milk
What are the role of prostaglandins in pregnancy?
- Establish and maintain labor
- Increase uterine SM contraction
- Maintains patency of ductus arteriosus
therefore NSAIDS used
- Induce labor
- Close patent ductus arteriosus in prems
Why is paracetamol not considered a NSAID?
Does not exhibit significant anti-inflammatory properties
Unknown mechanism
