8.2- NSAIDs Flashcards
What are the main therapeutic effects of NSAIDs?
Physiologically name 2 actions of NSAIDs
- analgesia
- anti-inflammation
- antipyresis in fever
- antiplatelet
- vasoconstrictor
How is arachidonic acid produced?
- Phospholipase A2 is needed to produce arachidonic acid from phospholipid in the cell membrane
- acid is the biggest pro-inflammatory mediator in the body
What is the action of Cyclo-oxygenase?
- Cyclo-oxygenase is produced from Arachidonic acid
- produces PGH2 which produces prostaglandins and thromboxane
- Thromboxane causes platelet proliferation
- Prostaglandins act on endothelium
What is another general group of arachidonic acid metabolites?
LIPOXYGENASE
5- HPETE
produces leukotrienes
How do inflammatory mediators cause pain?
activate the nociceptors on Adelta and C fibres resulting in pain and sensitisation
Where are PGE2 released? ( prostaglandins)
- brain
- kidney
- smooth muscle
- Platelets
Where are prostglandins PGD2 used?
- mast cells
- airways
- inflammation
- pain
- allergic reactions
How do NSAIDs act on COX2?
COX-2 inhibitors
therefore no prostaglandin production in endothelium
no thromboxane production—> no platelets
reduced pain
What are prostaglandins?
- Arachidonic acid metabolits
- produced by almost all nucleated cells
- inflammation, immune response, muscle constriction and relaxation
Describe the molecular structure and pharma of prostaglandins
- short half life
- autocrine and paracrine
- lipophilic
Where are PGF2alpha and PGE2 used?
in obstetrics to soften and shorten the cervix for pre-induction cervical ripening
- PGF2 acts on uterus, eye and smooth muscle
Describe the types of NSAIDs
NSAIDs act through inhibition of the two isoforms of cyclooxygenase ( COX) ; COX1 and COX2
- Non-selective NSAIDs; act on both COX1 and COX2
- Specific COX-2-inhibitors; act on COX-2 enzymes only
Describe COX 1
- normal constituent in the body for homeostasis
- continuously produced in
- Gastric mucosa- gastric cytoprotection
- Kindey-sodium and water balance/renal perfusion
- Platelets for aggregation
Describe COX2
- INDUCED in presence of injury and inflammation, in inflammatory cells, producing the inflammatory mediators
also a normal constituent in kidney,brain, endothelium, ovary and uterus
Name one for each:
a) Non-selective NSAID
b) Semi-selective NSAID
c) COX-2 inhibitor
a) Aspirin, ibuprofen
b) Diclofenac
c) Celecoxib
What are the potential complications of the use of NSAIDs?
- Prostaglandins normally MAINTAIN renal blood flow by
- INDUCING VASODILATION in afferent arterioles
BUT
- NSAIDs inhibit prostaglandin production–> harmful hypoperfusion of kidneys and reduced GFR
How is PGE2 affected by COX inhibitors?
- PGE2 is involved in the protection of gastric mucosa; inhibits acid secretion and stimulates mucosal production
- PGE2 INHIBITION by COX inhibitors will
- increase mucosal permeability
- decrease mucosal blood flow and protection
can damage stomach, ulceration, haemorrhage, perforation ( in high doses)
Give an example of :
a) Selective COX1 Inhibitor
b) Non-selective COX inhibitor
c) Selective COX 2 inhibitor
a) Aspirin
b) Ibuprofen, Naproxen
c) Diclofenac
What are some risk factors for GI adverse effects of NSAIDs? (5)
- age>65
- history of GI bleed or ulcer
- concurrent use of drugs that increase risk of GI adverse events; steroids
- Heavy smoking/ alcohol use
- prolonged NSAID use
What are some highly protein bound drugs that can interfere with NSAIDs?
- sulphonylurea ( increased can cause HYPOGLYCAEMIA)
- warfarin (displaced by aspirin for plasma protein binding–> therefore increased active free conc of Warfarin; INCREASED BLEEDING
- Methotrexate
What 3 drugs make up the Triple Whammy?
concurrent used of :
- ACE inhibitor
- NSAID
- Diuretic
Explain the dangers of each drug in the Triple Whammy
- ACEi: decrease glomerular filtration by causing vasodilation of efferent renal arteriole
- NSAIDs; block COX-2–> prevent prostacyclin synthesis; causing afferent arteriolar constriction
- Diuretics; contribute to AKI by causing hypovolaemia
What do you do if the triple whammy of meds cannot be avoided ie it is necessary?
- baseline testing of serum creatinine and electrolytes
- patients should be advised to maintain adequate fluid intake
If triply whammy side effects, develop, main goals are
- Restoration of fluid balance
- withdrawal of nephrotoxic medicines
Give a side effect of ns-NSAID in asthma patients
- non-specific NSAIDs can cause bronchoconstriction in sensitive asthmatic patients
*
Can NSAIDs treat gout?
- yes
- they inhibit the phagocytosis of urate crystals
Name 5 contraindications for the use of NSAIDs
- Pregnancy 3rd trimester
- Hypertensive
- Renal and liver disease
- Asthma
- Stomach ulcer
How do NSAIDs cause side effects?
- NSAIDs competitively block COX1 and COX2 therefore inhibiting prostaglandin synthesis
- directly irritate GI tract—> increase bleeding time ( inhibit thromboxane A2)
- cause a renal glomerular vasoconstriction ( prostaglandin inhibition)
Give an example of:
a) A protein pump inhibitor
b) Histamine antagonist
a) Omeprazole
b) Ranitidine
Give some side effects of Mefenamic acid
- acute pain including dysmenorrhoea
- menorrhagia
Describe the pharmacology of paracetamol
- inhibits COX1 and COX2 through metabolism by peroxidase function of these isoenzymes
- inhibits COX3 predominantly in the brain—> this inhibition of prostaglandin synthesis in the CNS—> produces its antipyretic and analgesic effect
gets metabolised in liver–> to glucoronide and sulpjaye conjugates that are then excreted renally.
Describe the absorption of paracetamol
- time taken to reach maximum plasma concentration (Tmax) is 15-30 minutes
- well tolerated when taken orally
- On oral administraton, it is absrobed from the intestine (70%), stomach and colon ( 30%)
- rate of absorption is rapid and depends on the dose
Describe the elimination of paracetamol
paracetamol is metabolised in the liver and only 2-5% is excreted unchanged
What are the indications for paracetamol use?
- analgesic drug for mild to moderate pain
- First line treatment for chronic pain conditions e.g. osteoarthritis, back pain
Name 2 combos/ routes for paracetamol
- Paracetamol + Codeine co-codamol
- Paracetamol + dihydrocodeine co-dydramo
What are the hepatic and renal cautions for use of paracetamol?
- if Liver impairment, use w caution or omit as it is metabolised in the liver
- in patients w renal impairment, reduce dose of paracetamol
What are the cautions of paracetamol?
- alcohol dependency/ liver disease
- malnutrition
- chronic dehydration
- body weight < 50 kg
- Use of liver enyme (CYP450) inducing drugs e.g. Rifampicin, carbamazepine, phenytoin
- increasing age/ frailty
Why is paracetamol use cautioned in older people?
- with increasing age and frailty, there is a reduction in clearance
- elderly people hvae comorbidities and polypharmacy–> can increase risk of inadvertent paracetamol toxicity and overdose
Describe the overdose of paracetamol
- saturation of Phase II paracetamol pathway ( normal/ zero order) bc enzymes are saturated
- drug is INSTEAD metabolised via phase I CYP450
- NAPQI intermediate is conjugated with glutathione but if glutathione reserves are depleted due to excess dose of paracetamol
- Therefore the reactive intermediate (NAPQI) will exert its toxic effect
Give signs of paracetamol overdose
- nausea and vomiting ( but normally none)
LATER FEATURES:
12-36 hrs; abdominal pain
24+ hrs; loin pain, haematuria and proteinuria=signs of renal failure
2-3 days; right subcostal pain, vomiting and jaundice after 2-3 days are features of Hepatic Necrosis
What is defined as a paracetamol overdose?
How would you resolve it?
- Single doses> 10g ( ie 20 tablets) potentially fatal to thsoe with compromised hepatic function or alcoholics
- ANTIDOTE: N-acetylcysteine (NAC) for paracetamol poisoning—> most effective when administered within 8-10 hrs after ingestion
Describe the pharmacokinetics of aspirin
- irreversibly inhibits COX enzymes and blocks the production of thromboxane
- half life is less than 30 mins; rapidly hydrolysed in plasma to salicylate
- absorbed from stomach
- converted to salicylate acid, gut liver and plasma
- 80-85% is bound to plasma proteins and crosses placenta and CSF
How exactly does aspirin work?
- TXA2 is synthesized in platelets
- PGI2 is synthesixed in vascular endothelium
When aspirin inhibits COX, the platelets cannot regenerate TXA2. The vascular endothelium, however, can synthesise PGI2.This creates a relative excess of PGI2 so inhibiting platelet aggregation.
How long does aspirin effect on platelets last if only given in a single dose?
7-10 days then a new cohort of platelets is produced
What are the respiratory effects of aspirin?
Direct Stimulation of respiratory centre—> Hyperventilation (occurs due to uncoupling
If phosphorylation ↑ CO2 in Overdose this is the cause of death
– Resp. Alkalosis – Renal Compensation – ↓BP, Resp Acidosis + Metabolic Acidosis
What are the metabolic effects of aspirin?
- Increased Cellular Metabolism
- Increased Utilization of glucose reducing Blood sugar
What are the most common signs of aspirin overdose?
- Hyperventilation
- Respiratory alkalosis
- Metabolic acidosis after resp alkalosis–> increased anion gap bc of
- accumulation of intracellular lactate
- excretion of bicarbonate by kidney to compensate for resp alkalosis
Name some mild signs of aspirin overdose
- Nausea and vomiting • Tinnitus
- Deafness
- lethargy or dizziness.
Name 4 moderate to severe signs of aspirin overdose
- dehydration
- sweating
- restlessness
- warm extremities
What is Reye syndrome?
caused by using aspirin to treat a viral condition in children/ teenagers w an underlying fatty acid oxidation disorder
Children 4-12yrs
• Presents with Encephalopathy & Liver disease
• Diagnosis based on History and presentation
• Medical Emergency - NO ASPIRIN FOR CHILDREN
Compare and contrast aspirin with Paracetamol
ASPIRIN:
- Irreversible inhibitor of COX1 and COX2
- 70% absorbed from upper GI
- metabolised by esterases in gut wall and liver
- renal excretion
PARACETAMOL:
- selective inhibitor of COX3 in CNS
- upper GI 70-90% absorption
- metabolised in liver
- renal excretion
Give 3 toxic effects of aspirin and 3 of paracetamol
Aspirin:
- Reyes syndrome in children
- Hepatic/renal impairment
- GI upset
PARACETAMOL:
- Thrombocytopenia
- Liver necrosis
- GI upset
