Lecture 33: Analgesic drugs 2 Flashcards
NSAID stands for?
Non Steroidal Anti-Inflammatory Drugs
Main action of NSAIDs?
- They inhibit the cyclo-oxygenase enzymes (COX1 and COX2) leading to supression of prostanoid production in the cells
- Newer agents can inhibit COX2 enzyme slectively
- most inhibitions are reversible and incomplete
- Aspirin selectively acetylates a single serine residue of the enzyme and inactivates it irreversibly.
Effects of NSAIDs?
- decreased inflammation by decreased PG
- Relieve mild pain by decreased PG
- anti-pyretic by decreased PG E2
- Anticoagulation - inhibits platelet aggregation by dec. TXA2 (thromboxane A2)
What are prostaglandins?
- A large group of lipid compounds derived from fatty acids
- Highly potent
- Short half life
- produced by almost all cells (except RBC)
- Autocrine signally
AA? synthesis, process involved in?
Arachidonic acid
- synthesised from the essential FA linoleate
- ingested in the diet
AA is esterified to cell membrane phospholipids
Many stimuli liberate AA from the cell membrane by activting phospholipase.
COX1 and 2 then convert AA to Prostanoids (prostaglandins, prostacycline and thromboxane)
COX 1 Pathway?
- AA goes through the COX1 pathway.
- COX1 is constitutive in that it is always there in the cell.
- Breaks AA to PGs important for homeostatic functions.
- Inhibition by NSAIDs undesirable
COX 2 Pathway? Use of inhibition?
- COX 2 is induced and not there all the time like COX1
- COX 2 is induced by cytokines, TNF, GF
- Produced certain PG that cause pain and inflammation
- Deseribale inhibition by NSAID and Glucocorticoids
BUT, COX2 inhibitors are
- Associated with gastric side effects
- associated with increased serious adverse events like heart attacks and strokes
Pharmacokinetics of NSAIDs?
availability, action speed, half life, metabolism?
- All NSAIDs are highly lipophilic
- Rapid and complete absorption from oral administration
- NSAIDs undergo very little first-pass metabolism
- High protein binding thus, small VOD
- Onset of action is slow and with variable T1/2
- Metabolised by the Liver through a variety of pathways mostly to inactive products
Drug interactions of NSAIDs?
They interact with other protein binding drugs
eg.
- Oral anticoagulants
- anti-cancer (methotrexate)
- digoxin
Compete for active renal tubular secretion with other organic acids (eg. uric acid)
Inhibitors and inducers of NSAIDs?
Some drugs inhibit like cimetidine and valproic acid
Some drugs induce like carbamazepine and phenobarbitone
They may enhance or decrease the anti-inflamm activity of NSAIDs
Excretion of NSAIDs? Eg. Aspirin? Rate of excretion?
Excreted in the urine as:
- Glucouronides
- sulfate conjugates
- small percentage excreted unchanged (eg. 10% of aspirin)
Rate of exretion of acidic drugs is increased by urine alkinisation
Side effects of NSAIDs?
Mainly due to the blockage of COX1 enzymes
- Bleeding
- GI tract, renal and liver complications
- Pregnancy/lactation complications
- Reye’s syndrome
Aspirin is _______?
absorption and pathway of action?
Excaerbates _________ due to ______?
- Aspirin is Acetylsalicylic acid
- Is absorbed in the stomach and the upper intestine by passive diffusion
- Once in the blood it is de-acetylated to salicylic acid which is responsible for anti-inflamm and analgesic effects
- Salicylate bound to serum albumen and is conjugated in the liver with glycie (mainly) and glucuronic acid and excreted in urine.
- Competes with uric acid secretion in the kidneys so will exacerbate gout
How does Aspirin cause bleeding?
Benefits of this feature?
Aspirin irreversibly acetylates platelets COX1 inhibiting formation of TXA2 causing decresed platelet aggregation
Reduced risk of heart attack and stroke and in low doses doesn’t effect endothelial prostacyclin PGI2 causing vasodilation
Risks of NSAIDs and Bleeding?
Increased bleeding time in patients on aspirin or other NSAIDs
- May increase operative blood loss
- Epidurals (for pain relief eg. during labour) may be at risk of developing a haematoma
NSAIDs effects in GI tract?
Normally Epith. produces a gastric cytoportective prostanoid (PG) to protect against acid damage. Synthesis is inhibited by aspirin and other NSAIDs.
The production of this gastric PG is increased by mucosal injury and irritants (eg. ethanol)
NSAIDs block this and can cause bleeding and ulcers
They are organic acids so they they can irritate mucosa
= N + V + dirrhoea
Effects of Gastric cytoprotective prostanoid?
- Decreased gastric acid secretion
- increases bicarb and therefore pH
- increased mucus secretion
- increased mucosal thickness
- Dilates gastric blood vessels and increase mucosal blood flow
Aspirin and asthma correlation?
Aspirin-induced asthma (AIA)
Symptoms appear at an everage age of 30 (very rare in children)
May be severe and life threatening and occur 1-3 hours after ingestion of aspirin.
Aspirin (or Samter’s) triad?
- Aspirin intolerance = rhinitis and facial flushing (decreased PGE2, a bronchodilator)
- Severe asthma (activation of lipoxygenase pathway > bronchospasms)
- Nasal polyps = appear at a later stage
Reye’s syndrome and aspirin?
An acute metabolic encephalopathy (in children)
- Brain - (encephalopathy)
- Liver - (fatty, inc ammonia, inc liver enz.)
- Very rare and 40% fatality, children more prone after a viral ilness (hence, not advisable to give aspirin to children with a viral ilness)
NSAIDs and the kidney?
So called analgesic nephropathy in patients with compromised kidneys already.
NSAIDs and pregnancy
Prostaglandins establish and maintian labour, cause inc uterine smooth muscle contraction and maintains patency of ductus arteriosus.
Can be used to inhibit labour or for closure of patent ductus arteriosus in premature infants
Paracetamol is an ______ and ________?
metabolism? Is it a NSAID?
Side effects and overdose?
Paracetamol is an analgesic and antipyretic
Metabolised in the liver by Cytochrome P450
Is a weak anti-inflammatory
NOT considered a NSAID because it doesn’t exhibit significant anti-inflammatory activity
few side effects but fatal hepatic damage from N-acetyl benzo quinine with N acetyl cystiene as an antidote.
