3. Pharmacology
          3.6. NSAIDs
              3.6.2. Nonspecific NSAIDs
 3.6.2.1. Aspirin

Aspirin (acetylsalicylic acid)

[SH4:p282-p285; PI (solprin) on MIMS]

Usage

  • Analgesic for low intensity pain
  • Antipyretic
  • Antiplatelet

Structure

  • Acetylsalicylic acid --> a salicylate

Pharmacodynamics

Mechanism of action

  • Irreversibly acetylate COX enzyme
    --> a decrease in synthesis of prostagladins
  • Active metabolite (orthohydroxybenzoic acid) exert action in different way
  • Relatively weak inhibitor of renal prostaglandin synthesis
    --> Unlikely to exert any clinically relevant effect at doses below the antiinflammatory range
  • Leukotriene pathway remains intact in the presence of aspirin

Effects

Analgesia

  • Confine to a small dose range
  • Below the range --> Little analgesic effect
  • Above the range --> Increased toxicity without much increase in analgesia

Antipyretic

  • Prevents pyrogen-induced release of prostaglandins in the CNS (e.g. hypothalamus)

Antiplatelet

  • Mainstay therapy for patients with angina and acute MI
  • Due to irreversible acetylation of platelet COX-1
    --> Inhibition of thromboxane A2 synthesis
    --> Inhibition of platelet activation and aggregation (as well as vasoconstriction)
  • Acetylation effect is fast
    * Appears before the aspirin appears in blood
    * Possibly take place in the portal circulation
    * Antiplatelet action is unrelated to systemic bioavailability
  • Most of the aspirin-induced prolongation of bleeding time disappears by 48 hours.

Histamine and serotonin

  • No effect on histamine or serotonin release

Side effects

Gastric irritation and ulceration

  • GIT intolerance is the most common adverse effect of aspirin
  • Dose-related
  • Can be prevented by enteric-coated tablets

Prolongation of bleeding time

  • Platelet inhibition is irreversible, and last for the entire lifespan of the platlet (7-10 days)
  • Chronic adminstration of large dose aspirin
    --> Decreased production of prothrombin
    --> Prolonged prothrombin time

CNS stimulation

  • Excessive dose of aspirin
    --> Stimulation of CNS
    --> Hyperventilation and seizures
    * Hyperventilation is due to direct stimulation of medullary ventilatory cenre
  • N&V also occurs
    * Low dose --> irritation of GIT mucosa
    * High dose --> Direct stimulation of medullary chemoreceptor trigger zone

Overdose

  • Salicylate overdose
    --> Depression of renal function + derangement of carbohydrate metabolism
    --> Metabolic acidosis (more common in children than adults)
  • Hyperthermia and dehydration also happens in salicylate overdose
  • Acidosis increases movement of salicylic acid into CNS
  • Tinnitus
    * Due to drug-induced increases labyrinthine pressure or an effect on hair cells of the cochlea
    * Earliest sign of salicylate overdose
  • Severe salicylate intoxication
    --> Fatty infiltration of liver and kidneys
  • Metabolic derangement
    * Hyperglycemia
    * Glycosuria
    * Depletion of liver and skeletal muscle glycogen
    * Decrease lipogenesis
Treatment of overdose
  • Sodium bicarbonate administration
    * Decreases movement of salicylic acid into CNS
    * Increase renal excretion

Hepatic dysfunction

  • Salicylates can be associated with increasing plasma transaminase enzymes

Renal function

  • In contrast to other NSAIDs (especially paracetamol), aspirin has NOT been associated with increased incidence of ESRD

Uterine effect

  • Salicylate may prolong labour by inhibiting the uterotropic effects of prostaglandins

Allergy

  • Rare
    * But aspirin is more likely to cause allergy than salicylate
  • Appear within minutes
  • Include:
    * Vasomotor rhinitis
    * Laryngeal oedema
    * Bronchoconstriction
    * CVS collapse
  • Cross-react to all inhibitors of prostaglandin synthesis

Aspirin-induced asthma

  • Occurs in 8-20% of all asthmatic adults
  • Occurs within an hour of ingestion
  • Bronchoconstriction
    * Due to derangement of arachidonic acid metabolism --> increased production of leukotrienes
  • Mechanism is NOT immunological
    * Therefore NOT an allergic reaction

Others

  • Possible association between use of aspirin in children (for treatment of fever) and the development of Reye syndrome

Pharmacokinetics

Absorption

  • Rapid absorbed from small intestine
    * Also absorbed from stomach to a lesser extent
  • Gastric absorption of aspirin depends on
    * Dissolution rate of the tablet
    * Gastric emptying time
    * Acidity (low pH increases absorption)

Metabolism

  • Aspirin is rapidly hydrolysed in liver and also in GIT mucosa [PI]
    * Into salicylic acid (orthohydroxybenzoic acid)
    * Aspirin itself is pharmacologically acitve
  • Butyrylcholinesterase is involved in the hydrolysis
    * [CEACCP 2004 Vol 4(5) "Anticholinesterases and anticholinergic drugs" p165]

Orthohydroxybenzoic acid

  • Active metabolite
  • Inhibits prostaglandin synthesis by a nonacetylation mechanism
  • Lacks acetylating capacity
  • Metabolised in liver
    * First order kinetic
    * Zero-order kinetics at very large dose
  • Conjugated with glycine to form
    * Salicyluric acid
    * Salicylic phenolic glucuronide
    * Salicyclic acyl glucuronide

Elimination

  • Salicyluric acid is excreted in urine with free orthohydroxybenzoic acid
  • Renal excretion of free orthohydroxybenzoic acid is highly variable
    * Up to 85% in alkaline urine
    * To 5% in acidic urine
  • Alkalinisation of urine increases urinary excretion of aspirin

Action profile

  • Elimination half-time for aspirin = 15-20 minutes
  • Elimination half-time for salicylic acid = 2-3 hours

Physicochemical properties

  • Weak acid

 

Clinical

Administration

Antiplatelet

  • Single loading dose of aspirin 200-300 mg
    * Followed by daily dose of 75 to 100mg
  • In unstable angina, aspirin is supplemented with heparin

Contraindications

Risk of haemorrhage

Aspirin should be avoided in patients with

  • Severe hepatic dysfunction
  • Vitamin K deficiency
  • Hypoprothrombinaemia
  • Haemophilia

--> Excessive haemorrhage

 

Special consideration

Exaggerated response

  • Some normal patients are very sensitive to aspirin's antiplatelet action
    --> Bleeding time is much prolonged
  • These patients are likely to have a mild form of von Willebrand disease
  • Uremic patients are also sensitive to aspirin's antiplatelet effect


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