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 prostaglandins
• 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 centre
• 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