Download of aspirin

NSAIDs II
(ASPIRIN)
LEARNING OBJECTIVES
By the end of the lecture students must be able to know about Aspirin
regarding:
• General properties.
• Classification of salicylates.
• Pharmacokinetics of aspirin.
• Pharmacodynamics.
• Aspirin toxicity.
• Drug interactions.
• Clinical application.
• Contraindications.
INTRODUCTION
• Aspirin is the prototype drug of NSAIDs; hence the other NSAIDs
are often referred to as aspirin-like drugs.
• Its Chemical name is Acetyl Salicylic Acid.
• It is the oldest NSAID.
• It belongs to chemical subclass Salicylates.
• Its most common clinical use is for the prevention of Ischemic Heart
Disease and stroke, as antiplatelet agent.
CLASSIFICATION OF SALICYLATES:
• Salicylic Acid
• Acetylsalicylic Acid (Aspirin)
• Sodium Salicylate.
PHARMACOKINETICS
OF ASPIRIN
ABSORPTION
• Orally ingested aspirins are absorbed rapidly, partly from the
stomach but mostly from the upper small intestine.
• Appreciable concentrations are found in plasma in less than 30
minutes; after a single dose, a peak value is reached in about 2
hours and then gradually declines.
DISTRIBUTION
• After absorption, aspirin is distributed throughout most body
tissues and most transcellular fluids, primarily by pHdependent passive processes.
• Aspirin is actively transported by a low-capacity, saturable
system out of the CSF across the choroid plexus.
• The drug readily crosses the placental barrier.
BIOTRANSFORMATION
AND EXCRETION
• The biotransformation of aspirin takes place in many tissues, but
particularly in the hepatic endoplasmic reticulum and mitochondria.
• The three chief metabolic products are salicyluric acid (the glycine
conjugate), the ether or phenolic glucuronide, and the ester or acyl
glucuronide.
PHARMACODYNAMICS
OF ASPIRIN
MECHANISM OF ACTION
• Irreversible, non-selective COX inhibitor (causes acetylation of COX).
• Aspirin covalently modifies both COX-1 and COX-2, thus resulting in an
irreversible inhibition of cyclooxygenase activity.
• In the structure of COX-1, aspirin acetylates serine 530, preventing the
binding of arachidonic acid to the active site of the enzyme and thus the
ability of the enzyme to make prostaglandins.
• In COX-2, aspirin acetylates a homologous serine at position 516.
ACTIONS
• Platelets are especially susceptible to aspirin-mediated irreversible
inactivation of cyclooxygenase because they have little or no capacity for
protein biosynthesis and thus cannot regenerate the cyclooxygenase
enzyme.
• In practical terms, this means that a single dose of aspirin will inhibit the
platelet cyclooxygenase for the life of the platelet (8 to 11 days); in human
beings, a daily dose of aspirin as small as 40 mg is sufficient to produce this
effect.
ANALGESIA:
• The types of pain usually relieved by aspirin are those of low intensity that arise
from integumental structures rather than from viscera, especially headache,
myalgia, and arthralgia.
• Aspirins are more widely used for pain relief than are any other classes of drugs.
• Long-term use does not lead to tolerance or addiction, and toxicity is lower than
that of opioid analgesics.
• Aspirin alleviates pain by virtue of a peripheral action; direct effects on the CNS
also may be involved.
ANTIPYRETIC EFFECT:
• Aspirin has no effect on temperature in normal persons, but reduces the body
temperature when patient is febrile.
• The antipyresis is usually associated with profuse sweating, fall in body
temperature is partly due to cutaneous vasodilatation.
• Aspirin decreases the pyrogen induced synthesis of prostaglandins, inhibits
release of IL –I from macrophages and reset the thermoregulatory center in
hypothalamus.
URICOSURIC EFFECT:
• Uric acid filtered by glomerulus is reabsorbed by the proximal tubules and
then secreted at distal tubules and is excreted in urine.
• In low doses (≤ 2 grams/day) aspirin blocks the secretion of uric acid at distal
tubules, this increases uric acid levels in blood.
• In high doses (≥ 4 grams/day) aspirin blocks the reabsorption of uric acid by
proximal tubules and increase its excretion thus produce uricosuria.
NEUROLOGICAL EFFECTS:
• Aspirin induces nausea and vomiting, which result from stimulation of sites that are
accessible from the cerebrospinal fluid (CSF), probably in the medullary
chemoreceptor trigger zone.
• In high doses, aspirin has toxic effects on the CNS, consisting of stimulation
(including convulsions) followed by depression. Confusion, dizziness, tinnitus,
high-tone deafness, delirium, psychosis, stupor, and coma may occur. The tinnitus
and hearing loss caused by aspirin poisoning are due to increased labyrinthine
pressure or an effect on the hair cells of the cochlea, perhaps secondary to
vasoconstriction in the auditory microvasculature.
RESPIRATION:
• Aspirin stimulates respiration directly and indirectly. Full therapeutic doses of aspirin
increase oxygen consumption and CO2 production (especially in skeletal muscle); these
effects are a result of aspirin- induced uncoupling of oxidative phosphorylation. The
increased production of CO2 stimulates respiration.
• Aspirin can directly stimulate the respiratory center in the medulla. This results in marked
hyperventilation, characterized by an increase in depth and a pronounced increase in rate.
Patients with aspirin poisoning may have prominent increases in respiratory minute
volume, and respiratory alkalosis develops.
• A depressant effect of aspirin on the medulla appears after high doses or after prolonged
exposure.
CARDIOVASCULAR EFFECTS:
• Ordinary therapeutic doses of aspirins have no important direct
cardiovascular actions. The peripheral vessels tend to dilate after
large doses because of a direct effect on their smooth muscle.
• Toxic amounts depress the circulation both directly and by central
vasomotor paralysis.
• Antithrombotic effect of low dose acetyl salisylic acid helps in
prevention of IHD.
GASTROINTESTINAL EFFECTS:
• The ingestion of aspirin may result in epigastric distress, nausea, and
vomiting.
• Aspirin also may cause gastric ulceration; exacerbation of peptic ulcer
symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive
gastritis.
• All have been reported in patients on high-dose therapy but also may occur
even when low doses are administered.
HEPATIC AND RENAL EFFECTS:
• At least two forms of hepatic injury.
• In one form, hepatotoxicity is dose- dependent and usually is associated with plasma
concentrations that are maintained above 150 mg/ml.
• Severe hepatic injury and encephalopathy observed in Reye's syndrome (Combined
encephalopacy and liver disorder – 20-40% lethality). This syndrome is a rare but often
fatal consequence of infection with varicella and various other viruses, especially the
influenza virus. It has been proposed that aspirin and the viral illness may act to damage
mitochondria.
• The use of aspirins in children or adolescents with chickenpox or influenza is
contraindicated.
MISCELLANEOUS EFFECTS:
• Salicylates decrease the ESR in rheumatic fever, they increase the
adrenaline release from adrenal medulla.
• In large doses they can produce hyperglycemia, and glycosuria in
normal persons.
ADVERSE EFFECTS
• Most common side effects of salicylates are nausea & vomiting,
epigastric distress, gastric ulceration, gastrointestinal hemorrhage.
• Gastric irritation can be reduced by giving the drug after meals and by
using enteric-coated preparation.
• Prostaglandin derivative misoprostol and proton pump inhibitor
omeprazole are used for prevention and treatment of aspirin induced
ulcer.
• Salicylates increase bleeding time, they increase the serum uric
acid levels and can precipitate the attack of acute gout. They also
produce fluid electrolyte and respiratory disturbances. In high
doses salicylates produce hyperpyrexia. Salicylates also produce
hepatitis and hypersensitivity reactions.
• Prolonged administration of salicylates in the treatment of rheumatic
fever/arthritis may produce a condition of mild salicylate poisoning termed as
SALICYLISM.
• It is characterized by headache, dizziness, tinnitus, drowsiness, mental
confusion, nausea & vomiting and respiratory alkalosis.
• Chronic use of salicylates also produces iron deficiency anemia due to
chronic blood loss.
ASPIRIN TOXICITY
SIGNS AND SYMPTOMS:
• Mild chronic aspirin intoxication is termed salicylism.
• When fully developed, the syndrome includes headache,
dizziness, ringing in the ears, difficulty in hearing, dimness of
vision, mental confusion, lassitude, drowsiness, sweating, thirst,
hyperventilation, nausea, vomiting, and occasionally diarrhea.
• A more severe degree of aspirin intoxication is characterized by more
pronounced CNS disturbances (including generalized convulsions and
coma), skin eruptions, and marked alterations in acid-base balance. Fever
is usually prominent
• Treatment: The treatment is directed at cardiovascular and respiratory
support and correction of acid-base abnormalities plus use of measures to
speed excretion of aspirin.
DRUG INTERACTIONS
• Aspirin displaces many drugs from plasma proteins and increase the toxicity
of the drugs like tolbutamide, chlorpropamide, methotrexate, phenytoin and
other salicylates.
• Probenecid and sulphinpyrazone decrease the urinary excretion of
salicylates.
• Antacids decrease the absorption of salicylates.
• Salicylates potentiate the effects of anticoagulants.
CONTRAINDICATIONS
• Aspirin is contraindicated in patients with bleeding disorders like
hemophilia, pregnancy, peptic ulcer, gout, and in infants with viral
infections (as there are chances of development of Reyes
syndrome that is a type of fatal encephalopathy).
THERAPEUTIC USES
• ANALGESIC:
For relieving mild to moderate pain of varied origin. Aspirin and other
NSAIDs are often combined with opioid analgesics for treatment of
cancer pain.
• ANTIPYRETIC:
Aspirin is an effective antipyretic agent in febrile conditions.
• ANTI-INFLAMMATORY:
Aspirin in large doses is effective for the management of rheumatoid
arthritis, rheumatic fever and other inflammatory conditions.
• ANTITHROMBOTIC:
Aspirin in low doses decreases the incidence of stroke, coronary
artery thrombosis, unstable angina, myocardial infarction and
thrombosis after coronary artery bypass grafting.
• ANTIRHEUMATIC:
Antirheumatic application of aspirin requires high doses. CNS effects of its
high dose are possible (tinnitus, nausea, etc.) So other NSAIDs have been
developed as alternative.
Differences b/w
Aspirin & Paracetamol
ASPIRIN
PARACETAMOL
It has anti-inflammatory properties.
It has no significant anti-inflammatory
activity.
Inhibits platelet aggregation.
It has no effect on platelets.
It interferes with uric acid excretion. No such effect.
Produces gastric irritation.
Does not produce gastric irritation.
It is bound to plasma proteins.
It is less bound to plasma proteins.
Thank You