Aspirin

Aspirin is a prototypical drug. Although so many newer drug are available, but it is still the most commonly used drug as analgesic and anti-platelet.

Glamour is not associated with aspirin, as is easily available and has been in use for such a long time.

Chemistry

Derivative of salicylic acid. Acetyl radical is attached. Salicylic acid itself is very irritant. Acetyl radical increases the oral use is improved. They have actions by virtue of salicylic acid, which inhibits COX. Acetyl radical gives extra properties:

1. Acetyl radical acetylates certain sites on COX enzyme. Other members reversibly inhibit the enzyme while aspirin does it irreversible. Every tissue will have to resynthesize enzyme before activity returns. Every tissue resynthesizes at different rates, depending on protein synthesis.
2. Platelets are anucleated and have no ability to synthesize proteins, thus proteins of the whole batch cannot aggregate

Aspirin is the only drug of this group used as anti-platelet.

Paracetamol etc. only reversibly inhibit the COX enzyme.

Mechanism of Action

1. Anti-inflammatory

Anti-inflammatory effect is seen only at very high doses, at 4-5 g/day. Ordinary tablet only contains 300 mg, thus if 15 tablets are taken.

It inhibits cyco-oxygenase, prostaglandins and prostacyclines and also directly:

• Interferes with kinin system
• Cause direct immunological suppression
• Inhibits movement of neutrophils
• Causes modification of ground substance of connective tissue, thus infection cannot spread.

2. Anti-pyretic action

At dose of 300-600 mg, every 4-6 hours (1-2 tablets).

3. Analgesic action

300-600 mg –same as anti-pyretic, enough to alleviate mild to moderate pain.

Therapeutic uses

1. Respiration

a. At normal dose

Produces direct and indirect effect on respiration:

1. Direct action –crosses BBB and stimulates respiratory center in medulla
2. Indirect action –produces uncoupling of oxidative phosphorylation, process which yields ATP (1g glucose yields 38 ATP), thus oxidative phosphorylation stops. Lot of carbon dioxide is produced, which stimulates the respiratory center.

This leads to an increase in rate and depth of respiration, leading to hyperventilation, which increases carbon dioxide washout from lungs, leading to respiratory alkalosis.

This is initially partially compensated by increase in bicarbonates loss along with sodium and potassium, thus electrolyte imbalance occurs.

b.    When drug is consumed in toxic dose

Suppression of respiratory and vasomotor center occurs, leading to respiratory acidosis and circulatory collapse.

2. CVS

In normal doses (300-600 mg 4-6 hours) hardly affect CVS.

At high doses, produce direct vasodilatation due to relaxation of smooth muscles.

At toxic doses, suppression of vasomotor center occurs, leading to circulatory collapse and shock due to: a. vasomotor center action b. vasodilatation

At low doses

75-150 mg/day are given for prevention of IHD. At this dose, platelet aggregation is inhibited, but has no effect on prostaglandins and prostacyclines.

• One one hand, low dose is less irritant to stomach mucosa
• Beneficial effects of prostaglandins and prostacyclines are not lost as we want to produce vasodilatation.
• Only thromboxane A2 is inhibited.

TIA (Transient ischemic attack)

Micro thrombi arise in heart, and enter brain, where they cause stroke for only few moments, then the person recovers. Low dose aspirin is also used because:

1. Irreversibly inhibits
2. High dose also inhibits prostaglandins and prostacyclines

3. GIT

Aspirin induced gastropathy

Aspirin is acidic and irritant to gastric mucosa, producing nausea, vomiting at low to normal doses.

At higher doses also stimulates the CTZ, leading to more vomiting.

The symptoms start from

1. nausea and vomiting
2. abdominal discomfort
3. abdominal pain
4. dyspepsia
5. feeling of indigestion
6. ulceration (frank ulcers
7. perforation and hemorrhage of GIT)
8. Decrease production of prostaglandins and prostacyclines under COX 1, which is constitutive in stomach, leading to decrease in production of mucous rich in bicarbonates, increasing acid production and decreasing blood flow.
9. Also inhibit platelet aggregation

Thus chances of gastropathy increases.

Prevention

• Not to take aspirin on empty stomach
• Avoid NSAIDS which are notorious, use paracetamol, which is safer
• Combine NSAIDS with PG analogs like misoprostol, thus useful effects are not lost; as NSAIDS inhibit production of PG, or give already prepared PG.
• Proton pump inhibitors can be combined with aspirin.

4. Effects on liver

At normal dose has minimal effect. High dose if used for longer time leads to hepatocellular damage, leading to increased levels of transaminases (ALT and AST).

It should not be used in children below 20 years of age. There has been increased incidence of Reye’s syndrome, leading to hepatic encephalopathy, damage, coma and death, when used in viral infections (measles, mumps, rubella, etc.)

Thus should refrain in every case.

Paracetamol and ibuprofen are safer.

Till 1986, aspirin was available as baby aspirin, but lots of deaths occurred, and has now been withdrawn.

5. Effects on kidneys

Normally aspirin has no effect. In certain conditions auto regulation of blood occurs under prostaglandins influence. This auto regulation is seen in cases of hypovolemia (either blood loss or third space hypovolemia).

In CCF, cirrhosis of liver, nephrotic syndrome, where auto regulation of blood flow is protective for the kidneys under prostaglandins influence, can lead to kidney failure due to inhibition.

Uricosuric effect

Effects vary in low and high doses.

1. Acid which is synthesized due to purine metabolism is excreted in kidneys at proximal convoluted tubules in S2 by active transport. This transporter also transports all other acids as well.
2. Also reabsorbed in proximal convoluted tubules.

At low doses

Secretion is inhibited by competitive inhibition. This decreases uric acid excretion, leading to hyperuricemia and precipitation of gout.

At high doses

Reabsorption is blocked, leading to increased excretion, known as uricosuric effect, which promotes uric acid excretion.

Aspirin is not used in treatment of gout.

6. Metabolic effects

Effects are dose related. At higher doses for longer periods, uncoupling of oxidative phosphorylation occurs, thus ATP is produced by anaerobic glycolysis. Accumulation of acetic acid, pyruvic acid and lactic acid occurs.

1. Aspirin is itself acidic
2. Increased accumulation of these acids can lead to metabolic acidosis

These reactions in which ATP is produced are not energy efficient, thus lot of heat is produced.

Aspirin causes increased sweating at higher doses, and can lead to hyperpyrexia.

Effect on carbohydrate metabolism

Higher doses cause increased epinephrine, increased glycogenolysis in muscles, leading to hyperglycemia.

Effects on protein metabolisms

High doses increase cortisol, which increases the metabolism of proteins, leading to aminoacid urea.

Effects on fat metabolism

Increase release of free fatty acids.

7. Effects on pregnancy

• Inhibition of prostaglandin synthesis can lead to increased period of gestation
• Anti-platelet action promotes antepartum and post partum hemorrhage
• Mother taking normal doses of aspirin over prolonged periods during pregnancy has low birth weight babies.
• No teratogenicity is known.

8. Effects on CNS

CNS effects are seen only in very high doses, also known as Salicylism. Symptoms include:

1. Nausea
2. Vomiting
3. Tinnitus
4. Vertigo
5. Blurred vision
6. Hearing deficiency
7. Confusion

By virtue of high doses of aspirin.

Similar symptoms also occur with quinine, known as cinchonism.

Pharmacokinetics

Absorption occurs from stomach as is acidic. Quantitatively greater is absorbed from upper part of small intestine, due to greater absorptive area.

Distribution is wide and is excessively plasma protein bound, thus can displace oral anticoagulents, etc.

Metabolism is dose related.

1. Below 600 mg/day aspirin shows 1^st order kinetics.
2. Above 600 mg/day rate of metabolism shows zero order kinetics.

Some is metabolized by glucuronidation.

Mostly is conjugated to glycine, producing salicyl uric acid.

1% of drug is converted to gentisic acid.

Excretion

1. Some is excreted as glucuronide conjugates
2. 75% as salicyl acid urea
3. 10% is excreted unchanged
4. 1% as gentisic acid.

Clinical Uses

Therapeutic uses are dose related.

1. Use as analgesic

Analgesic dose is 300-600 mg (1 to 2 tablets) every 4-6 hours. Used for:

1. Mild to moderate pain
2. Myalgia
3. Arthralgia
4. Neuralgia
5. Tooth ache
6. Head ache

The treatment is symptomatic

2. Anti pyretic

At dose of 300-600 mg, every 4-6 hours (1-2 tablets). Although out of favor as paracetamol is used, but still used as easily available.

3. Arthritis

Given in a dose of 4-5 g/day (acids accumulate adding to metabolic acidosis). Also used for:

1. Non-inflammatory arthritis
2. Osteoarthritis

It is also used in rheumatic fever. Aspirin is not usually given to children (Reye’s syndrome) but still used as drug of choice in children of rheumatic fever.

4. Anti platelet use

Dose is 75-150 mg/day. At this dose irreversibly blocks the cyclooxygenase enzyme. Thus they are knocked out for 8-11 days.

• This is used for treatment of heart diseases (TIA).
• Also used as anti platelet after bypass surgery
• Angioplasty
• Angiography

5. Primary dysmenorrhea

As blocks synthesis of prostaglandins

6. Bartter’s syndrome

Exact etiology is not known. There is hypokalemia, hyperrenninemia, hyperaldosteronism, despite normotension.

It is a congenital disease normally diagnosed early, and results from defect in ascending thick limb. The reabsorption of sodium cannot take place. More reaches the distal portion, increased loss of potassium occurs, leading to alkalosis. One of the effects is prostaglandin mediated, the hyperplasia of JG apparatus.

Aspirin is part of treatment, along with spironolactone, ACE inhibitors and potassium.

Aspirin can reverse the hyperplasia of JG cells.

Why normotension?

No vasoconstriction occurs, although increase in angiotensin I and II occurs, but prostaglandins produce vasodilatation. The disease is characterized by:

1. Polyuria
2. Polydipsia
3. Retardation of growth both neurological and physical

Minor Uses

1. In low dose used for prevention of colonic cancer
2. In low dose, used for prevention of eclampsia and pre-eclampsia.
3. Can be combined with a sulpha drug (sulpha salizine) for inflammatory bowel disease and ulcerative colitis.
4. Niacin therapy; given to hyperlipidemics causing decreased cholesterol, preventing IHD. But it causes PGD2 synthesis, resulting in vasodilatation of skin vessels, causing intense flushing. So aspirin is used, which decreases PG synthesis

Adverse effects and toxicity

These are dose related.

Normal dose

Produces antiplatelet, analgesic and anti pyretic actions.

1. Gastric intolerance
2. GI bleeding
3. Hypersensitivity
4. Impaired homeostasis –antiplatelet action
5. Reye’s syndrome esp. in measles, chicken pox

Mild toxic dose

1. Effects CNS –Salicylism

2. Tinnitus, vertigo, impaired hearing, psychosis

It is thought to be because of pressure on cochlear cells by constriction of labyrinthine vessels in ear

3. Hyperventilation –direct and indirect stimulation

4. Respiratory alkalosis

Moderate toxic dose

1. Leads to uncoupling of oxidative phosphorylation
2. Accumulation of acids –pyruvic, lactic
3. Metabolic acidosis

Excessively toxic dose

Vasomotor and respiratory collapse.

1. Toxic itself, causes fever, uncoupling of phosphorylation which is met by processes producing excessive heat.
2. Dehydration, leading to fever

Severe toxic dose

1. Comma
2. Vasomotor collapse

Lethal

1. Renal failure
2. Respiratory failure

150-175 mg/kg body weight can be fatal. Has no specific antidote, only supportive measures like

a. gastric lavage

b. treating dehydration

c. monitoring acid base balance

d. sponging, to reduce fever

e. alkalization of urine

f. enhance excretion of aspirin

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