Aspirin

Efficacy greater than acetaminophen as an anti-inflammatory agent

Aspirin inhibits synthesis of prostaglandins that are important in the pathophysiology, signs, and symptoms of a host of inflammatory or arthritic states. It does so, of course, by inhibiting both COX-I and -2. Acetaminophen lacks this property, and so acetaminophen is much less efficacious for managing inflammation. Aspirin and acetaminophen are equally efficacious (and, for all practical purposes, equipotent) for relieving simple headache for most patients.

(Note, however, when pain involves a component of inflammation, aspirin is clearly superior to acetaminophen because it suppresses both the inflammation and the pain caused by it.) Aspirin usually helps normalize or lower body temperature in febrile states, but this, too, involves inhibited

synthesis of prostaglandins (peripherally perhaps, leading to increased heat loss through diaphoresis, but also in such central structures as the hypothalamus, which is a prime temperature ¬regulating structure). Aspirin does not exert bacteriostatic or bactericidal effects (at any level encountered in vivo), and so antibiotic effects do not contribute to its antipyretic actions.

Although aspirin is an effective cyclooxygenase inhibitor, it has no effects on the lip oxygenase pathway that leads to leukotriene synthesis. It does not affect uric acid synthesis (xanthine oxidase) at all.

Warfarin

Arachdonic acid metabolites are formed by two classes of enzymes such as Cycloxygenases and Lipoxygenases.

Cycloxygenase pathway is mediated by COX1 and COX2 enzymes leading to the formation of Prostaglandins and Thromboxanes.

In low doses, aspirin inhibit cycloxygenase irreversibly by acetylating one of its serine residues. Return of cycloxygenase activity depends upon synthesis of fresh enzyme.

Aspirin clearly increases bleeding tendency (by its antiplatelet effects).

Aspirin acts as an anticoagulant by irreversibly inhibiting platelets, preventing the formation of a clot by blocking platelet adhesion and aggregation.

Since this platelet mass acts as a matrix for fibrin clot formation, blocking platelets prevents clot formation.

This mechanism has been utilized in patients with atherosclerotic disease to prevent intravascular clot formation, but may aggravate bleeding conditions such as this.

• Azapropazone
• Phenylbutazone
• Naproxen
• Mefenamic acid
• Ibuprofen

Aspirin irreversibly acetylates and inhibits cyclo-oxygenase. Platelets cannot regenerate cyclo-oxygenase and so thromboxane A2 is not formed in platelets. Hence there is decreased platelet aggregation. Therefore, aspirin is useful in prevention of heart attack.

In the formation of prostaglandins from fatty acids, cyclo oxygenase catalyzes formation of a cyclo- pentane ring and the introduction of three oxygen atoms.

The type of prostaglandin produced depends on the starting fatty acid, which is always a derivative of an essential fatty acid. Aspirin, like indomethacin, decreases prostaglandin synthesis by inhibiting the oxygenase activity of cyclooxygenase. 

Ans. is ‘b’ i.e., Peptic ulcer

• Contraindications of aspirin are peptic ulcer, bleeding tendencies, chronic liver disease and children with chicken pox and influenza. Aspirin should be used with cautions in patients with G6PD deficiency, diabetes and in CHF with low cardiac reserve.

Ans. is ‘a’ i.e., Fluids

o Treatment of aspirin poisoning is symptomatic and supportive.

o Most important is external cooling and i.v. fluid with Na^±, HCO3- and glucose : according to need determined by repeated monitoring.

o Gastric lavage to remove unabsorbed drug; alkaline diuresis or haemodialysis to remove absorbed drug is indicated in severe cases.

o Blood transfusion and Vitamin K should be given if bleeding occurs.

Ans. is ‘c’ i.e., Anaphylacotid reaction

Ans. is ‘b’ i.e., Nasal polyposis

• Samter’s triad consists of Nasal polypi, bronchial asthma and aspirin sensitivity.

Ans. is ‘a’ i.e., Thromboxane A₂ synthesis inhibition

o Aspirin acetylates and inhibits the enzyme cycloxygenase (Cox) – inactivating it irreversible.

o Because platelets are exposed to aspirin in the portal circulation before it is deacetylated during first pass in the liver and because platelets cannot synthesize fresh enzyme (have no nuclei) TXA₂ formation is suppressed at very low doses and till fresh platelets are formed.

o Aspirin also inhibits COX and PGI₂ synthesis in vessel wall. However, since intima cells can synthesize fresh enzyme, activity returns rapidly.

o So at low doses TXA₂ formation by platelets is selectively suppressed, whereas higher doses may decrease both TXA₂ and PGI₂ production.

Note:-

According to KDT, aspirin inhibits TX-synthatase also, but no other book (Goodman & Gilman, Katzung, Laurence, Satoskar) has mentioned this.

Ans. is ‘b’ i.e., Inhibit cyclooxygenase

Aspirin (in low doses) —> inhibits synthesis of TXA₂ by inhibiting the enzyme cycloxygenase So that immediate precursor (prostaglandins) of TXA₂ are not synthesized.

o Ticlopidine, clopidogrel -4 they block ADP mediated cAMP inactivation.

Ans. is ‘a’ i.e., Decrease thromboxane A₂ synthesis

Ans. is ‘b’ i.e., Antiplatelet action

Ans. is ‘a’ i.e., Reye’s Syndrome

B i.e. Patient on aspirin 

– Centrineuraxial anesthesia is not associated with increased risk with most antiplatelet agents (eg. aspirinQ & NSAIDs).

Neuroxial block is combined name given to Spinal, Epidural and Caudal Blocks. Principal site of action for neuroaxial blok is Nerve root Q.

Ans. is ‘b’ i.e., Stop aspirin for 7 days and then do surgery 

 “Aspirin should be stopped 1 week before elective surgery.” – KDT

Aspirin, even in small doses, irreversibly inhibits Thrombooxane A2 (TXA2) synthesis by platelets. Thus it interferes with platelet aggregation and increase the bleeding time. This effect lasts for a week, the turnover time of platelets.

Answer is A (Prolonged bleeding time (BT)

Bleeding time is indicative of function of platelets. Aspirin ingestion results in defective platelet function and hence the deranged parameter will be Bleeding time. PT, APTT and Clotting time (CT) are parameters of coagulation defects, and will be normal in isolated disorders of platelet function.

‘Ingestion of Aspirin and other Nonsteroidal Antiinflammatory drugs, significantly prolongs the bleeding time’.

`Aspirin even in small doses irreversibly inhibits T xA2 synthesis by platelets. Thus it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value’-

Note:

• Aspirin irreversibly inhibits COX –1 and COX – 2. (Harrison)
• COX inhibition leads to prevention of TXA2 synthesis and impairment of platelet secretion and aggregation
• The effect of aspirin on platelet function occur within 1 hour and lasts for the duration of the affected platelet’s life span ie. 1 week.^Q
  

Answer is C (Nasal polyp):

`Aspirin associated Asthma usually begins with perennial vasomotor rhinitis that is followed by a hyperplastic rhinosinusitis with nasal polyps’ — Harrisons

Aspirin associated Asthma:

• Primarily affects adults, although the condition may occur in childhood.
• Usually begins with perennial vasomotor rhinitis that is followed by hyperplastic rhinosinusitis with nasal polyps.
• Progressive asthma then appears.
• On exposure to even very small quantities of aspirin affected individual typically develop ocular and nasal congestion and acute, often severe episodes of airways obstruction.
• Death may follow ingestion of aspirin.

Answer is B (Aspirin + Low molecular weight Heparin):

The recommended treatment for women with recurrent pregnancy loss associated with antiphospholipid syndrome includes combined Aspirin and Heparin therapy.

‘In pregnant SLE patients with Antiphospholipid antibodies and prior fetal loss, treatment with heparin (standard or low –molecular- weight) plus low dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births’. – Harrison’s 17th/2082

‘Combined aspirin and heparin therapy has proven effectiveness and is the preferred treatment for women with recurrent pregnancy loss associated with antiphospholipid syndrome’ – Speroff 7th/1084

Antiphospholipid syndrome in pregnancy

• The risk of pregnancy loss in women with APS and prior pregnancy loss may exceed 60%
• History of recurrent fetal loss in a pregnant woman with Antiphospholipid antibodies is an indication of treatment during pregnancy as these are identifiable and treatable immunologic disorders
• Treatment options include Antiplatelet agents such as Aspirin, Anticoagulants such as Heparin / LMWH, and corticosteroids

Aspirin along with Heparin / LMWH is the recommended treatment of choice.

Corticosteroids should be avoided ifpossible. If required to control maternal SLE, these should be used at the lowest effective doses for the shortest time required.

Answer is A (SLE)

Low dose aspirin therapy has definite indication in preecclampsia, IUGR and post MI. There appears no rationale of using low dose aspirin for manifestation of SLE. Nevertheless low dose aspirin is of definite benefit in antiphospholipid antibody syndrome. SLE is thus the single best answer of exclusion here.

Low dose aspirin therapy markedly decreases thromboxane production but only partially blocks prostocyclin and prostaglandin E₂ production.

• Pre-ecalmpsia: In preeclamptic woman, thromboxane is increased and prostaglandin E2 and prostacyclin are decreased, resulting in vasoconstriction and sensitivity to infused angiotensin II. Low dose aspirin as explained above enhances concentration of vasodilating prostanoids and restores refractoriness to infused angitensin II.
• Post MI: No confusions on this one. Low dose aspirin is advised to such patients.
• IUGR: Early antiplatelet therapy with low dose aspirin may prevent uteroplacental thrombosis, placental infarction, and idiopathic fetal growth retardation in women with a history of recurrent severe fetal growth restriction. -Williams 20^`”/ 849

Further Williams 21st/1212 says: “Low dose aspirin & Dipyridamole are beneficial in reducing incidence of superimposed preeclampsia & growth restriction”.

SLE: Arthralgias, arthritis, myalgias, fever and, mild serositis may improve on NSAID’s including salicyclates. However there appears no rationale of using low dose aspirin therapy for the same. (However low dose aspirin is beneficial in “Antiphospholipid antibody syndrome”).

Answer is D (Aspirin reduces risk of TIA):

• Antiplatelet therapy (including Aspirin) is recommended for medical therapy in patients with asymptomatic carotid stenosis to reduce the risk of TIA’s.
• Carotid artery stenosis is not common in the External Carotid Artery
  • Carotid Artery stenosis is common at the bifurcation of the common carotid artery and internal carotid artery. -Harrison
• Embolism in the Middle Cerebral Artery does not lead to ipsilateral hemiplegia
  • Embolic material can dislodge from a plaque at the bifurcation of the common carotid artery and occlude a more distal middle cerebral artery.
  • However such occlusion will lead to contralateral hemiplegia and not ipsilateral hemiplegia.
• Bruit does not always indicate the severity of lesion
  • Bruit may he associated with tight stenotic lesions, but as the stenosis grows tighter and flow distal to the stenosis gets reduced, the bruit becomes fainter and may disappear when complete occlusion is imminent.

Ans. D: Aspirin

Cyclooxygenase is required for prostaglandin and thromboxane synthesis.

Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.

Very low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation.

This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin 12 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition

The main undesirable side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses.

In children and adolescents, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses, because of the risk of Reye’s syndrome.

Tranexaemic acid, EACA and aprotinin are antifibrinolytic drug

Ans. B: Thromboxane A2

Ans. B: Aspirin

Thrombocytopenia-inducing medications include

• Direct myelosu ppressi on

– Valproic acid

Methotrexate

–  Carboplatin

– Interferon

Isotretinoin

– H2 blockers and Proton-pump inhibitors have shown increased Thrombocytopenia symptoms, such as red dots near the bottom of the legs.

— Ticlopidine

• Immunological platelet destruction

– Datg binds Fab portion of an antibody. The classic example of this mechanism is the quinidine group of drugs. The Fc portion of the antibody molecule is not involved in the binding process.

– Drug binds to Fc, and drug-antibody complex binds and activates platelets. Heparin induced thrombocytopenia (HIT) is the classic example of this phenomenon. In HIT, the heparin-antibody-platelet factor 4 (PF4) complex binds to Fc receptors on the surface of the platelet. Since Fc portion of the antibody is bound to the platelets, they are not available to the Fc receptors of the reticulo-endothelial cells, so therefore this system cannot destroy platelets as usual. This may explain why severe thrombocytopenia is not a common feature of HIT.

— Abciximab induced thrombocytopenia.

Aspirin inhibits the release of ADP from platelets and their sticking to each other. However, it has no effect on platelet survival time and their adhesion to the damaged vessel wall.

Ans. A: Cyclo Oxygenase

Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane by inhibiting coxl and tx-synthetase, which under normal circumstances binds platelet molecules together to create a patch over damage of the walls within blood vessels.

Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk for developing blood clots

Ans. is ‘c’ i.e., 3 – 6 g/d

The anti-inflammatory action of aspirin is exerted at high doses of 3 – 6 g/ day or 100 mg/ Kg/ day.

The anti-inflammatory action is mainly due to inhibition of COX, causing inhibition of PGs synthesis.

In addition to COX inhibition, quenching of free radicals may contribute to its anti-inflammatory action.

Ans. is ‘a’ i.e., Aspirin

Ans. is ‘a’ i.e., Acetyl salicylic acid

Ans. is ‘c’ i.e., Associated with nasal polyp

Ans. a. Aspirin + LMWH

Ans. is ‘c’ i.e., Anaphylacotid reaction

Ans. is ‘a’ i.e., Gastritis

Adverse effects of aspirin

Side effects

• Occur at analgesic dose (0.3 – 1.5 mg/day)
• Symptoms are nausea, vomiting, epigastric distress, increased occult blood loss in stools. 
• The most important adverse effect of aspirin is gastric mucosal damage.

Salicylism

• Occurs at antiinflammatory dose (dose dependent).
• Symptoms are dizinness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion.
• Hyperventilation and electrolyte imbalance also occur.

Acute salicylate poisoning

• More common in children
• Fatal dose in adults is estimated to 15-30 gm but is considerably lower in children.
• Manifestations are vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycemia, petechial haemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, Coma and death due to respiratory failure + Cardiovascular collapse.

Ans. is ‘b’ i.e., Peptic ulcer 

Contraindications of Aspirin

• Peptic ulcer
• Prostaglandin has cytoprotective function for gastric mucosa by inhibiting acid secretion and promoting secretion of mucus.
• Aspirin inhibits synthesis of cytoprotective PG -3 bleeding & perforation may occur.
• Children with chicken pox & influenza
• Aspirin can cause Reye’s syndrome (hepatic encephalopathy).
• Acknowledging this aspirin should not be given to children < 12 years, e.g. in JRA.
• Bleeding tendencies
• By its antiplatelet action, aspirin can exacerbate bleeding.
• Chronic liver disease
• Long-term therapy with high dose aspirin can cause insidious onset hepatic injury.

Precautions

• In CHF & low cardiac reserve patients
• Aspirin reduces renal blood flow by inhibiting synthesis of vasodilator PGs —* fluid & salt retention worsening of CHF and renal failure may occur.
• Aspirin should be stopped 1 week before elective surgery so that platelet function becomes normal.
• In G-6-PD deficiency
• High doses can cause hemolysis.
• In diabetics
• Aspirin causes increased utilization of glucose by increasing cellular metabolism, especially in skeletal muscle, due to uncoupling of oxidative phosphorylation blood sugar may decrease and liver glycogen may be depleted, especially in diabitics → dangerous hypoglycemia may occur.