Source: Health Products and Food Branch (CA) Revision Year: 2022
ASA interferes with the production of prostaglandins in various organs and tissues through acetylation of the enzyme cyclo-oxygenase. Prostaglandins are themselves powerful irritants and produce headaches and pain on injection in man. Prostaglandins also appear to sensitize pain receptors to other noxious substances such as histamine and bradykinin. By preventing the synthesis and release of prostaglandins in inflammation, ASA may avert the sensitization of pain receptors.
The antipyretic activity of ASA is due to its ability to interfere with the production of prostaglandin E1 in the brain. Prostaglandin E1 is one of the most powerful pyretic agents known.
The inhibition of platelet aggregation by ASA is due to its ability to interfere with the production of thromboxane A2 within the platelet. Thromboxane A2 is, largely, responsible for the aggregating properties of platelets.
In vitro studies have shown that ASA enhances the activity of the Nitric oxide (NO)-cGMP system and heme oxygenase-1 (HO-1) by acting on endothelial NO synthase site.
When ASA is taken orally, it is rapidly absorbed from the stomach and proximal small intestine. The gastric mucosa is permeable to the non-ionized form of acetylsalicylic acid, which passes through the stomach wall by a passive diffusion process.
Optimum absorption of salicylate in the human stomach occurs in the pH range of 2.15 to 4.10. Absorption in the small intestine occurs at a significantly faster rate than in the stomach. After an oral dose of 0.65 g ASA, the plasma acetylsalicylate concentration in man usually reaches a level between 0.6 and 1.0 mg % in 20 minutes after ingestion and drops to 0.2 mg % within an hour. Within the same period of time, half or more of the ingested dose is hydrolyzed to salicylic acid by esterases in the gastrointestinal mucosa and the liver, the total plasma salicylate concentration reaching a peak between one or two hours after ingestion, averaging between 3 and 7 mg %. Many factors influence the speed of absorption of ASA in a particular individual at a given time; tablet disintegration, solubility, particle size, gastric emptying time, psychological state, physical condition, nature and quantity of gastric contents, etc., all affect absorption.
Distribution of salicylate throughout most body fluids and tissues proceeds at a rapid rate after absorption. Aside from the plasma itself, fluids which have been found to contain substantial amounts of salicylate after oral ingestion include spinal, peritoneal and synovial fluids, saliva and milk. Tissues containing high concentrations of the drug are the kidney, liver, heart and lungs. Concentrations in the brain are usually low, and are minimal in feces, bile and sweat.
The drug readily crosses the placental barrier. At clinical concentrations, from 50% to 90% of the salicylate is bound to plasma proteins especially albumin, while acetylsalicylic acid itself is bound to only a very limited extent. However, ASA has the capacity of acetylating various proteins, hormones, DNA, platelets and hemoglobin, which at least partly explains its wideranging pharmacological actions.
The liver appears to be the principal site for salicylate metabolism, although other tissues may also be involved. The three chief metabolic products of ASA or salicylic acid are salicyluric acid, the ether or phenolic glucuronide and the ester or acyl glucuronide. A small fraction is also converted to gentisic acid and other hydroxybenzoic acids. The half-life of ASA in the circulation is from 13 to 19 minutes so that the blood level drops quickly after absorption is complete. However, the half-life of the salicylate ranges between 3.5 and 4.5 hours, which means that 50% of the ingested dose leaves the circulation within that time.
Excretion of salicylates occurs principally via the kidney, through a combination of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, as well as phenolic and acyl glucuronides. Salicylate can be detected in the urine shortly after its ingestion but the full dose requires up to 48 hours for complete elimination. The rate of excretion of free salicylate is extremely variable, reported recovery rates in human urine ranging from 10% to 85%, depending largely on urinary pH. In general, it can be stated that acid urine facilitates reabsorption of salicylate by renal tubules, while alkaline urine promotes excretion of the drug.
With the administration of 325 mg, elimination of ASA is linear following a first order kinetics. At high concentrations, elimination half life increases.
Absorption and clearance of salicylates are not affected by gender or age.
The analgesic effect of ASA has been recognized and utilized clinically for more than half a century. The degree of analgesia attained with ASA is moderate but it has proved highly suitable in the management of pathological pain of mild to moderate severity. As regards site of action, both peripheral and CNS factors appear to contribute significantly to the pain relief afforded by ASA. As for mechanism of action, the accumulated evidence of recent years indicates that ASA acts by interfering with the synthesis and release of prostaglandins, thereby averting the sensitization of pain receptors to mechanical stimulation or to other mediators.
Interference with the synthesis and release of prostaglandins is also involved in the antipyretic activity of ASA. ASA effects a significant reduction in elevated body temperature, but has little effect on normal body temperature. This latter is maintained by a delicate balance between heat production and heat loss, with the hypothalamus regulating the set point at which body temperature is maintained. Fever is induced by synthesis and release of prostaglandins in this temperature regulating area and ASA acts by interfering with this process. Heat production is not inhibited but dissipation of heat is augmented by increased peripheral blood flow and by sweating.
Components of the anti-inflammatory action of the salicylates are increased capillary resistance, thus reducing capillary leakage in response to local toxins, interference with the production of tissue-destructive lysosomal enzymes and inhibition of the synthesis of prostaglandin E compounds which have been shown to be potent mediators of the inflammatory process. Besides interfering with the synthesis of prostaglandins ASA also acts by interfering with lymphocyte activation and lymphokine production. Lymphokines are produced by activated thymus lymphocytes which are abundant in the inflammatory tissues of patients suffering from rheumatoid arthritis. They cause increased vascular permeability and white blood cell chemotaxis, activate macrophages and stimulate lymphocyte DNA synthesis. They also induce release of tissue-destructive lysosomal enzymes as well as prostaglandins. The prostaglandins themselves, besides causing many manifestations of inflammation also act as a potent negative feedback mechanism by inhibiting lymphokine production. An in-depth review of the effects of ASA on the lymphocyte-macrophage axis in inflammation has been published.
Platelets play an important role in normal hemostasis and clinical pathologic and experimental evidence indicates that their aggregation may play an equally important role in the evolution of a variety of disease states including cerebrovascular disease, ischemic heart disease and myocardial infarction. ASA inhibits platelet aggregation by irreversibly acetylating platelet cyclo-oxygenase, thereby blocking the production of prostaglandin endoperoxides PGG2 and PGH2 which are precursors of the major platelet-aggregating material, thromboxane A2, which is also a powerful vasoconstrictor. However, ASA does not prevent the adherence of platelets to damaged vessel walls or the release of granule contents from these adherent platelets. As the anuclear platelets are unable to synthesize new enzyme molecules to replace those that have been inactivated, inhibition of platelet aggregation by ASA thus persists for the life of the platelets.
Daily administration of 20 to 40 mg of ASA to healthy volunteers reduced platelet thromboxane production but inhibited platelet aggregation only partially. When administered to patients recovering from myocardial infarction, 50 mg ASA daily had the same effects on thromboxane production, platelet aggregation and bleeding times as 324 mg daily. Other studies show that ASA doses of 40 to 325 mg daily suppressed thromboxane production by at least 80%, but 80 mg ASA daily was the lowest dose required for maximum cumulative thrombocyte function inhibition. The protective effect of ASA against experimentally induced thrombosis or atherosclerosis has been demonstrated in several animal models.
Besides inhibiting the biosynthesis of thromboxane A2 by platelets, ASA also interferes with the production of prostacyclin (PGI2) by vascular endothelial cells, the above-mentioned prostaglandin endoperoxides being common precursors of both thromboxane A2 and prostacyclin. This latter compound is one of the most powerfully acting platelet deaggregators and vasodilators and thus it would appear that the interference with the hemostatic processes by ASA depends on the thromboxane-prostacyclin balance. In fact, it has been suggested that under some conditions, high doses of ASA may be thrombogenic. However, in contrast to platelets, the vascular endothelial cells are able to regenerate cyclo-oxygenase in a relatively short time and therefore therapeutic doses of ASA are likely to produce a lesser inhibition of the vascular prostacyclin system than of the platelet thromboxane-forming mechanism. In fact, there is no clinical evidence to indicate that high doses of ASA would result in an increased risk of thromboembolism. Indeed, quite the contrary was observed and, in a controlled study, paradoxical shortening of the bleeding time was not observed at a daily ASA dose of 3.6 g. Lower dosages of ASA make selective blocking of the TxA2-synthesis without a simultaneous blocking of PGI2-production possible.
The use of ASA in patients with a suspected acute myocardial infarction was investigated in a large multi-centre trial involving over 17,000 patients. Treatment with ASA resulted in a 23% reduction in the risk of vascular mortality versus placebo at 5 weeks. This use translates to a reduction of 24 deaths and 14 non-vascular events per 1000 patients treated.
The effect of time to therapy revealed that patients treated with ASA “early” (0 to 4 hours) versus “late” (5 to 24 hours) after symptom onset experienced reductions in the odds of vascular death of 25% versus 21%, versus placebo at 5 weeks. ‘Early’ treatment with ASA resulted in the saving of 4 additional lives per 1000 patients versus ‘late’ treatment.
Long term follow-up (up to 10 years) of patients in this study established that the early survival advantage to ASA persisted long term, and that this prolonged benefit was additive to that of fibrinolytic therapy.
The use of ASA for secondary prevention of thrombotic events is supported by a comprehensive overview of a number of clinical trials involving patients who already had some type of vascular disease (myocardial infarction, unstable angina, stroke or transient cerebral ischemia). Overall, these studies point to a 26-28% reduction of the combined endpoints of MI, stroke, or vascular deaths by treatment with ASA alone at doses of 75 to 325 mg daily. Studies which directly compared low doses with higher doses (30-1200 mg/day), indicated that the incidence of gastrointestinal adverse effects were significantly less common with the lower doses.
In a study in patients undergoing coronary artery bypass surgery (CABG), patients given ASA at a dosage of 80 mg to 650 mg within 48 hours of revascularization had a risk of dying reduced to 1.3% as compared to 4.0% for those who did not receive treatment (P <0.001). There was a reduction in the incidence of myocardial infarction of 2.8% vs. 5.4%, p <0.001. In total, the reduction in fatal and non-fatal outcomes was lower in those who received ASA, 10.6% vs. 18.6% in those who did not (p <0.001). The investigators Perioperative Ischemia Research Group (PIRG) concluded that early use of ASA after coronary by-pass surgery is safe and is associated with a reduce risk of death and ischemic complications involving the heart, brain, kidneys and gastrointestinal tract.
There was no ASA dose effect observed for either fatal or non-fatal outcomes with total doses lower than 325 mg daily.
Recent discussions have focused on the efficacy of ASA for the primary prevention of myocardial infarction and stroke. Two large scale randomized trials, aimed at evaluating prophylactic use of ASA, were conducted among apparently healthy male physicians (22,000 in the United States and 5,000 in the United Kingdom) and their results have been published. In the summary overview of the combined results presented by the principal investigators, the authors state that: "Taken together, these two primary prevention studies demonstrate a significant (p <0.0001) reduction in non-fatal myocardial infarction of about one third."
On the other hand, the same two studies have not indicated any reduction in overall vascular mortality and also suggested a slight increase in the risk of non-fatal disabling stroke. Current controversy exists about the applicability of these findings, obtained in a selected population, to the general public. As well, the optimum dosage regimen still remains an open question in this regard. Thus, the use of ASA for primary prevention should remain, in the words of the principal investigators:
“a matter of judgment in which the physician considers the cardiovascular risk profile of the patient and balances the known hazards of ASA…against the clearly established reduction in the incidence of a first myocardial infarction”.
Experimental data suggest that ibuprofen may inhibit the effect of low dose ASA (81-325 mg per day) on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release ASA dosing (81mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use. In a more recent double blind, randomized, placebocontrolled trial with healthy subjects by Cryer et. al, 2005, it has been shown that the drug-drug interaction is absent when immediate release ASA (81 mg) was taken 1 hour before taking ibuprofen (400 mg, TID) and also when ibuprofen was given 11 hours before the intake of low dose ASA. Thus, in order to adequately minimize potential interaction, the recommended dosing schedule for immediate release low dose ASA is to wait at least 11 hours after or 1 hour before taking up to a 400 mg dose of ibuprofen.
Not applicable.
The clinical and pathological signs of poisoning from toxic and lethal oral doses of ASA have been extensively described for man, much less extensively for other species.
The acute toxicity of ASA in animals has been studied and reviewed in detail by Boyd. The signs of poisoning in rats from doses in the lethal range are due to varying degrees of gastroenteritis, hepatitis, nephritis, pulmonary edema, encephalopathy, shock and minor toxic effects on other organs and tissues. Death is due to convulsions or cardiovascular shock. The major difference between species appears to be the ability to vomit toxic doses seen in man, cats and dogs, but not in mice, rats and rabbits. Otherwise, the pathological reaction to toxic doses of ASA is similar in all species in which such studies have been reported. The acute oral LD50 values have been reported as being over 1.0 g/kg in man, cat and dog, 0.92 g/kg in female and 1.48 g/kg in male albino rats, 1.19 g/kg in guinea pig, 1.1 g/kg in mouse and 1.8 g/kg in rabbit.
Chronic toxicity studies were reported in mice and rats. When ASA was administered at 2 to 20 times the maximum tolerated clinical dose to mice for up to one year, a dose-related deleterious effect was observed on mean survival time, number of young born and number of young raised to weaning age. No evidence of carcinogenic effect was found.
The chronic oral LD50 in male albino rats has been reported as 0.24 g/kg/day when given for 100 days. At these daily doses ASA produced no anorexia and no loss of body weight. It did produce polydipsia, aciduria, diuresis, drowsiness, hyperreflexia, piloerection, rapid and deep respiration, tachycardia, and during the second month, soft stools, epistaxis, sialorrhea, dacryorrhea and death in hypothermic coma. Autopsy disclosed the presence of a hypertrophied stomach, renal congestion, mild hepatitis and pneumonitis. While teratogenic effects were noted in animals at near lethal doses, there is no evidence to indicate that ASA is teratogenic in man.
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