Aspirin: Synthesis, Purpose and Toxicity of the Drug

Background:

First recorded around 400 BC, in the time of Hippocrates, when people chewed willow bark to relieve inflammation and fever. The bark from the willow tree—Salix Alba—contains a high amount of salicylic acid. The word 'aspirin was derived from Spiraea, a biological genus of shrubs that includes natural sources of the drug's key ingredient: salicylic acid. In 1897, Hoffman achieved acetylsalicylic acid as a chemically pure and stable compound in 1899, its therapeutic properties as an analgesic and anti-inflammatory compound were described and, in 1900, it was introduced into the market in the form of aspirin tablets. The Nobel Prize in medicine in 1982 was awarded to researchers who demonstrated the reason it inhibits the production of hormones called prostaglandins. Prostaglandins are responsible for the formation of clots that leads to heart attacks and strokes, and aspirin prevents that clotting.

Synthesis of Aspirin:

Aspirin is synthesized through the esterification of salicylic acid by the acetic anhydride, thus the hydroxyl group in the salicylic acid is replaced by and ester group. The reaction can be catalyzed by sulfuric acid.

Drug Target:

The development of prostanoids is catalyzed by at any rate three isoenzymes named cyclo‐oxygenases (COX). They are bifunctional synthases of arachidonic corrosive endoperoxides – prostaglandins (PG)G2 and PGH2. Their action, made out of cyclo‐oxidation and ensuing peroxidation, is a rate constraining advance in the biosynthesis of PGE2, PGD2 and PGF2α, and TXA2 and prostacyclin (PGI2). In blood, platelets are the wellspring of TXA2, framed by TX synthase. The response is constrained by free arachidonic corrosive from its ester subsidiaries in platelet films upon platelet enactment.

Cyclo‐oxygenase isoforms:

Cyclo‐oxygenase proteins have 59% indistinguishable amino acids and 72% homology. Protein variations created by elective joining incorporate COX‐3 – COX‐1 quality item holding first intron (dim dark) and sign peptide (dark). Littler particles, as pCOX‐1a emerge from exon skipping (white boxes) and need peroxidase action. Present in platelets COX‐2a variation is missing 110 amino acids enveloping serine buildup acetylated by ibuprofen. Glycosylation locales (GlcNAc), heme‐binding histidines, and cyclo‐Oxygene movement area are set apart on this arrangement. The develop COX‐1 peptide comprises of 576 amino acids and arachidonic corrosive gains admittance to its heme‐containing dynamic site through a hydrophobic pocket. Headache medicine irreversibly hinders COX action by acetylation of serine 530 in COX‐1 atom (serine 529 in people), which impedes any further substrate communication with the compound. Since blood platelets are anucleate particles, their ability for TXA2 combination is reestablished distinctly by new platelets, discharged from bone marrow.

The normal life expectancy of the platelets is 7–10 days and the impact of a solitary portion of ibuprofen rots inside a few days. The COX‐1 movement is available in many tissues, where the new compound atoms are shaped constantly. A solitary portion of ibuprofen has just a transient foundational impact on COX‐1, due to reclamation of the enzymatic movement inside hours, with the exception of the platelets. This selectivity of ibuprofen against platelets COX‐1 is particularly set apart with low portions of the medication in light of the fact that ASA is expeditiously deacetylated in the liver. As little portion of headache medicine as 40 mg can hinder platelets in the gateway course, without summing up COX concealment. The COX‐2 is available constitutively just in a predetermined number of cells and is inducible by the initiation of a few sign transduction pathways, including atomic factor‐κB (NFκB) and cAMP reaction element‐binding protein (CREB). This flagging happens predominantly at aggravation destinations and may include vasculature, including endothelial and smooth muscle cells. Platelets don't have clear COX‐2 content, aside from some extraordinary pathologic conditions.

The COX‐2 is covalently acetylated by headache medicine at serine 516, however, this doesn't prevent the catalyst from oxidation of arachidonic corrosive. Rather than PGG2, acetylated COX‐2 discharge 15‐hydroperoxide of eicosatetraenoic corrosive (15‐HPETE), a potential substrate for different eicosanoids go-between, for example, 15‐epi‐lipoxins. Along these lines, in an ongoing human preliminary, headache medicine in a portion of 81 mg day by day trigged blend of an anti‐inflammatory 15‐epi‐lipoxin A4 (ATL) and repressed TX. When ATL and TXB2 were analyzed, levels changed in a measurably noteworthy and inverse manner.

Mechanism of Action:

Acetylsalicylic acid acts as an acetylating agent. Thus, aspirin irreversibly inactivates cyclooxygenase (COX)-1 and suppresses the generation of prostaglandin H2 (a precursor of thromboxane A2). Aspirin achieves this effect through its acetyl group, which becomes covalently attached to Ser529 of the active site of the COX-1 enzyme. Aspirin interacts with the amino acid Arg120 and consequently blocks the access of arachidonic acid to the hydrophobic channel to Tyr385 at the catalytic site. Thus, aspirin inhibits the generation of prostaglandin H2. The antithrombotic effects of aspirin also involve the acetylation of other proteins of blood coagulation, including fibrinogen. Therefore, aspirin promotes fibrinolysis. Although aspirin can inhibit COX-2 by acetylating Ser516, this reaction is approximately 170-fold slower than the reaction with COX-1. The effect of aspirin on platelets is primarily related to the downregulation of dense granule release. Alpha granule secretion is not impeded by COX-1 blockade in platelets that are stimulated by adenosine diphosphate (ADP) or thrombin. Therefore, administration of aspirin in low doses can fully inhibit COX-1 (causing long-lasting defect), on repeat daily dosing, despite the fact that the half-life of aspirin is 15 to 20 minutes due to rapid presystemic hydrolysis that is catalyzed by esterase.

Aspirin-mediated prevention involves the inhibition of platelets. The binding of platelets and recruitment of neutrophils to the vascular endothelium is an early step in the development of deep vein thrombosis. Because the recruitment and rolling of leukocytes, as well as their initial attachment to vascular endothelium, is dependent on a glycoprotein called P-selectin, the inhibition of P-selectin is associated with a reduced weight of mice subjected to thrombus induced by ligation of the inferior vena cava. Additionally, platelet inactivation by aspirin results in the inhibition of the release of the following platelet-associated substances into the venous circulation: platelet factors V and XIII, fibrinogen, platelet factors 3 and 4, thrombospondin, von Willebrand factor (vWF), calcium ions, serotonin, and other substances that favor the development of venous thrombosis. Enzymatic complexes (especially prothrombinase complex) form on the surfaces of activated platelets, and a large number of receptors are available for these complexes.13 Aspirin also prevents thrombin formation that is catalyzed by the calcium ion-dependent complex of tissue factor (TF) and activated factor VII (FVIIa). The inhibition of this complex by aspirin promotes the inhibition of factors IX and X. The formation of the prothrombinase complex and thrombin is subsequently inhibited. Thrombin is the serine protease that converts fibrinogen to fibrin, which polymerizes to form a thrombus. The inhibition of thrombin production by aspirin can be explained by two additional mechanisms, as follows: increased secretion of TF pathway inhibitor (TFPI) as well as the acetylation of prothrombin and several membrane components. Some authors have proposed that aspirin impacts the quality of fibrin within the thrombus. Properties of fibrin are dependent on the structural characteristics at the molecular level and at the level of individual fibers. The properties also depend on the arrangements of the three-dimensional networks. Acetylation of fibrinogen is an important mechanism of action of aspirin. Acetylation increases the porosity of the fibrin network and therefore increases the rate of fibrinolysis. The antithrombotic effect of high doses of aspirin potentially stems from a reduced synthesis of coagulation factors in the liver, and this mechanism resembles those of VKAs. Furthermore, a reduction in thrombin levels reduces FXIII activation

Pharmacokinetics:

Aspirin is very rapidly absorbed from the gastrointestinal tract when taken orally It is rapidly hydrolyzed in the body to salicylic acid; the plasma concentration of the latter must be maintained within a relatively narrow range to obtain an adequate anti-inflammatory effect and to minimize systemic adverse effects. The two major pathways of salicylate elimination, i.e., the formation of salicylic acid and salicyl phenolic glucuronide, become saturated at relatively low body levels of the drug. Consequently, steady-state ('plateau') salicylate levels increase more than proportionately with increasing daily dose, and the time required to reach steady-state increases with increasing daily dose. The renal clearance of salicylic acid increases markedly with increasing urine pH; antacids capable of increasing urine pH can therefore cause a pronounced lowering of steady-state salicylate concentrations under clinical conditions. There are pronounced inter-subject differences in salicylate elimination kinetics; dosage must be individualized on the basis of plasma concentration and clinical response. The drug is readily transferred across the placenta and is only slowly eliminated by the newborn infant. The drug is also transferred from mother to nursing infant through breast milk.

Toxicity:

Acute toxicity:

Salicylate toxicity is a problem that may develop with both acute and chronic salicylate exposure. Multiple organ systems may be affected by salicylate toxicity, including the central nervous system, the pulmonary system, and the gastrointestinal system. Severe bleeding may occur. In the majority of cases, patients suffering from salicylate toxicity are volume-depleted at the time of presentation for medical attention. Fluid resuscitation should occur immediately and volume status should be monitored closely. Disruptions in acid-base balance are frequent in ASA toxicity.

Chronic toxicity and carcinogenesis:

Chronic ASA toxicity is frequently accompanied by atypical clinical presentations that may be similar to diabetic ketoacidosis, delirium, cerebrovascular accident (CVA), myocardial infarction (MI), or cardiac failure. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there no documentation available to suggest ASA was ingested. In older age, nephrotoxicity from salicylates increases, and the risk of upper gastrointestinal hemorrhage is increased, with higher rates of mortality 8. It is also important to note that ASA toxicity may occur even with close to normal serum concentrations. Prevention of chronic ASA includes the administration of the smallest possible doses, avoidance of concurrent use of salicylate drugs, and therapeutic drug monitoring. Renal function should be regularly monitored and screening for gastrointestinal bleeding should be done at regular interval.

Reference:

1. A.SZCZEKLIK J.MUSIAL,A.UNDAS ,M.SANAK (JOURNAL OF THROMBOSIS AND HAEMOSTASIS CELLS) : ASPIRIN TARGET
2. BOOK ON THE ORGANIC CHEMISTRY OF DRUG DESIGN AND DRUG ACTION
3. -RICHARD .B SILVERMAN &MARK W. HOLLADAY
4. Durnas C, Cusack BJ: Salicylate intoxication in the elderly. Recognition and recommendations on how to prevent it.. 1992 Jan-Feb;2(1):20-34. [PubMed:1554971Levy G: Clinical pharmacokinetics of aspirin. Pediatrics. 1978 Nov;62(5 Pt 2 Suppl):867-72. [PubMed:724339]
5. Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D, Hawk E, Vilar E, Bhattacharya P, Millward S: Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of aspirin and drug target Rev. 2017 Jun;36(2):289-303. doi: 10.1007/s10555-017-9675-z