Drug Monograph of Aspirin

Contents

Introduction……………………………………………………………………03

Mechanism of Action of the Drug……………………………………..03

Therapeutic Use and Efficacy……………………………………………06

Distribution in the Body…………………………………………………..09

Adverse Drug Reactions…………………………………………………..11

Drug Interactions…………………………………………………………….12

Contraindications……………………………………………………………14

Summary………………………………………………………………………..14

References……………………………………………………………………..15

Introduction

Figure 1: Chemical Structure of Aspirin¹

Table 1: Chemical Properties of Aspirin¹

Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) which is predominantly used as an analgesic, antipyretic or anti-inflammatory drug. The identification of salicylates as the active ingredient for the anti-inflammatory effects of willow bark led to the synthesis of aspirin. Aspirin was first synthesized in 1897 by Felix Hoffmann at the Bayer laboratories². The therapeutic effects of aspirin originate from its ability to inhibit cyclooxygenases (COXs). The identification of COX isoforms led to the characterization of aspirin as a nonselective inhibitor. Aspirin is normally administered by either an enteric-coated or buffered tablet¹.

Mechanism of Action

Aspirin is an irreversible inhibitor that inhibits the synthesis of thromboxane A2 (TXA₂) and prostaglandins (PGs)³. Aspirin binds to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is usually found in platelets, interstitial cells and blood vessels whilst COX-2 is usually found in parenchymal cells⁴.

As shown in figure 2, TXA₂ is synthesised in the COX-1 pathway. Firstly, Arachidonic acid is converted to a biological intermediate known as Prostaglandin H₂ (PGH₂). This reaction is catalysed by PGH₂ synthase. PGH₂ is then converted into TXA₂, which is catalysed by thromboxane synthase⁵.

Figure 2: Synthesis of TXA₂ and PGs⁵

TXA₂ releases ADP which causes a platelet to undergo a morphological change of shape. The change in shape is essential for the activation of platelets, especially for its role in an inflammatory response⁵. This physiological pathway is activated when tissue cells are damaged by either harmful substances or foreign invaders⁶.

Figure 3: Inhibition of COX-1⁷

As shown in figure 3, COX-1 is inhibited by aspirin. This occurs by an irreversible acetylation at the serine 529 residues of COX-1. This prevents Arachidonic Acid, from entering the catalytic site which prevents the synthesis of TXA₂. As the synthesis of TXA₂ decreases, there is a reduced aggregation of platelets. This reduced aggregation is sustained across the whole lifespan of a platelet which causes a significant decrease in the number of activated platelets⁸.

Figure 4: Platelet Aggregation⁹

Figure 5: Inhibition of COX-2¹⁰

As shown in figure 5, COX-2 is inhibited by aspirin. COX-2 is irreversibly acetylated at the serine 516 residues, which prevents the synthesis of PGs. Therefore, the catalytic activity of the pathway changes, leading to the synthesis of Lipoxins. Lipoxins are high-affinity receptors that play an essential role in the resolution of an inflammatory response. As the concentration of Lipoxins increase, there is a greater stimulation to stop the inflammatory response and initiate the repair process¹¹. Aspirin has a significantly greater affinity of inhibition for COX-1 in comparison to COX-2. This allows smaller dosages of aspirin to be used for its antithrombotic effect whilst high dosages of aspirin can be used for its anti-inflammatory effect⁶.

Figure 6: Inhibition of TXA₂ and PGs¹²

Therapeutic Use and Efficacy

Uses of Aspirin

Aspirin can be administered intravenously by a drip or enterally in the form of a tablet. This tablet can either be buffered, buccal or enteric-coated. A buffered tablet shortens the half-life of aspirin. A buccal tablet enables aspirin to bypass phase one metabolism. An enteric-coated tablet enables aspirin to be resistant to the stomach juices¹.

Table 2: Dosage of Aspirin¹³

A low dose of aspirin is used for its antithrombotic effect. Aspirin prevents the formation of TXA₂, which causes a reduction in platelet aggregation. As the number of activated platelets decreases, there is a reduced chance for the formation of a blood clot. A high dose of aspirin is used for its analgesic and antipyretic effect. As shown in table 2, the dosage of aspirin used is dependent on the health problem. This is due to aspirin having a significantly greater affinity of inhibition to COX-1 than COX-2. Aspirin is normally given to adults and not children. The only exception for a child to be given aspirin is when they have undergone heart surgery or have the Kawasaki disease¹⁴.

Table 3: Health Problems treated by Aspirin¹⁴

COX-2 has an important role in the inhibition of apoptosis, tumour promotion and the carcinogenesis in several cancers. As shown in table 4, there is supporting data that suggests aspirin can be used as a chemopreventive drug in several cancers.The combination of aspirin and chemopreventive compounds would potentiate aspirin’s therapeutic effects. In particular the chance to inhibit the proliferation of neoplastic cells and induce apoptosis¹⁵.

Table 4: Types of Cancers¹⁵

Efficacy of Aspirin

Table 5: Dose-Dependent Acetylation¹⁶

The efficacy of aspirin is independent of free salicylate because the mechanism of action is only dependent on the acetylation of aspirin. As shown in table 5, as the dosage of aspirin increases, there is a greater degree of inhibition of COX¹⁶.

Table 6: Efficacy Studies¹⁵

Distribution in the body

Absorption and Distribution

Figure 7: Bioavailability of Aspirin¹

Table 7: Pharmacokinetic Profile of Aspirin¹⁷

Aspirin can be taken by an individual intravenously, enterally or through buccal administration. The tablet is taken into the body through oral ingestion and travels down the oesophagus and into the stomach. The percentage of aspirin absorbed in the stomach is usually around 10%, by passive diffusion. Aspirin will then travel through the epithelium and cilia via the bloodstream¹⁸.

Blood consists of two main components, blood plasma and red blood cells. Within the blood plasma, there are specialised proteins that are made in the liver called Albumins. Albumin forms a complex with aspirin by binding to aspirin via the phenolic hydroxyl group¹⁹. This complex can be filtered out by the liver. The remaining aspirin molecules will have a therapeutic effect on the body. These aspirin molecules will travel into the liver by the hepatic portal vein and undergo phase one metabolism¹⁸.

Metabolism and Excretion

Figure 8: Hydrolysis of Aspirin^20-22

Table 8: Aspirin Half-Life²³

The metabolism of aspirin occurs in the liver and can be split into two phases, phase one and phase two. As shown in figure 8, the ethanoic acid group of aspirin is broken off, which converts aspirin into the metabolite salicylic acid. This process is carried out by the enzymes PAFAH1b2 and Butyrylcholinesterase (BChE). As shown in table 8, the time taken for aspirin to be hydrolysed depends on what bodily fluid it is in. The importance of this reaction is that salicylic acid has a low solubility, therefore it’s unlikely to be excreted in urine²⁴.

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In the second phase of metabolism, an ionized group is added to the salicylic acid group forming a metabolite called Glucuronide. Glucuronide is soluble in water which means that it can be excreted in urine. The remaining particles of aspirin will travel to the site of injury and have an effect. An individual that is administered aspirin intravenously or through a buccal tablet will have the maximum bioavailability for the body as it bypasses the liver¹⁸.

Table 9: Excretion of Metabolites²⁵

The excretion of aspirin mainly occurs as either salicylic acids or salicylic acid metabolites. The excretion of salicylic acids or its metabolites through urine is promoted by the alkalinisation of urine. This causes acids in the body to be dissociated which increases the amount of excretion by 5-10 times¹.

As shown in table 9, the most common metabolite for excretion is Salicyluric acid. The formation of Salicyluric acid is limited by capacity and cannot be altered by an increase in the dosage of aspirin. It is formed from the bonding of glycine and salicylic acid. The most uncommon metabolite that is excreted in urine is Gentisic acid. Gentisic acid is formed from the hydroxylation of salicylic acid²⁵.

Adverse Drug Reactions

Aspirin has a range of therapeutic uses, but there are undesirable side effects. This can include mucosal injury to the small intestine and the colon. As shown in table 10, in rare cases there is a chance of bleeding to occur in the brain²⁶.

Table 10: Side Effects of Aspirin²⁶

As shown in table 10, the side effect with the greatest incidence is gastric intolerances. Gastric intolerances can occur in patients taking either a low or high dose of aspirin. The most common symptoms of gastric intolerances are pyrosis, nausea and dyspepsia²⁶.

Figure 9: Relative Risk²⁷

Figure 10: Bleeding Time²⁸

As shown in figure 10, there is a positive correlation between the bleeding time and the dosage of aspirin. There is still ongoing research into the physiological mechanism of the prolonged bleeding. Currently, it is believed to be linked with the inhibition of TXA₂ which prevents the formation of thrombin. This is clinically important because a patient that has taken aspirin within a week of their surgery is at an increased risk of 50% of being subject to periprocedural bleeding²⁹.

Drug Interactions

A drug interaction is defined as the therapeutic effects of a drug being altered by the presence of food, drink or another drug. Aspirin has over 250 unique drug interactions, however; a significant proportion of these interactions are not clinically significant³⁰.

The absorption of aspirin is delayed when taken with food because the digestive system needs to deal with the food and aspirin at the same time. A study was carried out in which 25 healthy individuals in which some were fasting, which meant that they took aspirin with no food. The remaining people took a 600mg dose of aspirin with their food. The results showed that the serum salicylate levels were halved in the individuals that had aspirin with food³⁰.

There is a slight increase in the loss of gastrointestinal blood when aspirin is taken with alcohol. A study was carried out on 17 healthy individuals, in which they took aspirin alongside 180ml of whisky. The initial mean of blood loss was 3.1ml. This increased to 5.3ml when each individual started to take a 2.1g dose of aspirin³⁰.

Table 11: Drug Interactions of Aspirin³⁰

Contraindications

Aspirin should not be given to an individual that has an increased risk of internal bleeding, especially for those that have active peptic ulceration. The stronger the dosage and longer the time period in which an individual takes aspirin, the increased chance of bleeding within the stomach.

Summary

Aspirin is a prodrug that is currently being used in the treatment of individuals experiencing prolonged inflammation, a fever or pain relief. Aspirin is an NSAID that acts an irreversible inhibitor to COX-1 and COX-2. This prevents the formation of TXA₂ and PGs, which causes a reduction of platelet aggregation. Therefore, there is a reduced inflammatory response, which causes aspirin’s therapeutic effects. However, there are side effects associated with the use of aspirin for example, prolonged bleed or gastric intolerances.

The potential implications of aspirin being used as a chemopreventive agent are very significant. The inexpensive cost and easy accessibility to aspirin warrants ongoing research into aspirins potential uses in cancer. The knowledge gained from these ongoing studies could lead to the development of new treatment plans or a better understanding of how to use novel therapies to combat cancer.

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