Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead, 2191
Category and Class: A 2.8 Analgesic Combinations
Pharmacotherapeutic group: Other analgesics and antipyretics
ATC code: N02BA
The combination of aspirin, paracetamol and caffeine has analgesic, antipyretic and anti-inflammatory properties.
Aspirin has analgesic, antipyretic and anti-inflammatory properties. It inhibits the biosynthesis of prostaglandins, and produces analgesia through peripheral action by blocking pain impulse generation as well as by a central action.
Paracetamol has analgesic and antipyretic properties. It acts predominantly by inhibiting prostaglandin synthesis.
Caffeine has central nervous system stimulating effects.
Paracetamol has excellent bioavailability. Peak plasma concentrations occur within 30 to 60 minutes, and the t½ in plasma is ~2 hours after therapeutic doses.
Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of paracetamol to plasma proteins is variable.
Paracetamol primarily undergoes hepatic conjugation with glucuronic acid (~60%), sulphuric acid (~35%) or cysteine (~3%). Small amounts of the hydroxylated and deacetylated metabolites have also been detected. A small proportion of paracetamol undergoes CYP-mediated N-hydroxylation to form NAPQI, a highly reactive intermediate. This metabolite normally reacts with sulphydryl groups in glutathione (GSH) and thereby is rendered harmless. However, after ingestion of large doses of paracetamol, the metabolite is formed in amounts sufficient to deplete hepatic GSH and contributes significantly to the toxic effects of overdose.
Some 90 to 100% of paracetamol may be recovered in the urine within the first day of therapeutic dosing.
Orally ingested salicylates are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable concentrations are found in plasma in <30 minutes; after a single dose, a peak value is reached in ~1 hour and then declines gradually. The rate of absorption is determined by many factors, particularly the disintegration and dissolution rates of the tablets administered, the pH at the mucosal surface, and gastric emptying time.
After absorption, salicylates are distributed throughout most body tissues and transcellular fluids, primarily by pH-dependent passive processes. Salicylates are transported actively by a low-capacity, saturable system out of the cerebrospinal fluid (CSF) across the choroid plexus. The medication readily crosses the placental barrier.
The volume of distribution of usual doses of aspirin and sodium salicylate in normal subjects averages 170 ml/kg of body weight; at high therapeutic doses, this volume increases to 500 ml/kg because of saturation of binding sites on plasma proteins. Ingested aspirin mainly is absorbed as such, but some enters the systemic circulation as salicylic acid after hydrolysis by esterases in the GI mucosa and liver. Aspirin can be detected in the plasma only for a short time as a result of hydrolysis in plasma, liver and erythrocytes; for example, 30 minutes after a dose of 0,65 g, only 27% of the total plasma salicylate is in the acetylated form.
Roughly 80 to 90% of the salicylate in plasma is bound to proteins, especially albumin, at concentrations encountered clinically; the proportion of the total that is bound declines as plasma concentrations increase.
The biotransformation of salicylates takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicylic acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small fraction is oxidized to gentisic acid (2,5-dihydroxybenzoic acid) and to 2,3-dihydroxybenzoic and 2,3,5-trihydroxybenzoic acids; gentisuric acid, the glycine conjugate of gentisic acid, also is formed.
Salicylates are excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl glucuronides (5%), and gentisic acid (<1%). However, excretion of free salicylates is extremely variable and depends on the dose and the urinary pH.
The plasma t½ for aspirin is ~20 minutes, and for salicylate is 2 to 3 hours at antiplatelet doses, rising to 12 hours at usual anti-inflammatory doses.
Salicylate clearance is reduced and salicylate exposure is significantly increased in the elderly.
The plasma concentration of salicylate is increased by conditions that decrease glomerular filtration rate or reduce proximal tubule secretion, such as renal disease or the presence of inhibitors that compete for the transport system.
Caffeine is absorbed from the digestive tract.
Caffeine is distributed rapidly throughout all tissues and easily crosses the placental barrier.
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