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Opioid Analgesics/Non-Opioid Analgesics/Antipyretic.
Pharmacology: Tramadol hydrochloride: It is a centrally acting analgesic. It is a non selective pure agonist at μ, δ, and κ opioid receptors with a higher affinity for the μ receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.
Paracetamol: The mechanism of analgesic action has not been fully determined.
Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation.
The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.
Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation center to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.
Pharmacodynamics: Analgesics: Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is pure non selective agonists of the μ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of Tramadol has no respiratory depressant effect. Similarly, the gastrointestinal motility is not modified. The cardiovascular effects are generally slight. The potency of Tramadol is considered to be one-tenth to one-sixth that of morphine.
Mechanism of Action: The precise mechanism of the analgesic properties of Paracetamol is unknown and may involve central and peripheral effects.
Tramadol hydrochloride/Paracetamol is positioned as a step II analgesic in the WHO pain ladder and should be utilised accordingly by the physician.
Pharmacokinetics: Tramadol is readily absorbed after oral doses but is subject to some first-pass metabolism. Mean absolute bioavailability is about 70 to 75% after oral use and 100% after intramuscular injection.
Plasma protein binding is about 20%. Tramadol is metabolised by N- and O-demethylation via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6 and glucuronidation or sulfation in the liver. The metabolite O-desmethyltramadol is pharmacologically active. Tramadol is excreted mainly in the urine, predominantly as metabolites. Tramadol is widely distributed, crosses the placenta, and appears in small amounts in breast milk. The elimination half-life is about 6 hours.
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral doses. Paracetamol is distributed into most body tissues. It crosses the placenta and is present in breast milk. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. The elimination half-life of Paracetamol varies from about 1 to 3 hours.
Paracetamol is metabolised mainly in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged Paracetamol. A minor hydroxylated metabolite (N-acetyl-p-benzoquinone imine), is usually produced in very small amounts by cytochrome P450 isoenzymes (mainly CYP2E1 and CYP3A4) in the liver and kidney. It is usually detoxified by conjugation with glutathione but may accumulate after Paracetamol overdosage and cause tissue damage.
