Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: Medochemie Ltd, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: paracetamol, combinations without psycholeptics
ATC code: N02BE51
The analgesic and antipyretic actions of paracetamol are believed to be due, at least in part, to inhibition of prostaglandin synthesis in the central nervous system. Paracetamol 1 g has been shown to be an effective analgesic and antipyretic.
Pseudoephedrine is predominantly an indirect-acting sympathomimetic amine. Pseudoephedrine 60 mg has been shown to be an effective nasal decongestant, as measured by nasal airflow, in patients with the common cold and rhinitis.
At therapeutic doses, pseudoephedrine has no clinically significant effect on blood pressure in normotensive patients. Studies in patients with controlled hypertension have demonstrated that pseudoephedrine 60 mg has no, or minimal, effect on blood pressure and does not have sedative effects.
Chlorpheniramine produces a dose-dependent inhibition of histamine-induced wheal and flare in healthy subjects. Following a single dose of chlorpheniramine 4 mg, the effect is apparent within one hour and lasts at least 12 hours. Chlorpheniramine produces sedation in man although the effect is variable and tolerance develops. The anti-cholinergic properties of chlorpheniramine have been demonstrated in man. These anticholinergic properties are relevant clinically in conditions associated with rhinorrhoea since the seromucosal glands of the nose are under anticholinergic control.
Paracetamol is rapidly and completely absorbed from the gastro-intestinal tract with peak plasma levels occurring about 0.25‑2 hours after dosing. The absolute bioavailability is about 80% and is independent of dose in normal therapeutic doses (5‑20 mg/kg). It is not bound to plasma proteins. The volume of distribution is about 0.9 l/kg. The plasma half-life ranges from 1‑3 hours and is largely unaffected by age. It is metabolised in the liver and excreted in the urine as the glucuronide and sulphate conjugates. In overdose situations, saturation of the detoxification of a minor metabolite, N‑acetyl-p‑benzoquinoneimine, by conjugation with glutathione occurs and this leads to its accumulation and resultant liver damage.
Pseudoephedrine is rapidly and completely absorbed from the gastrointestinal tract after oral administration, with no presystemic metabolism. Peak plasma levels are achieved after 1‑2 hours. No protein binding data are available. The volume of distribution ranges from 2.64 to 3.51 l/kg in both single and multiple dose studies. The plasma half-life varies from 4.3‑7.0 hours in adults. There is little metabolism of pseudoephedrine in man with approximately 90% being excreted in the urine unchanged. Approximately 1% is eliminated by hepatic metabolism, by N‑demethylation to norpseudoephedrine.
As a weak base, the extent of renal excretion is dependent on urinary pH. At low urinary pH, tubular resorption is minimal and urine flow rate will not influence clearance of the drug. At high pH (>7.0), pseudoephedrine is extensively reabsorbed in the renal tubule and renal clearance will depend on urine flow rate.
Hepatic disease is unlikely to affect the pharmacokinetics of pseudoephedrine. Renal impairment will result in increased plasma levels.
Chlorpheniramine has relatively low oral bioavailability (25-50%) indicating extensive first pass metabolism in the liver. Administration with food reduces bioavailability. Peak plasma levels occur 2‑3 hours following administration of immediate release and 6‑8 hours following administration of immediate release formulations. The drug is extensively metabolised via demethylation in the liver to mono and didesmethyl derivatives and by deamination to polar alcoholic and acidic derivatives. There is considerable inter‑subject variation in the half-life of the drug: the overall mean from a range of studies in adults was 20.4 hours with a range from 3‑43 hours. The half‑life of the d‑isomer is approximately 60% longer than that of the l‑isomer suggesting stereoselective metabolism. The half-life in children appears shorter. Chlorpheniramine is primarily excreted via the kidneys. At steady state, approximately 34% of chlorpheniramine is excreted as the parent drug. Since clorpheniramine is a weak base, renal excretion will vary with urinary pH.
Preclinical safety data on paracetamol, pseudoephedrine and chlorpheniramine in the literature have not revealed findings which are of relevance to the recommended dosage and use of the product and which have not been mentioned elsewhere in the summary.
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