Source: Medicines Authority (MT) Revision Year: 2023 Publisher: TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany
Pharmacotherapeutic group: analgesics, anilides
ATC code: N02BE71
Daleron COLD3 film-coated tablets contain paracetamol, an analgesic and antipyretic, pseudoephedrine hydrochloride, an oral decongestant, and dextromethorphan hydrobromide, an antitussive. The drug relieves several symptoms that usually accompany common cold.
The mechanism of action of paracetamol has not been completely elucidated yet. The analgesic effect is probably a result of the inhibition of cyclooxygenase and the synthesis of prostaglandins in the CNS. Paracetamol has nearly no effect on prostaglandin synthesis at the sites of inflammation; therefore, it exerts only slight antiphlogistic action. Because of a weak effect on prostaglandin synthesis in peripheral tissues, it causes fewer gastrointestinal undesirable effects compared to nonsteroidal anti-inflammatory agents. The antipyretic action of paracetamol results from its direct action on the centre for body temperature regulation in the hypothalamus. Paracetamol indirectly increases the emission of heat by vasodilation of peripheral blood vessels, and by promotion of blood flow and sweating.
Pseudoephedrine is a sympathomimetic amine with direct and indirect effects on adrenergic receptors. It acts as an agonist on β-adrenergic receptors in the heart and bronchial smooth muscles, and on peripheral αadrenergic receptors; it indirectly acts on the release of neurotransmitters (norepinephrine) from the adrenergic neurons.
The decongestant effect is a result of direct agonistic action on α-adrenergic receptors of the vascular smooth muscles in the respiratory tract mucosa. Due to the constriction of dilated arterioles, it reduces blood flow in the nasopharyngeal mucosa and oedema, thus relieving the feeling of nasal congestion and reducing nasal discharge.
Compared to ephedrine, it stimulates β-adrenergic receptors to a much lesser extent. Pseudoephedrine has a mild stimulating effect on the CNS. When taken at therapeutic doses, it practically does not elevate blood pressure.
Dextromethorphan is a D-isomer of the codeine analogue levorphanol. It acts centrally on the cough centre by elevating the cough reflex threshold. In this way, it relieves irritating cough associated with the irritation of the throat in common cold. The antitussive effect of the active substance is approximately equivalent to that of codeine, but dextromethorphan has no significant analgesic effect, it does not inhibit the respiratory centre or cause dependence.
After oral administration, it is rapidly and completely absorbed from the gastrointestinal tract. Peak blood levels occur 15 to 90 minutes after administration, depending on the pharmaceutical form of the drug. The bioavailability is about 80%.
It is rapidly and relatively uniformly distributed throughout the body. The volume of distribution is 0.8 to 1.36 l/kg body weight. It is poorly protein-bound (about 10%), except in overdose (20 to 50% of the active substance).
Paracetamol is metabolised primarily in the liver, a very small amount also in the intestine and kidneys. The main metabolic pathway is formation of conjugates with glucuronic and sulphuric acids.
When administered at usual doses, paracetamol is metabolised into sulphates and glucuronides. A small portion of the active substance is converted into N-acetyl-p-benzoquinonimine, which is a highly reactive metabolite and exerts toxic effects on liver cells. It is usually rapidly bound to the cell component glutathione and excreted via the kidneys as conjugates. After the intake of an overdose, larger quantities of N-acetyl-pbenzoquinonimine are formed. When glutathione stores are depleted, the excess toxic metabolites are covalently bound to the vital cell components and cause acute hepatic necrosis.
The plasma elimination half-life ranges from 1.5 to 3 hours (the mean elimination half-life is 2.3 hours). In the elderly, the mean plasma elimination half-life is the same (2.17 hours); therefore, no dosage adjustments are necessary. In stable chronic liver diseases, paracetamol can be safely administered at therapeutic doses. For patients with liver failure, some authors recommend prolongation of the dosing interval.
A very small amount of paracetamol (2–5%) is excreted unchanged via the kidneys; the drug is mainly excreted in the urine as glucuronides (55–60%) and sulphates (30–35%). A very small amount is excreted in the bile. About 90% of paracetamol is eliminated from the body within 24 hours.
After an oral dose, it is rapidly and well absorbed from the intestinal tract (>95%). The decongestant effect occurs 15 to 30 minutes and the maximum effect 30 to 60 minutes after administration, depending on the pharmaceutical form.
The volume of distribution ranges from 2.4 to 2.6 l/kg body weight.
It is incompletely metabolised in the liver via N-demethylation.
Within 24 hours, 70 to 90% of the dose is excreted unchanged in the urine; the rest is excreted as metabolites. One to 6% of the active substance is excreted as the active metabolite norpseudoephedrine, which stimulates the central nervous system. The elimination half-life depends on the pH of the urine: It is 9 to 16 hours at pH 5.5 to 6; it may be prolonged to 50 hours in alkalinised urine and reduced to 1.5 hours in highly acidic urine.
Pseudoephedrine is excreted in human milk; the levels of the active substance in human milk are even 2 to 3 times those reached in the plasma. Since pseudoephedrine and its metabolites are primarily excreted via the kidneys, dosage adjustments are required in patients with impaired renal function.
It is rapidly absorbed after an oral dose. The effect occurs as early as 15 to 30 minutes after administration; peak serum levels are achieved in 2.5 hours.
After a single oral dose, the effect persists for 5 to 6 hours.
Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. It is metabolised in the liver by oxidative O- and N-demethylation and then conjugated with glucuronic and sulphuric acids. Genetically controlled O-demethylation (CYP2D6) is the main determinant of dextromethorphan pharmacokinetics in human volunteers.
It appears that there are distinct phenotypes for this oxidation process resulting in highly variable pharmacokinetics between subjects. Unmetabolised dextromethorphan, together with the three demethylated morphinan metabolites dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3-hydroxymorphinan and 3-methoxymorphinan have been identified as conjugated products in the urine.
Dextrorphan, which also has antitussive action, is the main metabolite. In some individuals metabolism proceeds more slowly and unchanged dextromethorphan predominates in the blood and urine. Among the white European population, there are about 10% of people who metabolise this drug poorly; therefore, the blood levels of the active substance may be much higher in these people, with a resultant higher risk of toxic effects.
Within 24 hours after an oral dose, more than 85% of the dose is excreted in the urine as free or conjugated metabolites and a very small amount of unchanged active substance. The elimination half-lives of dextromethorphan and dextrorphan are 1.4 to 3.9 hours and 3.4 to 5.6 hours, respectively. As the basic active metabolite dextrorphan is excreted via the kidneys, dosage adjustments are required in patients with impaired renal function.
After oral administration of paracetamol, the LD50 ranged between 295 and 1212 mg/kg body weight in mice and was higher than 4 g/kg body weight in rats. In dogs, the oral LD50 was 2404 mg/kg body weight and the lethal dose after intravenous administration was approximately 826 mg/kg body weight. Prolonged administration of very high doses of paracetamol (1 to 7 g/kg body weight/day) caused liver and kidney damage in laboratory animals. Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available. No mutagenic and carcinogenic effects of paracetamol have been found.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
Pseudoephedrine hydrochloride is moderately toxic to laboratory animals. The oral LD50 in mice was 371 mg/kg body weight. Parenteral doses of 75 mg/kg body weight in rabbits, 371 mg/kg body weight in rats and 400 mg/kg body weight in mice did not induce mortality. The active substance reduces body weight gain and food consumption in pregnant rats and has no teratogenic effects on the foetuses (it reduces body weight gain; it has an effect on ossification). According to the NTP (National Toxicology Program), IARC (International Agency for Research on Cancer) and OSHA (Occupational Safety and Health Agency), pseudoephedrine hydrochloride is not carcinogenic. There are no data on repeated dose toxicity and mutagenicity in the available literature.
The LD50 that increases from 125 to 423 mg/kg body weight after oral and subcutaneous administration of dextromethorphan hydrobromide to laboratory animals indicates moderate toxicity of the active substance. Following intravenous administration, the LD50 was below 30 mg/kg body weight. High doses of dextromethorphan hydrobromide have neuroprotective and neurotoxic effects (general reduction in activity, convulsions, respiratory depression); the ED50 does not cause behavioural changes. The active substance acts centrally in the medulla oblongata by elevating the cough threshold. There are no data on repeated dose toxicity, mutagenicity and effects on reproduction in the available literature. According to the NTP (National Toxicology Program), IARC (International Agency for Research on Cancer) and OSHA (Occupational Safety and Health Agency), dextromethorphan hydrobromide is not carcinogenic.
The preclinical effects of paracetamol, pseudoephedrine hydrochloride and dextromethorphan hydrobromide were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
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