Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group:
Analgesics; Other analgesics and antipyretics; Anilides
ATC Code: N02BE01

Mechanism of action
The precise mechanism of the analgesic and antipyretic properties of paracetamol has still to be estab- lished; it may involve central and peripheral actions.

Pharmacodynamic effects
Paracetamol B. Braun 10 mg/ml provides onset of pain relief within 5 to 10 minutes after the start of administration. The peak analgesic effect is obtained in 1 hour and the duration of this effect is usual- ly 4 to 6 hours.

Paracetamol B. Braun 10 mg/ml reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Adults
Absorption:
Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated admin- istration during 24 hours.
The bioavailability of paracetamol following infusion of 500 mg and 1 g of Paracetamol B. Braun 10 mg/ml is similar to that observed following infusion of 1 g and 2 g propacetamol (containing 500mg and 1 g paracetamol respectively). The maximal plasma concentration (Cmax) of paracetamol observed at the end of 15-minutes intravenous infusion of 500 mg and 1 g of Paracetamol B. Braun 10 mg/ml is about 15 μg/ml and 30 μg/ml respectively.

Distribution:
The volume of distribution of paracetamol is approximately 1 l/kg.
Paracetamol is not extensively bound to plasma proteins.
Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 µg/ml) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.

Biotransformation:
Paracetamol is metabolised mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulphuric acid conjugation. The latter route is rapidly saturable at doses that exceed the therapeutic doses. A small fraction (less than 4 %) is metabolised by cytochrome P450 to a reac- tive intermediate (N-acetyl benzoquinone imine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mer- capturic acid. However, during massive overdosing, the quantity of this toxic metabolite is increased.

Elimination:
The metabolites of paracetamol are mainly excreted in the urine. 90 % of the dose administered is excreted within 24 hours, mainly as glucuronide (60 – 80%) and sulphate (20 – 30 %) conjugates.
Less than 5 % is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 l/h.

Newborn infants, infants and children:
The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those observed in adults, except for the plasma half-life that is slightly shorter (1.5 to 2 h) than in adults. In newborn infants, the plasma half-life is longer than in infants i.e. around 3.5 hours. Newborn infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conju- gates than adults.

Table - Age related pharmacokinetic values (standardised clearance, *CLstd/Foral (l×h-1×70 kg-1) Age                    Weight (kg)     CLstd/Foral (l×h-1×70kg-1)
40 weeks post-conception               3.3                      5.9
3 months postnatal                    6                        8.8
6 months postnatal                    7.5                    11.1
1 year postnatal                     10                      13.6
2 years postnatal                    12                      15.6
5 years postnatal                    20                      16.3
8 years postnatal                    25                      16.3
*CLstd is the population estimate for CL

Special populations:
Renal insufficiency:
In cases of severe renal impairment (creatinine clearance 10 – 30 ml/min), the elimination of parace- tamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times slower in subjects with severe renal impair- ment than in healthy subjects. Therefore when giving paracetamol to patients with severe renal im- pairment (creatinine clearance ≤ 30 ml/min), the minimum interval between each administration should be increased to 6 hours (see section 4.2).

Elderly subjects:
The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.