Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: anxiolytics, benzodiazepine derivates.
ATC Code: N05BA01

Diazepam is a psychotropic substance of the class of the 1,4- benzodiazepines with pronounced tension, excitation and anxiety-reducing properties as well as with sedating and hypnotic effects. Moreover, in higher doses, diazepam has depressant and anticonvulsive effects on the muscular tonus.
Diazepam binds to specific receptors in the central nervous system as well as in individual peripheral organs. The benzodiazepine receptors in the central nervous system are in close functional relation with the receptors of the GABA transmitter system. After binding to the benzodiazepine receptor, diazepam enhances the inhibiting effect of the GABA transmission.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The pharmacokinetic properties of diazepam show great inter-individual variability.
Absorption, maximum plasma concentration
After intravenous administration of an aqueous solution for injection, maximum plasma and serum concentrations of diazepam are reached immediately after injection.
After intramuscular injection, the absorption of diazepam is slower and corresponds to that of oral administration (up to 1 hour).
Serum concentration after I.V/I.M. administration of 10 mg diazepam ranges between         250-600 ng/ml. As the plasma concentration of diazepam after a single I.V. injection decreases very quickly because of rapid distribution, repeated injection is necessary after         20-30 min.

Protein binding, volume of distribution
Plasma protein binding ranges between 95-99 %; people suffering from renal or hepatic diseases present lower values.
Depending on age, the volume of distribution varies between 0.95 and 2 l/kg body weight.

Biotransformation, elimination
The degradation of diazepam takes place mainly in the liver into the equally pharmacologically active metabolites, N-desmethyldiazepam (nordazepam), temazepam and oxazepam, which appear in the urine as glucuronides. Only 20 % of the metabolites appear in the urine in the first 72 hours.
The active metabolites have the following plasma half-lives:
N-desmethyldiazepam                      30-100 h
Temazepam                                10-20 h
Oxazepam                                 5-15 h
During repeated dosing of diazepam, the proportion of N-desmethyldiazepam prevails, with large interindividual differences. This main metabolite has a longer terminal half- life than the parent substance.

During chronic medication with diazepam, elimination is additionally prolonged by accumulation, and therapeutically relevant serum concentrations of the main metabolite appear.

The elimination of diazepam and its main metabolite from the plasma is very slow. The 1st elimination phase has a half-life of 1 h; the values obtained for the 2nd elimination phase – depending on age and hepatic function - range between 20-100 h. Excretion is mainly renal and partially biliary. It also depends on age and renal and hepatic function.
The metabolism and elimination of diazepam in the newborn is considerably slower than in children and adults.
In the elderly, the elimination is slowed by a factor of 2 to 4.
In impaired renal function, the elimination is also slowed .
In patients with hepatic disorders (hepatic cirrhosis, hepatitis), the elimination is slowed by a factor of 2.

Passage into cerebro-spinal fluid
Diazepam is lipophilic and passes rapidly into cerebro-spinal fluid with its active main metabolite.

Passage into the placenta, lactation
Diazepam and its main metabolite N-desmethyldiazepam cross the placenta and are secreted in breast milk. Diazepam accumulates in the fetal compartment and in the blood of the newborn, can reach concentrations that are three times those of the maternal serum concentration.
In preterm babies elimination is delayed because of immature hepatic and renal function and can take up to 10 days.
If diazepam was given prior to or during delivery or if the mother had been administered higher doses on multiple occasions, Apgar scores are significantly lower in preterm babies and in the newborn, the frequency of hyperbilirubinemia is significantly higher, and pronounced edemas and muscle hypotonia have been observed up to 4 days after delivery.

Bioavailability
The systemic availability of diazepam after intravenous administration is 100 %; however, after intramuscular administration it is considerably lower and corresponds to that of oral administration – depending on the pharmaceutical composition, i.e. approx.
75-80 %.