Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties:

Pharmacotherapeutic group: a drug used in cases of benign prostatic hypertrophy. ATC code: G04C A 01

Alfuzosin is a derivative of quinazoline, which is active via the oral route.

It is a selective antagonist of the postsynaptic alpha-1-adrenergic receptors. Pharmacological studies conducted in vitro confirmed the selectivity of alfuzosin for the alpha-1 receptors at the trigonum of the bladder, urethra and prostate.

Studies in vivo in animals indicate that alfuzosin reduces urethral pressure and thus the resistance to micturition.

In the case of benign hypertrophy of the prostate the occurrence and intensity of functional urinary symptoms are not only related to the volume of the prostate but also to the sympathetic (nervous) tone.

An alpha-adrenergic nerve was demonstrated in the smooth muscle of the prostate stroma.
Alfuzosin exhibits a tissue distribution selective for the prostate.
The hypertrophy of the prostatic stroma concerns the smooth muscle tissue. Stimulation of postsynaptic alpha-1 receptors increases the muscle tone of the urinary tract while blockage of these receptors by alfuzosin leads to relaxation of smooth muscle fibres.

Alfuzosin shows a certain degree of urological selectivity: inhibition of the hypertonic response of the urethra appears earlier than the effect on the vascular walls.

In humans alfuzosin improves evacuation parameters by reducing urethral tone and resistance at the bladder neck, thereby promoting emptying of bladder.
Clinical placebo-controlled studies in patients with benign prostatic hypertrophy showed that alfuzosin:

- increases the maximum flow rate (Qmax) significantly in patients where the Q max is 15 ml/s, by 30% on average. This improvement is observed from the first dose.
- significantly decreases the detrusor pressure and increases the volume, leading to a strong need to urinate.
- significantly reduces the residual volume.

These positive urea dynamic effects lead to a clearly demonstrated improvement in the lower urinary tract symptoms, both in terms of filling (irritation symptoms) and evacuation (obstructive symptoms).

In treated patients the frequency of acute urinary retention is decreased compared to patients who are not treated patients. In addition alfuzosin significantly increases the rate of successful spontaneous voiding after catheter removal in men experiencing acute urinary retention due to benign prostatic hypertrophy.

Paediatric population
Xatral is not indicated for use in paediatric patients (see section 4.2) The efficacy of alfuzosin hydrochloride was not demonstrated in the two studies conducted in 197 patients aged 2 to 16 years with increased detrusor leak point pressure (LPP ≥40 cm H2O) of a neurological nature. Patients were treated with alfuzosin hydrochloride 0.1 mg/kg/day or 0.2 mg/kg/day with adapted paediatric formulations.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Absorption
On average the relative bioavailability of Xatral XL 10 mg prolonged-release tablets is 104.4% compared to the immediate-release formulation (2.5 mg 3 times daily) in healthy middle-aged volunteers, and maximum plasma levels are reached 9 hours after administration.
The studies showed a logical pharmacokinetic profile when the product was administered after a meal.

Distribution
Binding to plasma proteins is approximately 90%, 68.2% to serum albumin and 52.5% to serum α1-glycoproteins.

Biotransformation
Alfuzosin is highly metabolised in the liver, while only 11% of the product is excreted unchanged in the urine.
CYP3A4 is the major hepatic isoenzyme involved in the metabolism of alfuzosin. Ketoconazole is a very potent CYP3A4 inhibitor. Repeated daily doses of 200 mg ketoconazole for 7 days resulted in a 2.11-fold increase in Cmax and 2.46-fold increase in AUCload after the administration of 10 mg alfuzosin after a meal. The other parameters, such as tmax and t1/2Z, had not changed. Repeated daily doses of 400 mg ketoconazole for 8 days increased the Cmax of alfuzosin by 2.3 times, the AUCload and the AUC by 3.2 and 3.0 times, respectively (see section 4.5).

Elimination
Most metabolites (without pharmacodynamic activity) are excreted in the faeces (75 to 91%).
The apparent elimination half-life is 9.1 hours.

Renal insufficiency
The mean values of Cmax and AUC are slightly increased in patients with renal impairment without change in apparent elimination half-life, compared to those whose renal function is normal.
This change is not considered clinically significant and does not require a dose adjustment.
In patients with renal impairment, with or without the need for dialysis, the volume of distribution and the clearance of alfuzosin are increased due to the increased free fraction.

Hepatic insufficiency
In patients with severe hepatic insufficiency the elimination half-life was prolonged, the values of Cmax doubled, and those of AUC tripled. Bioavailability is increased compared to healthy volunteers.

Elderly patients
The pharmacokinetic parameters (Cmax, AUC) of Xatral XL 10 mg prolonged-release tablets did not increase in the elderly compared to healthy middle-aged volunteers.
In patients older than 75 years the reabsorption of alfuzosin is faster and the maximum concentrations are higher. Bioavailability may be increased and a reduction in the volume of distribution is seen in certain patients. The elimination half-life remains unchanged.

Chronic cardiac insufficiency
In the case of chronic cardiac insufficiency, the pharmacokinetic profile of alfuzosin is not affected.