Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha and beta blocking agents, ATC code: C07AG01 
Mechanism of action
Labetalol lowers the blood pressure by blocking alpha adrenoceptors on peripheral arterioles, thus reducing the peripheral resistance; the concurrent beta blockade protects the heart from the reflex sympathetic drive that would otherwise occur.


Pharmacodynamic effects
Cardiac output is not significantly reduced at rest or after moderate exertion. The increase in systolic blood pressure during exertion is reduced, but the corresponding changes in the diastolic pressure are essentially normal. All these effects would be expected to benefit hypertensive patients.

In patients with angina pectoris co-existing with hypertension, the reduced peripheral resistance decreases myocardial afterload and oxygen requirements. All these effects would be expected to benefit hypertensive patients as well as those with co-existing angina.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Pharmacokinetics
Absorption
Chemically, labetalol consists of four stereoisomers with different pharmacodynamic effects.
Labetalol is rapidly absorbed from the gastrointestinal tract and the maximum plasma levels occur 1- 2 hours after oral administration. There is significant first pass metabolism which yields bioavailability of 25%, but there are significant variations. The bioavailability of labetalol increases in the elderly.

Distribution
Labetalol is around 50 % protein bound in the blood. In animal studies, only negligible amounts of labetalol have passed the blood-brain barrier. Labetalol passes the placental barrier and is excreted in human milk.

Biotransformation
Labetalol is metabolised primarily through conjugation to inactive glucuronide metabolites.

Elimination
The glucuronide metabolites are excreted both in urine and via the bile into the faeces. Less than 5% of the labetalol dose is excreted unmodified in the urine and bile. The half-life of labetalol in plasma is approximately 4 hours.

Specific patient populations

• Hepatic failure
Labetalol undergoes significant but varied first pass metabolism when administered orally. In a study of 10 patients with histologically confirmed cirrhosis, the exposure for oral labetalol increased approximately threefold compared with the healthy control group. Individual variations in both patients and the control group were large (approximately 2.5 times). Patients with hepatic failure may require lower oral doses of labetalol (see section 4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use).