Labetalol

Labetalol lowers the blood pressure by blocking peripheral arteriolar alphaadrenoceptors thus reducing peripheral resistance, and by concurrent betablockade, protects the heart from reflex sympathetic drive that would otherwise occur.

Pharmacodynamic effects

Cardiac output is not significantly reduced at rest or after moderate exercise. Increases in systolic blood pressure during exercise are reduced but corresponding changes in diastolic pressure are essentially normal.

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

Chemically, labetalol consists of 4 stereo-isomers with different pharmacodynamic effects.

Distribution

The plasma half-life of labetalol is about 4 hours. About 50% of labetalol in the blood is protein bound. Only negligible amounts of the drug cross the blood brain barrier in animal studies. Labetalol crosses the placenta barrier and is excreted in breast milk.

Biotransformation

Labetalol is metabolised mainly through conjugation to inactive glucuronide metabolites. These are excreted both in urine and via the bile into the faeces.

Elimination

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

Special patient populations

Liver dysfunction

Labetalol undergoes a significant but variable first-pass metabolism when it is taken orally. In a study with 10 patients with historically proven cirrhosis the exposure to oral labetalol was around three times as much compared to healthy members of the control group. The variability between the subjects in both the control group and the patient group was high (around 2.5 times).

Renal dysfunction

In patients with renal dysfunction lower oral dosages of Labetalol may be necessary.

Carcinogenesis, mutagenesis, teratogenesis

No evidence of mutagenic potential was shown in in-vitro and in-vivo tests.

Labetalol did not show any evidence of carcinogenicity in long term studies performed in rats and mice. No teratogenesis has been observed in rats or rabbits after oral dosages respectively 6 to 4 times as high as the maximum advised human dose.

Increased foetal resorption has been noted in both species treated with dosages about equal to the maximum advised human dosage, a teratology study using labetalol in rabbits, with intravenous dosages of 1.7 times the maximum advised human dosage, showed no evidence of drug-related damage to the foetus.