Propranolol

Propranolol is a competitive antagonist at both beta, and beta2-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1-3mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta-blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta-agonists such as isoprenaline.

Propranolol as with other beta-blockers, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.

Propranolol is a racemic mixture and the active form is the S(-) isomer of propranolol. With the exception of inhibition of the conversion of thyroxine to triiodothyronine, it is unlikely that any additional ancillary properties possessed by R(+) propranolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.

Propranolol is effective and well tolerated in most ethnic populations, although the response may be less in black patients.

Potential mechanisms of action of propranolol in proliferating infantile haemangioma described in the literature could include various mechanisms all in close relationship:

• a local haemodynamic effect (vasoconstriction which is a classical consequence of beta-adrenergic blockade and a decrease of infantile haemangioma lesion perfusion);
• an antiangiogenic effect (decrease of vascular endothelial cells proliferation, reduction of the neovascularization and formation of vascular tubules, reduction of the secretion of Matrix Metalloproteinase 9);
• an apoptosis-triggering effect on capillary endothelial cells;
• a reduction of both VEGF and bFGF signalling pathways and subsequent angiogenesis/proliferation.

Pharmacodynamic effects

Propranolol is a beta-blocker that is characterised by three pharmacological properties:

• the absence of cardioselective beta-1 beta-blocking activity,
• an antiarrhythmic effect,
• lack of partial agonist activity (or intrinsic sympathomimetic activity).

Adults

Absorption and distribution

Propranolol is almost completely absorbed after oral administration. However, it undergoes an extensive first-pass metabolism by the liver and on average only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.

Administration of protein-rich foods increases the bioavailability of propranolol by about 50% with no change in time to peak concentration.

Propranolol is a substrate for the intestinal efflux transporter, P-glycoprotein (P-gp). However, studies suggest that P-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The volume of distribution of propranolol is approximately 4 L/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.

Biotransformation and elimination

Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation.

The percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major final metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies indicated that CYP2D6 (aromatic hydroxylation), CYP1A2 (chain oxidation) and to a less extent CYP2C19 were involved in propranolol metabolism.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers and poor metabolizers with respect to oral clearance or elimination half-life. The plasma half-life of propranolol ranges from 3 to 6 hours. Less than 1% of a dose is excreted as unchanged drug in the urine.

Paediatric population

The pharmacokinetics of repeated administrations of HEMANGIOL at 3 mg/kg/day given in 2 intakes has been investigated in 19 infants aged 35 to 150 days at the beginning of treatment. The pharmacokinetic evaluation was performed at steady-state, after 1 or 3 months of treatment.

Propranolol was rapidly absorbed, the maximum plasma concentration generally occurring 2 hours after administration with a corresponding mean value around 79 ng/mL whatever the infant age.

Mean apparent oral clearance was 2.71 L/h/kg in infants aged 65-120 days and 3.27 L/h/kg in infant aged 181-240 days. Once corrected by the body weight, primary pharmacokinetic parameters for propranolol (such as plasma clearance) determined in infants were similar to those reported in the literature for adults.

The 4-hydroxy-propranolol metabolite was quantified, its plasma exposure accounting for less than 7% of the parent drug exposure.

During this pharmacokinetic study including infants with function-threatening haemangioma, haemangioma in certain anatomic locations that often leave permanent scars or deformity, large facial haemangioma, smaller haemangioma in exposed areas, severe ulcerated haemangioma, pedunculated haemangioma, efficacy was also studied as a secondary evaluation criteria. Treatment with propranolol resulted in a rapid improvement (within 7-14 days) in all patients and resolution of the target haemangioma was observed in 36.4% of patients by 3 months.

In animals, after an acute dosing, propranolol is considered as a moderately toxic drug with an oral LD₅₀ of about 600 mg/kg. The main effects reported after repeated administration of propranolol in adult and juvenile rats were a transient decrease in body weight and body weight gain associated with a transient decrease in organ weight. These effects were completely reversible when treatment was discontinued.

In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. Although some data were equivocal, based on the overall available in vitro and in vivo data, it can be concluded that propranolol is devoid of genotoxic potential.

In adult female rats, propranolol given into the uterus or by intravaginal administration is a powerful anti-implantation agent at dose ≥4 mg per animal, the effects being reversible. In adult male rats, repeated administration of propranolol at high dose levels (≥7.5 mg/kg) induced histopathological lesions of the testes, epididymis, and seminal vesicles, decrease in sperm motility, sperm cell concentration, plasma testosterone levels and significant increase in sperm head and tail abnormalities.

The effects generally totally reversed after treatment cessation. Similar results were obtained following intra-testicular administration of propranolol and using in vitro models. However, in the study conducted in juvenile animals treated all over the development period corresponding to infancy, childhood and adolescence, no effect on male and female fertilities was observed.

The potential effects of propranolol on the development of juvenile rats were evaluated following daily oral administration from post-natal Day 4 (PND 4) to PND 21 at dose-levels of 0, 10, 20 or 40 mg/kg/day.

Mortality with unknown although unlikely relationship to treatment was observed at 40 mg/kg/day, leading to a NOAEL of 20 mg/kg/day for juvenile toxicity. In terms of reproductive development, growth and neurological development there were no propranolol-related effects or toxicologically significant findings at 40 mg/kg/day, correlating to safety margins of 1.2 in females and 2.9 in males, based on mean propranolol exposures on PND 21.