Terbutaline

Terbutaline is a selective beta₂-adrenergic stimulant having the following pharmacological effects:

• In the lung: bronchodilation; increased mucociliary clearance; suppression of oedema and anti-allergic effects.
• In skeletal muscle: stimulates Na+/K+ transport and also causes depression of subtetanic contractions in slow-contracting muscle.
• In uterine muscle: inhibition of uterine contractions.
• In the CNS: low penetration of the blood-brain barrier at therapeutic doses, due to the highly hydrophilic nature of the molecule.
• In the CVS: administration of terbutaline results in cardiovascular effects mediated through beta₂-receptors in the peripheral arteries and in the heart e.g. in healthy subjects, 0.25-0.5mg injected s.c. is associated with an increase in cardiac output (up to 85% over controls) due to an increase in heart rate and a larger stroke volume. The increase in heart rate is probably due to a combination of a reflex tachycardia via a fall in peripheral resistance and a direct positive chronotropic effect of the drug.

Basic parameters have been evaluated in man after i.v and oral administration of therapeutic doses, e.g.

i.v single dose:

Volume distribution (vss): 114 L

Total body clearance (cl): 213 ml/min

Mean residence time (mrt): 9.0 h

Renal clearance (clr): 149 ml/min (males)

Oral dose:

Renal clearance (clr): 1.925 ml/min (males)

Renal clearance (clr): 2.32 ml/min (females)

The plasma concentration/time curve after iv administration is characterised by a fast distribution phase, an intermediate elimination phase and a late elimination phase. Terminal half-life (t_½) has been determined after single and multiple dosing (mean values varied between 16-20 h).

Bioavailability

Food reduces bioavailability following oral dosing (10% on average).

Fasting values of 14-15% have been obtained.

Metabolism

The main metabolite after oral dosing is the sulfate conjugate and also some glucuronide conjugate can be found in the urine.

Respiratory route of administration

After inhalation, the absolute pulmonary bioavailability is about 16% of the delivered dose at a normal inhalation flow rate. Following administration of a single 1.5 mg dose (3 inhalations of 0.5 mg), maximum plasma concentration (C_max) of terbutaline of 12 nmol/L was achieved around 1.3 hours post-dose (t_max); the area under the plasma concentration-time curve (AUC_inf) was 96.6 nmol*h/L and elimination half-life (t_1/2) was about 12 hours. Terbutaline is mainly metabolised by conjugation with sulphuric acid and excreted as the sulfate conjugate. No active metabolites are formed. Data suggest that inhaled terbutaline acts topically in the airways.

The major toxic effect of terbutaline, observed in toxicological studies in rats and dogs at exposures in excess of maximum human exposure, is focal myocardial necrosis. This type of cardiotoxicity is a well known pharmacological manifestation seen after the administration of high doses of beta₂-agonists.

In rats, an increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long term exposure to high doses of beta₂-agonists