232 Selective adrenergic agonists

Pharmacology and toxicology

.^-adrenergic drugs specifically act at .^-receptors. The intermediate-acting ^-adrenergic agonists bitolterol, fenoterol, metaproterenol, pir-buterol, reproterol, salbutamol (albuterol), terbutaliiie, and tulobuterol, and the long-acting ^-adrenergic agonists jormoteral and salmeterol, belong to this group and are used for the treatment of asthma.

,^-agonists cause bronchodilation. They also inhibit uterine contractions in the second and third trimesters, and therefore are effective in the treatment of premature labor. They can be given orally, by inhalation, or by subcutaneous or intravenous injection. Inhalation is as effective as the other routes, and is preferred since the side effects are minimal.

.^-agonists are well-absorbed when given orally, but have a low systemic availability. Plasma protein binding is low, elimination is by the kidneys, and the half-life (3-6 hours) is short in the intermediate-acting agonists but much longer (over 12 hours) in the long-acting agonists formoterol and salmcterol. .^-agonists rapidly cross the placenta. Lyrenas and colleagues found an increase in the clearance of terbutaline during pregnancy resulting in lower plasma concentrations (Lyrenas 1986).

Therapy with inhaled ^-adrenergic agonists appears to be safe during pregnancy. No increase in the rate of congenital malformations or other adverse pregnancy outcome has been reported (Schatz 2004, 1997, 1988). Most data are available for mctaproterenol, salbutamol (albuterol) and terbutaline. There is insufficient experience with bambuterol, clenbuterol, pirbuterol, and tulobuterol during the first trimester; however, there is no indication yet for teratogenicity.

The experience with the use of the newer long-acting ,l2-agonists formoterol and salmetero! during pregnancy is limited. High serum concentrations can occur with the use of these substances. In animal experiments, malformations have been found after prenatal exposure to salmeterol.

Adverse reactions in the fetus and the newborn (tremors, tachycardia, hypoglycemia, and hypokalemia) have been reported, especially when high doses of 32-agonists are used. The effects are less common when used by inhalation, and they are reversible. Raker and Flanagan reported a case of maternal and fetal tachycardia after inadvertanl inhalation of high doses of albuterol for 24 hours in week 33 (Baker 1997). The heart rale became normal after the discontinuation of albuterol.

High doses at the end of pregnancy can cause an inhibition of labor. Large intravenous doses of salbutamol as given for premature labor can produce hyperglycemic ketoacidosis in diabetic women.

Recommendation, (^adrenergic agonists can be safely used during pregnancy. The short-acting salbutamol (albuterol), metaproterenol and terbutaline are first-choice drugs in the treatment of pregnant women. According to therapy guidelines, their use by inhalation is preferred. The dose may need to be adjusted. The long-acting ;-i2-agonists formoterol and salmeterol should only be used if they are essential to an optimal treatment. A tocolytic potential and betamimetic effects in the fetus have to be considered in case of a treatment at the end of pregnancy.

2.3.3 Corticosteroids

Sec also Chapter 2.15.

Pharmacology and toxicology

Inhaled corticosteroids are effective in the treatment of asthma and are first choice drugs. Stenius-Aarniala and colleagues reported that treatment with inhaled corticosteroids clearly reduces the risk of having an acute attack of asthma during pregnancy {Stenius-Aarniala 1996).

Inhaled corticosteroids have anti-inflammatory properties and increase the sensitivity of the bronchial system for 1-adrenergic drugs. Beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone, and triamcinolone acetonide are available for this purpose.

Topically active corticosteroids have minimal or no systemic side effects when used at the recommended doses. It is only high doses of inhaled corticosteroids that have been associated with systemic side effects, especially adrenal suppression (e.g. beclomethasone at a daily dose of 1500 Mg or more).

All inhaled corticosteroids except for beclomethasone dipropionate pass into the systemic circulation as unchanged active drug. Beclomethasone dipropionate undergoes first-pass activation in the lungs and nose. They all arc rapidly cleared after absorption.

Corticosteroids have been found to inducc cleft palate in the mouse. There is no strong evidence that they are teratogenic in the human.

Beclomethasone has been used for many years in pregnant women without evidence of adverse effects on pregnancy or fetal development (Dombrowski 2004, 1997, Schatz 2004, 1997, Greenberger 1983).

In several large studies covering more than 6000 pregnancies, no increased incidence of congenital malformations or other adverse pregnancy outcome could be found after maternal exposure to inhaled budesonide (Gluck 2005, Norjavaara 2003, Kallen 1999) and other inhaled cortisteroids (Rahimi 2006).

Maternal use of inhaled corticosteroids does not impair fetal growth (Rahimi 2006, Bakhireva 2005, Namazy 2005).

High doses of systemic corticosteroids for longer periods may cause intrauterine growth restriction, and are best avoided (Bakhireva 2005). In cases where higher doses arc required, fetal growth should be monitored during treatment.

Several authors have found that pregnant women who used oral corticosteroids had an increased risk of hypertensive disorders. As oral corticosteroids were used mainly by women with severe asthma, it was difficult to separate the effects of the drug from those associated with the asthma. The authors concluded that, when indicated, there is no reason to withhold oral corticosteroids from pregnant women (Schatz 2004, 1997, Alexander 1998, Stenius-Aarniala

1988). Rahimi and colleagues could not confirm an increased risk of inhaled corticosteroids for hypertensive disorders (Rahimi 2006).

Intranasal corticosteroids are effective in the treatment of allergic rhinitis. They are safe, and there is no evidence of systemic cffccts. Bioavailability is higher than after inhalation, but the recommended dose for allergic rhinitis is lower than the dose given by inhalation. For this indication, beclomethasone has also been shown to be safe during pregnancy (Gilbert 2005). Data on pregnancy outcome after maternal exposure to intranasal budesonide are limited, but as pharmacological studies did show a much lower systemic exposure after intranasal administration, their safety is comparable to orally inhaled budesonide (Gluck 2005).

Recommendation. Inhaled corticosteroids are the first drugs of choice for the treatment of asthma in pregnant women. The use of beclomethasone or budesonide is preferred, because these have been widely used in pregnancy and have a good safety record. Systemic use of the corticosteroids, prednisone, and its metabolite, prednisolone, is indicated In case of acute exacerbations of asthma or severe asthma during pregnancy. In the case of long-term treatment (for months), it is recommended that fetal growth and neonatal adrenal function be monitored, especially if higher doses are used. For allergic rhinitis, intranasal corticolds may be used. The use of inhaled or systemic corticosteroids in the first trimester is not an Indication for the termination of pregnancy or for invasive diagnostics.

2.3.4 Anticholinergic drugs

Pharmacology and toxicology

Bronchodilating effects can also be achieved by drugs that act on the vagus nerve, such as anticholinergic drugs.

Inhaled ipratropium bromide is the drug of choice for the long-term treatment of chronic bronchitis. Its bronchodilating activity is about two-thirds of that of ยก^-adrenergic drugs, and it may augment the bronchodilator responsiveness to [32-agonists. Ipratropium is available as a single drug or in combination with a ^-agonist (fenoterol and salbutamol). Side effects are minimal.

Data on the use of inhaled ipratropium during pregnancy are limited, but the drug has not been related to an increased risk of congenital malformations or other adverse pregnancy outcomes.

There is no or very limited experience with the treatment of oxitropium bromide and tiotropium bromide during pregnancy.

Recommendation. Inhaled ipratropium bromide can be used during pregnancy if needed, Inadvertent use of oxitropium bromide or tiotropium bromide is not an indication for the termination of pregnancy or for specific diagnostics.

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