Salbutamol and Terbutaline

Mechanism

💊 Salbutamol (Albuterol)

• Formulation: Pressurized metered dose inhaler (pMDI), nebulizing solution, tablets.
• Selectivity: High selectivity β₂ (≈ 650 times greater than for β₁).
• Onset of action: 3 - 5 minutes.

🧪 Terbutaline

• Formulation: Dry powder inhaler (DPI), subcutaneous/intravenous injection solution.
• Selectivity: Structure with a resorcinol ring that gives it greater resistance to metabolism by COMT.
• Onset of action: 5 minutes.

Mechanism of action

SABAs bind selectively to the binding pocket of the transmembrane β₂ adrenergic receptor. This binding stabilizes the active conformation of the receptor, inducing the exchange of GDP for GTP in the α subunit of the G_s protein. The G_{α s}-GTP subunit dissociates and directly activates cell membrane-coupled adenylate cyclase.

The subsequent accumulation of cAMP activates PKA, which acts through three main relaxation pathways:

1. MLCK phosphorylation: Reduces the affinity of this enzyme for the calcium-calmodulin complex, preventing the phosphorylation of myosin and the formation of cross-bridges with actin.
2. Stimulation of the Na⁺/Ca²⁺ exchanger and the SERCA pump: Promotes the capture of calcium in the sarcoplasmic reticulum and its expulsion to the extracellular space, lowering the concentration of [Ca²⁺]_i.
3. Opening of high-conductance calcium-activated potassium channels (K_Ca): Induces hyperpolarization of the bronchial myocyte cell membrane, preventing the opening of voltage-dependent calcium channels.

Pharmacokinetics

Pharmacokinetics

Indicators and dose

Approved clinical indications

• Rescue and immediate symptomatic relief of acute bronchospasm in bronchial asthma and COPD.
• Prevention of exercise-induced bronchospasm (EIB): Administration 15 minutes before physical effort.
• Treatment of severe hyperkalemia: (Hospital use of nebulized or IV salbutamol) to induce transcellular entry of potassium by stimulation of the Na⁺/K⁺-ATPase pump in skeletal muscle.

Dosage and clinical adjustment

Adults:

• Mild/moderate asthma attack (pMDI 100 µg/puff): 2 to 4 inhalations every 20 minutes during the first hour. In severe hospital crises, up to 10 inhalations with a spacer chamber or continuous nebulization of 2.5 - 5 mg of salbutamol diluted in physiological solution.
• Terbutaline Turbuhaler (500 µg/inhalation): 1 inhalation in case of symptoms, maximum 4 per day.

Renal and Hepatic Failure: No dose adjustment is required in renal or hepatic dysfunction for intermittent inhaled doses. In continuous intravenous systemic treatments for refractory bronchospasm, the infusion should be reduced by 50% if the glomerular filtration rate is < 30 mL/min to avoid plasma accumulation of unchanged drug.

Security

Adverse effects (ADRs)

Most side effects are due to stimulation of β receptors outside the bronchial musculature, especially by escape of systemic selectivity at high doses:

• Fine tremor of extremities: Due to stimulation of β₂ receptors in skeletal muscle (the most common adverse effect, ≈ 10%).
• Sinus tachycardia and palpitations: Direct stimulation of β₂ receptors in the cardiac atrium and peripheral vasodilation with reflex tachycardia.
• Hypokalemia: Mobilization of plasma potassium into the skeletal muscle by activation of the Na⁺/K⁺-ATPase (extreme caution in patients receiving thiazide or loop diuretics).
• Prolongation of the QTc interval and transient hyperglycemia: Due to hepatic glycogenolysis and concomitant hypokalemia.

Drug interactions

• Non-selective beta-blockers (e.g. Propranolol): Direct mutual pharmacodynamic antagonism. They can trigger severe bronchospasm in asthmatic patients.
• Kaliuretic diuretics (Furosemide, Hydrochlorothiazide): Potentiation of the risk of severe hypokalemia.
• Tricyclic antidepressants and MAO inhibitors: Increased risk of cardiovascular toxicity (arrhythmias, hypertensive crisis) due to potentiation of the catecholaminergic response.

Safety in Pregnancy and Breastfeeding

Pregnancy: FDA Category C. Inhaled use is safe and widely recommended, as the risks of fetal hypoxia secondary to uncontrolled asthma significantly outweigh the side effects of the medication. Intravenous terbutaline has been used as a tocolytic (uterine relaxant), so high doses of SABA at the end of labor can prolong the expulsion period.

Breastfeeding: Compatible. Minimal quantities are excreted in breast milk that have no clinical impact on the infant.