Core pharmacology

Class Group

BRONCHODILATORS - METHYLXANTHINES

Legacy Cicm Level

Level 2

Indications Uses

1. Asthma
2. COPD
3. Used to reduce frequency of central apnoea in premature neonates
4. Heart failure

Chemical Pharmaceutics

Aminophylline is a Methylxanthine derivative
80% theophylline and 20% ethylenediamine (no therapeutic effects)

Presentation

Oral and IV preparations

Main Action

Non-selective inhibitor of all 5 phosphodiesterase isoenzymes

Mechanism of action

Non-selective inhibitor of all 5 phosphodiesterase isoenzymes, which hydrolyse cAMP and possible cGMP leading to increases in their levels. This potentiates the effects of Beta-2 receptors. In addition it interferes with translocation of calcium into smooth muscle and stabilizes mast cells by antagonizing the actions of adenosine

Physiological effects

Resp
- Bronchodilation
- Increased sensitivity of the respiratory center to CO2
- Increased diaphragmatic contraction
- In its IV form it impairs hypoxic pulmonary vasoconstriction and therefore requires oxygen therapy
CVS
- Mild positive inotropic and chronotropic effects and causes coronary and peripheral vasodilation
- Lowers threshold for arrhythmias, particularly ventricular
Renal
- Increases renal blood flow and GFR
- Decreased sodium reabsorption leading to a natriuretic and diuretic effect and may precipitate hypokalaemia
Metabolic/Other
- Hypokalaemia
- SIADH

Adverse Effects Toxicity

1. Co-administration with drugs that inhibit CYP450 (cimetidine, erythromycin, cipro) will elevate plasma levels
2. In high concentrations it antagonizes NMDR
3. Above concentrations of 35mcg/ml enzymes become saturated and its kinetics change from first order to zero order resulting in toxicity. This manifests as cardiac toxicity (arrhythmias), CNS toxicity (seizures) and rhabdo

Absorption

Rapidly absorbed orally with bioavailability of 90%

Protein binding

50% protein bound

Volume of distribution

Vd 0.5L/Kg

Metabolism

- Low ER and metabolism is independent of blood flow
- Hepatic metabolism to active and inactive metabolites including a 3-methylxanthine derivative that is active
- Cigarette smoking increases clearance

Excretion

Approximately 10% excreted in urine unchanged

Half-life

First order kinetics
T1/2 is 8 hours

Route And Dose

PO/IV

Doses:
Loading dose 5.7 mg/kg IV

Maintenance dose: Continuous infusion
- Adults 60yrs: 0.38 mg/kg/hr (max 500mg/day)
- 0.25mg/kg/hr (max 500mg/day): Reduced dose with Cardiac decompensation / cor pulmonale/ Sepsis with MOF

Dosing should be adjusted based on serum levels