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9780521704632c12 CUFX213A/Peck 9780521618168 December 28, 2007 12:15
Section IIICardiovascular drugs
Cardiovascular – it has mild positive inotropic and chronotropic effects and causes
some coronary and peripheral vasodilatation. It lowers the threshold for arrhyth-
mias (particularly ventricular) especially in the presence of halothane.
Central nervous system – the alkyl group at the 1-position (also present in caffeine)
is responsible for its central nervous system stimulation, resulting in a reduced
seizure threshold.
Renal – the alkyl group at the 1-position is also responsible for its weak diuretic
effects. Inhibition of tubular Na+reabsorption leads to a naturesis and may pre-
cipitate hypokalaemia.
Interactions – co-administration of drugs that inhibit hepatic cytochrome P450
(cimetidine, erythromycin, ciprofloxacin and oral contraceptives) tend to delay the
elimination of aminophylline and a reduction in dose is recommended. The use of
certain selective serotonin re-uptake inhibitors (fluvoxamine) should be avoided
with aminophylline as levels of the latter may rise sharply. Drugs that induce hep-
atic cytochrome P450 (phenytoin, carbamazepine, barbiturates and rifampicin)
increase aminophylline clearance and the dose may need to be increased.Kinetics
Aminophylline is well absorbed from the gut with a high oral bioavailability (>90%).
About 50% is plasma protein bound. It is metabolized in the liver by cytochrome
P450 to inactive metabolites and interacts with the metabolism of other drugs
undergoing metabolism by a similar route. Owing to its low hepatic extraction ratio
its metabolism is independent of liver blood flow. Approximately 10% is excreted
unchanged in the urine. The effective therapeutic plasma concentration is 10–20
μg.ml−^1 .Cigarette smoking increases the clearance of aminophylline.Toxicity
Above 35μg.ml−^1 ,hepatic enzymes become saturated and its kinetics change
from first- to zero-order resulting in toxicity. Cardiac toxicity manifests itself as
tachyarrhythmias including ventricular fibrillation. Central nervous system toxic-
ity includes tremor, insomnia and seizures (especially following rapid intravenous
administration). Nausea and vomiting are also a feature, as is rhabdomyolysis.Selective phosphodiesterase inhibitors
Enoximone
The imidazolone derivative enoximone is a selective phosphodiesterase III inhibitor.Presentation and uses
Enoximone is available as a yellow liquid (pH 12) for intravenous use containing 5
mg.ml−^1 .Itissupplied in propyl glycol and ethanol and should be stored between
5 ◦Cand 8◦C. It is used to treat congestive heart failure and low cardiac output states