Phosphodiesterase inhibitor

[PHW2:p204-p208]

 

Non-selective phosphodiesterase inhibitors

Aminophylline

[PHW2:p204]

Methylxanthine derivative
* 80% theophylline and 20% ethylenediamine

Pharmacodynamics

Mechanism of action

[PHW2:p204]

Non-selective inhibitor of all five phosphodiesterase isoenzymes
--> Increase intracellular concentration of cAMP (and maybe cGMP)

May also cause release NE from sympathetic neurones

Synergism with catecholamines

Interferes with translocation of Ca2+ into smooth muscles

Inhibition of degranulation of mast cells
* By blocking their adenosine receptors and potentiating prostaglandin synthetase activity

 

Effects

[PHW2:p204]

CVS

Mild positive inotropic and chronotropic actions

Some coronary and peripheral vasodilation

Lower threshold for arrhythmias

CNS

Reduced seizure threshold
* Due to alkyl group at the 1-position

CNS stimulation

 

Renal

Weak diuretic effect
* Due to alkyl group at the 1-position

Inhibition of tubular Na+ reabsorption
--> Naturesis
--> Hypokalaemia

 

Interaction

Interacts with other drugs which inhibit or induce cytochrome P450

 

NB:

[PHW2:p205]

Cytochrome P450 inhibitors include
* Cimetidine
* Erythromycin
* Ciprofloxacin
* Oral contraceptives

Cytochrome P450 inducers include
* Phenytoin
* Carbamazepine
* Barbiturates
* Rifampicin

 

Toxicity

[PHW2:p205]

Above plasma level of 35 microgram/mL
--> Hepatic enzyme saturated
--> Become zero-order kinetics

 

Pharmacokinetics

[PHW2:p205]

Good oral absorption
* Oral bioavailability > 90%

50% plasma protein bound

Low HER
--> Metabolism is independent of liver blood flow

Metabolised in liver by cytochrome P450 system

Metabolites inactive

10% excreted unchanged in urine

Halflife 6 hours

 

Cigarette smoking increase aminophylline clearance

 

Selective phosphodiesterease inhibitors

Enoximone

[PHW2:p205-207]

Selective phosphodiesterase III inhibitor

Yellow fluid (pH 12)

Propyl glycol and ethanol

May take up to 30 minutes to act

Pharmacodynamics

Mechanism of action

[PHW2:p206]

Prevents degradation of cAMP (and possibly cGMP) in cardiac and vascular smooth muscles

Cardiac effect
--> Increased slow Ca2+ inward current during the cardiac action potential
--> Increased Ca2+ release and thus increased intracellular Ca2+ level
--> Positive inotropic effect

Vascular smooth muscle
--> ?Inhibition of Ca2+ influx into vascular smooth muscle
--> Vasodilation

 

Effects

[PHW2:p207]

CVS

Also called "Inodilator" because of inotropic and vasodilator effects

Increased CO in heart failure

BP may be unchanged or fall

HR may be unchanged or increase slightly

 

Others

Agranulocytosis

 

Pharmacokinetics

[PHW2:p207]

Well absorbed from gut, but extensive first-pass metabolism
--> Not useful orally

70% protein-binding

Hepatic metabolism

Active metabolite
* 10% of activity and terminal half-life of 7.5 hours

Small amounts are excreted unchanged in urine

Terminal half-life of 4.5 hours

Wide therapeutic ratio and low risk of toxicity

Milrinone

[PHW2:p207]

Selective phosphodiesterase III inhibitor

Associated with higher mortality when given orally to patients with severe heart failure

70% protein-binding

Elimination half-life of 1-2.5 hours

80% excreted unchaged in urine

Amrinone

[PHW2:p208]

Selective phosphodiesterase inhibitor

40% excreted unchanged in urine

1 in 40 patients suffer reversible dose-dependent thrombocytopenia