This group of drugs includes such familiar substances as caffeine (coffee), theophylline (tea) and theobromine (chocolate). Most of the drugs used in veterinary practice are esters of theophylline, such as aminophylline or etamiphylline. Newer PDIs specific for cardiac phosphodiesterase have been produced for human use, these include amrinone, milrinone and enoximone. Pimobendan started out as one of these, but has been diverted tot he veterinary market. “Viagra” (sildenafil) started out as one of these until its interesting side effects were noted. Oxpentifylline (pentoxyfylline USAN) is a theophylline type drug which is rather more specific for PDE 4 and has a number of different effects such as TNFα antagonism. It could be useful in CHF but is not usually used.
(inotropes diagram) Phosphodiesterase normally inactivates cAMP. Inhibition of cAMP degradation leads to increases in intracellular cAMP concentration, and consequent increases in activity of cAMP-dependent protein kinase. This activates many intracellular enzymes by phosphorylation. Calcium dependent enzymes are also activated, leading to stimulation of contractility due to increased effects of intracellular calcium. Their effects are additive with digoxin.
These drugs increase the rate and force of myocardial contraction. They also cause some bronchial and systemic arterial dilatation and increase the alertness of the animal, all of which is useful in dogs with CHF. There are at least 11 different types of phosphodiesterase (and numerous subtypes), so the range of effects is large.
| enzyme | subtypes | tissue | inhibitors |
| PDE1 | A, B, C | CNS, blood vessels | |
| PDE2 | A | ||
| PDE3 | A, B | myocardium, blood vessels | milrinone, pimobendan |
| PDE4 | A, B, C, D | airways, inflammatory cells, CNS, stomach | rolipram, oxpentifylline |
| PDE5 | A | blood vessels, platelets | sildenafil |
| PDE6 | A, B, C, D, G, H | retina | sildenafil |
| PDE7 | A, B | skeletal muscle | |
| PDE8 | A, B | ||
| PDE9 | A | ||
| PDE10 | A | ||
| PDE11 | A |
Phosphodiesterase isoenzymes. Theophylline (and papaverine) are non-specific inhibitors.
The cardiac specific phosphodiesterase inhibitors (PDI3s) were initially widely touted as an alternative to digitalis in man but are going out of fashion as although they alleviate congestive heart failure, they reduce survival time in man. They seem to improve the quality of life but increase the chances of sudden death, probably from arrhythmias. This is probably acceptable in animals.
PDI4s are currently undergoing investigation as anti-inflammatory drugs. Sildenafil is a PDI5.
Methylxanthines (usually theophylline esters such as aminophylline or etamiphylline) are also adenosine A2 receptor antagonists. Adenosine is secreted by most cells in response to high energy usage compared to oxygen availability, and acts as an autacoid to decrease the oxygen demand and to increase oxygen availability through alterations to blood flow.
Effects
Methylxanthines act as weak positive inotropes, but more importantly they relax smooth muscle in bronchi and pulmonary vasculature. They induce diuresis both by increasing cardiac output and hence renal blood flow, and by increasing renal blood flow directly through blockade of adenosine's vasoconstrictive actions in renal vessels. Methylxanthines may also cause central stimulation which is probably a major part of their clinical effect (a previously lethargic dog becomes active again). The relative importance of these effects is different for each drug.
Side effects
Indications
mild congestive heart failure, for bronchodilator effects in patients with myocardial
failure, pulmonary oedema or asthma.
Care
use with caution in animals with
Dose
Theophyllines have a low therapeutic index so determine dosage correctly. Dose obese animals on their lean body weight. Sustained release products offer the advantage of less frequent dosing, better owner compliance and less fluctuation in blood levels but results may be erratic in animals. im injection is painful; iv injection must be very slow, though because of good bioavailability of oral preparations it is rarely used.
Amrinone was the first specific cardiac phosphodiesterase inhibitor but is no longer available in NZ. An intravenous bolus of amrinone in dogs leads to a 60 -100% increase in cardiac contractile force which lasts 5 - 20 minutes, and a 10 - 30% increase in systemic arterial blood pressure. In humans amrinone improves left ventricular performance and this effect is sustained. Withdrawal of therapy results in cardiac decompensation. It was used for short term management of congestive heart failure refractory to other treatment. Its long term efficacy for congestive heart disease has not been evaluated in animals, in people long term survival is reduced.
Milrinone is the only cardiac specific PDI available here. It is a methylcarbonitrile derivative of amrinone which is 20 to 30 times more potent than amrinone. Its cardiovascular effects are reported to be similar to those of amrinone but without increases in heart rate. In one trial approxiamately 70% of dogs with myocardial failure responded well to this drug.
Its short half life and duaration of action in dogs mean that it usually has to be given four times daily so is not really practical for outpatients.
Milrinone has a large therapeutic ratio. Ventricular arrhthymias occur in < 5% of dogs with myocardial failure.
Pimobendan is a similar drug for use in dogs. In addition to PD inhibition, it is also supposed to "sensitise" the myocardium to calcium. This effect is likely to be useful since it involves no extra oxygen consumption and the myocardial calcium modulation is impaired in CHF. It prolongs life in dogs in dilated cardiomyopathy but not in valvular insufficiency. It is usually used in combination with ACE inhibitors and frusemide. Like the methylxanthines, its major effect in many dogs may be in the CNS to make the dog feel better.
Oxpentifylline (pentoxyfylline USAN) is not normally used to treat CHF, but may be useful, both as a PDE inhibitor and as a tumour necrosis factor α antagonist (reduces myocardial inflammation).
