Phosphodiesterase type III inhibitors

Amrinone

Adverse reactions to amrinone [ ] include thrombocytopenia (10%), hypotension, tachydysrhythmias (sometimes resulting in syncope and death) (9%), worsening cardiac ischemia (7%), worsening heart failure (15%), gastrointestinal disturbances (39%), neurological complications (17%), liver damage (7%), fever (6%), nephrogenic diabetes insipidus, hyperuricemia, flaking of the skin, brown discoloration of the nails, and reduced tear secretions. The figures in parentheses are taken from a study of the use of amrinone in 173 patients with chronic ischemic heart disease or idiopathic cardiomyopathies [ ].

Other reported adverse reactions include acute pleuropericardial effusions, perforated duodenal ulcer, acute myositis and pulmonary infiltrates, vasculitis with pulmonary infiltrates and jaundice, influenza-like illnesses, chest pain, headache, dizziness, anxiety, maculopapular rash, and night sweats [ ].

Enoximone

The most common adverse reactions to enoximone are gastrointestinal and cardiac. The gastrointestinal effects include anorexia, nausea, vomiting, and diarrhea [ , ]. Other rarely reported adverse effects include thrombocytopenia, leukocytosis, increased appetite, increased serum activity of alanine aminotransferase, hyperglycemia, headache, lethargy, anxiety, dyspnea, and skin rashes [ ].

Milrinone

Although the long-term oral use of inhibitors of phosphodiesterase type III is associated with increased mortality [ ], milrinone has been used intravenously in patients with heart failure, both for short-term and longer-term therapy [ ]. It has been suggested to be particularly useful in tiding patients over while they are waiting for definitive treatment.

• A 48-year-old man with an inflammatory aneurysm of the ascending aorta and severe heart failure due to massive aortic regurgitation was given a continuous intravenous infusion of milrinone 0.5 micrograms/kg/minute [ ]. His pulmonary arterial pressure fell and his symptoms improved over 7 weeks while he was taking corticosteroids. The diseased tissue was successfully replaced at operation and the milrinone was tapered uneventfully.

The authors suggested that continuous milrinone infusion may be suitable for patients with surgically correctable inflammatory cardiovascular diseases complicating severe heart failure in whom maintenance of optimal hemodynamics is necessary for several weeks before operation.

The disappointing results with positive inotropic drugs in treating acute and chronic heart failure may be due to the fact that they increase both systolic and diastolic calcium concentrations in the myocardium [ ].

Olprinone

Olprinone is given intravenously and is mostly eliminated by the kidneys. Its pharmacological effects have been reviewed [ ]. Major adverse reactions are cardiac dysrhythmias and thrombocytopenia, the latter with a reported incidence of 0.43%.

Pimobendan

Pimobendan derives its inotropic effect from a combination of phosphodiesterase III inhibition and sensitization of myocardial contractile proteins to calcium [ ].

Sulmazole

Sulmazole commonly causes adverse gastrointestinal effects; dose-related anorexia, nausea, and vomiting have been reported in about 50% of patients given an intravenous infusion [ , ] and also after single oral doses [ ]. Cardiac dysrhythmias, mostly ventricular, have been reported occasionally with sulmazole [ ]. Other reported adverse reactions in small numbers of patients include headache [ ], temporary visual disturbances [ , ], discoloration of the urine (attributed to a metabolite) [ ], and a small reduction in platelet count [ ].

Vesnarinone

Vesnarinone increases the risk of sudden cardiac death in patients with congestive heart failure and can cause neutropenia. It has also been used to treat cancer, and its effects have been reviewed [ ]. It has immunomodulatory effects, including suppression of tumor necrosis factor-induced activation of NF-κB, NK cell activity, and endotoxin-induced production of inflammatory cytokines, and altered expression of E selectin in endothelial cells, and it induces apoptosis and suppresses growth in a variety of in vitro cell lines. The precautions for using vesnarinone and its adverse effects have been reviewed [ ]. The most important adverse effects are an increased risk of sudden death and neutropenia. They are dose-related in the therapeutic range of doses (i.e. collateral adverse effects). Patients with renal impairment should not receive vesnarinone and care should be taken in patients who are also taking drugs that inhibit CYP3A.

Observational studies

In a retrospective study of the effects of long-term combination therapy with intravenous milrinone and oral beta-blockers in 65 patients with severe congestive heart failure (New York Heart Association class IV and ejection fraction less than 25%) refractory to oral therapy, 51 successfully began beta-blocker therapy while receiving intravenous milrinone [ ]. The mean duration of milrinone treatment was 269 (range 14–1026) days and functional class improved from IV to II–III. In 24 patients beta-blocker up-titration was well tolerated and milrinone was stopped. During combination therapy 16 patients died; one died of sudden cardiac death (on day 116) and the other 15 died of progressive heart failure or other complications.

There has been a study of the use of intermittent intravenous milrinone in 10 patients with end-stage congestive heart failure [ ]. Some hemodynamic benefit was obtained, but this was an open uncontrolled study and firm conclusions are impossible. There was also some improvement in the quality of life. The drug was well tolerated and only one patient had an increase in dysrhythmias (an increased frequency of ventricular extra beats).

On the premise that phosphodiesterase inhibitors also inhibit the production of cytokines, milrinone has been used in the treatment of nine patients with the systemic inflammatory response syndrome and compared with seven patients with congestive heart failure [ ]. In both groups milrinone significantly altered cardiac index, pulmonary capillary wedge pressure, and left ventricular stroke work index. In the patients with cardiac failure it also reduced systemic vascular resistance index, and the dose of adrenaline had to be increased substantially during milrinone infusion to counteract vasodilatation.