Side effects associated with phosphodiesterase inhibitors:
Prog Cardiovasc Dis 1995 Sep;38(2):167-180 ; Electrophysiologic and proarrhythmic effects of intravenous inotropic agents.;
Tisdale JE, Patel R, Webb CR, Borzak S, Zarowitz BJ
The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors.
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Eur J Clin Pharmacol 1994;46(3):191-196 ; Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis.; Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, Fareh S, de Breyne B
Unite de Pharmacologie Clinique, Hopital Cardiologique, Lyon, France.
We examined the influence of phosphodiesterase inhibitors (PDIs) on mortality in patients with overt chronic heart failure. A total of 13 randomised, placebo-controlled trials of PDIs involving 2808 patients were selected. Meta-analysis, using data for all patients, showed that there was a non-significant (P = 0.16) increase of about 17% in the mortality rate of patients receiving a PDI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.94-1.46]. However, the observed treatment effects were found to be heterogeneous due to the results from the trials on vesnarinone. The heterogeneity became non-significant (P = 0.77) when these trials were removed, and a significant increase in the mortality rate was observed under treatment with the other PDIs (OR 1.41, 95% CI 1.11-1.79). In the subgroups of patients with or without additional vasodilator (VD) treatment, similar results were observed (PDI with VD: OR 1.3, 95% CI 1.03-1.7; PDI without VD: OR 2.04, 95% CI 1.1-3.8). These results indicate that PDIs (with the exception of vesnarinone) should not be prescribed for long-term use in patients with overt chronic heart failure. Additional vasodilator treatment in patients receiving PDIs for chronic heart failure does not explain the increased mortality seen with PDIs. This toxicity must, therefore, arise by other mechanisms. Further experimental and clinical evaluation is needed to confirm the beneficial influence of vesnarinone on survival in chronic heart failure patients and to identify the mechanism(s) differentiating this agent's therapeutic effect from that of other PDIs.
(Comment: Patients with heart failure are at increased risk of cardiac arrhythmias . However, when a drug is used in a large population, even a slight increase in risk may translate to a clinically significant side-effect. Patients with cardiac disease are also more likely to be impotent, due to similar underlying diseases that cause these conditions. Therefore, their risk of cardiac problems may be greater than that in the general population. LB)
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Drug Saf 1993 Dec;9(6):404-409 ; Phosphodiesterase inhibitors. Do the risks outweight the benefits?; Andrews R, Cowley AJ; Division of Cardiovascular Medicine, University Hospital, Nottingham, England.
Despite the justifiable concern about the use of oral cyclic adenosine monophosphate phosphodiesterase (cAMP PDE) inhibitors, the intravenous preparations are clearly effective in the treatment of acute heart failure, whether it occurs de novo or complicating chronic congestive heart failure (CHF), and in low output states following cardiac surgery. There are no grounds to curtail their use in these areas, though any advantages over conventional agents such as dobutamine need further investigation with regard to end-points other than haemodynamic parameters. The long term use of oral cAMP PDE inhibitors in the treatment of chronic CHF should remain restricted by the increase in mortality now confirmed in severe CHF. However, in view of the distressing nature of the condition there remain subgroups of patients in whom the benefits may outweight the risks.
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Cardiovasc Drugs Ther 1993 Aug;7(4):655-660 ; Phosphodiesterase III inhibitors: long-term risks and short-term benefits.; Cruickshank JM
Royal Brompton National Heart and Lung Hospital, London, UK.
Heart failure is now viewed as a disorder of the circulation, not merely the heart, which becomes manifest only when certain compensatory mechanisms break down. After treatment with diuretics, the two main strategies in treating heart failure involve decreasing the work of the heart by vasodilatation or increasing ventricular contractility by positive inotropic agents. It is now apparent, however, that the resulting hemodynamic benefit need not equate with long-term clinical improvement or increased longevity; indeed, the reverse can be true. Inhibitors of phosphodiesterase III, which is specific for the breakdown of cyclic adenosine monophosphate (cAMP), produce useful hemodynamic effects following intravenous and oral dosing, but have not fulfilled their initial promise in the chronic oral treatment of heart failure patients. The reason for reduced survival in the long-term studies of milrinone is not clear, but cardiac arrhythmias, possibly resulting from the increased intracellular levels of cAMP, may be responsible. However, intravenous usage may not suffer from the same limitations as chronic oral dosing. Short-term intravenous administration produces the expected beneficial hemodynamic effects of positive inotropism and vasodilatation. Though infusions of milrinone have been shown to enhance atrioventricular conduction in some, but not all, studies, there appears to be no significant increase in ventricular premature contractions, or ventricular or sustained tachyarrhythmias. Because milrinone does not have a significant adverse effect on His-Purkinje conduction, its use should be well tolerated in patients with intraventricular conduction disturbances. However, accurate assessment of the mortality risk and benefit of short-term intravenous treatment remains to be made in sufficiently powerful prospective, randomized controlled studies.
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Clin Cardiol 1993 Jan;16(1):5-14 ; Inotropic therapy of the failing myocardium.; Om A, Hess ML
Division of Cardiopulmonary Laboratories and Research, Medical College of Virginia, Virginia Commonwealth University, Richmond.
The clinical syndrome of congestive heart failure remains a therapeutic dilemma and challenge for the physician in 1992.... Unfortunately, the phosphodiesterase inhibitors--amrinone, milrinone, and enoximone--have demonstrated unacceptable clinical side effects and have been withdrawn from further clinical study.....
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Br J Urol 1997 Jun;79(6):958-963 ; Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro.
Jeremy JY, Ballard SA, Naylor AM, Miller MA, Angelini GD
Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, UK.
OBJECTIVE: To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation of cGMP and cAMP in the corpus cavernosum of the rabbit. MATERIALS AND METHODS: Male New Zealand White rabbits (2.5 kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were then incubated with various concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the cGMP and cAMP concentrations measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as an erectogen. RESULTS: In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing dose; the increase was greatest (about 28-fold) when cGMP was stimulated with SNP (up to 10 mumol/L). At all stimulatory concentrations of SNP, the effective concentrations for 50% stimulation (EC50) of sildenafil were 430-520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (> or = 10 mumol/L). CONCLUSIONS: Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide-mediated relaxation pathways. The erectogenic effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafil as a potent and highly selective inhibitor of cGMP-specific PDE.
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Boolell M, et al. ;
Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.
Int J Impot Res. 1996 Jun 1; 8(2): 47-52.
PMID: 8858389; UI: 97011379. |
