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Shock is a common presentation to the ED, with the incidence of septic shock increasing in Australasia over the last decade. The choice of inotropic agent is likely dependent on previous experience and local practices of the emergency and other critical care departments. The relatively short duration of stay in the ED before transfer leaves little room for evaluating the appropriateness of and response to the agent chosen. Delays in transfer to inpatient facilities means that patients receive advanced critical care within the ED for longer, requiring initiation and titration of vasoactive agents in the ED. This article discusses the general concepts of shock and the indicators for inotrope and vasopressor use, revises the various agents available and reviews the current evidence for their use.

Possible arrhythmogenic side-effects of the positive inotropic agent prenalterol were studied in conscious dogs, three to four days after coronary artery ligation. Prenalterol showed a propensity to cause arrhythmias in one out of eight dogs, thereby confirming published data from clinical studies.

Dopamine is a commonly used positive inotropic agent for the treatment of hypotension in small animals. Two dogs that had undergone surgery, under isoflurane anaesthesia, developed a sudden and profound bradycardia when a dopamine infusion was administered. Bradycardia was attributed to the activation of the Bezold-Jarisch reflex, an inhibitory reflex, characterised by bradycardia and hypotension.

Background: There are currently many on-going clinical trials assessing therapies for the treatment of patients with heart failure. Aims: The purpose of this series of papers is to present concise summaries of current randomised trials in the field of heart failure and myocardial infarction (MI). Methods: Data from large double-blind, placebo-controlled trials, which are on-going or have only recently been published, are given in a format allowing easy comparison. Where appropriate, data from smaller studies are included. Results: Major studies which are examined in this issue include CIBIS II, MERIT-HF, RESOLVD, SPICE, VEST, MACH-1, ATLAS, RALES, CIDS and CASH. These trials assess the efficacy and safety of beta-blocker, angiotensin-II-receptor blocker, positive inotropic agent, calcium antagonist, angiotensin-converting enzyme (ACE) inhibitor, aldosterone receptor blocker, and antiarrhythmic interventions in the treatment of heart failure. Conclusions: The presentation of data from these on-going trials should allow an up-to-date assessment, by physicians, of the most appropriate and effective treatment for patients with heart failure. It is evident that some therapies may play no further role in the treatment of heart failure, due to the increased risk of mortality associated with their administration, whilst others may convey significant benefits.

A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.

SK&F 94836, a selective PDE III inhibitor is a positive inotropic agent with vasodilator activity. The syntheses of (-)-[N-methyl-14C]SK&F 94836, (+)-[N-methyl-14C]SK&F 94836 and [carbonyl-14C] SK&F 94836 are described. The racemate, labelled in the dihydropyridazinone heterocycle was obtained in 24.6% overall yield from K[14C]CN. The chiral compounds were radiolabelled by reacting a resolved precursor with [14C]methylamine.

1. UK 14,275 (Pfizer) an inotropic agent with cardiac phosphodiesterase inhibitory activity, was administered to ten healthy male volunteers. 2. The inotropic activity was assessed by non-invasive measurement of systolic time intervals (STI). 3. The compound had significant inotropic activity in the doses administered, as judged by the shortening of pre-ejection period (PEP), without any significant chronotropic activity. 4. The inotropic effect was abolished when measurements were repeated following beta-adrenoceptor blockade with oral propranolol. 5. The inotropic activity was compared to that of intravenous isoprenaline.

Inocor™ brand of amrinone1 (5-amino-3,4-bipyridin-6(1H)-one-514C) a new positive inotropic agent was obtained [14C] labelled at Carbon 5 in 55% overall yield.

[14C]Pelrinone (1,4-dihydro-2-methyl-4-oxo-6[(3-pyridinylmethyl)-amino]-5-pyrimidine-[14C]-carbonitrile hydrochloride; AY-28,768 hydrochloride), a potent inotropic agent, was prepared by reacting chloroacetic acid with [14C]sodium cyanide to give the labelled cyanoacetic acid. The acid was esterified, converted to the bis-S-methyl compound, condensed with acetamidine hydrochloride, coupled with 3-aminomethylpyridine, and treated with methanolic hydrochloric acid. Two batches of [14C]pelrinone were produced, giving a combined overall yield of 15.6% from [14C]sodium cyanide (sp. act. 66.2 ± 1.5 and 64.2 ± 1.9 μCi/mg; 98.8 and 98.0% radiochemical purity, respectively).

1 BM 10.188 (Doxaminol, Boehringer Mannheim, GmbH) is a recently developed beta-sympathomimetic agent which has shown promising positive inotropic activity in experimental animal models. It is a dibenzoxepine derivative. 2 The effects of 20 mg oral BM 10.188 on systolic time intervals and standard echocardiographic parameters have been studied in six normal healthy male volunteers. 3 When assessed by repeated measured analysis of variance, QS2 and LVET shortened significantly (P less than 0.005) in the 8 h period following BM 10.188. Mean maximum shortening values were: QS2, 25.7 +/- 25.6 (s.d.) ms at 155 min and LVET, 10.7 +/- 9.5 (s.d.) ms at 155 min. There was a corresponding small but significant increase of 4.2 +/- 3.9 (s.d.) ml in stroke volume at 6 h (P less than 0.025). 4 These results indicate that in normal volunteers, BM 10.188 exhibits effects on noninvasive cardiological indices similar to those observed after cardiac glycosides.

A patient with severe cardiac failure due to idiopathic congestive cardiomyopathy resistant to conventional therapy, responded to amrinone, a new non-glycosidic non-catecholamine positive inotropic agent. Amrinone produced significant haemodynamic improvement during both intravenous and oral administration. Thrombocytopaenia, however, was induced, necessitating cessation of the drug. Amrinone is a promising, orally effective inotropic agent for patients with refractory congestive cardiac failure, but is limited by its tendency to cause thrombocytopaenia.