Acute electrophysiologic consequences of pyridostigmine inhibition of cholinesterase in humans

The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.

Teste de esforço cardiopulmonar durante estimulaçäo colinérgica com dose única de piridostigmina em indivíduos saudáveis / Exercise stress testing in healthy subjects during cholinergic stimulation after a single dose of pyridostigmine

OBJETIVE: The evaluation, by exercise stress testing, of the cardiorespiratory effects of pyridostigmine (PYR), a reversible acetylcholinesterase inhibitor. METHODS: A double-blind, randomized, cross-over, placebo-controlled comparison of hemodynamic and ventilation variables of 10 healthy subjects who underwent three exercise stress tests (the first for adaptation and determination of tolerance to exercise, the other two after administration of placebo or 45mg of PYR). RESULTS: Heart rate at rest was: 68 + or - 3 vs 68 + or - 3bpm before and after placebo, respectively (P=0.38); 70 + or - 2 vs 59 + or - 2bpm, before and after pyridostigmine, respectively (P<0.01). During exercise, relative to placebo: a significantly lower heart rate after PYR at, respectively, 20 per cent (P=0.02), 40 per cent (P=0.03), 80 per cent (P=0.05) and 100 per cent (P=0.02) of peak effort was observed. No significant differences were observed in arterial blood pressure, oxygen consumption at submaximal and maximal effort, exercise duration, respiratory ratio, CO2 production, ventilation threshold, minute ventilation, and oxygen pulse. CONCLUSION: Pyridostigmine, at a dose of 45mg, decreases heart rate at rest and during exercise, with minimal side effects and without interfering with exercise tolerance and ventilation variables.

Reduçäo da dispersäo do intervalo QTc: potencial mecanismo de proteçäo cardíaca do brometo de piridostigmina / Reduction of QTc interval dispersion: potential mechanism of cardiac protection of pyridostigmine bromide

OBJECTIVE: Parasympathetic dysfunction is an independent risk factor in individuals with coronary artery disease, and cholinergic stimulation is a potential therapeutical option. We determined the effects of pyridostigmine bromide, a reversible anticholinesterase agent, on electrocardiographic variables of healthy individuals. METHODS: We carried out a cross-sectional, double blind, randomized, placebo-controlled study. We obtained electrocardiographic tracings in 12 simultaneous leads of 10 healthy young individuals at rest before and after oral administration of 45 mg of pyridostigmine or placebo. RESULTS: Pyridostigmine increased RR intervals (before: 886 + or - 27 ms vs after: 1054 + or - 37 ms) and decreased QTc dispersion (before: 72 + or - 9ms vs after: 45 + or - 3ms), without changing other electrocardiographic variables (PR segment, QT interval, QTc, and QT dispersion). CONCLUSION: Bradycardia and the reduction in QTc dispersion induced by pyridostigmine may effectively represent a protective mechanism if these results can be reproduced in individuals with cardiovascular diseases.

Estimulaçäo colinérgica com piridostigmina. Análise Hemodinâmica e ecocardiográfica em indivíduos normais / Cholinergic stimulation with pyrodostigmine, hemodynamic and echocardiographic analysis in healthy subjects

Objetivo - Crescentes evidências indicam que a morte súbita em pacientes pós-infarto agudo do miocárdio (IAM) correlaciona-se com desequilíbrio do sistema nervoso autônomo. Drogas parassimpaticométricas têm sido testadas com a finalidade de reverter essas alterações. Porém, seus efeitos sobre a função ventricular necessitam de uma avaliação específica. Nosso objetivo foi analisar o efeito da pridostigmina (PIR) sobre variáveis hemodinâmicas e ecocardiográficas da função ventricular. Métodos - Vinte voluntários sadios foram submetidos a avaliações ecodopplercardiográficas e aferições de pressão arterial (PA) e freqüência cardíaca (FC) em repouso, antes e 120min após a ingestão de 30mg de PIR ou placebo, seguindo-se um protocolo duplo-cego, placebo-controlado, cruzado e randomizado, em dias diferentes. Resultados - PIR foi bem tolerada e não provocou alterações de PA ou função sistólica ventricular. A FC apresentou redução de 10,9+1,3 por cento (p<0,00001). Houve redução da onda A ao fluxo mitral (p<0,01) e aumento da relação E/A (p<0,001) sem alterar os demais índices de função diastólica (p>0,05). Conclusão - A PIR reduz a FC e aumenta a relação E/A, sem prejuízo hemodinâmico ou alteração da função ventricular.

Different effects of pyridostigmine on growth hormone (GH) response to GH-releasing hormone in endogenous and exogenous hypercortisolemic patients

1. Somatostatin may play a role in the inhibition of growth hormone (GH) response to GH-releasing hormone (GHRH) in hypercortisolism. To examine this hypothesis we studied the effect of pyridostigmine, a cholinergic agonist that decreases hypothalamic somatostatin, on the GH response to GHRH in 8 controls, in 6 patients with endogenous hypercortisolism (3 with Cushing's disease and 3 with adrenal adenomas) and in 8 patients with exogenous hypercortisolism (lupus erythematosus chronically treated with 20-60 mg/day of prednisone). Each subject received GHRH(1-29)NH2,100 micrograms iv twice, preceded by pyridostigmine (120 mg) or placebo, orally. 2. The GH response to GHRH was significantly blunted in all hypercortisolemic patients compared to controls both after placebo (GH peak, 5.8 +/- 1.6 vs 46.2 +/- 15.9 micrograms/l, mean +/- SEM) and after pyridostigmine (15.7 +/- 5.6 vs 77.2 +/- 19.8 micrograms/l). 3. The GH response was absent in endogenous hypercortisolemic patients compared to the exogenous group, both after placebo (2.2 +/- 0.3 vs 8.5 +/- 2.4 micrograms/l) and after pyridostigmine (4.9 +/- 2.5 vs 23.8 +/- 8.7 micrograms/l). The GH release after GHRH/pyridostigmine for the exogenous group was similar to the response of controls treated with GHRH/placebo. 4. These results confirm that the GH response to GHRH is blunted in hypercortisolism, although more pronounced in the endogenous group. Pyridostigmine partially reversed this inhibition in the exogenous group. Therefore, somatostatin may play a role in the inhibition of GHRH-induced GH release in exogenous hypercortisolemic states

Influence of pretreatment of carbamates on dynamic pulmonary mechanics in rats exposed to sarin aerosols.

The effect of pretreatment of two carbamates, pyridostigmine and physostigmine on dynamic pulmonary mechanics has been studied in rats exposed to sarin aerosols. Sign-free dose of pyridostigmine (0.075 mg/kg, i.m.) or physostigmine (0.1 mg/kg, i.m.) did not significantly alter the parameters of the dynamic pulmonary mechanics 20 min after treatment. However, sarin (51.2 mg/m3, for 15 min) depressed the respiratory rate, air flow and minute volume and enhanced the transthoracic pressure and tidal volume. Pretreatment with carbamates 20 min prior to sarin exposure significantly modified or counteracted the above induced changes. It is concluded that the protective effect of carbamates is mainly due to the correction of respiratory changes caused by sarin aerosols in rats.

Efeitos cardiovasculares dos relaxantes neuromusculares / Cardiovascular effects of neuromuscular relaxants

O autor faz uma revisäo das açöes farmacológicas dos relaxantes neuromusculares sobre o sistema cardiovascular. Os mecanismos básicos pelos quais os relaxantes neuromusculares induzem efeitos cardiovasculares säo sumarizados. Entre estes incluem a liberaçäo de histamina, bloqueio ganglionar, bloqueio dos receptores muscarínicos no sistema cardiovascular e a recaptaçäo das catecolaminas a nível neural. Consideraçöes sobre os mais recentes agentes, atracúrio e vecurônio, säo feitas, especialmente quanto aos seus efeitos hemodinâmicos

Antagonismo do bloqueio neuromuscular / Neuromuscular blockade antagonism

O autor faz uma revisäo da farmacocinética e farmacodinâmica dos anticolinesterásicos, que constituem os principais antagonistas dos relaxantes neuromusculares. Os fatores que alteram o antagonismo säo discutidos além das possíveis interaçöes com outras drogas. A monitorizaçäo da atividade da junçäo mioneural, bem como a avaliaçäo do antagonismo, säo abordadas do ponto de vista clínico