naloxone and Myotonic-Dystrophy

In persons with myotonic dystrophy (DM), the ACTH response to CRH is greater than normal, while it is delayed in response to arginine vasopressin. Since influx of extracellular Ca2+ ions is a common step in signal transduction by both of these secretagogues, an abnormality of cellular Ca2+ transport may underlie the disturbances of hypothalamic-pituitary-adrenal axis function in this condition. Seven myotonic patients were given naloxone, which stimulates endogenous CRH release, and nifedipine, which blocks L-type voltage-dependent Ca2+ channels. Each subject underwent three tests, using different drug combinations, in a single blind, placebo-controlled protocol. Pretreatment with nifedipine delayed the time of the peak plasma hormone responses after naloxone [ACTH, 32.1 +/- 2.1 vs. 51.4 +/- 4.5 min (P < 0.05); cortisol, 42.9 +/- 2.1 vs. 70.7 +/- 4.3 min (P < 0.02); for naloxone and nifedipine/naloxone, respectively]. Additionally, nifedipine significantly reduced the proportion of the mean integrated ACTH response that had occurred by 30 min after naloxone administration (32.0 +/- 4.0% for naloxone vs. 17.6 +/- 2.4% for nifedipine/naloxone; P < 0.02) and the proportion of the mean integrated cortisol response by 45 min after naloxone administration (34.7 +/- 3.5% for naloxone vs. 25.0 +/- 2.6% for nifedipine/naloxone; P < 0.02). However, the total integrated responses did not change [ACTH, 1182.6 +/- 548.9 vs. 905.5 +/- 157.0 pmol/min.L (P = NS); cortisol 17,353 +/- 2,984 vs. 18,469 +/- 3,561 nmol/min.L (P = NS); for naloxone and nifedipine/naloxone, respectively]. We conclude that nifedipine delays, but does not reduce, the ACTH and cortisol responses to naloxone in DM. Since nifedipine has a different effect on normal controls (reduced response with unchanged timing), these findings imply an abnormality of dihydropyridine-insensitive Ca2+ transport (such as T-type Ca2+ channels) in the corticotrophs of DM patients.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Biological Transport; Calcium; Child; Dihydropyridines; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Myotonic Dystrophy; Naloxone; Nifedipine; Pituitary-Adrenal System; Reference Values

Patients with Myotonic Dystrophy show an unpredictable response to several anesthetic drugs including opioids, neuromuscular blocking agents and especially reversal agents like neostigmine. We describe the case of a 40 year old patient with myotonic dystrophy who underwent laparoscopic cholecystectomy and ovarian cyst removal under general anesthesia. The authors suggest the use of the new reversal agent suggamadex, for reversing neuromuscular blockade caused by rocuronium, in patients suffering from neuromuscular disease and especially from Myotonic Dystrophy, because it rapidly and completely reverses any residual neuromuscular blockade, but also underline the increased susceptibility of these patients to opioids.

Topics: Adult; Analgesics, Opioid; Androstanols; Anesthesia Recovery Period; Anesthesia, General; Cholecystectomy, Laparoscopic; Female; gamma-Cyclodextrins; Humans; Meperidine; Myotonic Dystrophy; Naloxone; Narcotic Antagonists; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Ovarian Cysts; Pain, Postoperative; Respiratory Insufficiency; Rocuronium; Sugammadex

Myotonic dystrophy (MyD) is a common genetic neuromuscular disorder in which chromosome 19 gives rise to an abnormal expansion of CTG-trinucleotide repeats. MyD is a highly variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being uncovered. Herein we present three unrelated cases with MyD with abnormally elevated serum potassium; 2 of the 3 cases presented clinically with cardiac dysrhythmias. Hyperkalaemic conditions such as renal failure, cortisol deficiency, pseudohyperkalaemia, and hyperkalaemic periodic paralysis were excluded. Further endocrine evaluation revealed baseline hypoaldosteronism associated with elevated renin activity. Perturbation of the renin-angiotensin-aldosterone system resulted in appropriately enhanced renin activity but with a subnormal aldosterone response, which appeared to be due to adrenal hyporesponsiveness. The treatment of all cases with fludrocortisone was without effect. Whether the apparent mineralocorticoid abnormality in MyD is due to associated hormonal perturbations (i.e. excessive ACTH responsiveness. elevated cytokines, elevated atrial natriuretic hormone, etc.), adrenal atrophy, and/or a manifestation of the underlying kinase dysfunction is uncertain, but merits further evaluation in view of the clinical consequence of hyperkalaemia.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Adult; Diuretics; Female; Fludrocortisone; Furosemide; Humans; Hydrocortisone; Hyperkalemia; Hypoaldosteronism; Male; Mineralocorticoids; Myotonic Dystrophy; Naloxone; Renin; Stimulation, Chemical; Treatment Failure; Trinucleotide Repeat Expansion

Myotonic dystrophy (DM) is an autosomal dominant disorder causing myotonia, progressive muscle weakness, and endocrine abnormalities including hypothalamic-pituitary-adrenal (HPA) axis hyperresponsiveness to CRH-mediated stimuli. This ACTH hyperresponsiveness appears directly related to the underlying genetic abnormality. Naloxone (Nal)-mediated CRH release causes ACTH release in normal humans and an ACTH hyperresponse in DM. Alprazolam (APZ) attenuates the ACTH release in response to Nal in normal individuals, probably by inhibiting CRH release. This study investigates the effects of APZ on Nal-induced HPA axis stimulation in DM. The ACTH response to Nal in DM subjects was significantly reduced by APZ. Despite this DM patients have a relative resistance to APZ inhibition of Nal-induced ACTH/cortisol release. APZ caused a smaller percentage reduction in AUC for ACTH in DM compared with controls. These findings provide further insight into the mechanism(s) of the HPA axis abnormalities in DM. In DM, there may be an increase in tonic opioid inhibition to CRH release with compensatory increases in stimulatory pathways. Alternatively, these patients may have a basal increase in pituitary vasopressin levels or an enhanced AVP/CRH synergistic mechanism at the level of the corticotroph.

Topics: Adrenocorticotropic Hormone; Adult; Alprazolam; Drug Combinations; Female; GABA Modulators; Humans; Male; Middle Aged; Myotonic Dystrophy; Naloxone; Narcotic Antagonists; Reference Values

We previously showed that CRH-mediated stimuli, including exogenous CRH, cause ACTH hypersecretion in many myotonic dystrophy (DM) patients. We confirmed this by giving naloxone, a stimulator of endogenous CRH release, to a large number of DM patients and controls. DM patients, first degree relatives, and normal controls received i.v. naloxone at 1400 h, and blood was taken for ACTH (RIA) and cortisol (high pressure liquid chromatography) measurements from 15 min before to 120 min after naloxone treatment. DM patients had basal ACTH levels approximately twice those of controls, and their ACTH responses were 4 times those of controls. In contrast, DM basal cortisol levels were not significantly different from those of relatives and were slightly higher than those of normal subjects. Cortisol responses were similar in the three groups, probably due to attenuation at high levels of adrenocortical stimulation, although some patients with inappropriately low cortisol responses for their level of ACTH stimulation warrant further investigation. Nineteen of the 36 patients whose ACTH responses were greater than 3 SD above the normal mean were classed as hyperresponders. Seven patients, who were tested more than once, had reproducible responses relative to those of the normal subjects. We conclude that ACTH hypersecretion after CRH-mediated stimuli, including naloxone, is an inherent, but variable, feature of DM, caused by expression of the genetic mutation at the anterior pituitary. The mechanism is probably a defect in the intracellular pathway initiated by CRH-receptor interaction as a result of abnormal levels of a cAMP-dependent kinase, DMPK, the product of the gene undergoing mutation in DM.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Blood Pressure; Child; Corticotropin-Releasing Hormone; Female; Humans; Hydrocortisone; Male; Middle Aged; Myotonic Dystrophy; Naloxone; Reference Values

The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.

Topics: Adrenocorticotropic Hormone; Adult; Aspirin; Chromatography, High Pressure Liquid; Female; Humans; Hydrocortisone; Male; Middle Aged; Myotonic Dystrophy; Naloxone; Radioimmunoassay; Sensitivity and Specificity; Time Factors