Chronic Overdose Research Articles

Lithium

Lithium is used widely in the treatment of manic depressive psychosis. Chronic overdoses are relatively common because the therapeutic index of lithium is narrow.

Thyroxine and Tri-iodothyronine

Only a small percentage of patients who ingest even a substantial single overdose of thyroxine (T4) or tri-iodothyronine (T3) develop features of toxicity. However, chronic overdose in patients taking replacement therapy presents with the typical features of hyperthyroidism.

L‐thyroxine‐induced vasodilation impairment and increased vascular response to norepinephrine are mediated by dysfunctional NO release

AbstractHyperthyroidism causes a series of changes in the cardiovascular system. The effects of excess thyroid hormone on NO‐mediated vasorelaxation and vasocontractility were investigated. A pathological hyperthyroid rat model was developed. Thoracic aorta was isolated and isometric changes were recorded in both control and thyroxine‐treated animals. In the vasorelaxation study, the overall acetylcholine‐induced vasorelaxation was greatly reduced in aortae from thyroxine‐treated animals. L‐NO‐arginine (100 mM) was used to define the NO‐dependent and NO‐independent components of acetylcholine‐induced relaxation: in control animals 56±2% of relaxation is NO‐dependent and 44±2% is NO‐independent and in the thyroxine model the ratio was 31±2% vs. 69±5%. L‐arginine (10 μM), an NO synthase substrate, did not increase the relaxation in the control (2%), but markedly increased relaxation (18%) in the thyroxine model. This indicates that L‐arginine could partially rescue the vasorelaxation impairment induced by L‐thyroxine. In vasocontractility studies, the maximal aorta responses to NE in the thyroxine group were reduced significantly, but the responses to low concentrations of NE were enhanced comparing with control. The basal release of NO from the endothelium is compromised in the thyroxine model: +28±5% in the thyroxin‐treated group vs. +39±5% in the control. (P<0.01). The AUC was shifted downward in both groups, but was relatively larger by –66±5% in the thyroxine model compared with –56±4% in control (P<0.01) after the application of L‐arginine. When L‐NO arginine was added to aortae pretreated with L‐arginine, vascular tone was increased in control tissues, but no change was observed in thyroxine‐treated tissues. In conclusion, chronic overdose of L‐thyroxine significantly impairs the acetylcholine‐induced vasorelaxation activity by affecting both the NO‐dependent and NO‐independent relaxing components of relaxation. The impaired maximal contraction of vascular smooth muscle to high concentrations of NE is likely attributed to the imbalance of energy supply and the enhancement of the vascular tension to NE at low concentration is attributed both to an impairment of the basal release of NO and to an overload of intracellular calcium. Drug Dev. Res. 58:116–121, 2003. © 2003 Wiley‐Liss, Inc.

Chronic acetaminophen toxicity: a case report and review of the literature

Acetaminophen is one of the most frequently used medications in the United States. While usual dosing of acetaminophen is considered harmless, both acute and chronic overdoses can be fatal. The majority of reported cases of chronic acetaminophen toxicity in adults occur in chronic alcohol abusers, patients taking P450-inducing medications, or following massive dosing. We describe a case of toxic hepatitis free of the aforementioned risk factors associated with chronic ingestion of moderately excessive doses of acetaminophen. Our patient ingested approximately 5.0 to 6.5 g of acetaminophen daily for 6 to 8 weeks via multiple medications. The inclusion of acetaminophen in numerous medications combined with the frequency of use of acetaminophen necessitates an increased concern for not only acute but also chronic acetaminophen toxicity.

Comparable Effects of DIGIBIND and DigiFab in Thirteen Digoxin Immunoassays

Digoxin is widely prescribed for the treatment of cardiac conditions (1). Because of its narrow therapeutic range, digoxin-related toxicity resulting from acute or chronic overdose is common. Metabolites of digoxin as well as related compounds, including digitoxin, tanshinones, bufandienolide, and oleander, can contribute to or independently produce digoxin toxicity (2)(3). Digoxin toxicity can be rapidly and safely reversed by administration of anti-digoxin immune fragments (Fab) such as DIGIBIND®, which has been available in the US since 1986. Therapeutic Fab products act by binding digoxin with high affinity (109–1010 L/mol), favoring movement of digoxin out of tissue and thus promoting elimination. Factors that impact dosing with Fab products include known or suspected digoxin load, patient weight and history, and renal function (4)(5)(6)(7). Monitoring the free digoxin concentration after Fab administration may help ensure appropriate dosing, prevent deadly recrudescent toxicity, and determine when digoxin therapy should be resumed (8)(9)(10). Monitoring free digoxin in serum is challenged by the positive interference that has been extensively described with DIGIBIND, which interferes with immunoassays by competing with assay capture antibodies. The degree of interference depends on incubation times, washing steps, and the affinity of capture antibody for bound vs free digoxin (11)(12)(13). Consequently, monitoring of free digoxin in ultrafiltrates is a popular strategy for managing DIGIBIND-treated patients. Although ultrafiltration eliminates interference produced by large molecules, such as endogenous digoxin-like immunoreactive factors (DLIFs) and DIGIBIND, it does not eliminate interferences produced by small molecules known to interfere with digoxin immunoassays, such as spironolactone (14). In addition, ultrafiltration methods are not standardized, may require matrix-specific calibration, add expense and manual manipulation, and lengthen turnaround time (8)(15)(16). DigiFabTM is a …

Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose

Aspirin (acetylsalicylic acid) is widely available without prescription. Although self-poisoning is rare, if severe it may be life threatening. Haemodialysis has been recommended in severe cases when salicylate levels exceed 7.3 mmol l(-1). We describe three cases of severe salicylate poisoning, which were treated with continuous veno-venous haemodiafiltration (CVVHDF). All patients survived. The first case had already undergone haemodialysis before transfer to the ICU, where CVVHDF was commenced because salicylism persisted at 3 mmol l(-1). A small reduction in serum salicylate was noted. In the second case, serum salicylate decreased from 8.5 to 3.5 mmol l(-1) after 3 h of CVVHDF even though only minimal urine was produced. Our third case is a chronic overdose in whom serum salicylate decreased from 6.2 to 4 mmol l(-1) after 4 h and to 1.4 mmol l(-1) after a further 7 h. No bicarbonate was administered to this patient and elimination can only be attributed to CVVHDF and urinary clearance, which is known to be slow. We discuss the pathogenesis of severe salicylate toxicity and postulate that CVVHDF, which is widely used in the intensive care setting, may be a useful therapy in severely poisoned patients who are unstable and cannot undergo haemodialysis or in situations where haemodialysis is unavailable.

The many faces of ecstasy.

References to the word ecstasy in popular culture can mean different things to different individuals. The most common form of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]), is an amphetamine with some hallucinogenic properties at high doses. It is directly neurotoxic to the human brain and has been linked to a number of deaths worldwide. Deaths result from hyperthermia, hyponatremia, or cerebral edema. A naturally occurring metabolite of gamma-aminobutyric acid, gammahydroxybutyrate (GHB) is a potent central nervous system depressant. Although GHB is a Schedule I drug, analogs remain widely available for consumption. Acute intoxication with GHB or its analogs leads to coma and respiratory depression. Chronic use of GHB or its analogs is associated with a withdrawal syndrome characterized by autonomic excitation. Herbal ecstasy refers to ephedrine-containing preparations. Acute and chronic overdoses of herbal ecstasy have been linked to hypertension, tachydysrythmias, myocardial infarctions, cerebrovascular accidents, and deaths. There is no regulation of the ephedrine content of available herbal ecstasy products.

Respiratory Distress Caused by Salicylism Confirmed by Lung Biopsy

For decades, salicylates have been recognised as one of the leading causes of drug overdoses. Deaths attributable to salicylates alone can be as high as 20.6% per year of analgesic drug deaths.[1] The incidence of salicylate poisonings, especially those with a chronic component, is difficult to ascertain because of the under-reporting of such cases and the poor correlation with serum levels. However, it is perceived to be low and usually occurs in patients with chronic pain.[2] Classic signs and symptoms in mild cases of acute salicylate toxicity include tachypnoea, lethargy, vomiting and hyperthermia without overt acidosis. In severe cases, symptoms worsen and, in addition, the patient may have metabolic acidosis and/or coma.[3] These symptoms correlate with the Done nomogram, which is used to assess the severity of acute salicylate poisoning.[4] Unfortunately, the severity of chronic salicylate overdoses is difficult to determine since serum concentrations do not accurately correlate with the Done nomogram.[5] Data illustrating the clinical ramifications of mixed acute and chronic intoxication of salicylates are scarce. Pulmonary injury has been well documented with chronic salicylate toxicity. Animal lung biopsy studies of salicylate poisoning have demonstrated increased permeability of alveoli.[6] To the best of our knowledge, these findings have not been confirmed in humans other than at autopsy.[7] This case illustrates the magnitude of diffuse pulmonary damage resulting in respiratory failure from long-term salicylate use as well as histological evidence in an otherwise healthy individual.

Evaluating Acetaminophen and Salicylate Poisoning in an Emergency Setting

The poisoned patient often presents as a diagnostic and therapeutic dilemma. The emergency department physician (or medical toxicologist) not only depends upon the history of the patient and clinical findings of a specific drug or toxin, but also relies heavily on the clinical laboratory to provide information to guide proper patient management. The medical necessity of these results can often vary in an acute vs a chronic overdose. Two of the most common poisonings encountered in the emergency department are overdoses of acetaminophen and aspirin (acetylsalicylic acid). With both drugs, the laboratory plays a major role in the diagnosis and treatment of these patients.

REVISED FOOD AND DRUG ADMINISTRATION (FDA) LABELING GUIDELINES FOR THEOPHYLLINE ORAL DOSAGE FORMS

The revised labeling for oral theophylline products recently issued in January 1995 by the United States' Food and Drug Administration is reviewed. Important revisions have been made in the following sections: Clinical Pharmacology, Indications and Usage, Warnings, Precautions, Overdosage, and Dosage and Administration. Specifically, factors known to alter theophylline absorption, disposition, and metabolism are now listed in the Clinical Pharmacology section, as are mean values for clearance and half-life of the drug in different populations (age groups, physiologic states). Theophylline is no longer indicated for the treatment of acute bronchoconstriction (consistent with present treatment guidelines), but only as maintenance therapy for chronic asthma symptoms. In the Warnings and Precautions sections, drugs and other factors that necessitate a change in theophylline dose are listed and details for properly monitoring serum theophylline concentrations have been added. The revised overdosage section now notes the frequency of clinical manifestations of overdosage, differences between acute and chronic overdose, and contains new recommendations for overdose management. Finally, in the Dosage and Administration section a slow (9-day) dosage titration scheme, aimed at reducing transient caffeine-like adverse effects, and a lower target peak serum concentration of 10 to 15 µg/mL are recommended.

Sudden Death Putatively Related to Desipramine Treatment in Youth: A Fifth Case and a Review of Speculative Mechanisms

ABSTRACT A 14-year-old boy with attention-deficit/hyperactivity disorder was prescribed desipramine for over 12 months, and had been generally stable on 300 mg daily at the time of his death. Three months before, his plasma desipramine level was 132 ng/mL while taking 225 mg daily. Family history included cardiac disease but not sudden death. After diving in a pool for several minutes, he climbed out of the pool, sat down, and lost consciousness. Witnesses described body movements that might have been a seizure. Despite extensive resuscitation, the patient died within 1 h. There was no evidence of acute or chronic overdose, suicidality, pill hoarding, or missing pills. Autopsy uncovered an anomaly in the size of the right coronary artery. This is the fifth reported case of sudden unexplained death of a youth during tricyclic antidepressant treatment that is not attributed to overdose. All five cases have involved desipramine, and three occurred during or just following physical exertion. Despite ample ava...

Emergency management of drug overdose

Successful management of patients presenting after intentional, accidental, acute or chronic overdose depends on prompt identification of drugs ingested, an organized approach of care that centers around stabilization, patient assessment, gastric evacuation, GI/systemic elimination, patient education and psychiatric evaluation.

Chronic overdose of oral antidiabetic drugs

The introduction of new drugs into medical practice is accompanied by the need to solve such a problem as the correct choice of the drug, the identification of its toxic manifestations and side effects. Of practical importance is the syndrome of chronic insulin overdose (CSI) - Samoji syndrome, which is characterized by paradoxical hyperglycemia in response to an increase in the dose of insulin.

Inappropriate Use of High-Dose Glyburide to Treat Uncontrolled Type 2 Diabetes Mellitus

To report a case of chronic glyburide overdose. A patient with noninsulin-dependent diabetes mellitus (NIDDM) who had previously developed secondary failure while taking a maximal dosage of glipizide was switched to glyburide 5 mg/d. The patient initially experienced adequate glycemic control while taking glyburide, but subsequently experienced deterioration in glycemic control. This necessitated gradual increases in the dosage of glyburide until the maximum dosage of 20 mg/d was reached. Because the patient's diabetic control did not improve with this dosage of glyburide, she decided independently to increase the dosage further. She ingested an average daily dose of 37.7 mg of glyburide over the 18 days that preceded her clinic visit without experiencing any glyburide-related adverse effects. Progression of NIDDM may be responsible for the development of secondary sulfonylurea failure in NIDDM patients treated with oral sulfonylurea drugs. Consequently, these patients should be treated as patients dependent on insulin. NIDDM patients treated with oral sulfonylurea drugs require long-term blood glucose monitoring to detect the development of secondary sulfonylurea failure. Patients who experience secondary failure to a particular sulfonylurea drug do not appear to develop long-term blood glucose control when switched to a different oral sulfonylurea drug. These patients should be treated with insulin therapy.

Pharmacokinetics of drugs in overdose.

The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution may delay or broaden peak serum concentrations. The pathophysiological effects of a drug may also limit or augment absorption. Altered distribution of drugs in overdose results from changes in the extent of protein binding and size of the volume of distribution. Saturation of hepatic enzyme systems in overdose is manifested by delayed metabolism or elimination of many drugs; renal elimination of unchanged drug may take on greater importance in this instance. Familiarity with the toxicokinetic profile of a given drug enables the physician to exploit these principles in order to limit toxicity. Delayed or prolonged absorption allows for late decontamination. Multiple doses of activated charcoal are effective in interrupting both entero-enteric and enterohepatic recirculation. Alkalinisation-induced ion trapping enhances renal elimination of unchanged drugs which normally undergo hepatic transformation. For several drugs, chronic overdose due to altered distribution is associated with a greater severity of toxic manifestations despite relatively low serum drug concentrations. Conversely, with some drugs, induction of metabolic pathways may lead to more rapid drug elimination in chronic overdose. Knowledge of the pharmacokinetic alterations which occur in drug overdose enables the physician to predict toxicity with greater accuracy and to institute optimum therapy in a timely manner.

Cause of death in an emergency department

A retrospective review was done of 601 consecutive emergency department deaths. Nontrauma causes accounted for 77% of the deaths and this group had an average age of 64 years and a male to female ratio of 1.9:1. Trauma caused 23% of the fatalities and this group had a younger average age of 29 years and a male to female ratio of 4.6:1. The most common causes of nontrauma death were sudden death of uncertain cause (34%), coronary artery disease (34%), cancer (5%), other heart disease (4%), chronic obstructive lung disease (3%), drug overdose (3%), and sudden infant death syndrome (2%). The most common causes of trauma death were motor vehicle accidents (61%) and gunshot wounds (16%). The overall autopsy rate was 40%. Death certificates were often in error.

The differences between acute and chronic theophylline overdose

The differences between acute and chronic theophylline overdose

Peripheral blood flow in chronic ergotism.

Muscle blood flow (MBF) was determined in 11 patients on chronic overdoses of ergotamine tartrate and in 12 controls, using the local 133xenon clearance method. The difference in MBFs between the groups was insignificant, 59.7 +/- 21.4 and 61.6 +/- 10.8 ml/100 g/min, respectively. Six patients taking ergotamine in doses exceeding 0.25 mg/kg/week showed a significant (p less than 0.01) reduction of MBF (45.2 +/- 10.7 ml/100 g/min). This reduction could be measured before the manifestation of symptoms or signs of circulatory insufficiency.

"Thyroid Storm" Produced by Acute Thyroid Hormone Poisoning

Case Studies1 April 1966"Thyroid Storm" Produced by Acute Thyroid Hormone PoisoningEDWIN S. SCHOTTSTAEDT, M.D., MARVIN SMOLLER, M.D.EDWIN S. SCHOTTSTAEDT, M.D.Search for more papers by this author, MARVIN SMOLLER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-64-4-847 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThyrotoxicosis resulting from chronic overdose of thyroid hormone is a well-recognized, frequently reported syndrome (1, 2), but the production of a severe hyperthyroid state resembling "thyroid storm" by a massive overdose of thyroid hormone appears to be exceedingly rare. The only case in the literature of acute thyroid hormone poisoning with severe hyperthyroid symptoms was reported by Levy and Gilger (3) in 1957; a 15-month-old child ingested 3.2 gr of desiccated thyroid. In 1954 Atkinson (4) described a case of ingestion of desiccated thyroid and amphetamine and development of a moderately severe hyperthyroid state, but it was unclear how much...

Changes in oral structures of the dog persisting after chronic overdoses of vitamin D

Young dogs receiving daily excessive doses of vitamin D 2 and D 3 for a five-month period manifested profound pathologic changes, which included distorted and deformed roots, pathologic calcifications of connective tissues of the paradentium, hypercementosis, pulp stone formation, and advanced paradentosis. The changes persisted following a recovery period of similar duration. No evidence of healing or repair could be demonstrated. The warnings of other investigators regarding the danger of administering chronic excessive doses of vitamin D are further emphasized.