CASE NO. 3. Jeh, a 21 year old female was brought to the ER in generalized seizures. On query, she was found sprawled on the floor, unresponsive despite her dorm mate’s efforts to wake her by shaking her and slapping her cheeks. Vomitus and unknown white tablets (INH) were littered around her. It took 15 minutes to reach the ER. During transport, aides claimed she went into active seizures twice with upward rolling of eyeballs, stiffening of extremities followed by jerky movements and increased salivation. Upon entering the ER, she went into active seizures again.

How do you manage the patient? Initial Vital signs: Blood pressure140/90Normal Valves Circulatory rate110 Respiratory rate22 Temperature37 oC I. PROPERTIES: ISONIAZID Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5. 5-6. 5. pH (5% aqueous solution) 6-8. INH is a chemical synthetic molecule (Meyer and Nelly,1912), a pyridine derivative of nicotinamide. Chemical name: isonicotinic acid hydrazide, Molecular formula: C6H7N3O, Molecular weight: 137.

14 Solubility: 1 g in 8 g water, 1 g in 50 mL alcohol; slightly soluble in chloroform and very slightly soluble in ether. A 10% solution has a pH of 6. 0 to 8. 0. The solution for parenteral injection is a clear, colourless liquid. The pH ranges between 5. 6 and 6. 0 (B. P. injection) or between 6. 0 and 7. 0 (U. S. P. injection). It is recommended that sugars such as glucose, fructose and sucrose should not be used in INH preparations because the absorption of the drug is impaired by the formation of a condensation product. Sorbitol might be a suitable substitute.

Absorption: T max is 1 to 2 h. Distribution: Diffuses readily into cerebrospinal, pleural, and ascitic fluids, tissues, organs, saliva, sputum, feces, placental barrier, and in breast milk. Metabolism: Primarily by acetylation and dehydrazination. Elimination: 50% to 70% excreted in the urine in 24 h. Adults: PO / IM 5 mg/kg/day as single daily dose (max, 300? mg/day) or 15 mg/kg 2 to 3? times/wk (max, 900 mg). Infants and Children: PO / IM 10 to 20? mg/kg/day in single daily dose (max, 300? mg/day) or 20 to 40 mg/kg 2 or 3 times/week (max, 400? mg).

Adults: Acute exposure: Doses of 30 to 40 mg/kg may produce seizures. In adults with prior seizure disorders, seizures may occur after ingestion of doses as low as 14 mg/kg. Doses of 80 to 150 mg/kg produce seizures and can cause death. Dose of 150 to 200 mg/kg are often fatal not treated. Chronic toxicity. Symptoms of chronic toxicity may appear after therapeutic doses. II. MECHANISM OF TOXICITY The exact mechanism of action of INH is not known. INH may act by inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms.

Since mycolic acids are unique to mycobacteria, this action explains the high degree of selectivity of the antimicrobial activity. Mutation conferring resistance may occur in susceptible microorganisms. There is a cross resistance between INH, rifampicin and ethambutol. However the simultaneous use of two of these drugs markedly delays the emergence of resistant mutants either agent. Toxicodynamics: Tonic-clonic seizures and severe metabolic acidosis are the most common features in INH Overdose. Seizures: The precipitating mechanism of the seizures is not exactly known but it may be related to the INH-induced deficiency of pyridoxine.

INH produces pharmacologic changes in pyridoxine metabolism: Increased renal excretion of pyridoxine by formation of INH-pyridoxine hydrazones. The hydrazones competitively inhibit pyridoxine kinase, the activating enzyme that converts pyridoxine to the physiologically active pyridoxal phosphate. Inactivation of the pyridoxal containing enzymes. The subsequent reduction in pyridoxine and pyridoxal phosphate inhibits the formation of the inhibitory neurotransmitter, gamma aminobutyric acid or GABA (Wood & Peesker, 1972). This reduction in GABA levels may explain the seizures in patients with INH poisoning.

The major route of isoniazid metabolism is hepatic acetylation by N-acetyl transferase which produce acetylisoniazid. The rate of acetylation is genetically determined. Acetyisoniazid is further hydrolysed to isonicotinic acid and acetylhydrazine, both of which are excreted in the urine. Isonicotinic acid is conjugated with glycine. Acetylhydrazine is further metabolised to diacetylhydrazine and may be converted by the hepatic microsomal enzymes to the reactive metabolite (presumed to be hydrazine) which are thought responsible for INH-induced hepatotoxicity.

Acid labile hydrazones of isoniazid are formed with a-ketoglutarate and pyruvate, but since these do not appear to any extent in the blood, they are thought to be produced in the bladder III. MANIFESTATION OF TOXICITY Acute Poisoning Toxic manifestations usually appear after a delay of 1 to 2 hours but they may occur from 30 minutes up to 7 hours following ingestion. The higher the dose, the shorter the delay of onset of symptoms. The first manifestations include: nausea, vomiting, blurred vision, coloured lights, spots, dizziness, slurred speech.

A second phase follows rapidly, including severe grand mal seizures, respiratory distress, coma and severe metabolic acidosis. Signs and symptoms may include: fever, lethargy, stupor, coma, tonic clonic seizures, respiratory depression, respiratory distress during seizures, vomiting, nausea, abdominal pain, tachycardia, hypotension. Respiratory depression with resultant hypoxemia and cyanosis is frequent during seizures or intractable. Chronic poisoning: grand mal seizures, aspiration pneumonia may occur hypoventilation with Kussmaul-type respiration maybe observed between the periods of seizure activity.

IV. CLINICAL/LABORATORY ANALYSIS Observation and monitoring: Systematically monitor vital signs, ECG, blood pressure, respiration and diuresis. Immediate venous access is indicated for alkalinization, drug injection and hydration. EEG monitoring in order to confirm the cessation of cerebral seizure activity. Monitor arterial blood gases as a guide to therapy Blood gases, serum electrolytes, glucose and BUN determinations should be performed. Severe metabolic disorders may be observed: lactic acidosis, hyperkalaemia, Hypocalcaemia, hyperglycaemia and ketonuria increase in hepatic and muscle enzymes.

Measurement of INH serum levels are not useful for the clinical management of INH overdose. V. MANAGEMENT Treatment depends on the dose ingested, the symptomatology and the delay following ingestion. It includes: Early gastric lavage after control of seizures and protection of airway Oral activated charcoal Supportive treatment: control seizures with diazepam and or pentothal correct metabolic acidosis by infusion of sodium bicarbonate solution manage respiratory failure by oxygen and artificial ventilation correct hypotension and shock by plasma expanders and/or dopamine Antidote: administration of pyridoxine.

Intravenous: 1 g pyridoxine for each 1 g INH ingested. If the dose ingested is unknown, initial administration of pyridoxine may be 5 g intravenously in severly poisoned patients, and repeated until seizures are under control. Life supportive procedures and symptomatic/specific treatment Supportive care with early artificial ventilation, administration of pyridoxine and anticonvulsant drugs are indicated in severe poisoning with seizures. Antidote treatment: Adults INH induces pharmacologic changes in pyridoxine metabolism and pyridoxine is used as antidote. Pure pyridoxine (vitamin B6) is recommended as the antidote for INH poisoning.

In situations where this is not available and a combination vitamins B1, B6 and B12 is used, there is a risk of anaphylactoid reactions if vitamin B1 (thiamine) is given in doses of more than 1 g. Pyridoxine may be given in smaller aliquots every 10 minutes until the pyridoxine deficiency is corrected. Acute poisoning: Correction of pyridoxine deficiency contributes to the control of seizures and the correction of metabolic acidosis. In acute ingestion of more than 80 mg/Kg, administration of IV pyridoxine should be considered, even in asymptomatic patients The recommended dose is 1 g of pyridoxine for each gram of isoniazid ingested.

Administer 5 g IV in the first minutes in severely symptomatic patients with seizures and acidosis, and repeat administration until seizures are controlled (Poisindex). If the dose ingested is known follow the same protocol. Chronic poisoning: Treatment of isoniazid-induced neuropathy is effected with pyridoxine 100 to 200 mg daily and withdrawal of INH when possible. For the prevention of isoniazid-induced neuropathy: 10 mg pyridoxine daily is adequate in high risk patients. Higher doses could interfere with antibacterial efficacy and are unnecessary. Children Management discussion

Asymptomatic patients with suspected isoniazid poisoning should be monitored for at least 6 hours. Give an intravenous bolus of pyridoxine (5 g in adults, 1 g in children) as soon as isoniazid toxicity is suspected. The total dose of pyridoxine required is 1 g per gram of INH ingested. Potentiate the antidotal (anticonvulsant) effects of pyridoxine with diazepam. Administration of sodium bicarbonate should be reserved to cases with severe acidosis (pH < 7. 2). After pyridoxine treatment and supportive care, gastric lavage and administration of activated charcoal may be performed.

Blood samples should be sent for monitoring of biological parameters. Ensure adequate diuresis. Forced diuresis is not useful. Dialysis is only indicated in the most severe cases unresponsive to adequate supportive care, anticonvulsant drugs and pyridoxine therapy. Rhabdomyolysis, neuropathy and coagulopathy may occur and should be treated appropriately. Prophylactic coadministration of pyridoxine (6 to 50? mg/day) is recommended in malnourished patients and those predisposed to neuropathy (eg, alcoholics, diabetics). VI. PRECAUTION AND PREVENTION General

All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction Use of isoniazid should be carefully monitored in the following: 1. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.

2. Patients with active chronic liver disease or severe renal dysfunction 3. Age > 35. 4. Concurrent use of any chronically administered medication 5. History of previous discontinuation of isoniazid 6. Existence of peripheral neuropathy or conditions predisposing to neuropathy 7. Pregnancy. 8. Injection drug use 9. Women belonging to minority groups, particularly in the postpartum period 10. HIV seropositive patients. Toxic effects can be minimized by prophylactic therapy with pyridoxine and careful surveillance of the patient.

Patients with tuberculosis who have hepatitis attributed to isoniazid should be given appropriate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement. Patients should be instructed to immediately report signs or symptoms consistent with liver damage or other adverse effects.

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