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Carbamazepine Toxicity - - Anticonvulsant structurally similar to TCA’s Clinical Uses: Txt of Trigeminal Neuralgia, Suppression of nonconvulsive and convulsive partial seizures, and Bipolar Disorder. Mechanism of Action: Blocks voltage and frequency dependent fast sodium currents. Sodium channels are kept in the inactivated state, which inhibits the spread of synchronized depolarization that is associated with the onset of seizures. Therapeutic levels are usually 4-12mg/L. Ataxia & nystagmus may occur at levels greater than 10 mg/L. CV effects are usually seen at levels greater than 12 mg/L. Induces hepatic enzyme function to hasten the metabolism of numerous compounds, including itself. o Accelerates the metabolism of valproic acid, ethosuximide, corticosteroids, anticoagulants, and antipsychotic drugs. o Drugs that inhibit the metabolism of carbamazepine sufficiently to cause toxic effects include cimetidine, propoxyphene, diltiazem, verapamil, isoniazid, and erythromycin. Toxicity: o Ocular Mydriasis Nystagmus Ophthalmoplegia o Cardiovascular Tachycardia Hypotension o Neurologic Ataxia Slurred speech Dystonia, myoclonic activity Varying degrees of CNS depression progressing to coma Seizures, Headache, confusion, and athetosis Increased or decreased deep tendon reflexes o Respiratory depression, apnea o Delayed gastric emptying, abdominal pain o Oliguria, urinary retention o Skin Bullous skin eruptions, Toxic epidermal necrolysis Rash, dermatitis, DRESS Drug rash w/ Eosinophilia & Systemic Symptoms. Stevens-Johnson syndrome o Blood dyscrasias Pancytopenia Splennomegal Lymphadenopathy Vasculitis Agranulocytosis Ketorolac Renal Dysfunction / Fenoldopam Ketorolac: Prostaglandins protect the kidney during injury. COX makes prostaglandins from arachadonic acid. Since ketorolac inhibits COX for 8-24 hrs, this can remove the protective effect of prostaglandins. In a healthy kidney this isn’t a problem, in an at risk kidney (ESRD, CHF, etc), this can be the tipping point. From Miller (7th ed): “Perioperative NSAID-induced renal dysfunction may occur in high-risk patients, such as those with hypovolemia, abnormal renal function, or abnormal serum electrolytes, because prostaglandins dilate the renal vascular beds and mediate diuretic and natriuretic renal effects. Euvolemic patients with normal renal function are unlikely to be affected; a meta-analysis did not demonstrate any significant reduction in urine volume or cases of postoperative renal failure requiring dialysis, and there does not appear to be a benefit in using COX-2 inhibitors instead of traditional nonselective NSAIDs in reducing the incidence of renal complications.... Postoperative analgesia with a single analgesic such as ketorolac is extremely unlikely to cause injury in a relatively young, healthy, well-hydrated patient. The risk of nephrotoxic injury increases exponentially with the addition of concomitant nephrotoxins (e.g., contrast dye, aminoglycosides) in the presence of acute or chronic cardiovascular instability.” Review: COX-1 - constitutive - platelet aggregation, hemostasis, and gastric mucosal protection COX-2 - inducible - pain, inflammation, and fever Fenoldopam: Also from Miller (7th ed) is a dopamine agonist with activity at the DA1 receptor and α2-receptor. - systemic vasodilation => reduction in systemic blood pressure - preferentially dilates the renal and splanchnic vascular beds, has shown some early promise as a renoprotective drug. - fenoldopam infusion prevented the decrease in RPF induced by radiocontrast media. - Large, multicenter randomized clinical trial on 315 patients with preexisting renal insufficiency (creatinine clearance < 60 mL/min) showed that it had no benefit on renal function compared with placebo. Ketamine Ketamine is a CNS depressant the produces dissociative anesthesia conjectured to be due to electrophysiologic inhibition of thalamocortical pathways and stimulation of the limbic systems. Intense analgesia (somatic greater than visceral) is present as well as amnesia (anterograde), but not necessarily loss of consciousness. Mechanism of Action: * N-methyl-D-aspartate (NMDA) antagonist-accounts for most of its analgesic, psychomimetic, and amnestic effects. * Analgesia is thought to occur through the selective depression of the medial thalamic nuclei, as well as suppression of spinal cord activity necessary from transmission of pain to higher centers. * Also interacts with opioid, nicotinic, and muscarinic receptors. Key Words: Local Anesthetic Methemoglobinemia The hallmark of methemoglobinemia is cyanosis unresponsive to high-flow oxygen in the absence of cardiac or pulmonary disorders. Acutely developing methemoglobinemia is infrequently encountered in clinical practice. Several drugs used in anesthesiology, surgery, and medicine can cause methemoglobinemia (see table below). These include local anesthetics. Methemoglobinemia results from exposure to chemicals that oxidize the ferrous iron in hemoglobin to the ferric state at a rate that exceeds the reducing capacity of the methemoglobin reductase enzyme in erythrocytes. Methemoglobin is useless for oxygen carrying. In addition, methemoglobin shifts the oxygen-hemoglobin dissociation curve to the left and changes the sigmoid shape of the curve into a more hyperbolic one, thus hindering unloading of oxygen to tissues. These effects are proportional to the concentration of methemoglobin and are reversible. Intravenous administration of methylene blue (1–2 mg/kg) as a 1% solution over 5 minutes quickly relieves cyanosis due to methemoglobinemia. Intravenous methylene blue is indicated for methemoglobin fractions over 30% and at lower fractions in patients with anemia or cardiovascular disease. The dose may be repeated if no clinical response is observed within 1 hour. A dose greater than 7 mg/kg of methylene blue by itself can cause methemoglobinemia. Supplemental oxygen should also be administered. Ascorbic acid has also been used in the treatment of methemoglobinemia, but its action is slower than that of methylene blue. -‐ -‐ -‐ -‐ -‐ -‐ Acetaminophen Toxicity Used for analgesic and antipyretic effects; does not produce gastric irritation, alter platelet function, or antagonize uricosuric drugs. Weak anti-inflammatory effects. Metabolites (especially p-aminophenol) are concentrated in the hypertonic renal papillae which may explain the occurrence of papillary necrosis as a hallmark of analgesic-induced nephropathy. Hepatic necrosis and death may result from a single dose of acetaminophen of >15g. Hepatic toxicity can occur when daily dosages exceed 4g and at even lower daily doses in the presence of alcohol abuse. Mechanism: high doses result in formation of N-acetyl-p-benzoquinone, which is normally scavenged by glutathione. With an overdose, glutathione stores are exhausted and this allows the toxic reactive metabolite to accumulate and bind to hepatocytes. Note: alcoholics are at increased risk for toxicity at lower doses because of increased P450 enzyme activity and decreased glutathione stores. Clinical manifestations of overdose, jaundice and coagulation defects, occur 2-6 days after overdose. Bx = centrilobular necrosis. Treatment: Acetylcysteine is an antioxidant that substitutes for glutathione as a scavenger and is very effective in preventing lever damage from acetaminophen when given within the first 8 hours after overdose. Keyword: Doxorubicin (Adriamycin) complications with Anesthesia Anthracycline Anti-neoplastic agent that inhibits DNA and RNA synthesis (via intercalating mechanism) Many Adverse effects and several black box warnings: #1: cardiac toxicity (i.e. Cardiomyopathy/Arrhythmias) -Acute effects: SVT, VT dysrythmias, ST and T wave conduction abnormalities; will resolve 1-2 months after Doxorubicin is DC’ed -Chronic Toxicity is seen when cumulative dose >550mg/M^2. Dilated cardiomyopathy and CHF. -hepatic impairment, -bone marrow suppression -tumor lysis syndrome, -secondary malignancy, -tissue necrosis with extravasation...may produce -hemolysis in patients with G6PD. Bottom Line: Any patient being evaluated preoperatively that has taken or is taking this drug should have an ECG and Echo. Basic labs like CBC and chem panel, and coags will also be instrumental in ruling out the bone marrow suppression, electrolyte disturbances associated with tumor lysis and hepatic synthetic function. Fun Facts: turns Urine red; called the “red death” Organophosphate Toxicity is due to due to cholinergic overdrive at muscurinic, nicotinic and CNS sites. Signs and symptoms are remembered by the pneumonic “SLUDGE” ( Salivation, Lacrimation, Urination, Defication, GI Irritation, Erection ) along with Bradycardia, Bronchoconstriction and Pupillary Constriction. Common causes are insecticides, and nerve gases (SARIN, SOMAN, TABUN, VX). Specific antidotes include: - Atropine, adult 2-5 mg IV, children 0.05 mg/kg IV with repeat doses every 10-30 minutes - Pralidoxine( reactivates cholinesterase) – adults 1-2 gm IV, children 25-50 mg/kg with repeat dosing within 1 hour. - Obidoxine Dichloride (similar to Pralidoxime – could only find in med chem text book – but is listed in reference 2. - Pyridostigmine is listed as prophylactic antidote (2). Tumescent liposuction complications Lidocaine is the preferred local anesthetic (compliations from toxicity can arise) recommended dose is 35-45 mg/kg and doses should not exceed 55 mg/kg wt. recommended concentration of epinephrine in tumescent solutions is 0.25-1.5 mg/L. not to exceed 50 microg/kg. side effects: bruising, hematomas, seromas, and pain. Abstract BACKGROUND: The technique of tumescent liposuction involves the subcutaneous infusion of a solution containing lidocaine, followed by the aspiration of fat through microcannulas. Although the recommended doses of lidocaine are as high as 55 mg per kilogram of body weight, few safety data are available. Since reporting of adverse events associated with tumescent liposuction is not mandatory, the incidence of complications and deaths is unknown. METHODS: We identified 5 deaths after tumescent liposuction among 48,527 deaths referred to the Office of Chief Medical Examiner of New York City between 1993 and 1998. The patients' records and postmortem examination results were reviewed to identify common contributory factors. RESULTS: The five patients had received lidocaine in doses ranging from 10 to 40 mg per kilogram. Other drugs, such as midazolam, were also administered. Three patients died as a result of precipitous intraoperative hypotension and bradycardia with no definitively identified cause. Postmortem blood lidocaine concentrations in two of the patients were 5.2 and 2 mg per liter. One patient died of fluid overload, and one died of deep venous thrombosis of calf veins with pulmonary thromboembolism after tumescent liposuction of the legs. CONCLUSIONS: Tumescent liposuction can be fatal, perhaps in part because of lidocaine toxicity or lidocaine-related drug interactions.