Download Carbamazepine Toxicity - Anticonvulsant structurally similar to TCA`s

Carbamazepine Toxicity
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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.
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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.