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129: GENERAL MANAGEMENT OF
THE POISIONED PATIENT
CHARACTERISTICS
50% of total, 10% of hospital admissions due to poisonings, 5% of fatalities Should consider abuse, drug abuse, suicide attempts depending on age Rule = any poisioning in child > 5yo w/ normal intellect is suspicious 50% of total, 90% of admissions, 95% of fatalities EVALUATION

hypo/hyperthermia frequently accompanies toxic exposures and may interfere w/ tx if not identified and treated properly Anticholinergic, Acetylcholinesterase inhibition, Cholinergic, Narcotic, Sympathomimetic, Withdrawl, Extrapyramidal, Hemoglobinopathies, Metal Fume Fever Respiratory: airway, ventilation, ARDS, bronchospasm CV: arrhytmias (torsades w/ anything that increases QT interval like quinidine or amiodarone od), bradyarrthmias, hypo/hypertension Neurological: Sz, change in LOC, behavioural abnormalities ED MANAGEMENT
Ipecac: NO role in ED b/c emesis will only dec absp by 30%. May be indicated for use at the home adv: immediate recovery of gastric material, control lavage duration, direct access for instillation of charcol disadv: invasive, efficacy is questionable a/f 1-2h post-ingestion, aspiration risk (decreased by trendelenberg) agent of choice for gastrointestinal decontamination
in acute
theory: speed up GI motility :. shortening time for absorption but: not shown to improve pt outcome and may increase absortpion disadv: frequent liquid stools, dehydration and lyte imbalances esp in children used in body stuffers and sustained-release or enteridc-coated medication overdoses NG tube then goGo-Litely @ 1-2 L/hr until objects removed or effluent clear TCA example: changing pH from 7.45 to 7.50 increases albumin binding from 95 - 96% of drug :. free drug (which is active) goes from 5% to 4% which is a 20% reduction in the amount of free drug.
Alkalinization also changes the intracellular pH and allows the open of H/M ? gates of the Na+ channel and release of the TCA Ion Trapping of ASA in the urine b/c the alkalinized form is not reabsorbed as well.
Airway protection: intubation if necessary ARDS: high-flow oxygen, +ve pressure ventilation, consider PEEP hypotension: fluids only (vassopressors rare) seizures: very dangerours, standard tx w/ benzos and phenobarb, paralyzing agents may be needed initially to control prolonged sz (pancuronium) behavioural abnormailities: chemical sedation is dangerous b/c of cardioresp compromise :. use physical restraints if possible: ativan and haloperidol are effective if necessary All poisoned pts should get oxygen, glucose, and naloxozone (narcan) Elimination: example is alkalinization of urine in ASA od SUMMARY OF ED APPROACH
AIRWAY + C-SPINE: O2, sat monitor
BREATHING: Ventilator if needed
CIRCULATION: Vitals, Monitors, IV, ACLS interventions
DRUGS and UNIVERSAL ANTIDOTE (Coma Cocktail)
Glucose: 1g/Kg (D50W in adults, D25W in peds) Naloxozone: 2mg bolus IV/IM/SL/SC/ETT then 10mg repeat if no effect (peds: 0.01mg/kg bolus then 0.1mg/Kg repeat) DRAW BLOOD
CBC, urea, Cr, lytes, Ca, MG, PO4, glucose, LFTs, Les, osmolality DECREASE TOXIN
Alkalinization of serum (TCA) or urine (ASA) EXAMINE PT/EXPOSE/TOXIDROMES?
FULL VITALS, ECG MONITOR, FOLEY
GIVE SPECIFIC ANTIDOTE
Acetaminophen
Salicylates - alkalinize urine, resotre K+TCA’s 130: TRICYCLIC ANTIDEPRESSANTS
INTRODUCTION
Anticholinergic (muscarinic): dry eyes/mouth, can’t see, can’t pee, constipation, urinary retension, delirium (esp elderly), narrow angle glaucoma Alpha adrenergic antagonism: dizziness, orthostatic hypotension Main advantage: more effective in severe depression b/c of multiple actions, less expensive, only class of antidepressants with correlation w/ plasma level :. can get blood levels Main disadvantage: major OD risk; one week supply is generally lethal, anticholinergic
and cardiac effects make it potentially lethal, low therapeutic index
More serotonergic, anticholinergic, sedative, ortho hypotension Elavil (amitriptyline), Tofranil (imipramine), Anafranil (clomipramine), Surmontil (trimipramine), Sinequan (doxepin) More selective for norepinephrine, less adverse effects Aventyl/Pamelor (nortriptyline), Pertrofane/Norpramin (desipramine), Triptil (protiptyline) PHARMACOLOGY (t130-2, p741)
Norepinephrine: tacchycardia, early mild hypertension Serotonin: myoclonus, hyperreflexia, seizures, rigidity Central: sedation, delirium, hallucinations, sz, abnormal speech, resp depression, myoclonus Peripheral: dry mouth, mydriasis, blurred vision, dry axillae, tacchycardia, ileus, urinary retension, hyperthermia Hypotension, reflex tacchycardia, miosis (NB: counteracts mydriasis :. pt can have dilated, constricted, or normal pupils) QRS prolongation, PR prolongation, Ventricular arrythmias, heart blocks, bradyarrythmias, impaired contractility/hypotension, seizures Alkalinization and increasing Na+ have additive affect to overcome sodium channel blockade. IV sodium bicarb is the best method.
QT prolongation: sinus tacchy actually protects from prolongation of QT which can lead to torsades PHARMACOKINETICS
TOXICITY
CLINICAL FEATURES

Presentation varies: mild anticholinergic s/s to fatal cardiotoxicity Sinus tacchycardia most frequent arrythmia (70%) Mild to Moderate OD: drowsiness, confusion, slurred speech, ataxia, dry mm, sinus tach, ileus, urinary retension, myoclonus, hyperreflexia, mild HTN Serious OD: coma, cardiac conduction delays, SVT, hypotension, resp depression, PVCs, Vtach, seizures Progression: sinus tach, widening of QRS, decreased ionotropy, increased PR interval, finally decreased HR. (NOT all follow this order) Right axis deviation > 120 degrees predicts TCA toxicity (sensitivity, specificity are poor) QRS prolongation is also poor predictor of TCA toxicity DIFFERENTIAL DIAGNOSIS

Medications that produce seizures, wide QRS, anticholinergic carbamezipine, phenothiazines, quinidine, antihistimine, quinine, procainamide, disopyramide, cyclobenzaprine Medications that produce seizures, wide QRS, no anticholinergics propranolol, class IC antiarrytmics, cocaine, local anesthetics, lithium, propoxyphene Medications that are sympathomimetic and produce narrow complex tachy with HTN, SZ, no anticholinergics GENERAL MANAGEMENT
Drugs as per ACLS and universal antidotes (Narcan, Oxygen, Glucose, Thiamine) Do NOT give flumazenil to pts w/ mixed BZ and TCA overdose b/c it will ppt seizures\ Most symptomatic pts require urinary catheter for retension Activated charcoal: effective, all pts should receive 1g/Kg, multiple dosing?? Gastric lavage + activated charcoal: may be superior to charcoal alone if pt presents early Hypotension refractory to fluid challenges Bolus of 1 - 2 mEq/Kg and repeat until pt improves or pH > 7.50 (further alkalinization can be dangerous). Continous infusions as 2 amps (50mEq/50ml) in 1L DW5 or ½ NS and run at 2 mL/Kg/hr IV potassium usu requried and should be followed Asymptomatic a/f 6hrs do not require admission for toxicological reasons TREATMENT OF SPECIFIC COMPLICATIONS

Agitation: reassurance, sedation with BZD, physostigmine to control agitation only when other measures have failed Generalized, focal are atypical and require investigation BZDs are the drug of choice then phenobarb if resistant (AVOID dilantin) Fluids challenge then NaHCO3 if no improvement Vasopressors: norepi is most effective b/c it competes with TCAs at alpha1 site Asymptomatic wiht sinus tach, isolated PR and QT prolongation, or first degree AVB do not require tx Conduction blocks greater than first degree are worrisome Ventricular dysrythmias: immediate tx w/ sodium bicarb, lidocaine is second choice, bretylium is third line (avoid procainamide). Torsades tx with 1 - 2 gm Magnesium sulphate iv Contraindicated: class IA, class IC, BB, CCB, phenytoin
131: NEWER ANTIDEPRESSANTS AND
SEROTONIN SYNDROME
GENERAL PRINCIPLES

Do NOT inhibit cardiac Na+, K+, or Ca+ channels NOT associated w/ significant cardiotoxicity Hemodialysis and forced diuesis doesn’t work b/c of high protein binding SSRIs: Selective Serotonin Reuptake Inhibitors
Antidepressant of choice for new prescriptions Safer in overdose :. much more popular than TCAs In general, less side-effects but may actually not work as well as TCAs Uses: depression, OCD, panic disorder, social anxiety, PTSD, Bulemia, social phobia, migraines All have similar efficacy and side-effects: ie, if a patient doesn’t respond to one SSRI, they probably won’t respond to another one Drug interactions are very common and important Most are potent inhibitors of P450 system (2D6 and 1A2) Tremors, headaches, nervousness, anxiety, insomnia, anorexia, suicidal ideation, depression, worsening of mood swings EPS including akathisia and dystonia can occur Sexual dysfunction: 20 - 70% (decreased libido, anorgasmia)
Serotonin Syndrome:
altered LOC, nausea, diarrhea, palpitations, hyperthermia, chills, neuromuscular irritability, BP change, hyperreflexia, CV collapse AVOID use of concomitant sertonin agents (MAOIs, SSRIs, TCAs, tryptophan, lithium, sumatriptan) Prozac (fluoxetine): start at 20mg in am; >20mg should be divided; max 80mg od Luvox (fluvoxamine): start at 50mg qhs then inc to 100mg qhs if tolerated; increase dose by 50mg as needed; usu need 100-200mg; max is 300mg/d Paxil (paroxetine): start at 20mg in am; increase by 10mg every 2wks; max 50mg per day Zoloft (sertaline): start at 50mg in am; increase gradually, max 200mg/d SNRI: Serotonin and NE Reuptake Inhibitor
Less drug interactions than SSRIs b/c no enzyme inhibition and no protein binding Similar to SSRI except NO sexual dysfunction Watch for aggravation of HTN in HTN pt (inc DBP 5mmHg) Dose: 75 - 375 mg/d. New extended release capsule is od and may increase tolerance and efficacy. Regular release given bid.
SARI: Serotonin-2 Antagonists and Reuptake Inhibitors
Serzone (nefazodone) and Desyrel (trazadone) Promoted as an SSRI with antianxiety properties (anxiolytic) Do NOT use in SSRI non-responders b/c it is basically a SSRI Too sedating for an antidepressant thus now used mainly as a sedative Also causes orthostatic hypotension and reports of priaprism(MUST warn of painful, prolonged erections) NDRI: Norepinephrine and Dopamine Reuptake Inhibitors

Only antidepressant to avoid the serotonin system :. complements SSRIs well b/c of different mechanism Useful for: psychomotor retardation, hypersomnia, cognitive slowing, inattension (ADHD), cravings (smoking cessation) Side effects: anxiety, insomnia, H/As, GI, sz Main disadvantage: seizures
Contraindicated if hx of seizures or bulemic TRAZADONE (DESYREL)
PHARMACOLOGY
ADVERSE EFFECTS

Sedation, hypotension, dizziness, dry mouth ACUTE OVERDOSE TOXICITY
Serious toxicity unlikely < 2g ingestion PE: decreased LOC, ataxia, seizures, orthostasis (responds to fluids) MANAGEMENT
1 - 2g: AC + observation for 6hrs (some would use gastric lavage) > 2g: AC + gastric lavage + observation Norepinephrine (alpha agonist) if necessary (do NOT use dopamine or epi B agonists) Admit if symptomatic a/f 6hrs, resp depression, coingestants or for psych BUPROPRION (WELLBUTRIN)
PHARMACOLOGY
ADVERSE EFFECTS
DRUG INTERACTIONS
ACUTE TOXICITY
Toxicity can occur at maximal recommended dose of 450 mg/d Significant toxicity usu occurs w/ > 5mg/Kg Pure buproprion OD: tacchycardia, lethargy, tremor, generalized seizure, confusion MANAGEMENT
Generalized < 5min: no anticonvulsants Focal > 5min: BZD first line, phenobarb 2nd line, phenytoin 3rd line Observe for 6 hrs and d/c if asymptomatic Admit for seizures, sinus tach, lethargy, symptomatic a/f 8hr PHARM
ADV EFFECTS
DRUG INT
ACUTE TOXICITY
Significant toxicity > 1500mg of fluoxetine Sinus tach, drowsiness, tremor, N/V, serotonin syndrome ECG: sinus tach, NO prolongation of PR, QRS, QT MANAGEMENT
Admit for tacchycardia, lethargy a/f 6hrs or serotonin syndrome, or mixed OD VENLEFAXINE (EFFEXOR)
SEROTONIN SYNDROME
Definition = change in cognition + autonomic alteration + neuromuscular activity Can occur w/ any drug that increases 5HT activity at post-synaptic 5HT1a brain stem receptors Drug assoc. w/ serotonin syndrome: see table 131 -1 p748 Can be precipitated by demerol + MAO-I or SSRI Avoid demerol, codeine, dextromorphan w/ MAO-Is and SSRIs Use morphine or fentanyl (NSAIDs, tyelenol, ASA safe) Cognitive: agitation, anxiety, restlessness ANS: sinus tach, mild HTN, diaphoresis, diarrhea 132: MONOAMINEOXIDASE
INHIBITORS
INTRODUCTION
Nardil (phenelzine), Parnate (tranylcypromine), Manerix (moclobemide) Enzyme within noradrenergic nerve terminals, liver and intestinal epithelial cells (COMT is in neural and non-neural tissue and breaks down all catecholamines) MAO-A: oxidizes NE, 5HT :. MAO-A inhibitors good for depression MAO-B: oxidizes DA, tyramine :. MAO-B inhibitors good for parkinson’s Serotonin syndrome: esp occurs w/ using demerol, prozac, clomipramine,
tryptophan, dextromorphan
MAO - nonselective, irreversible inhibitors (inhibits until new enzymes are made in 14d) Ensure washout period of 14d (5wks w/ prozac) b/f switching to these Many drug interactions: Demerol, etc —> must look up!! Hypertensive Crisis/Tyramine Reaction .
Tyramine rich foods: blue cheese, red wine, pickles, draught beer, sausage, soy sauce, fava beans, 30 - 90 min a/f ingestion; severity variable H/A, diaphoreses, mydriasis, stiff neck, neuromusc exictation, increased SBP and DBP, fatality from ICH/MI Severe HTN: phentolamine (nonspecific alpha ant) 2.5 - 5.0 mg iv q10min until BP controlled Admission if symptoms do not resolve in 6hrs Reversible Inhibitor of MAO type A
MAO-B is not inhibited :. is free to metabolize tyramine and tyramine deficient diet is NOT necessary (still avoid excessive tyramine) MAO-A restored in 24 - 48hrs a/f stopping drug Dose: 150 mg bid then 450 - 600mg/day given bid DRUG INTERACTION

ACUTE OVERDOSE

Symptom onset can be delayed b/w 6 - 12h (even up to 24hrs) Effects due to hyperadrenergic state and increased 5HT H/A, agitation, restless, N, palps, tremor Sinus tach, hyperreflexia, mydriasis, hyperventilation, nystagmus, flushing Rigidity, diaphoresid, CP, HTN, marked hyperthermia Dec HR, cardiac arrest, hypoxia, papilledema, dec BP, SZ, coma, inc inc temp Sympathomimetics: amphetamines, cocaine, etc Medical condition: pheo, hypglycemia, thyrotoxicosis, heat stroke, meningitis, sepsis, tetanus, rabies, encephalitis Look for complications: hypoxia, rhabdomyolysis, renal failure, hyperK+, met acidosis, hemolysis, DIC MANAGEMENT OF OD

Risks of SZ, coma, resp depresion, hyperadrenergic stor, CV collapse < 4hrs since ingestion: gastric lavage + AC 1g/kg (no repeat) No role for diuresis, dialysis, acidification, and ipecac is contraindicated Phentolamine (alpha 1 and 2 blocker) 2.5 - 5.0 mg q10min until controlled Alternative: Nitroprusside infusion 1ug/kg/min Vasopressers: NE 1st line, epi 2nd line (b/c of beta activity) Follow protocols but caution w/ BB b/c of unopposed VC GA or paralysis may be req’d in status epilepticus 133: NEUROLEPTICS/
ANTIPSYCHOTICS
INTRODUCTION
Neuroleptic: antipsychotics and major tranquilizers used in tx of schizophrenia and psychosis Indications: scizophrenia and psychotic disorders, mood disorders w/ psychosis, violent behaviour, autism, organic mental disorders, tourette’s, somatiform disorder Dopamine antagonism (D2) decreases +ve symptoms Serotonin antagonism (5HT) decreases -ve symptoms (newer, atypical antipsychotics) Choose antipsychotics based on s/e profile, previous success, success in family Dosing po by pills or elixir; short and long acting depo im injection Many available including haldol, clopixol, etc SIDE-EFFECTS OF ANTIPSYCHOTICS
Alpha-antagonism: orthostatic hypotension urinary retension, blurry vision, dry mouth, constipation, dizziness, delirium, acute angle closure glaucoma, delayed ejaculation, acute toxic dose: confusion, agitation, delirium Remember: Mad as a hatter, red as a beet, dry as a bone, blind as a bat) Anticholinergic psychosis: physostigmine 0.5 - 1.0 mg im/iv Neuroleptic Malignant Syndrome
Most common w/ haldol; increased risk w/ concomitant drugs Typical presentation: young male with decreased/altered LOC and fever High fever (up to 41), delirium, rigidity (lead-pipe rigidity), autonomic instability, fluctuating LOC (confusion -> coma) Leukocytosis, inc CPK, myoglobinuria, inc AST/ALT, acidosis, normal CSF, all cultures (blood, urine, CSF) are -ve Ddx: menigitis, encephalitis, tetanus, strychnine OD, CVA, malignant hyperthermia, heat stroke, fatal catatonia Complications: apsiration, resp failure, rhabdomyolysis, arrythmias, DIC, szs Precipitants: dehydration, changing neuroleptics, malnourishment ExtraPyramidal Side-effects (EPS)
Involuntary contraction of mouth, neck (torticollis), face, laryngospasm, oculogyric crisis Most common in young men in first few days of starting Rx Tx: cogentin 2mg iv/im then po X 3/7 or diphenhydramine 50mg Compulsion to be in motion; anxiety, figiting, agitation Tx: change drug or lower dose; may use BB, BZD, or benadryl Abnormal, involuntary mvmts of the tongue, mouth and less commonly the trunk and extremities (chorea, athetosis) Most common in older women a/f minimum 3mo of Rx Tx: decrease dose, or d/c drug, consider atypical neuroleptic TRAP: Tremor, Rigidity, Akinesia, Posturing More common in older women usu a/f wks - months of Rx May be mistaken for depression or negative symptoms Tx: oral anticholinergic, lower dose, change drug TYPICAL ANTIPSYCHOTICS
Indication: management of all types of psychosis Selection: similar efficacy, different s/e Alliphatic and Piperidine Phenothiazines: Largactil, Nozinan, serentil, Mellaril, Piporitl, Neuleptil) More antiadrenergic s/e: ortho hypotension Piperazine phenothiazines, Thioxanthenes, Butyrophenone, Diphenlbutylpiperidines, Dibenzoxapapines: Haldol, Orap, Loxapine, Navane, Fluanxol, Moditen.
ATYPICAL ANTIPSYCHOTICS
Effective against both positive and negative schizophrenic symptoms Less EPS s/e and no reports of tardive dyskinesia First line therapy of psychosis
S/e: sedation, increased prolactin, hypersalivation, anorgasmia (ejaculation), wt gain, “typical” features w/ high doses >10mg/d D1-4 + 5HT2,3,6 blockage + muscarinic, adrenergic, histaminergic S/e: sedation, wt gain, anticholinergic but NO agranulocytosis S/e: orthostasis, hypothyroid, wt gain, ?cataracts D2 specific + 5ht2,3 + muscarinic + histamininc NOT first line b/c of agranulocytosis
S/e: agranulocytosis in 2% (monitor CBC q1wk X 6mo then q2wk),
seizures, hypersalorrhea, severe neurological s/e like tardive dyskinesia
treatment resistance a/f 6wks of traditional antipsychotic OTHER ANTIPSYCHOTICS
Thioxanthene class w/ similar efficacy to traditional antipsychotics Several forms: po tab od, im depot q2wk, acute im injection (Accuphase) ACUTE OVERDOSE

Gen: sedation ------> coma, may have Szs, abnormal motor mvmts (EPS) Vit: hypotension and reflex tacchycardia, inc or dec temp ECG: some w/ increased PR, QT, wide QRS, torsades, SVT Supportive and GI decontamination is mainstay ABCs initial focus: cardiac monitor and ECG mandatory Arrthmias: avoid Ia (quinidine, procainamide, disopyramide) Investigations: blood levels NOT helpful, AXR showing radiopaque
phenothiazine, basic metabolic w/u
Gastric lavage for large OD esp if requiring intubation or large numbers of pills seen on AXR SZ treated w/ BZD, phenobarb, then phenytoin asymptomatic w/ normal VS, PE, and ECG a/f 6hrs of obs no suspicion of thioridazine or mesothoridazine which require admission for 24hr cardiac monitoring 134: LITHIUM
INTRODUCTION
Best studied, most effective prophylactic agent, combined w/ antipsychotic for acute mania Indications: prophylaxis of bipolar illness, augmentation of antidepressant Rx in unipolars, acute mania, recurrent depression, schizoaffective disorder Less common indications: MR, borderline, alcoholics MOA: exact mechanism unknown but it competes w/ Na, K, Ca and interferes w/ cAMP second messenger systems of hormones Must screen for: pregnancy (teratogenic), thyroid disease, renal disease, CV disease, SZ disorder, other neurological disease Dose: 900 - 1800 mg single dose qhs once stable (may preserve kidney function) Wait 3 - 5 days b/f checking level and check 12hrs a/f pt take Li Drug interactions: NSAIDs decrease clearance Check blood levels biweekly then q2mo when steady Toxicity: supportive, may require dialysis GI: N/V/D s/ePolydipsia/uria, nephr DILethargy, fatigue, H/A SIDE EFFECTS

As above and see table 134-1 p. 757 Risk for toxicity w/ DM, RF, HTN, low Na diet TOXICITY/OVERDOSE
Toxic level > 2.0 mEq/L not that helpful b/c it doesn’t measure intracellular Li which is imp in toxicity Gastric lavage is mainstay: repeat lavage in 2 - 4hr if it was sustained release NS iv will help replace Na and increase Li excretion Supportive: cardiac monitor, watch lytes and Rfn, fluids, may need ICU ?? role of alkalinization of urine and osmotic diuresis Hemodialysis is effective. Indications .
Poor clinical condition: SZ, coma, arrythmias Li serum level < 20% decreased a/f 6hrs 135: BARBITUATES
PHARMACOLOGY
Barbituates have a binding site on Cl- inhibitory channels and enhance the action of GABA which also acts on the Cl- channels Important: barbituates can have a direct effect on the Cl- channels at high doses by
opening the channels even w/o GABA present. The channels then b/c stuck open and all
action potentials are blocked -----------> this is the reason behind the potential for
respiratory depression and death
Classification: see table 135-1 p. 758 CLINICAL PRESENTATION OF OD

Blood levels unreliable predictors: determine severity clinically Lethargy, emotional lability, impaired thinking, slurred speech, nystagmus (similar to etoh intoxication) CNS depression ranging from lethargy –> coma CVS: hypotension, shocky (due to VD), asystole if very severe Other: hypothermia, flaccid tone, decreased or absent DTRs, pupils variable Late: ARDS, aspiration, pneumonitis, cerebral edema, RF MANAGEMENT

ABC: intubation/resuscitation more important than gastric lavage Hypotension: bolus of fluid, dopamine if neccessary Forced diuresis and alkalinization of urine useful for long-actingbarbituate ODs (pheonbarbital) but not for short acting. NaHCO3 1mEq/Kg q4h to keep urine pH > 7.5 Minor s/s (24hrs): anxiety, insomnia, A/N/V, cramps, tremor for 3 - 7 days Major s/s (2-3d): hypertonicity, jerking, sz, hallucination, delirium, hyperthermia, CV collapse, death Tx: BZD for seizures or phenobarb if bzd fails (prevent w/ gradual w/drawl) 136: BENZODIAZEPINES
INTRODUCTION
Indications: anxiety disorders, insomnia, alcohol w/drawl, barbituate w/drawl, organic brain syndrome (agitation in dementia), akathisia due to antipsychotics, seizure disorders, msk disorders BZD MOA: bind to benzodiazepine receptors which potentiates the efficiency of GABA (Cl- channels) which leads to inhibition of the neurons. Note: BZD have no ability to directly open Cl- channel on its own w/o binding of GABA thus low lethal potential Compare to barbituates which can open Cl- channel directly w/o binding of GABA and hence much more lethal potentials Dependance is major issue. Should be used for brief period if possible.
Tolerance: receptor down regulation
Withdrawal is major issue if stopped to fast
Low dose w/drawl: tacchycardia, HTN, panic, insomnia, anxiety, perception disturbance, poor memory/concentration, tremors High dose w/drawl: hyperpyrexia, seizures, psychosis, death Always consider this w/ organic brain syndrome Major depression, pregnancy, breast feeding AVOID in alcohol abuse b/c of potentiated CNS depression CNS: drowsiness, cognitive impairment, reduced motor coordination, memory impairment COMMON ANXIOLYTICS
Less severe withdrawal, problems w/ liver dysfunction or elderly Valium (diazepam), Rivotril (clonazepam), Dalmane (flurazepam) In general used more for generalized anxiety, panic disorder, seizure prophylaxis, and sleep Ativan (lorazepam), Xanax (alprazolam), Serax (oxazepam), Restoril (temazepam) Easily metabolized and preferred in elderly Xanax sublingual available for rapid action for panic attacks Rapid onset, more tolerance and withdrawal Non-bzd with less dependancy, sedation, drug interaction Best used in naive pt (doesn’t work well if has been on other BZD) BENZODIAZEPINE OD

Primarily neurologic: drowsy, slurred speech, confusion, ataxia, decreased mental fn, dizzy Coma is atypical: think of something else if in coma (medical dz, coingestant)
Respiratory depression or decreased BP possible but uncommon :. think of coingestant Consider coingestants is most imp part of Mx Ipecac contraindicated b/c it increases CNS depression mainly used for reversal of sedation for procedures dose: 0.2mg iv q1min until response or max of 3mg role in OD not well defined . may do more harm than good considering the relatively safe nature of BZD ODs 143: SALICYLATES
INTRODUCTION

Asparin, oil of wintergreen (methyl salicylate) is an extremely toxic form PATHOPHYSIOLOGY AND CLINICAL FEATURES
Gastritis, UGI hemorrhage, profuse vomiting Metabolic acidosis + Respiratory Acidosis (stimulation of resp centres)
Confusion, lethargy, resp arrest, coma, brain death Cerebral death is a common cause of death Lyte abnormalities, hyperthermia, heart failure, PVCs, Vtach, Vfib Pulmonary edema (ARDS); more common in children TOXIC DOSES AND SALICYLATE LEVELS
Peak absorption may not occur for 18 - 24hr Changes in volume of distribution make serum levels difficult to interpret < 150 mg/Kg: vomiting from gastritis, no other significant toxicity 150 - 300 mg/Kg: mild to moderate toxicity w/ hyperpnea, vomiting, diaphoresis, tinnitus, A/B disturbance Done Nomogram predicts toxicity w/ acute ingestion (f143-1, p785) ACUTE versus CHRONIC POISONING
TREATMENT
Activated charcoal (AC) better than ipecac AC 1g/Kg should be given to anyone who has ingested toxic amounts Ddx: acute iron poisoning, Reye’s syndrome, DKA, theophyline od, caffeine od, sepsis, meningitis Phenistix = urine dipstick detects mod - large amounts of salicylates in urine All pts w/ CNS depression or seizures should be assumed to be hypoglycemic and given DW50 if chemstrip not immediately available Alkalinization to keep arterial pH > 7.4. This enhances urinary excretion of salicylates.
Monitor ABGs, lytes, urine pH Q2h in severly ill Bolus 1 mEq/Kg NaHCO3 iv until arterial 7.5. Continuous iv infusion of 1 L DW5 + 50 - 100 mmol NaHCO3 + 40 mEq KCL is run at 3Xs the maintenance rate. Monitor urine pH, lytes, gases q2 - 4h. Massive amounts of K+ may be necessary Contraindicated: trap ASA in CNS and increase mortality Deterioration despite support and alkaline urine Deterioration and alkalinization of urine cannot be achieved Encephalopathic, Comatose, or severe cardiac toxicity ARDS in whom salicylate levels are not rapidly falling CNS deprssion common in chronic ingestion Continued deterioration in LOC is an ominous sign and is an immediate indication for dialysis 144: ACETAMINOPHEN
INTRODUCTION
Hepatoxicity predictable from nomogram according to amount and time of ingestion N-acetyl cysteine effective if started w/i 24hrs Hepatic injury may not become evident until 24 - 36hrs when liver enzymes rise Acetaminophen level :. should be routinely checked in all overdoses b/c evidence of
hepatic injury @ 24+ hrs is too late for N-acetylcysteine (mucomyst)
PHARMACOLOGY
PATHOPHYSIOLOGY
Minimal dose causing liver toxicity in acute ingestion .
CLINICAL FEATURES
anorexia, nausea, vomiting, malaise, pallor, diaphoresis suspect other substance if cardiotoxicity, resp deprssion, CNS depression b/c these are not common with tyelenol AGMA also very rare and should suggest other cause abdominal pain, liver tenderness, elevated hepatic enzymes, oliguria (dehydration or ATN) peak enzyme abnormalities, increased bili and PT +/- jaundice, AST/ALT may be massively elevated increased Scr/BUN, proteinuria, glucosuria, hematuria, pyuria, granular casts with renal toxicity resolution of hepatotoxicity or progressive hepatic failure recover: hepatic fn returns to normal, liver bx normal progress: encephalopathy, jaundice, coagulopathy, hypoglycemia, renal failure (hepatorenal syndrome), ECG changes with myocardial injury Combined renal and hepatic toxicity with ingestion of therapeutic or slightly grater doses of tylenol in alcoholics. They present with dehydration, jaundice, marked enzyme elevation, coagulopathy, hypoglycemia +/- ATN in 50%.
Nonalcoholics: children, acute starvation, chronic malnutrition are also suceptible at small od levels PROGNOSIS AND ANTIDOTAL RATIONALE
Hepatotoxicity defined as AST or ALT > 1000 IU/L (lesser elevation is not clinically sign) Serum acetaminophen level 4 - 24 hr post single acute ingestion is best prognostic
indicator for hepatotoxicity
Rumack - Matthew nomogram for acetaminophen poisoning predicts hepatotoxicity N-acetylcysteine (NAC) is the treatment of choice: mechanism is not exactly defined but thought to increase the supply of glutathione and decreasing the amount of the acetaminophen metabolite NAPBQI DIFFERENTIAL DIAGNOSIS
Viral hepatitis, alcoholic hepatitis, hepatobiliary disease, drug/toxin induced hepatitis Three causes of massive hepatocellular enzyme elevation .
Very high levels of transaminases with rapid progression is characteristic of acetaminophen od. Inhalational gas hepatitis are only other thing to increase enzymes so high.
GENERAL MANAGEMENT
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Children< 140 mg/Kg and Adults < 7.5 g Activated charcoal recommended for 100 - 140 mg/Kg if < 4hrs since ingestion Persistent GI symptoms: suggest more was taken :. manage as below Children > 140 mg/Kg and Adults > 7.5 g GI decontamination recommended for all presenting w/i 4hrs of ingestion Decontamination also useful @ > 4hrs if food, anticholinergics, or narcotics were also ingested (dec gastric emptying) More effective than ipecac or gastric lavage AC also absorbs the mucomyst but this is clinically unimportant b/c of routine overkill with mucomyst dosing. Also, AC is given initially whereas NAC (mucomyst) is often given later when levels are Measure acetaminophen level ASAP; level > 150ug/ml indicates req’t for mucomyst Mucomyst administration requires admission ANTIDOTAL TREATMENT
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Dilute mucomyst to a 5% solution with soft drink or fruit juice. N/V/D are frequent s/es. Repeat the dose if vomiting occurs w/i 1 hr of administration. Antiemetics can help. Alternate doses of AC and NAC q 2h if multiple AC dosing is being used IV administration of NAC has also been used CARBON MONOXIDE
INTRODUCTION
Specific gravity very close to that of air thus it does not stratify (ie; layer out) High affinity for Hb and displaces oxygen to form carboxyHb Symptoms are vague leading to high rate of misdiagnosis . must suspect!
SOURCES
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Normally produced in body during metabolism of heme products Normal production leads to serum COHb levels of 0.4 - 0.7% Slight increase in levels (5%) can be seen in hemolytic anemia Exogenous CO produced by incomplete combustion of organic fuels Vehicle exhaust, furnaces, home water heaters, gas heaters, pool heaters, wood stoves, kerosene heaters, indoor charcoal fires, industrial mills/plants, fires.
Smoke contains a lot of CO and smokers may have COHb levels b/w 9 -20% The most common cause of immediate death in fires is CO poisioning Must suspect CO poisioning in all patients in a fire
PATHOPHYSIOLOGY
Reversible binding to Hb with 250 times affinity than oxygen Thus, significant COHb levels can occur with relatively small exposure COHb decreases the oxygen carrying capacity of blood thus leading to tissue hypoxia which is the predominant toxicological property of CO Binding of a CO molecule to one of the four binding sites on Hb results in some change such that the Hb binds the remaining oxygen more tightly and shifts the curve to the left; ie, less oxygen released at the tissue level CO has high affinity for cardiac myoglobin Carboxymyoglobin reduces the oxygen available to the myocardium thus decreases cardiac performance; also risk of ischemia and arrythmias CO binds to cytochromes A3 and P450 which may inhibit cellular respiration CO leads to oxygen free radical production in the brain causing neuronal damage; similar to reperfusion injury CLINICAL PRESENTATION
Vague presentation makes diagnosis difficult without obvious exposure risk Headache, weakness, nausea, dizziness --------> often diagnosed as “the flu” Symptoms and signs generally correlate with COHb levels impaired judgement, nausea, dizziness, visual disturbance, fatigue
SYSTEMIC MANIFESTATIONS
Brain and heart have highest metabolic requirements and are most susceptible Fundus: flame retinal hemorrhages + bright red retinal veins Skin: cherry red skin is rare; usually pale or cyanotic Fetal: fetus is particularly susceptible thus treat longer and more aggressively; CO is teratogenic in up to 60% and has high fetal mortality Pediatric: think of if riding in back of pickup truck or other vehicle Neurologic: most common complications; headache, dizziness, weakness, near syncope, seizures CLINICAL EVALUATION
Think of with vague complaints: it the thought of some weird viral syndrome, being a whinner, or somatization crossess your mind, think CO (nausea, fatigue, headache, vague abd complaints, visual disturbance) Chronic low level exposures may not give hx of exposure Clue: another person in same environment has similar complaints Helps define severity and identify complications Measure COHb levels in all suspected cases COHb level may be deceptively low if oxygen has been given; yet, symptoms may continue to be severe Note that Pa02 is not affected because the amount of oxygen dissolved in blood is relatively unchanged Note that Sa02 is not affected b/c the pulsoximeter cannot differentiate b/w oxygenated Hb and carboxyHb Saturation gap correlates with the COHb level (Sat of 93% and COHb is 5% the true saturation is 88%) ECG: look for sinus tach, ST segment changes CK may help identify myocardial damage and rhabdomyolysis Urine for myoglobins to detect rhadomyolysis BAL and drug screen based on presentation (ie; attempted overdose?) GENERAL MANAGEMENT
100% 02 via tight-fitting, non-rebreather mask (simple mask not adequate) Continue oxygen until asymptomatic and COHb < 10% Usually 100% oxygen at 2 - 3 atm pressure for 46 to 120 min and repeat in 6h if symptoms persist Lowers t1/2 to 23 min compared to 60 min for 100% 02 and 240 min for RA Role in pregnant females not well defined
SPECIFIC GUIDELINES
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COHb < 30% with NO signs or symptoms of impaired CV or neuro function All patients with underlying cardiac disease should be admitted and observed COHb 30 - 40% with NO signs or symptoms of impaired CV or neuro function COHb > 40% OR signs and symptoms of impaired CV or neuro function
Transport to hyperbaric chamber if immediately available, or treat for four hours and then must transfer if no improvement in cardiac or neurological function INTRODUCTION
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Used in industry in electroplating, silver recovery from Xray film, ore extraction, fumigation, and as a fertilizer One production of combustion of nylon, polyurethane, woll, silk, and cellulose Must consider in fires
Absorbed through lungs, rapid onset, interferes with cytochrome oxidase system CLINICAL FEATURES
Weakness, dizziness, headache, palpitations Rapidly progressing dyspnea without cyanosis Bitter almond scent on breath and body but only 1/3 of population can smell this
Draw blood for COHb and cyanide levels (cyanide levels won’t return in acute setting) MANAGEMENT
General management is 100% oxygen by NRB mask and Fluids/pressors for hypotension Contains amyl nitrite, sodium nitrite, and sodium thisulfate The nitrites causes the formation of methemoglobin so the cyanide unbinds the cytochrome oxidase system Thiosulfate combines with cyanide to form thiocyanide which is excreted by the kidneys Administration: crush amyl nitrite and hold under nose or put in ambu bag or face mask for 30 sec out of a minute; 10 ml of 3% solution of sodium nitrite is injected over 3 min as soon as possible; then give sodium thisulfate 50 ml of 25% solution iv HYDROGEN SULFIDE
Found in sewers, septic tanks, decaying organic matter, industrial settings Odor of rotten eggs but it quickly causes olfactory fatigue thus smell desaturates rapidly
Similar to cyanide: binds cytochrome oxidase system Treatment: amyl nitrite, sodium nitrite (NOT thiosulfate) Big problem with rescuer/bystander mortality METHEMOGLOBINEMIA
Acquired: exposure to nitrates (including NTG), explosives, aniline dye, sulfonamides Brown color of arterial blood and cyanosis that do NOT respond to oxygen are clues
Cyanosis may be present in absence of respiratory distress Treatment: oxygen, remove dermal exposure, methylene blue is antidote
PATHOPHYSIOLOGY
Excess iron is directly caustic to GIT resulting in hemorrhagic gastroenteritis with hypovolemia Iron mainly accumulates in liver after acute OD but may affect any organ Iron is concentrated in the mitochondria where it disrupts oxidative phosphorylation and catalyzes the formation of oxygen free radicals leading to lipid peroxidation Also causes venodilation and venous pooling Increases capillary permeability and leads to significant third spacing Lactic acidosis from hypovolemia and tissue hypoperfusion, anaerobic metabolism secondary to inhibition of oxidative phosphorylation Coagulopathy from direct inhibition of thrombin etc (even b/f hepatic dysfunction) OD can lead to hepatic dysfunction only or major organ failure and death TOXIC DOSE
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CLINICAL FEATURES
Gastroenteritis, think of possibility
of Iron Poisoning
Due to direct corrosive effects of iron on GIT Abdominal pain, nausea, vomiting, diarrhea Lethargy, shock, and metabolic acidosis are due to hypovolemia, anemia, and tissue hypoperfusion GI symptoms frequently resolve and patient apparently improves (falsely reassuring) Early in severe, hours after second stage if not severe Toxic amounts of iron have moved from blood into tissues disrupting cellular metabolism causing third spacing and venous pooling Shock and metabolic acidosis can be due to persistent hypovolemia, anemia, hepatic dysfunction, impaired oxdative phosphorylation, heart failure, and renal failure Hepatic injury unusual when serum peak iron levels < 500 ug/dL Gastric outlet or small bowel obstruction secondary to scarring from the original injury TREATMENT
No treatment required if asymptomatic and normal PE a/f 6hrs post ingestion Gastric lavage for anything > 20 mg/kg No role for cathartics in patients already with diarrhea Draw level 5 hours a/f ingestion and d/c home if < 350 ug/dL Look for increased wbc and low glucose to support diagnosis (does not r/o) Chelator that removes iron from plasma and tissues IV infusion of 15 mg/kg/hr is preferred (over im route) Gastric lavage with deferoxamine not recommendeds Do not rely on serum iron levels to guide need for deferoxamine b/c iron may be already out of serum and in tissues: deferoxamine removes iron from tissues and serum. Patients can die with normal serum iron levels.
NEVER wait for serum iron levels to return before starting deferoxamin in a significantly symptomatic patient Give deferoxamine after adequate hydration to .
any moderately or severely symptomatic patient (hypotension, gastroenteritis, lethargy) even if iron levels are below the TIBC, haven’t returned, or are not available any patient with serum iron > 350 ug/dL Do not rely on serum iron level < TIBC in symptomatic pt Do not delay deferoxamine treatment until lab results return Do not rely on inc wbc or low glucose to r/o iron ingestion

Source: http://remergs.com/WEBPAGE%20Notes/Toxicology/toxicology-overview.pdf