PDP 406 CLINICAL TOXICOLOGY

Pharm.D

Fourth Year

Management of overdose and poisoning

Mr.D.Raju.M.Pharm.,Lecturer

General- evaluation

recognition of poisoningidentification of agents involved assessment of severity prediction of toxicity

General- management

provision of supportive careprevention of poison absorptionenhancement of elimination of poisonadministration of antidotes

Supportive care

ABCVital signs, mental status, and pupil size Pulse oximetry, cardiac monitoring, ECGProtect airwayIntravenous access cervical immobilization if suspect traumaRule out hypoglycaemiaNaloxone for suspected opiate poisoning

History

Pill bottlesAlcoholDrug history including accessRemember OTC drugsSuicide noteNational Poisons Information Centre *

Examination

Physiologic excitation –anticholinergic, sympathomimetic, or central hallucinogenic agents, drug withdrawal

Physiologic depression –cholinergic (parasympathomimetic), sympatholytic, opiate, or sedative-hypnotic agents, or alcohols Mixed state –polydrugs, hypoglycemic agents, tricyclic antidepressants, salicylates, cyanide

Drug detection

Drug levels

Preventing absorption

Gastric lavage

Not in unconscious patient unless intubated (risk aspiration)

Flexible tube is inserted through the nose into the stomach

Stomach contents are then suctioned via the tube

A solution of saline is injected into the tube

Recommended for up to 2 hrs in TCA & up to 4hrs in Salicylate OD

Induced VomitingIpecac - Not routinely recommended Risk of aspiration

Preventing absorption

Activated charcoalAdsorbs toxic substances or irritants, thus inhibiting GI absorption Addition of sorbitol →laxative effectOral: 25-100 g as a single dose repetitive doses useful to enhance the elimination of certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products)not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, lithium

Elimination of poisons

Renal eliminationMedication to stimulate urination or defecation may be given to try to flush the excess drug out of the body faster.

Forced alkaline diuresisInfusion of large amount of NS+NAHCO3Used to eliminate acidic drug that mainly excreted by the kidney eg salicylatesSerious fluid and electrolytes disturbance may occurNeed expert monitoring

Hemodialysis or haemoperfusion: Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of distributionmay also be used temporarily or as long term if the kidneys are damagdue to the overdose.

Antidotes

Does an antidote exist?Does actual or predicted severity of poisoning warrant its use?Do expected benefits of therapy outweigh its associated risk?Are there contraindications?

Specific overdoses

OpiatesAntidote – naloxone

MOA: Pure opioid antagonist competes and displaces narcotics at opioid receptor sites

I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg every 2-3 minutes as needed

Lower doses in opiate dependence

Elimination half-life of naloxone is only 60 to 90 minutes

Repeated administration/infusion may be necessary

S/E BP changes; arrhythmias; seizures; withdrawal

Benzodiazepines

Antidote – flumazenil

MOA: Benzodiazepine antagonist

IV administration 0.2 mg over 15 sec to max 3mg

S/E N&V; arrhythmias; convulsions

C/I concomitant TCAD; status epilepticus

Should not be used for making the diagnosis

Benzodiazepines may be masking/protecting against other drug effects

Tricyclic antidepressants

PHARMACOLOGY —TCAs have several important cellular effects, including inhibition of:

Presynaptic neurotransmitter reuptake

Cardiac fast sodium channels

Central and peripheral muscarinic acetylcholine receptors

Peripheral alpha-1 adrenergic receptors

Histamine (H1) receptors

CNS GABA-A receptors

TCAD overdoseclinical features

Arrhythmias

- widening of PR, QRS, and QT intervals;

heart block; VF/VT

Hypotension

Anticholinergic toxicity

- hyperthermia, flushing, dilated pupils,

intestinal ileus, urinary retention, sinus tachycardia

Confusion, delirium, hallucinations

Seizures

Diagnosis

History

Blood/urine toxicology screen

Levels not clinically useful

TCAD overdose -Treatment

ABC – many require intubationConsider gastric lavage if taken < 2hrsActivated charcoalTreatment of hypotension with isotonic salineSodium bicarbonate for cardiovascular toxicityAlpha adrenergic vasopressors (norepinephrine) for hypotension refractory to aggressive fluid resuscitation and bicarbonate infusion Benzodiazepines for seizures

Sodium Bicarbonate in TCA overdose

Hypertonic sodium bicarbonate (NaHCO3)

- QRS widening >100 msec; ventricular

arrhythmias, and/or refractory hypotension

↑ serum pH promotes protein binding and ↓ free drug

concentrations; narrows the QRS complex, ↑ systolic blood

pressure, and controls ventricular arrhythmias

1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent

NaHCO3) rapid IV push large bore IV then infusion if working

reasonable goal pH is 7.50 to 7.55 then taper dose

S/E Volume overload, hypernatreamia, and metabolic alkalosis

Special Cautions in TCAD overdose

Class IA and IC antiarrhythmic agents are

contraindicated eg quinidine;disopyramide,

flecainide; propafenone

Class IB Lignocaine, phenytoin used

Phenytoin may precipitate arrhythmias

Magnesium may be useful

Flumazenil must not be given

Salicylate overdose

Aspirin (acetylsalicylic acid)Methyl salicylate (Oil of Wintergreen)5 ml = 7g salicylic acidHerbal remediesFatal intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children

Salicylate levels

Plasma salicylate concentration

Rapidly absorbed; peak blood levels usually occur

within one hour but delayed in overdose 6-35 hrs

Measure @ 4 hrs post ingestion & every 2 hrs until

they are clearly falling

Most patients show signs of intoxication when the

plasma level exceeds 40 to 50 mg/dL (2.9 to 3.6

mmol/L)

Salicylate overdose

Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanesStimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomitingDirect toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopeniaActivation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosisUncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosis

Clinical features

Early symptoms of aspirin toxicity include tinnitus,

fever, vertigo, nausea, hyperventilation, vomiting,

diarrhoea

More severe intoxication can cause altered mental

status, coma, non-cardiac pulmonary oedema and

death

Metabolic abnormalities

Stimulate the respiratory center directly, early fall in the PCO2

and respiratory alkalosis

An anion-gap metabolic acidosis then follows, due to the

accumulation of organic acids, including lactic acid and ketoacids

Mixed respiratory alkalosis and metabolic acidosis with ↑ anion

gap

Arterial Ph variable depending on severity

Metabolic abnormalities

Metabolic acidosis increases the plasma concentration of protonated salicylate

thus worsening toxicity by allowing easy diffusion of the drug across cell membranes

Salicylate overdose - treatment

directed toward increasing systemic pH by the administration of sodium bicarbonate

IV fluids +/- vasopressors

Avoid intubation if at all possible (↑ acidosis)

Supplemental glucose (100 mL of 50 percent dextrose in adults) to patients with altered mental status regardless of serum glucose concentration to overcome neuroglycopaenia

Hemodialysis

Alkalinization of plasma and urine

Alkalemia from a respiratory alkalosis is not a contraindication to sodium bicarbonate therapy

A urine pH of 7.5 to 8.0 is desirable

Blood gas analysis every two hours

Avoid severe alkalemia (arterial pH >7.60)

Haemodialysis - indications

Altered mental status

Pulmonary or cerebral edema

Renal insufficiency that interferes with salicylate excretion

Fluid overload that prevents the administration of sodium bicarbonate

A plasma salicylate concentration >100 mg/dL (7.2 mmol/L)

Clinical deterioration despite aggressive and appropriate supportive care

Paracetamol

Widely available

Potential toxicity underestimated

Toxicity unlikely to result from a single dose of less than 150

mg/kg in child or 7.5 to 10 g for adult

Toxicity is likely with single ingestions greater than 250 mg/kg

or those greater than 12 g over a 24-hour period

Virtually all patients who ingest doses in excess of 350 mg/kg

develop severe liver toxicity unless appropriately treated

Factors influencing toxicity

Dose ingested

Excessive cytochrome P450 activity due to induction by

chronic alcohol or other drug use eg carbamazepine,

phenytoin, isoniazid, rifampin

Decreased capacity for glucuronidation or sulfation

Depletion of glutathione stores due to malnutrition or chronic

alcohol ingestion

Acute alcohol ingestion is not a risk factor for hepatotoxicity

and may even be protective by competing with

acetaminophen for CYP2E1

Clinical featuresStage I (0.5 to 24 hours)

No symptoms; N&V Malaise

Stage II (24 to 72 hours)

Subclinical elevations of hepatic aminotransferases (AST, ALT)

right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident

Stage III (72 to 96 hours)

Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, death

Stage IV (4 days to 2 weeks)

Recovery phase that usually begins by day 4 and is complete by 7 days after overdose

Paracetamol overdose

The risk of toxicity is best predicted by relating the time of ingestion to the serum paracetamol concentration

The dose history should not be used as studies have found no correlation

Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparations

May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested

Check level at >= 4 hrs

Paracetamol overdose treatment

Activated charcoal within four hours of

ingestion

May reduce absorption by 50 to 90 percent

Single oral dose of one gram per kilogram

Inhibits absorption of oral methionine

N-acetylcysteine

Antidote – MOA: a glutathione precursor

Limits the formation and accumulation of NAPQI

Powerful anti-inflammatory and antioxidant effects

IV infusion or oral tablets (also oral methionine)

150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg over next 16 hrs up to 36hrs

Beyond 8 hours, NAC efficacy progressively decreases

S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse

Paracetamol overdose treatment

At the end of NAC infusion, a blood sample should be taken for determination of the INR, plasma creatinine and ALT. If any is abnormal or the patient is symptomatic, further monitoring is required and advice sought from the NPIS

Patients with normal INR, plasma creatinine and ALT and who are asymptomatic may be discharged from medical care. They should be advised to return to hospital if vomiting or abdominal pain develop or recur

Indications for liver transplantation

Liver transplantation is life-saving for fulminant hepatic necrosis The indications for liver transplantation are:1 - Acidosis (pH < 7.3), or 2 - PT > 100 sec 3 - Creatinine > 300 mcg/l 4 - Grade 3 encephalopathy (or worse)It is better to contact the local liver transplant centre earlier than this. Grossly abnormal prothrombin times should trigger referral:PT > 20 sec at 24 hr PT > 40 sec at 48 hr

Alcohol poisoning

Clinical features of acute alcohol poisoning include:

Ataxia and anaesthesia leading to accidental injury

Dysarthria and nystagmus

Drowsiness which may progress to coma

Inhalation of vomit which can be fatal & should be prevented

Hypoglycaemia in children and some adults

Check BM stix and give 50% glucose i.v. if required

Coma (alcohol induced)In cases of alcohol induced coma exclude:

1. Coincident head injury2. Hepatic failure 3. Meningitis4. Wernicke’s encephalopathy 5. Other associated drug ingestion

A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemiaThe airway and circulation must be maintainedBut glucose- containing fluids may precipitate Wernicke's encephalopathyThiamine should given to allIntravenous naloxone has reversed coma in a proportion of cases