PDP 406 CLINICAL TOXICOLOGY

Pharm.D Fourth Year

Management of overdose and poisoning

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

General- evaluation „ „ „ „

recognition of poisoning identification of agents involved assessment of severity prediction of toxicity

General- management „ „ „ „

provision of supportive care prevention of poison absorption enhancement of elimination of poison administration of antidotes

Supportive care „ „ „ „ „ „ „ „

ABC Vital signs, mental status, and pupil size Pulse oximetry, cardiac monitoring, ECG Protect airway Intravenous access cervical immobilization if suspect trauma Rule out hypoglycaemia Naloxone for suspected opiate poisoning

History „ „ „ „ „ „

Pill bottles Alcohol Drug history including access Remember OTC drugs Suicide note National 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 Vomiting „ „

Ipecac - Not routinely recommended Risk of aspiration

Preventing absorption Activated charcoal „

„ „ „

„

Adsorbs toxic substances or irritants, thus inhibiting GI absorption Addition of sorbitol →laxative effect Oral: 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 elimination „

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

Forced alkaline diuresis „ „ „ „

Infusion of large amount of NS+NAHCO3 Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates Serious fluid and electrolytes disturbance may occur Need expert monitoring

Hemodialysis or haemoperfusion: „ „ „

Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of distribution may also be used temporarily or as long term if the kidneys are damag due 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

Opiates „ „

„

„ „

Antidote – 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 overdose clinical 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 intubation Consider gastric lavage if taken < 2hrs Activated charcoal Treatment of hypotension with isotonic saline Sodium bicarbonate for cardiovascular toxicity Alpha 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 acid Herbal remedies Fatal 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 thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting Direct toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopenia Activation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosis Uncoupled 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 features „

Stage 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) „ 1. 2. 3. 4. 5. „ „ „ „

„ „

In cases of alcohol induced coma exclude: Coincident head injury Hepatic failure Meningitis Wernicke’s encephalopathy Other associated drug ingestion A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemia The airway and circulation must be maintained But glucose- containing fluids may precipitate Wernicke's encephalopathy Thiamine should given to all Intravenous naloxone has reversed coma in a proportion of cases