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