Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 58. Management of the Poisoned Patient

Management of the Poisoned Patient: Introduction

Toxic substances include therapeutic agents as well as agricultural and industrial chemicals that have no medical applications. Most chemicals are capable of causing toxic effects when given in excessive dosage; even for therapeutic drugs, the difference between a therapeutic action and a toxic one is most often a matter of dose. Many toxic effects of therapeutic agents have been discussed in previous chapters. Common toxic syndromes associated with major drug groups are summarized in this chapter. This chapter also reviews the principles of management of the poisoned patient.

High-Yield Terms to Learn

ABCDs Mnemonic for the supportive initial treatment of all poisoned patients that stands for Airway, Breathing, Circulation, and Dextrose or Decontamination Anion gap The difference between the serum concentrations of the major cations (Na+/K+) and (HCO- 3/CI -); an increased anion gap indicates the presence of extra anions and is most commonly caused by metabolic acidosis

Antidote A substance that counteracts the effect of a poison Osmolar gap The difference between the measured serum osmolality and the osmolality that is calculated from serum concentrations of sodium, glucose, and BUN; an increased osmolar gap is associated with poisoning due to ethanol and other alcohols

Toxicokinetics, Toxicodynamics, & Cause of Death

Toxicokinetics

This term denotes the disposition of poisons in the body (ie, their pharmacokinetics). Knowledge of a toxin's absorption, distribution, and elimination permits assessment of the value of procedures designed to remove it from the skin or gastrointestinal tract. For example, drugs with large apparent volumes of distribution, such as antidepressants and antimalarials, are not amenable to dialysis procedures for drug removal. Drugs with low volumes of distribution, including lithium, phenytoin, and salicylates, are more readily removed by dialysis and diuresis procedures. In some cases, renal elimination of weak acids can be accelerated by urinary alkalinization, whereas renal elimination of some weak bases can be accelerated by urinary acidification. The clearance of drugs may be different at toxic concentrations than at therapeutic concentrations. For example, in overdoses of phenytoin or salicylates, the capacity of the liver to metabolize the drugs is usually exceeded, and elimination changes from first-order (constant half-life) to zero-order (variable half-life) kinetics.

Toxicodynamics

Toxicodynamics denotes the injurious effects of toxins (pharmacodynamic effects). A knowledge of toxicodynamics can be useful in the diagnosis and management of poisoning. For example, hypertension and tachycardia are typically seen in overdoses with amphetamines, cocaine, and antimuscarinic drugs. Hypotension with bradycardia occurs with overdoses of calcium channel blockers,  blockers, and sedative-hypnotics. Hypotension with tachycardia occurs with tricyclic antidepressants, phenothiazines, and theophylline. Hyperthermia is most frequently a result of overdose of drugs with antimuscarinic actions, the salicylates, or sympathomimetics. Hypothermia is more likely to occur with toxic doses of ethanol and other central nervous system (CNS) depressants. Increased respiratory rate is often a feature of overdose with carbon monoxide, salicylates, and other drugs that cause metabolic acidosis or cellular asphyxia. Overdoses of agents that depress the heart are likely to affect the functions of all organ systems that are critically dependent on blood flow, including the brain, liver, and kidney.

Cause of Death in Intoxicated Patients

The most common causes of death from drug overdose in the United States reflect the drug groups most often selected for abuse or for suicide. Sedative-hypnotics and opioids cause respiratory depression, coma, aspiration of gastric contents, and other respiratory malfunctions. Drugs such as cocaine, PCP, tricyclic antidepressants, and theophylline cause seizures, which may lead to vomiting and aspiration of gastric contents and to postictal respiratory depression. Tricyclic antidepressants and cardiac glycosides cause dangerous and frequently lethal arrhythmias. Severe hypotension can occur with any of these drugs. A few intoxicants directly damage the liver and kidney. These include acetaminophen, mushroom poisons of the Amanita phalloides type, certain inhalants, and some heavy metals. (see Chapter 57).

Management of the Poisoned Patient

Management of the poisoned patient consists of maintenance of vital functions, identification of the toxic substance, decontamination procedures, enhancement of elimination, and, in a few instances, administration of a specific antidote.

Vital Functions

The most important aspect of treatment of a poisoned patient is maintenance of vital functions, as indicated by the mnemonic, ABCDs. The most commonly endangered or impaired vital function is respiration. Therefore, an open and protected airway (A) must be established first and effective ventilation (B for breathing) must be ensured. The circulation (C) should be evaluated and supported as needed. The cardiac rhythm should be determined, and if ventricular fibrillation is present, it must be corrected at once. The blood pressure should be measured but rarely needs immediate treatment except in cases of traumatic hemorrhage. Because of the danger of brain damage from hypoglycemia, intravenous 50% dextrose (D) should be given to comatose patients immediately after blood has been drawn for laboratory tests and before laboratory results have been obtained. Thiamine should be administered to prevent Wernicke's syndrome in patients with suspected alcoholism or malnourishment. In patients with signs of respiratory or CNS depression, intravenous naloxone offsets possible toxic effects of opioid analgesic overdose.

Identification of Poisons

Many intoxicants cause a characteristic syndrome of clinical and laboratory changes. Table 58-1 summarizes toxic syndromes associated with major drug groups and the key interventions called for. The toxic features of selected individual agents are listed in Table 58-2. When the toxic agent cannot be directly examined and identified, the clinician must rely on indirect means to identify the type of intoxication and the progress of therapy. In addition to the history and physical examination, certain laboratory examinations may be useful. A few intoxicants can be directly identified in the blood or urine, especially when information in the history narrows the search. In the more common situation of a comatose patient unable to provide a history, general tests for replacement of anions or osmotic equivalents in the blood (anion gap, osmolar gap) may be useful. A few intoxicants can be identified or strongly suspected on the basis of electrocardiographic or radiologic findings.

TABLE 58-1 Toxic syndromes caused by major drug groups.

Drug Group Clinical Features Key Interventions Antimuscarinic drugs (anticholinergics) Delirium, hallucinations, seizures, coma, tachycardia, hypertension, hyperthermia, mydriasis, decreased bowel sounds, urinary retention Control hyperthermia; physostigmine may be helpful, but not for tricyclic overdose Cholinomimetic drugs (carbamate or organophosphate cholinesterase inhibitors) Anxiety, agitation, seizures, coma, bradycardia or tachycardia, pinpoint pupils, salivation, sweating, hyperactive bowel, muscle fasciculations, then paralysis Support respiration. Treat with atropine and pralidoxime. Decontaminate Opioids (eg, heroin, morphine, methadone) Lethargy, sedation, coma, bradycardia, hypotension, hypoventilation, pinpoint pupils, cool skin, decreased bowel sounds, flaccid muscles Provide airway and respiratory support. Give naloxone as required Salicylates (eg, aspirin) Confusion, lethargy, coma, seizures, hyperventilation, hyperthermia, dehydration, hypokalemia, anion gap metabolic acidosis Correct acidosis and fluid and electrolyte imbalance. Alkaline diuresis or hemodialysis to aid elimination Sedative-hypnotics (barbiturates, benzodiazepines, ethanol) Disinhibition initially, later lethargy, stupor, coma. Nystagmus is common, decreased muscle tone, hypothermia. Small pupils, hypotension, and decreased bowel sounds in severe overdose Provide airway and respiratory support. Avoid fluid overload. Consider flumazenil for benzodiazepine overdose Stimulants (amphetamines, cocaine, phencyclidine [PCP]) Agitation, anxiety, seizures. Hypertension, tachycardia, arrhythmias. Mydriasis, vertical and horizontal nystagmus with PCP. Skin warm and sweaty, hyperthermia, increased muscle tone, possible rhabdomyolysis Control seizures, hypertension, and hyperthermia Tricyclic antidepressants Antimuscarinic effects (see above). The "3 C's" of coma, convulsions, Control seizures. Correct acidosis cardiac toxicity (widened QRS, arrhythmias, hypotension) and cardiotoxicity with ventilation, sodium bicarbonate, and norepinephrine (for hypotension). Control hyperthermia

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.)

TABLE 58-2 Toxic features of selected agents.

Agent Toxic Features Acetaminophen Mild anorexia, nausea, vomiting, delayed jaundice, hepatic and renal failure Botulism Dysphagia, dysarthria, ptosis, ophthalmoplegia, muscle weakness; incubation period 12-36 h Carbon monoxide Coma, metabolic acidosis, retinal hemorrhages Cyanide Bitter almond odor, seizures, coma, abnormal ECG Ethylene glycol Renal failure, crystals in urine, increased anion and osmolar gap, initial CNS excitation; eye examination normal Iron Bloody diarrhea, coma, radiopaque material in gut (seen on x-ray), high leukocyte count, hyperglycemia Lead Abdominal pain, hypertension, seizures, muscle weakness, metallic taste, anorexia, encephalopathy, delayed motor neuropathy, changes in renal and reproductive function Lysergic acid (LSD) Hallucinations, dilated pupils, hypertension Mercury Acute renal failure, tremor, salivation, gingivitis, colitis, erethism (fits of crying, irrational behavior), nephrotic syndrome Methanol Rapid respiration, visual symptoms, osmolar gap, severe metabolic acidosis Mushrooms (Amanitaphalloides type) Severe nausea and vomiting 8 h after ingestion; delayed hepatic and renal failure Phencyclidine (PCP) Coma with eyes open, horizontal and vertical nystagmus

Osmolar Gap

The osmolar gap is the difference between the measured serum osmolarity (measured by the freezing point depression method) and the osmolarity predicted by measured serum concentrations of sodium glucose and BUN:

This gap is normally zero. A significant gap is produced by high serum concentrations of intoxicants of low molecular weight such as ethanol, methanol, and ethylene glycol.

Anion Gap

The anion gap is the difference between the sum of the measured serum concentrations of the 2 primary cations, sodium and potassium, and the sum of the measured serum concentrations of the 2 primary anions, chloride and bicarbonate:

This gap is normally 12-16 mEq/L. A significant increase can be produced by diabetic ketoacidosis, renal failure, or drug-induced metabolic acidosis. Drugs that cause an anion gap include cyanide, ethanol, ethylene glycol, ibuprofen, isoniazid, iron, methanol, phenelzine, salicylates, tranylcypromine, valproic acid, and verapamil.

Serum Potassium

Myocardial function is critically dependent on serum potassium level. Drugs that cause hyperkalemia include -adrenoceptor blockers, digitalis (in suicidal overdose), fluoride, lithium, and potassium-sparing diuretics. Drugs associated with hypokalemia include barium, -adrenoceptor agonists, methylxanthines, most diuretics, and toluene.

Decontamination

Decontamination is the removal of any unabsorbed poison from the skin or gastrointestinal tract (Figure 58-1). In the case of topical exposure (insecticides, solvents), the clothing should be removed and the patient washed to remove any chemical still present on the skin. Medical personnel must be careful not to contaminate themselves during this procedure. For most cases of ingested toxins, activated charcoal,given orally or by stomach tube, is very effective in adsorbing any toxin remaining in the gut. Poisons that can be removed by multiple treatments with activated charcoal include amitriptyline, barbiturates, carbamazepine, digitalis glycosides, phencyclidine, propoxyphene, theophylline, tricyclic antidepressants, and valproic acid. Charcoal does not bind iron, lithium, or potassium, and it binds alcohols and cyanide poorly. Less commonly, gastric lavage with a large-bore tube is used to remove noncorrosive drugs from the stomach of an awake patient or from a comatose patient whose airway has been protected with a cuffed endotracheal tube. In the past, decontamination was attempted by inducing vomiting (emesis), mostly by administering syrup of ipecac in a conscious patient. (Fluid extract of ipecac should not be used because it contains cardiotoxic alkaloids.) However, this approach has fallen out of favor because the risks involved, particularly of aspiration, have been shown to outweigh the benefits. Whole bowel irrigation with a balanced polyethylene-glycol electrolyte solution can enhance gut decontamination of iron tablets, enteric-coated pills, and illicit drug-filled packets. Cathartics such as sorbitol can decrease absorption and hasten removal of toxins from the gastrointestinal tract.

FIGURE 58-1

Important measures for the decontamination and enhanced elimination in poisonings.

Enhancement of Elimination

Enhancement of elimination is possible for some toxins (Figure 58-1), including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity caused by fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidification may be useful in toxicity caused by weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to prevent acidosis and renal failure in rhabdomyolysis. Hemodialysis, an extracorporeal circulation procedure in which a patient's blood is pumped through a column containing a semipermeable membrane that allows the removal of many toxic compounds, is used commonly to remove toxins such as ethylene glycol, lithium, metformin, procainamide, salicylates, and valproic acid, and to correct fluid and electrolyte imbalances.

Antidotes

Antidotes exist for several important poisons (Table 58-3). Since the duration of action of some antidotes is shorter than that of the intoxicant, the antidotes may need to be given repeatedly. The use of chelating agents for metal poisoning is discussed in Chapter 57.

TABLE 58-3 Important antidotes.

Antidote Poison(s) Acetylcysteine Acetaminophen; best given within 8-10 h of overdose Atropine Cholinesterase inhibitors Bicarbonate, sodium Membrane-depressant cardiotoxic drugs (eg, quinidine, tricyclic antidepressants) Calcium Fluoride; calcium channel blockers Deferoxamine Iron salts Digoxin antibodies Digoxin and related cardiac glycoside Esmolol Caffeine, theophylline, sympathomimetics Ethanol Methanol, ethylene glycol Flumazenil Benzodiazepines, zolpidem Fomepizole Methanol, ethylene glycol Glucagon Beta adrenoceptor blockers Glucose Hypoglycemics Hydroxocobalamin Cyanide Naloxone Opioid analgesics Oxygen Carbon monoxide Physostigmine "Suggested" for muscarinic receptor blockers, NOT tricyclics Pralidoxime Organophosphate cholinesterase inhibitors

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.)

Skill Keeper: Cyanide Poisoning

(See Chapters 11 and 12)

Cyanide forms a stable complex with the ferric ion of cytochrome oxidase enzymes and inhibits cellular respiration. What is the connection between the management of cyanide poisoning and the drugs amyl nitrite and nitroprusside? The Skill Keeper Answer appears at the end of the chapter.

Checklist

When you complete this chapter, you should be able to:

 Describe the steps involved in the supportive care of the poisoned patient.

 Identify toxic syndromes associated with overdose of the major drugs or drug groups frequently involved in poisoning.

Outline the methods used for identification of toxic compounds, including descriptive signs and symptoms and laboratory methods.

 Describe the methods available for decontamination of poisoned patients and for increasing the elimination of toxic compounds.

 List the antidotes available for management of the poisoned patient.



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