Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Drugs and Antidotes in Acute Intoxication


Objectives

This chapter will:

  • 1.

    Provide an overview of drugs and antidotes in acute intoxication.

  • 2.

    Highlight clinical pitfalls in the management of toxicity.

  • 3.

    Identify the clinically significant toxidromes.

  • 4.

    Describe the effects of sodium and potassium channel blockers.

  • 5.

    Present a review of specific poisons and antidotes.

  • 6.

    Review poisons that have significant effects on the kidney.

Deliberate self-poisoning, accidental poisoning, and recreational drug abuse and chemical exposure are increasing in frequency across the world. The Toxic Exposure Surveillance System (TESS) database of poison control centers of the United States reported a frequency of approximately 6.7 exposures per 1000 population in 2014.

Calls from healthcare facilities regarding human exposures have increased consistently over the last 14 years (3.3% since 2000). Human exposures with more serious outcomes have increased by 4.29% since 2000. Although children younger than 6 years of age were involved in 47.7% of poisoning reports, they incurred just 2.2% (26) of the recorded 1173 fatalities. Forty-six percent of poisoning fatalities occurred in persons 20 to 49 years of age. Analgesics were thought to be responsible for most of the fatalities, with the next most common cause attributable to stimulants and “street drugs.” However, sedatives/hypnotics/antipsychotics have demonstrated the most rapid increase in serious outcomes over the last few years. Of all reported exposures, 16.7% of inquiries were described as intentional exposure, a majority as a result of a suspected suicide (11.2%). Therapeutic errors accounted for 12.6% of exposures. Overall, 22.3% of the patients required evaluation in a healthcare facility, of whom 3.2% were admitted to an acute inpatient bed and 4.7% to a critical care unit. Of all of the reported exposures, therapies other than decontamination were used 11.5% of the time.

Although poisoning should be suspected in any patient with multisystem involvement of unknown cause until proven otherwise, the clinician also should be aware of common pitfalls in the workup of the patient with suspected or known poisoning ( Box 98.1 ).

Box 98.1
Pitfalls in Clinical Management of Suspected Toxicity

  • Not all patients with a presumed overdose have, in fact, overdosed. The young patient with altered state of consciousness may have suffered a primary neurologic event, and a careful neurologic examination looking for focal signs must always be part of the evaluation in such cases.

  • A poisoned patient may have suffered a secondary event after the overdose or exposure (e.g., neurologic and cardiac sequelae of cocaine intoxication are well documented).

  • Polypharmacy is the rule. In one study, acetaminophen was the drug most commonly implicated in overdose (54%), but polypharmacy ingestions were the next most frequent (38%). In multiple-ingestion overdoses, the poisoned patient will not follow a “predictable” path of recovery, because other substances may have different time courses for the development of toxicity (e.g., a patient who has overdosed on sustained-release verapamil may not display any signs of poisoning for up to 18 hours, at a time when toxicity from other substances co-ingested may be resolving).

  • Recovery may be prolonged as a result of therapeutic intervention (e.g., development of aspiration pneumonia after gastrointestinal tract decontamination).

  • Poisoning may occur from routes other than oral. Dermal absorption, as in the case of organophosphate poisoning, poses a particular risk for the rescuer or healthcare worker who attends the patient, without protective clothing, before decontamination. Inhalation absorption, as with exposures involving some noxious gases (e.g., products of combustion), puts rescuer and victim at risk.

  • Intravenous substance abuse has been associated with risk of infection, of which hepatitis and HIV infection are well known, but at present the leading cause of botulism in the United States is the use of contaminated needles.

HIV, Human immunodeficiency virus.

Toxidromes

In many clinical circumstances, the poison is unknown, at least initially. In these circumstances, after appropriate life support measures have been instituted, the toxic treatment paradigm is to group signs and symptoms together into a toxidrome. Toxidrome describes clinical presentations common to a number of toxins.

The most common toxidromes are the following:

  • Anticholinergic (antimuscarinic)

  • Cholinergic

  • Adrenergic

  • GABAergic

  • Sodium and potassium channel blocker related

  • Serotoninergic

  • Opiate-related

Anticholinergic Toxidrome

The most common toxidrome by far is due to anticholinergic toxicity. Anticholinergic drugs continue to increase in serious exposures every year.

In 2014, 10,774 exposures were reported, of which 4.2% were reported to be minor or moderate seriousness. One death was reported.

Anticholinergic toxicity is defined more appropriately as antimuscarinic poisoning. It occurs when the acetylcholine postsynaptic muscarinic receptor is antagonized. This receptor is found on the parasympathetic postganglionic receptor.

Dawson and Buckley describe four mechanisms contributing to anticholinergic delirium:

  • 1.

    Predominant muscarinic antagonists such as atropine, benztropine, and many plants

  • 2.

    Muscarinic antagonists with other mixed effects, such as antihistamines, tricyclic antidepressants, and antipsychotics

  • 3.

    Decreased acetylcholine release after carbamazepine, opiate, and clonidine ingestion

  • 4.

    Decreased acetylcholine synthesis as a result of thiamine deficiency

Anticholinergic toxicity can be central, peripheral, or both. Peripheral toxicity may or may not be present before central toxicity develops, and vice versa.

Characteristics of central anticholinergic toxicity include the following:

  • Biphasic effect of central nervous system (CNS) excitation followed by depression

  • Distinctive mumbling or fragmentary speech pattern

  • Atypical behavior, especially inappropriate undressing

  • Repetitive “picking” movements (e.g., tugging at the bedclothes or a catheter or grasping at space)

  • Hallucinations, more commonly visual

  • Movement disorders of an ataxic or clonic nature in some cases

Patients with severe central manifestations (e.g., hallucinations, psychoses, seizures, coma) have the highest morbidity rates.

Characteristics of peripheral anticholinergic syndrome, in order of onset, include the loss of ability to salivate, sweat, and lacrimate, followed by blurred vision (caused by decreased ability to accommodate and papillary mydriasis) and then an increase in heart rate and a decrease in bladder motility (leading to urinary retention). Finally, gut peristalsis is lost, leading to constipation.

An important clinical clue is that tachycardia with dry axillae distinguishes the anticholinergic toxidrome from the adrenergic toxidrome.

Anticholinergic syndrome can be summarized as follows:

  • Mad as a hatter *

    * Hat manufacturers applied mercury to the felt of their hats and as a result developed mercury poisoning. Thus, in reality, hatters were mad for reasons other than anticholinergic poisoning.

  • Hot as a hare

  • Blind as a bat

  • Red as a beet

  • Dry as a bone

Many drugs and substances cause anticholinergic toxicity. Box 98.2 provides a list of common anticholinergic agents.

Box 98.2
Common Anticholinergic Agents

Antihistamines

  • Chlorpheniramine

  • Cyproheptadine

  • Doxylamine

  • Hydroxyzine

  • Dimenhydrinate

  • Diphenhydramine

  • Meclizine

  • Promethazine

Tricyclic Antidepressants

  • Amitriptyline

  • Amoxapine

  • Clomipramine

  • Desipramine

  • Doxepin

  • Imipramine

  • Nortriptyline

  • Protriptyline

Mydriatics (Easily Systemically Absorbed)

  • Atropine

  • Cyclopentolate

  • Homatropine

  • Tropicamide

Class 1 Antiarrhythmics

  • Disopyramide

  • Plants

  • Atropa belladonna (deadly nightshade)

  • Cestrum nocturnum (night-blooming jasmine)

  • Datura suaveolens (angel's trumpet)

  • Datura stramonium (jimson weed)

  • Hyoscyamus niger (black henbane)

  • Lantana camara (red sage)

  • Solanum carolinensis (wild tomato)

  • Solanum dulcamara (bittersweet)

  • Mushrooms (e.g., Amanita muscaria )

Antipsychotics

  • Phenothiazines (e.g., chlorpromazine)

  • Clozapine

  • Mesoridazine

  • Olanzapine

  • Quetiapine

  • Thioridazine

Antiparkinsonian Drugs

  • Benztropine (also used to control extrapyramidal effects from the major tranquilizers)

Motion Sickness Preparations

  • Scopolamine patches

Muscle Relaxants

  • Orphenadrine (Norflex)

Others

  • Carbamazepine

Antidote Considerations: Physostigmine

Little role exists for the routine use of physostigmine in the management of a patient displaying anticholinergic toxicity. Physostigmine is an acetylcholinesterase inhibitor and, unlike neostigmine, crosses the blood-brain barrier. Thus it can increase central and peripheral levels of acetylcholine.

The clinical response to physostigmine can be dramatic, controlling agitation and reversing delirium 96% and 87%, respectively, compared with benzodiazepines, which control agitation in only 24% and have no effect on delirium. The use of physostigmine is not without adverse effects, with seizure, bradycardia, and even asystole being reported when used in the management of overdose, especially in the setting of tricyclic antidepressant toxicity. It is postulated that in this situation, the anticholinergic-induced tachycardia, which may be helpful in offsetting the negatively inotropic effect of sodium channel blockade, when antagonized acutely leads to cardiac or pump failure and dysrhythmia. Although physostigmine has a short half-life (minutes), the clinical effect is longer. Therefore physostigmine should be used only after consultation with a toxicologist, in a setting in which full resuscitation facilities are available. Alternatives such as tacrine, donepezil, rivastigmine, and galantamine do not have sufficient evidence to support use in this setting.

The dose is 2.0 mg administered intravenously in 0.5-mg aliquots, given 5 to 10 minutes apart.

Cholinergic Toxidrome

The parasympathetic nervous system has acetylcholine as its neurotransmitter at central and peripheral receptors. The central preganglionic receptor is a nicotinic receptor (Nn type). The sympathetic nervous system uses two neurotransmitters: acetylcholine acts on Nn receptors in the preganglionic central chain, and norepinephrine acts on the peripheral α and β receptors. The somatic nervous system has acetylcholine as its neurotransmitter, acting on the nicotinic Nm receptor subtype to innervate striped (skeletal) muscle.

The cholinergic toxidrome is manifested by signs of stimulation of the muscarinic and the nicotinic receptors in autonomic and somatic nervous systems.

Stimulation of the muscarinic receptors leads to the “classic” SLUDGE syndrome:

  • Salivation

  • Lacrimation

  • Urination

  • Diarrhea

  • Gastrointestinal cramps

  • Emesis

In addition, muscarinic cholinergic stimulation leads to bronchoconstriction and bronchorrhea.

Stimulation of central nicotinic receptors affects sympathetic and parasympathetic neurons. This causes a release of norepinephrine and acetylcholine. An initial excitation phase, manifested by tachycardia and hypertension, may occur as a result of sympathetic nervous system stimulation. After the initial stimulation, however, prolonged ganglionic blockade and adrenal suppression occur (nicotinic receptors also are located in the adrenal medulla). At this point, hypotension and bradycardia predominate. Nicotinic receptor stimulation in the brain leads to altered mental status, with confusion, agitation, restlessness, and vomiting. This may be followed by onset of seizure and neurologic depression with coma.

Acetylcholinergic stimulation of Nm receptors on skeletal muscle causes initial excitation, with fasciculation and tonic clonic jerks, followed by blockade and muscle weakness. Hypotonia, decreased tendon reflexes, and motor paralysis sequentially occur.

Agents that cause a cholinergic toxidrome can be divided into two main groups, according to their mechanism of action:

  • Direct nicotinic receptor stimulation plant alkaloids such as nicotine and coniine (found in poison hemlock), nicotine-based insecticides, cigarette butts (at least three whole butts in a young child)

  • Increased acetylcholine levels, organophosphates, and carbamates

Organophosphates

Organophosphates are agricultural insecticides. These agents inhibit the enzyme acetylcholinesterase, which is responsible for the degradation of acetylcholine. The organophosphate binds to the enzyme, causing it to undergo a conformational change at its binding site to acetylcholine. If the organophosphate does not leave the acetylcholinesterase enzyme within 24 to 48 hours, it is bound irreversibly to the enzyme, which is permanently inactivated; this process is called “aging.” Recovery from poisoning occurs only with resynthesis of new enzyme, a process that takes several weeks. The treatment of organophosphate poisoning is twofold:

  • 1.

    Symptomatic treatment with atropine to overcome muscarinic stimulation by acetylcholine. The dose given is that sufficient to “atropinize” the patient—to abolish signs and symptoms (see later).

  • 2.

    Reactivation of acetylcholinesterase with an oxime such as pralidoxime. Oximes cleave the organophosphate from acetylcholinesterase and bind circulating free organophosphate. In addition, pralidoxime displays antimuscarinic properties of its own. Because of the aging of the organophosphate-acetylcholinesterase complex, the earlier oximes are administered, the earlier acetylcholinesterase can be re-formed. Resolution of symptoms and a rising acetylcholinesterase level indicate response to therapy.

In military or disaster scenarios, atropine and an oxime are combined in “autoinjectors.” Pralidoxime is discussed here, but in other parts of the world, including the United States, other oximes are used, the most frequent being obidoxime. Oxime effectiveness and dosing have been the subject of much discussion because of the lack of randomized trials evaluating organophosphate treatment. A recently published article by Pawar et al. showed that higher-dose continuous infusion of pralidoxime iodide (1 g/hr of pralidoxime for 48 hours) was superior to intermittent dosing (a bolus of 1 g/hr every 4 hours).

Antidote Considerations

Atropine.

Atropine is a physiologic antidote to the muscarinic features of organophosphate toxicity, acting to competitively inhibit acetylcholine at muscarinic receptors but with no effect at ganglionic or neuromuscular nicotinic receptors. It also may be useful in carbamate toxicity, which may be clinically indistinguishable from organophosphate toxicity.

The dose is 2 mg (0.05 mg/kg in children), repeated at 10- to 30-minute intervals until drying of excessive secretions occurs. There is no upper limit of dose in the treatment of a severe organophosphate poisoning. Severe toxicity may require extremely large doses to achieve atropinization (up to 1000 mg/24 hours has been used). An atropine infusion at 5 to 20 mg/hr may be required. Pupillary dilatation and tachycardia are not reliable therapeutic end points. Normalization of peripheral vascular resistance may be a better end point but is not normally measurable outside an ICU environment. Atropine may be useful in the treatment of hypotension without bradycardia. In the randomized controlled trial, the atropine was administered as a 1.8- to 3.0-mg bolus on admission, followed by an infusion with intermittent boluses to achieve control of secretions from the tracheobronchial tree, return pupils to their normal size, and stabilize the pulse rate at between 80 and 100 beats per minute.

Adverse reactions to atropine may include the following:

  • Ventricular arrhythmias may occur if adequate tissue oxygenation is not achieved before the use of atropine.

  • Atropine excess may cause anticholinergic symptoms: mydriasis, tachycardia, hyperpyrexia, ileus, delirium, facial flushing, urinary retention, drying of secretions.

Pralidoxime.

The dosage is 1 to 2 g (25 to 50 mg/kg in children) given over 30 minutes, followed by an infusion of 200 to 500 mg/hr. Infusions usually must be continued for at least 48 hours in significant exposures. The dose should be reduced in the presence of renal failure.

Adverse reactions reported after pralidoxime iodide injection include dizziness, blurred vision, diplopia and impaired accommodation, headache, drowsiness, nausea, tachycardia, hyperventilation, and muscular weakness, but it is very difficult to differentiate the toxic effects produced by the organophosphate compounds from those of the drug. When atropine and pralidoxime iodide injection are used together, the signs of atropinization may occur earlier than may be expected when atropine is used alone, and less atropine may be required. Excitement and manic behavior occurring immediately after recovery of consciousness have been reported in several instances. However, similar behavior has been described in cases of organophosphate poisoning that were not treated with pralidoxime iodide injection.

Recent studies have cast doubt on the efficacy of pralidoxime in the treatment of organophosphate poisoning. A randomized double-blind placebo-controlled trial comparing pralidoxime to saline showed no difference in mortality (28% vs. 26%) or length of ICU stay. A previous study by Eddleston reported that despite showing a reactivation of red blood cell acetylcholinesterase in the pralidoxime-treated group, there was increased case fatality mortality (although not statistically significant) in those treated with pralidoxime. At the time of publication there has been no change to the World Health Organization recommendations pralidoxime regime.

Adrenergic Toxidrome

Box 98.3 lists common causes of the adrenergic toxidrome. The adrenergic toxidrome is caused by sympathomimetic agents. Neurologic manifestations include hyperthermia, agitation, seizures, and coma. Cardiovascular effects include tachycardia, hypertension, peripheral vasoconstriction, arrhythmias, and myocardial infarction. Metabolic disturbances from increased circulating catecholamines cause elevation of glucose levels and the white blood cell count. Hypokalemia in the absence of vomiting usually does not require correction, because the cause is not a potassium deficit but rather an intracellular shift, which will settle as the toxidrome abates. Other signs and symptoms include bronchodilation, nausea, and vomiting; diaphoresis and rhabdomyolysis also may occur.

Box 98.3
Common Causes of the Adrenergic Toxidrome

  • Recreational drugs

    • Cocaine

    • Amphetamines and other “designer drugs” a

      a Up to 80% of ecstasy tablets sold in Australia are actually methamphetamine.

      —“ecstasy” (3,4-methylenedioxymethamphetamine [MDMA]); 3,4- methylenedioxyamphetamine (MDA); 3,4- methylenedioxyethylamphetamine (MDEA); paramethoxyamphetamine (PMA); methamphetamine

  • β 1 -Adrenergic agents

    • Salbutamol

    • Theophylline

  • Inotropic agents

    • Norepinephrine

    • Epinephrine

    • Isoproterenol

  • Over-the-counter cough and cold preparations and nasal decongestants

    • Phenylpropanolamine

    • Pseudoephedrine

  • Amphetamine-like agents prescribed for ADD or weight loss

    • Methylphenidate

    • Dextroamphetamine

  • Psychostimulants

ADD, Attention deficit disorder.

No specific antidotes are available. Management consists of lowering body temperature and blood pressure and achieving central sedation, usually with a benzodiazepine and other supportive measures. Hypertension requiring pharmacologic intervention is treated with a specific alpha blocker or smooth muscle antihypertensive (e.g., hydralazine or sodium nitroprusside). Beta blockers have the potential to precipitate a vasoconstriction crisis by unopposed alpha stimulation. If the patient exhibits psychosis in the setting of amphetamine or cocaine toxicity without significant cardiovascular toxicity, an agent such as haloperidol may improve the patient's mental status by means of dopamine antagonism. Phenothiazines such as chlorpromazine should be avoided because they lower the seizure threshold and may exacerbate hyperthermia because of anticholinergic activity. “Ecstasy” (i.e., 3,4-methylenedioxymethamphetamine [MDMA]) poisoning may respond to antiserotoninergic medication such as cyproheptadine (see later).

Note About Recreational Drugs

The 2015 National Institute on Drug Abuse Survey on the prevalence of use of various recreational substances reported that between the ages of 12 to 17, 28.4% used alcohol in the past year, 8.1% cigarettes, 17.5% some form of illicit drug consisting of cocaine (0.6%), hallucinogens (2.1%), and LSD (1%). Amphetamine derivatives MDMA, methamphetamines, and others were used by 2.1% within the past year. In the over 18 age group, this increased to 14.5%.

Methamphetamines are produced by reduction of ephedrine or pseudoephedrine, found in decongestants and other household products, making them relatively simple drugs to produce.

Psychostimulants cause an overall increase in the amount of monoamine neurotransmitters—norepinephrine, dopamine, and serotonin—by increasing their release and blocking reuptake. Amphetamines, MDMA, and cocaine have the greatest effect on norepinephrine, serotonin, and dopamine, respectively. Ecstasy primarily increases serotonergic activity, whereas methamphetamine primarily increases adrenergic activity. Cocaine also blocks fast sodium channels, causing local anesthetic and proarrhythmic effects.

A majority of ecstasy users do not experience adverse events that precipitate a hospital visit. Serious complications are rare and partly dependent on individual susceptibility and circumstances. The common adverse acute physiologic and psychologic effects that psychostimulants elicit constitute an exaggerated “fight or flight” response.

Extreme dehydration and water intoxication have been associated with MDMA toxicity. Dehydration is due to a lack of awareness of thirst in the setting of extreme physical activity. Water intoxication can be a consequence of increased antidiuretic hormone secretion and consumption of too much water (to prevent dehydration), leading to complications associated with hyponatremia. Cardiac ischemia can occur with any of these drugs but is particularly associated with cocaine. It is due to a combination of increased myocardial demand, coronary vasoconstriction, and increased thromboxane A 2 activity and thrombus formation.

The most commonly repeated findings in studies of MDMA, methamphetamine, and cocaine use have been problems in the area of learning and memory. Animal and human studies have yielded evidence of neurotoxicity, but whether this is permanent and irreversible after chronic use in humans is inconclusive. However, the evidence for neurotoxicity continues to accumulate.

GABAergic Toxidrome

γ-Aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter located in the CNS. The other important inhibitory neurotransmitter, glycine, is situated centrally and peripherally, where it is involved in inhibitory stimuli to tendon stretch reflexes. This peripheral action is demonstrated in strychnine poisoning, in which glycine receptors are inhibited by strychnine, leading to abnormal muscle activity and painful spasms in affected patients, who retain a normal mental status.

The GABAergic toxidrome refers to the effects of stimulation of the GABA A receptor. The GABA A receptor is a chloride ion receptor complex that causes chloride ions to enter the nerve cell, causing hyperpolarization on stimulation. This action produces inhibitory neurotransmission. Antagonism of the GABA A receptor causes excitation.

Most CNS depressants work by enhancing GABA A neurotransmission. Benzodiazepines and barbiturates, anticonvulsants such as valproate, and to some degree, carbamazepine, general anesthetics, and ethanol are some examples. All of these agents must bind to GABA to produce their neuroinhibitory effect. In isoniazid overdose, in which GABA formation has been stopped, seizures are refractory to control with GABA-dependent anticonvulsants, such as barbiturates and benzodiazepines.

Antagonists of the GABA A receptor include toxins such as chlordane, an organochlorine pesticide, and lindane, used in the treatment of lice. High-dose penicillin, used in animal models to induce seizures, antagonizes the receptor, as does the administration of ciprofloxacin. All of these agents may precipitate seizures.

Antidote Considerations: Flumazenil

Flumazenil is a benzodiazepine antagonist that binds to the benzodiazepine receptor, displacing other benzodiazepine agonists, without neuroinhibitory effects. Thus it antagonizes the neuronal depression caused by GABA stimulation at the GABA A receptor. The routine use of flumazenil in the management of benzodiazepine overdose is not recommended, because withdrawal seizures may be precipitated in patients who are chronically dependent on benzodiazepines, or in those who are not, the abrupt reversal of benzodiazepines may unmask the effect of an excitatory drug taken as a co-ingestant (e.g., tricyclic antidepressants), also with the potential for causing seizures. A recent meta-analysis of adverse events associated with the use of flumazenil reported a risk ratio of 2.85 (compared with placebo), increasing to 3.81 when only serious adverse events were included. A further consideration is the relatively high safety index (toxic-to-therapeutic dose ratio) of benzodiazepines.

Sodium and Potassium Channel—Blocking Agents

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts