Toxicology

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Chapter 7 Toxicology

The field of toxicology is a broad-based multidisciplinary science that examines the harmful effects of substances on living organisms, including humans. There are several major subdivisions of toxicology.

image Descriptive toxicology focuses on toxicity testing with the intent of defining the degree of risk associated with substances.
image Environmental toxicology involves the detection and understanding of environmental pollutants and their effects on humans and other organisms.
image Forensic toxicology is primarily concerned with detection and quantification of toxic substances for legal purposes.
image Mechanistic toxicology is focused on determining the mechanisms by which substances exert toxic effects.
image Regulatory toxicology uses toxicologic data to establish policies regarding exposure limits for toxic substances.
image Medical or clinical toxicology focuses on the diagnosis and treatment of toxic effects in humans.

This chapter focuses primarily on the concepts of medical toxicology. These concepts are similar in many respects, at least in principle, to those of pharmacodynamics and pharmacokinetics. This is not surprising, because any substance can be toxic under the appropriate conditions. Indeed, Paracelsus, an early toxicologist, stated, “All things are poison and nothing is without poison, only the dose permits something not to be poisonous.” In fact, even water in excess can exert toxic effects (water intoxication) by disrupting electrolyte balance. Thus toxicity may be associated with therapeutic agents and nontherapeutic agents alike.

General Principles

Terminology

Although toxicology has a long history, it is an evolving discipline, and consequently toxicologic terminology continues to evolve. There are ongoing efforts to standardize and codify toxicologic terminology (see Internet resources). The following are some useful definitions:

image Poison is any substance that may disrupt biologic function and potentially kill an organism.
image Toxin, by strict definition, is a poison of biologic origin that does not have the ability to replicate. However, the term toxin has been used more loosely. For example, environmental toxin has been used to describe toxic substances of nonbiologic origin.
image Venom is a toxin that is injected into the victim by some means (e.g., bee sting, snake bite).
image Toxicant is a general term that refers to any harmful substance and is generally interchangeable with poison.
image Toxicodynamics refers to the general concepts of pharmacodynamics (interaction with molecular targets and mechanisms of effects) as applied to interactions and mechanisms that generate toxic effects.
image Toxicokinetics refers to the general concepts of pharmacokinetics (absorption, distribution, biotransformation, and elimination) as applied to toxic substances.

General Mechanisms of Toxicity

Toxicity can be caused by both therapeutic and nontherapeutic substances. In terms of therapeutic drugs, toxicity may arise from a direct extension of the drug’s primary action. For example, central nervous system (CNS) depression or coma may occur with excessive doses of barbiturates used in the treatment of epilepsy. The toxic effect may also be unrelated to the primary therapeutic effect but related to the general pharmacology of the drug (nonsteroidal antiinflammatory agents may increase edema in heart failure patients). The toxic effect may also have no relationship to the therapeutic action of the drug (ototoxicity induced by aminoglycoside antibiotics).

Detailed discussion of the mechanisms of toxicity is beyond the scope of this text. Nevertheless, it is useful to identify several general mechanisms by which toxic effects occur. These mechanisms can be classified as follows:

image Physical. The physical presence of the toxicant triggers reactions that are harmful (e.g., asbestos fibers in the lung).
image Chemical. Toxicants react chemically with the tissues or body fluids such as blood to produce harmful effects (e.g., strong acids or bases cause burns).
image Pharmacologic. Toxicants interact with endogenous pharmacologic pathways, resulting in inhibition or overstimulation (e.g., botulinum toxin inhibits release of acetylcholine to cause paralysis).
image Biochemical. Toxicant reacts biochemically with cellular constituents to produce cellular damage (e.g., venom of many snakes contains phospholipases that destroy cell membranes).
image Genomic (genotoxic). Toxicant alters the genetic material of the cell, resulting in disruption of function. Genotoxic substances may be mutagenic or carcinogenic.
image Mutagenic (carcinogenic). Toxicants alter DNA structure or function sufficiently to cause mutations (benzene) or initiate and promote the development of cancers (polycyclic aromatic hydrocarbons such as benzo[a]pyrene, found in cigarette smoke).
image Immunologic. Toxicant may trigger an immune response that leads to cellular damage (e.g., penicillin-induced hemolytic anemia) or conversely suppresses the immune system, causing an increased susceptibility to infection (e.g., procainamide-induced agranulocytosis).
image Teratogenic. Toxicant alters fetal development, resulting in birth defects (e.g., phenytoin is associated with development of cleft lip).

Target Organs

Toxicity may be systemic, affecting the whole body, or it may be largely confined to select target organs, the so-called toxic effect organs. Some organs, such as the liver, brain, lungs, heart, and kidney, play a central role in poisonings (Figure 7-1). When toxicity is site specific, the word toxic is preceded by an indication of the specific target organ. Thus, hepatotoxicity refers to effects on the liver, nephrotoxicity refers to effects on the kidney, ototoxicity refers to effects on the auditory system, and so on. A number of factors interact to determine the susceptibility of organs to toxic effects. These include the organ’s anatomic location, blood flow, metabolic processes and activity, affinity for the toxicant, and capacity for self-repair. Major toxic effect organs include the following:

image Liver. The liver is exposed to a high concentration of toxic substances. Orally absorbed toxicants are presented first to the liver via the portal circulation. The liver also receives a large proportion of systemic blood flow. Enterohepatic cycling extends exposure to toxicants excreted through the bile. The high metabolic activity of the liver also results in the generation of reactive intermediates that may have toxic actions.
image Kidney. The kidney receives a high proportion of the cardiac output. Many toxic substances are excreted by the kidney. These toxicants are concentrated in the urine as fluid is reabsorbed from the renal tubule.
image Heart. The total blood volume passes through the heart. Thus it is exposed to all blood-borne toxicants.
image Lungs. The lungs represent an extremely large surface area for interaction with toxicants, particularly those that are airborne. The total cardiac output passes through the lungs, so blood-borne toxicants are also distributed extensively to the lungs.
image Brain. The brain is a critical target organ because of its central role in homeostasis. Thus toxicants that affect the brain may influence multiple systems and result in widespread systemic toxicity.
image

Figure 7-1 Major target organs.

Risk Assessment

Poisoning remains a significant public health issue that affects up to approximately 5% of the population per year in industrialized countries. Many countries have established national poison control centers that can serve as valuable sources of information. The World Health Organization maintains a directory of these centers (see Websites).

Because virtually all substances are potentially toxic, key questions in toxicology are how much risk is associated with a particular substance and under what conditions does this risk become apparent? In addition, the level of acceptable risk will vary. In some circumstances, very toxic substances (e.g., anticancer drugs) are used therapeutically despite their known toxic effects because the benefits of such treatments outweigh the risks. Accordingly, risk assessment is a primary consideration in the management of toxic events (Figure 7-2).

image

Figure 7-2 Risk assessment during management of toxic events.

Key factors contributing to risk assessment include the following:

image Hazard identification. What substances are involved and what are the adverse effects of each substance? Knowledge of the physicochemical properties, toxicokinetics, and toxicodynamics of the suspected toxicant(s) is invaluable in designing treatment strategies.
image Dose response. Is there a known dose response relationship for the toxic effects of the toxicant? Do toxic effects mirror plasma concentrations? At what dose (concentration) do toxic effects appear?
image Exposure assessment. Exposure assessment is a key process in determining the urgency and strategy for treatment of toxic events. Exposure assessment includes estimation of the following:

• Degree of exposure. An estimate of the degree of exposure is essential. This may be the dose of drug ingested, the concentration of chemical to which a patient was exposed, or some other measure (e.g., parts per million) of the amount of toxicant. Included in this assessment is whether the exposure was acute or chronic.
image Route of exposure. The route of exposure is an important determinant of both the extent and rate of absorption of the toxicant. For example, dermal exposure is generally associated with reduced rates and extent of absorption compared with oral ingestion or inhalation.
image Time since exposure. An estimate of the time since the exposure will be helpful in estimating the following:

• Degree of absorption at presentation.
• Usefulness of blood sampling. Blood sampling is useful for toxicants that exhibit a relationship between the plasma concentration and toxic effect(s). However, if the time of exposure has been long, it is most likely that plasma concentrations have reached a maximum value and are of lesser benefit compared with symptomatology in determining course of treatment.
• Value of certain therapies. The time since exposure will dictate to a certain extent the appropriateness of treatment approaches. For example, if the time since initial exposure has been very long, then therapies aimed at inhibiting absorption may have only a minor influence on the course of poisoning.

image Clinical status. In many cases, information about the degree and time of exposure may be lacking. In such cases, careful determination of the clinical status of the patient coupled with knowledge of potential hazards can assist in determining the type of toxicant (e.g., recognition of anticholinergic effects of mushroom poisoning), the suspected time course, and the treatment protocol. In addition, recognition of compromised airway, circulatory, or neural function requires immediate supportive measures.
image Patient characteristics. The specific characteristics such as anthropomorphic characteristics, genetic background, and preexisting conditions of each patient also factor into risk assessment. Some (e.g., weight) may affect the course of poisoning indirectly, whereas others may have a more direct effect (e.g., alcoholism) by influencing the production or elimination of toxic substances. Genetic polymorphisms may affect absorption, biotransformation, or elimination of toxicants.

General Strategies for Management of Toxic Events

In some cases of poisonings, there are specific treatments or antidotes available that prevent, interrupt, or reverse the toxicity. In such cases, hazard identification and knowledge of the toxicodynamics of the toxicant are critically important for selection of the appropriate antidote or treatment. Antidotes or specific treatments may act via a number of mechanisms including the following:

image Antibodies that neutralize toxicants or prevent their distribution to target organs (e.g., antivenin for snake bites)
image Compounds that sequester the toxicant, prevent its distribution, and promote its excretion (e.g., heavy metal chelators)
image Compounds that scavenge the toxicant to prevent its interaction with tissues (e.g., N-acetylcysteine [NAC] in acetaminophen poisoning)
image Pharmacologic antagonists that block receptors stimulated by the toxicant
image Pharmacologic agonists that stimulate receptors blocked by the toxicant
image Treatments that act physiologically to oppose the actions of the toxicant (e.g., pressor agents to reverse hypotension)
image Enzyme inhibitors that prevent the formation of toxic intermediates
image Enzyme activators that reverse enzymatic inhibition produced by toxicants

In addition to specific treatments, a number of generalized treatment strategies can be used in poisonings (Figure 7-3). These are toxicokinetic treatment strategies targeted at reducing or preventing the absorption of the toxicant, at reducing the distribution of the toxicant, at manipulating biotransformation to reduce formation of the toxicant, or at hastening excretion of the toxicant. These approaches rely heavily on the concepts of pharmacokinetics presented earlier, which will not be repeated here. These generalized approaches are very useful in situations in which there are no specific antidotes or the causative toxicant(s) and/or modes of action are not sufficiently well defined to allow application of a specific antidote.

image

Figure 7-3 General strategies in management of toxic events.

Reduction or Prevention of Absorption

Because the majority of poisonings occur via ingestion, approaches to limit absorption via this route will be discussed here. Approaches to limit absorption via other routes are generally common sense approaches. For example, moving the patient to fresh air if the exposure route was inhalational or flushing the skin with water in the case of dermal exposure. Several options are available to reduce oral absorption of toxicant. Collectively, these approaches are sometimes referred to as gastrointestinal (GI) decontamination.

Forced Emesis

Vomiting can remove toxicants present in the stomach. This approach may be useful if there is reason to believe that there is toxicant remaining in the stomach. This may be the case if the time since exposure is relatively short or if gastric emptying has been delayed. In the past, a number of approaches have been used to induce emesis. However, most have been abandoned. The most frequent method in current use is ingestion of syrup of ipecac.

image Mechanism of action
image Stimulation of sensory receptors in the GI tract
image Stimulation of chemoreceptor zone in the CNS
image Adverse effects
image Aspiration of vomitus into lungs
image Physical damage due to the act of vomiting (e.g., gastric tears)
image Impairment of other GI decontamination procedures since patient may continue to vomit for prolonged period
image Electrolyte imbalance
image Contraindications
image Ipecac should not be used with toxicants such as:
• Petroleum distillates (e.g., gasoline, furniture polish)
• Corrosives (strong acids, strong bases) (e.g., drain cleaner)
• CNS stimulants, because act of vomiting may trigger convulsions
image Unless a secure (intubated) airway has been established, ipecac should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

image Anticipated use of other GI decontamination procedures, because emesis would remove the treatments from the GI tract

In the past, the use of ipecac to induce forced emesis was promoted for GI decontamination in both hospital and home settings. Recommendations from a number of poison control organizations now indicate a much more conservative use of ipecac because of the potential for harm and the relative lack of evidence for definitive benefits. Available data suggest that ipecac may be of use in the following situations:

image In prehospital settings when there are no contraindications for use
image When the ingested toxicant poses substantial risk
image If no alternative means of GI decontamination are available
image When ipecac can be administered within 30 minutes of toxicant ingestion
image When there will be a substantial delay (>60 minutes) in reaching treatment facilities

Gastric Lavage

Gastric lavage involves placing a tube through the mouth (orogastric) or through the nose (nasogastric) into the stomach. Toxicants are removed by flushing saline solutions into the stomach, followed by suction of gastric contents.

image Mechanism of action

image Physical removal of toxicant

image Adverse effects

image Aspiration of lavage into lungs
image Mechanical injury caused by placement of the gastric tube
image Endotracheal placement (into the trachea and thus into the lungs) of gastric tube
image Electrolyte imbalance

image Contraindications

image Gastric lavage should not be used with toxicants such as the following:

• Petroleum distillates (e.g., gasoline, furniture polish)
• Corrosives (strong acids, strong bases) (e.g., drain cleaner)
• CNS stimulants, because the act of vomiting may trigger convulsions

image Unless a secure (intubated) airway has been established, gastric lavage should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

Although in theory gastric lavage would seem to be the most direct way of removing a toxicant, the available evidence does not support the routine use of gastric lavage. Gastric lavage may be useful in cases in which there has been very recent ingestion (30 minutes to 1 hour) of a life-threatening toxicant.

Activated Charcoal

Activation of charcoal by oxidization increases its adsorptive surface area. The large surface area of charcoal is capable of adsorbing many toxicants, thus sequestering them in the gut. Because only free molecules are able to diffuse across membranes, reduction of the concentration of free toxicant in the gut by charcoal greatly reduces absorption into the bloodstream (Figure 7-4). This treatment is administered as a slurry of the activated charcoal powder.

image Mechanism of action

image Toxicant molecules adsorbed to charcoal are not absorbed
image May increase elimination by decreasing free concentration of toxicant in gut
image May interrupt enterohepatic cycling

image Adverse effects

image Vomiting, particularly with premade solutions containing sorbitol (seen in up to 40% of patients)
image Aspiration; charcoal can cause marked lung damage
image Reduced absorption of other drugs or antidotes
image Constipation

image Contraindications

image Patients at risk for bowel perforation (e.g., ingestion of corrosives)
image Toxicants with significant potential for aspiration (e.g., petroleum distillates)
image Toxicants that are not adsorbed to charcoal

• Alcohols
• Iron
• Highly polar molecules and salts

image Unless a secure (intubated) airway has been established, activated charcoal should not be used in the following patients:

• Those who are unconscious
• Those with impaired airway reflexes

image

Figure 7-4 Activated charcoal reduces drug absorption.

Available data suggest that activated charcoal is effective at reducing the absorption of many toxicants. This treatment may be administered as single-dose activated charcoal (SDAC) or repeated as multiple-dose activated charcoal (MDAC). However, the efficacy of SDAC charcoal at preventing drug absorption is very time dependent and decreases rapidly with time from ingestion. SDAC is most effective if administered within 60 minutes of toxicant ingestion. MDAC is most frequently used in cases of poisoning with controlled-release substances, with the goal of binding toxicant as it is released from its formulation. In addition, MDAC also may be of benefit in increasing the elimination of toxicants. Current recommendations suggest that activated charcoal should be used in the following situations:

image When the toxicant is potentially fatal
image When no contraindications to its use are present
image If the toxicant binds to charcoal
image If the time since ingestion suggests toxicant is still present in the GI tract

Whole Bowel Irrigation and Cathartics

Whole bowel irrigation and cathartics are used to prevent the absorption of toxicants by increasing GI motility and passage of the GI contents, thereby reducing the time available for drug absorption. Cathartics use osmotic substances to draw fluid into the gut and produce diarrhea. The most commonly used cathartic is sorbitol. Available recommendations currently discourage the use of cathartics as sole therapy for poisonings because of the associated dehydration and electrolyte disturbances. Accordingly, cathartics will not be discussed further.

Whole bowel irrigation (also called whole gut lavage) is an evolution of the cathartic concept. This approach combines oral administration of high–molecular-weight substances, generally polyethylene glycol, with iso-osmolar electrolyte solutions (e.g., Golytely). This combination tends to prevent systemic electrolyte disturbances that complicate the use of cathartics alone. Large volumes of these solutions plus water are administered orally or by gastric tube.

image Mechanism of action

image Increased volume in GI tract promotes voiding
image Administration is continued until rectal discharge is clear

image Adverse effects

image Nausea, vomiting
image To date, systemic electrolyte disturbances have not been reported

image Contraindications

image Patients with impaired bowel function (e.g., ileus) or perforation
image Patients susceptible to aspiration if vomiting occurs

Whole bowel irrigation has been shown to decrease the bioavailability of certain toxicants. Although there are no consensus statements regarding specific indications for whole bowel irrigation, this approach may be best suited for intoxications for which the other methods of GI decontamination may not be appropriate. More specifically, whole bowel irrigation may be particularly useful in cases where there has been a long time lag between ingestion and treatment and in cases in which toxicants are released slowly. Current recommendations suggest that whole bowel irrigation should be used in the following situations:

image For poisonings with controlled-release substances
image When there is an extended time between ingestion and treatment (2 hours or more)
image For toxicants that are not well adsorbed by activated charcoal (e.g., iron tablets)
image For ingestion of transdermal patches or illicit drug packets

Manipulation of Distribution

After absorption, most toxicants must be distributed to the target tissues to exert harmful effects. Accordingly, another strategy for managing toxicity is to prevent the distribution of toxic substances. In general this is accomplished by binding the toxic substance in the blood and preventing access to its site of action.

image General mechanisms of action

image Antibodies

• Generally highly specific for toxicant
• Eliminated by renal excretion
• Often used as antigen binding fragments (Fab fragments) resulting from the proteolytic digestion of the whole antibody
• Use of Fab fragments tends to reduce the incidence of hypersensitivity reactions
• Antibody fragments also penetrate more readily to the interstitial spaces to neutralize toxicants that have already undergone distribution
• Major adverse effects are hypersensitivity reactions and delayed serum sickness
• Examples include:

image Antivenin
image Digoxin binding antibodies

image Chelating agents

• Contain reactive sites such as hydroxyl or sulfhydryl groups that bind target molecules
• Heavy metal chelators bind to metal ions to form stable complexes

image Reduces distribution of metal
image Shields metal from reacting with functional groups on cellular constituents
image Allows excretion of metal chelates in urine or feces (biliary excretion)

image Edetate calcium disodium (calcium disodium salt of ethylenediaminetetraacetic acid; EDTA)

• Binds iron, lead, copper, manganese, cobalt, and calcium
• Primarily used to treat lead intoxication
• Not effective for mercury poisoning
• Highly charged, so has poor oral bioavailability; requires parenteral administration (intravenous or intramuscular)
• When administered intramuscularly, has the propensity to cause pain at the injection site, so it is combined with local anesthetic agents
• Used as the calcium salt to prevent excessive binding of endogenous calcium and hypocalcemic tetany
• Short half life (<1 hour) necessitates frequent administration
• EDTA-lead chelates are excreted primarily in the urine
• Main adverse effect is nephrotoxicity

image Dimercaprol (British antilewisite)

• Useful in arsenic, mercury, lead, cadmium intoxication
• Rapidly oxidized in aqueous solutions so given intramuscularly in peanut oil
• Chelates primarily excreted in urine
• Thiol-metal ion bonds are labile in acidic solutions; alkalinization of urine is used to prevent release of metal ions in renal tubule and nephrotoxicity
• Main adverse effects include:

image Nausea, vomiting
image Marked hypertension
image Burning sensations

image Penicillamine

• Metabolite of penicillin
• Oral bioavailability sufficient to allow oral therapy
• Useful in intoxication from copper (Wilson’s disease), mercury, and lead
• Chelates excreted in urine
• Main adverse effects include the following:

image Dermatologic reactions
image Renal toxicity
image Hematologic toxicity (e.g., leukopenia)

• Patients who become intolerant to penicillamine during long-term therapy for copper intoxication can be switched to another copper chelator, trientine.

image Succimer

• Mercapto (thiol-containing) analogue of succinic acid
• Oral bioavailability sufficient to allow oral therapy
• Currently used as a chelator in lead toxicity, but may bind other heavy metals
• Water-soluble succimer chelates are excreted in the urine
• Less toxic than dimercaprol
• Half-life is approximately 2 days
• Main adverse effects include the following:

image GI complaints
image Rash
image Flulike symptoms

image Deferoxamine

• Poor bioavailability necessitates parental administration via intramuscular, subcutaneous, or intravenous (least preferred) route
• Extremely high affinity for iron; very effective for iron intoxication
• Eliminated by renal excretion, with a half-life of approximately 6 hours
• Adverse effects of note include the following:

image Allergic reactions
image Hypotension (especially via intravenous route)

• Reduced compliance with long-term regimens owing to need for parenteral administration

image Deferiprone

• Orally available iron chelator
• Available in European Union but not in Canada or United States
• Excreted in urine
• Half-life is less than 1 hour, necessitating frequent administration
• Major adverse effects include the following:

image GI disturbances
image Neutropenia
image Agranulocytosis
image Joint pain

• Up to 40% of patients on long-term therapy discontinue use.

image Deferasirox

• Orally available iron chelator
• Excreted primarily in the feces by biliary excretion
• Half life is 8 to 16 hours, allowing once-a-day administration
• Major adverse effects include the following:

image GI disturbances
image Skin rashes
image Mild decrease in glomerular filtration rate

• May be preferred over other iron chelators because deferasirox has more convenient administration and a good safety profile

Manipulation of Biotransformation

As discussed in the pharmacokinetics chapter, once a substance has been absorbed into the bloodstream it is subject to biotransformation. Biotransformation in most cases causes inactivation of substances. In theory, then, one strategy for reducing toxicity would be to accelerate inactivation of the toxicant. This could be achieved through metabolic enzyme induction. However, in most cases the time course of enzyme induction is too slow to be an effective treatment strategy.

In some cases, the primary toxicants are not especially harmful but biotransformation results in the formation of reactive intermediates or molecules that mediate the toxic effects. In these situations, an effective strategy for the management of toxicity is to reduce the formation of the toxic molecule.

image General mechanisms of action

image Inhibition of metabolic enzymes that produce toxic molecule
image Saturation of an enzyme with substrate that is converted to nonharmful substance
image Scavenging of reactive metabolites
image Treatments most effective when applied before formation of the toxic metabolite

Examples of this approach will be provided later in the discussion of treatment approaches for specific toxicants. (See treatment of acetaminophen toxicity, treatment of ethylene glycol toxicity.)

Enhancement of Toxin Excretion

Ultimately, the therapeutic goal in treating toxicity is to remove the toxicant from the body completely or at least to the point at which plasma concentrations decline to a nontoxic level. Several strategies have been used to increase removal of toxicant from the plasma or, in other words, to increase clearance. These involve enhancement of endogenous clearance mechanisms such as renal excretion and exogenous mechanisms such as extracorporeal elimination (e.g., hemodialysis, hemofiltration).

Renal Excretion

In principle, renal excretion could be enhanced by increasing glomerular filtration and/or tubular secretion or by decreasing tubular reabsorption of toxicants. The major concepts were discussed in the chapter on pharmacokinetics and are reviewed here only briefly.

Forced Diuresis

image Forced diuresis involves administration of diuretic agents and isotonic saline to increase glomerular filtration rate and urine flow.
image When combined with bicarbonate infusion, it is referred to as forced alkaline diuresis.
image Fluid overload, pulmonary edema, and electrolyte disturbances can complicate therapy in compromised patients, especially in the presence of cardiac, renal, or pulmonary dysfunction.
image Although it is important to maintain good urine flow during treatment of toxicities, increasing glomerular filtration through forced diuresis is not encouraged in most intoxications. However, this approach has been used with nephrotoxic drugs because of the dilutional effect on nephrotoxic agents in the renal tubules.

Urine Alkalinization

image As discussed in the pharmacokinetics chapter, many substances are reabsorbed from the renal tubules into the bloodstream, limiting the extent of their urinary excretion.
image Tubular reabsorption is dependent on the substance being in the nonionized form.
image The principles of ion trapping (see pharmacokinetics chapter) can be used to increase urinary excretion.
image Urine is generally acidic, and alkalinizing the urine (generally to above pH 7.5) increases ionization of acidic substances and thereby prevents their tubular reabsorption.
image Because pH is a logarithmic scale, each unit change in pH results in an approximately tenfold change in ionization and presumably excretion.
image Bicarbonate solution is infused intravenously while urine pH is monitored, with a goal of reaching a urine pH of 7.5 to 8.
image Urine alkalinization will be most effective for toxicants that are:

image Weak acids with a low pKa value
image Cleared primarily by the kidney

image Examples of toxicants whose clearance is increased by urine alkalinization include:

image Salicylates
image Chlorophenoxy herbicides (e.g., 2,4-D)
image Barbiturates
image Methotrexate

image Main adverse effect of urine alkalinization is:

image Hypokalemia (potassium shifts to intracellular space as a result of alkalemia)

Urine Acidification

image Acidification of urine could theoretically assist in renal excretion of toxicants that are weak bases.
image Urine is usually acidic, so it not clear how much additional benefit can be achieved by acidifying urine.
image Acidification of urine also carries the risk of inducing systemic acidosis.
image Acidification of urine is not encouraged but can be accomplished with administration of ammonium chloride or ascorbic acid.

Gastrointestinal Excretion

Although the majority of toxins are excreted in the urine, a number may be excreted in the feces. Biliary secretion is an important route of movement of conjugated toxicants from the plasma into the lumen of the GI tract. However, in many cases these conjugates are cleaved in the gut and the toxicants can be reabsorbed (enterohepatic cycling). Interruption of enterohepatic cycling can increase fecal excretion of toxicants. In addition, strategies to hold toxicants in the GI tract until they can be passed in the feces can be an effective means of detoxification.

Interruption of Enterohepatic Cycling

Treatments bind toxicants in the GI tract and prevent their reabsorption after cleavage of toxicant conjugates.

image Activated charcoal, particularly MDAC, may increase toxicant elimination in part by interrupting enterohepatic cycling.
image Special binding substances can be ingested to bind toxicants in the GI tract, interrupt enterohepatic cycling, and increase toxicant elimination in the feces.

image Bile acid binding resins increase fecal elimination of digoxin.
image Thiol-containing resins can be used to interrupt enterohepatic cycling of mercury.

Enterocapillary Exsorption (Gastrointestinal Dialysis)

Enterocapillary exsorption (GI dialysis) refers to the removal of toxicants that have already been absorbed into the bloodstream by increasing their transport into the lumen of the GI tract.

image Binding of toxicant in gut lumen decreases the free concentration of drug in the gut.
image The very low concentration of free toxicant in the gut lumen means that free toxicant concentrations in the plasma are higher than those in the gut. This blood-to-gut concentration gradient favors diffusion of toxicant from the blood into the gut lumen where the toxicant binds to the charcoal. The charcoal-bound toxicant is eventually excreted in the feces (Figure 7-5). As this cycle repeats itself, the blood is cleared of toxicant.
image Enterocapillary exsorption may contribute to the ability of MDAC to increase the elimination of drugs such as:

image Amitriptyline
image Carbamazepine
image Nadolol
image Piroxicam

image

Figure 7-5 Enterocapillary exsorption. Large amounts of activated charcoal in the gut promote drug excretion in the feces.

Pharmacologic Treatment of Specific Intoxications

The types of intoxications that may be encountered in practice are virtually unlimited, making a full discussion of treatment of intoxications beyond the scope of this text. However, it is useful to consider the treatment of some more common intoxications to illustrate the general principles discussed previously.

Analgesics

Intoxication with analgesics represents the most common form of toxicity requiring hospitalization.

Acetaminophen

image Acetaminophen poisoning causes hepatotoxicity and is one of the more common lethal poisonings in industrialized countries.
image Acetaminophen is present in many combination analgesic preparations. Although intentional overdose is a cause of acetaminophen toxicity, intoxication can also be inadvertent owing to use of multiple acetaminophen-containing analgesics (e.g., combining over-the-counter acetaminophen with prescription opioid-acetaminophen analgesics)
image Acetaminophen is not toxic per se but is metabolized to a reactive intermediate that is toxic (Figure 7-6, A).

image At therapeutic concentrations:

• Phase II conjugation to glucuronate or sulfate accounts for approximately 90% of metabolism.
• CYP450 metabolism accounts for approximately 5% to 10% of metabolism but results in the production of an electrophilic molecule, N-acetyl-p-benzoquinone imine (NAPQI).
• NAPQI is highly reactive and can form covalent bonds with cellular constituents, leading to cellular death.
• However, under normal conditions the relatively small amount of NAPQI formed is quickly scavenged by reaction with intracellular glutathione, which prevents NAPQI reaction with cellular constituents.

image At supratherapeutic concentrations:

• Phase II conjugation becomes saturated, shuttling the bulk acetaminophen metabolism through CYP450 pathways.
• Increased generation of NAPQI eventually exhausts cellular stores of glutathione, resulting in the accumulation of free NAPQI and hepatotoxicity.

image Acetaminophen toxicity may be exacerbated by:

image Induction of CYP450 metabolism

• Chronic alcohol abuse
• Concurrent anticonvulsant therapy

image Depletion of cellular glutathione stores

• Malnutrition

image Treatment of acetaminophen poisoning

image Activated charcoal

• Used to decrease absorption of acetaminophen
• Most effective if given within 2 hours of overdose

image N-acetylcysteine (NAC). A primary treatment strategy for acetaminophen toxicity is replenishment of cellular glutathione via the administration of NAC, a precursor of glutathione (see Figure 7-6, B).

• Mechanism of action

image As a precursor to glutathione, NAC increases production of glutathione.
image NAC also directly binds to NAPQI.
image Through these mechanisms, NAC scavenges NAPQI, prevents its interaction with cellular constituents, and prevents hepatic cell death.
image NAC is most effective at preventing acetaminophen toxicity when given within 8 hours of ingestion of the overdose, because it acts by preventing the accumulation of a toxic metabolite. However, beneficial effects of NAC can be expected at later times (even >24 hours) if acetaminophen blood concentrations remain above the threshold for saturation of phase II conjugation.

• Main adverse effects

image Oral formulation is associated with GI symptoms and vomiting.
image Antiemetics can be used to increase tolerance to oral NAC.
image Intravenous formulation can trigger anaphylactic reactions (rare).

• NAC does not react extensively with activated charcoal. The two treatments can be used concurrently.
• NAC is recognized as the antidote of choice for acetaminophen toxicity.

image

Figure 7-6 A, Therapeutic doses of acetaminophen are converted to nontoxic intermediates. Toxic doses of acetaminophen are converted to reactive intermediates that damage the liver. B, Treatment of acetaminophen toxicity involves the use of drugs that scavenge reactive intermediates.

Salicylates

image The salicylates comprise a large group of compounds derived from salicylic acid.
image Acetylsalicylic acid (aspirin) is the most recognizable and one of the oldest and most widely used agents for antiinflammatory, antipyretic, antiplatelet, and analgesic purposes.
image Significant quantities of salicylates are also present in a wide variety of compounds including rubs to treat minor aches and pains (e.g., methyl salicylate rubs) and keratolytics used to treat warts (e.g., salicylic acid) and acne. The antidiarrheal agent Pepto-Bismol contains subsalicylates. Some of these preparations have a very high salicylate content, such that even relatively small quantities can produce severe toxicity. Oil of wintergreen (methyl salicylate) contains approximately 7000 mg of salicylate per teaspoon, the equivalent of approximately 22 aspirin tablets.
image Salicylate toxicity (Table 7-1)

image The widespread availability of salicylate preparations has resulted in a relatively high incidence of salicylate poisoning. Acute ingestion of toxic quantities may occur in accidental overdoses or in suicide attempts. Toxicity may also occur chronically because at high therapeutic doses (e.g., antiinflammatory doses) elimination mechanisms are nearly or completely saturated and salicylates exhibit zero-order kinetics. Some of the early-phase signs and symptoms of salicylate poisoning (see later) may be apparent at high therapeutic doses.
image Salicylic acid is the primary toxicant, and toxicity is related to the amount of free salicylic acid present in the body.
image Salicylic acid is eliminated primarily by phase II conjugation with subsequent renal excretion of the conjugates. At low concentrations, salicylic acid is cleared by first-order kinetics with a half-life of approximately 2 to 5 hours. However, as mentioned previously, these conjugation mechanisms are near saturation at high therapeutic concentrations. Once the phase II conjugation mechanisms become saturated, elimination follows zero-order kinetics and the half-life may be extended to as much as 18 to 36 hours. In addition, renal excretion of free salicylic acid becomes the primary mechanism for clearance once phase II mechanisms are saturated.
image Salicylate toxicity manifests as progressive metabolic, neural, cardiovascular, and renal dysfunction.
image Accumulation of free salicylic acid has several toxic effects, which include:

• Direct irritation to tissues, especially the GI tract
• Stimulation of the chemoreceptor trigger zone to produce nausea and vomiting
• Stimulation of the respiratory center in the brain that causes:

image Hyperventilation
image Respiratory alkalosis

• Uncoupling of oxidative phosphorylation, which:

image Disrupts cellular adenosine triphosphate (ATP) production
image Triggers formation of metabolic acids (e.g., lactic acid)
image Causes metabolic acidosis
image Increases heat generation and causes hyperthermia

• Neurotoxicity via direct effects and disruption of cellular metabolism and glucose homeostasis, which causes:

image Ringing in the ears, loss of hearing (tinnitus, ototoxicity)
image CNS dysregulation leading to agitation initially with subsequent disorientation, seizures, and coma

• Dehydration arising from:

image Diuresis caused by acid-base imbalances
image Insensible water loss caused by hyperventilation and sweating
image Acidosis-induced increases in capillary permeability

• Cardiovascular collapse from acidosis-induced:

image Cardiac depression
image Vasodilation
image Dehydration

image Salicylate poisoning is progressive. The early (mild) phase involves:

• Stimulation of respiratory center and secondary compensation
• Direct irritant effects on GI and direct neural effects
• Signs and symptoms of the early phase include:

image Hyperventilation and consequent respiratory alkalosis (low Pco2)
image Excretion of alkaline urine as the kidney attempts to compensate for respiratory alkalosis
image Nausea, vomiting, abdominal pain
image Hearing loss
image Dizziness
image Mild dehydration
image Fever generally not present

image The moderate phase of salicylate poisoning involves:

• Progressive disruption of metabolic homeostasis as salicylic acid accumulates in cells and uncouples oxidative phosphorylation
• Activation of compensatory mechanisms to counteract metabolic acidosis
• Appearance of actions on other toxic effect organ systems such as the cardiovascular system
• Signs and symptoms of the moderate phase include:

image Mixed respiratory alkalosis (low Pco2) and metabolic acidosis (high lactate, ketones)
image Excretion of acidic urine as the kidney excretes metabolic acids
image Worsening of dehydration and neurologic symptoms (e.g., hearing loss, confusion, slurred speech)
image Cardiovascular involvement (tachycardia, hypotension)
image Fever

image The severe (late) phase of salicylate poisoning involves:

• Worsening of the disruptions of metabolism and organ systems
• Signs and symptoms of the severe phase include:

image Progression of CNS toxicity, wherein hyperventilation may switch to hypoventilation with consequent respiratory acidosis and hypoxemia
image Progression of metabolic acidosis to severe levels; blood pH is lowered (acidemia)
image Progression of dehydration to severe levels; urine output is low or absent
image Marked CNS dysfunction including convulsions, coma
image Cardiovascular abnormalities with significant hypotension, myocardial depression, and impaired perfusion of all organs
image Cerebral and pulmonary edema
image Cardiopulmonary arrest

image Treatment of salicylate poisoning

• Unfortunately, there are no specific antidotes for salicylate poisoning. Treatments include general measures to support ventilation and renal function and to maintain acid-base balance. Toxicokinetic treatments aimed at decreasing the absorption or increasing the elimination of the toxicant, salicylic acid, are also central to the treatment of salicylate poisoning.
• Reduction of absorption is attempted.

image Emesis not recommended
image Activated charcoal is used to decrease absorption of salicylates. MDAC may increase elimination and shorten the half-life of salicylic acid. MDAC is also useful in poisoning with enteric-coated or slow-release formulations.

• Whole bowel irrigation is performed.

image Useful when activated charcoal does not reduce salicylic acid levels or for poisoning with enteric-coated or slow-release preparations.

• Enhancement of elimination is undertaken.
• Urine alkalinization

image Salicylic acid is a weak acid with a pKa of approximately 3.5 and therefore will be ionized at alkaline pH.
image Later stages of toxicity are associated with acidic blood and urine; this acidity promotes the distribution of salicylic acid to the tissues and renal tubular reabsorption, which limits renal excretion.
image Standard of care recommends bicarbonate infusion (usually with potassium supplementation) (sometimes called bicarbonate diuresis).

• Bicarbonate diuresis

image It maintains normal or slightly alkalemic pH to reduce the distribution of salicylic acid to the intracellular compartment.
image It replenishes bicarbonate lost through renal excretion as the kidney attempts to compensate for respiratory alkalosis caused by hyperventilation.
image Alkalinization of urine converts salicylic acid to its ionized form and prevents its reabsorption from renal tubules (ion trapping).
image Alkalinization of urine from pH 5 to pH 8 may increase renal excretion of salicylic acid by tenfold to twentyfold.
image The main adverse effect is the potential to aggravate pulmonary or cerebral edema.

• Hemodialysis is indicated in cases of severe salicylate poisoning and in patients who exhibit refractory acidosis, refractory hypotension, CNS depression, or evidence of target organ damage (e.g., pulmonary edema, cerebral edema).

TABLE 7-1 Salicylate Toxicity

image

Opioid Analgesics

Opioid receptor agonists are used extensively therapeutically for their strong analgesic effect and illicitly for their psychotropic effects.

image Opioid toxicity

image Represents direct extension of the pharmacologic effects of neural depression
image Characterized by:

• Miosis (pupillary contraction)
• Respiratory depression (primary cause of morbidity and mortality)
• Reduced level of consciousness
• Hypotension

image Treatment of opioid toxicity

image Activated charcoal

• Activated charcoal is used to decrease absorption when opioids have been ingested.
• It is most effective when taken early after ingestion. However, opioids decrease gastric emptying and GI motility. Therefore activated charcoal may still be effective even when there is a substantial lag between ingestion and treatment.

image Whole body irrigation

• Whole body irrigation is used in cases of toxicity resulting from body packing, in which drug packets are transported by concealing the packets in the GI tract.

image Opioid receptor antagonists

• Because opioid toxicity is a direct extension of opioid receptor stimulation, opioid receptor antagonists are the most specific and effective treatment (antidote) for opioid toxicity.
• Examples include naloxone (used most frequently), nalmefene, and naltrexone.
• They may be given orally, intravenously, or intramuscularly.
• They compete with opioids for opioid receptor occupancy and reverse opioid toxicity.
• Naloxone has a short half-life (1 hour), and opioid toxicity may recur as naloxone concentrations fall.
• Naloxone may need to be given in multiple doses or intravenously, especially in the case of intoxication with controlled-release preparations or opioids with long half-lives.
• Because treatment involves competition for opioid receptors, high doses of naloxone may be required for intoxication with opioids that have high receptor affinity (e.g., fentanyl).
• Main adverse effects:

image Induction of withdrawal symptoms (nausea, vomiting, agitation)
image Aspiration from withdrawal-associated vomiting

• Opioid receptor antagonists are accepted as specific antidotes for opioid toxicity.

Ethylene Glycol, Methanol

image Although relatively infrequent, intoxication with alcohols such as ethylene glycol and methanol can result in a high rate of mortality if not treated appropriately.
image Ethylene glycol is present in automobile coolants, which may be ingested in suicide attempts or by children because of its sweet taste.
image Methanol is present in many household products (e.g., paint stripper, windshield washer).
image Neither ethylene glycol nor methanol is particularly toxic per se, but these compounds are biotransformed into toxic metabolites (Figure 7-7).
image Ethylene glycol

image Ethylene glycol is converted to glycoxylic acid and then oxalate, which forms crystals with calcium.
image Oxalate-calcium crystals precipitate in the renal tubules and cause nephrotoxicity.

image Methanol

image Methanol is converted to formaldehyde and then formic acid.
image Formic acid causes metabolic acidosis, which may lead to multiorgan failure and death.
image Formic acid causes damage to the retina and optic nerve and blindness.

image Oxidation of ethylene glycol and methanol by alcohol dehydrogenase is the initial step initiating these metabolic cascades.
image

Figure 7-7 Mechanisms and treatment of ethanol or methanol toxicity.

Treatment of Ethylene Glycol or Methanol Poisoning

The initial step in the production of the toxic metabolites of these alcohols is oxidation via alcohol dehydrogenase. Accordingly, treatment strategies are aimed at reducing the ability of alcohol dehydrogenase to metabolize ethylene glycol or methanol.

image Inhibition of metabolite formation

image Ethanol (ethyl alcohol)

• Ethanol has a greater affinity than ethylene glycol or methanol for alcohol dehydrogenase.
• Saturation of alcohol dehydrogenase with ethanol prevents access of ethylene glycol and methanol to alcohol dehydrogenase and their biotransformation to toxic metabolites.
• The main adverse effect is intoxication with ethanol, which may produce:

image Altered consciousness
image CNS depression
image Hemodynamic compromise

image Fomepizole

• Fomepizole is an alcohol dehydrogenase inhibitor that directly inhibits this enzyme and prevents biotransformation of ethylene glycol and methanol to toxic metabolites.
• Advantages include:

image Lack of CNS depression
image High specificity

• The main adverse effect is burning at the site of infusion.
• Treatment must be initiated as soon as possible because effectiveness relies on inhibiting the formation of toxic metabolites.
• Fomepizole has replaced ethanol as the treatment of choice and is considered an effective antidote for poisoning with ethylene glycol and methanol.

image Increasing elimination

• In cases of severe poisoning, hemodialysis may be used to increase the clearance of alcohols.

Cardiac Glycosides

image Used clinically in the treatment of heart failure and cardiac arrhythmias.
image Also found in a wide range of plants (e.g., foxglove, milkweed) and herbal remedies (e.g., oleander).
image Have a low therapeutic index. Poisonings may result from small changes in absorption or elimination of therapeutic doses or from accidental ingestion of pills or cardiac glycoside–containing plants.
image Cardiac glycoside toxicity

image Toxicity is a direct extension of the ability of cardiac glycosides to inhibit active transport of sodium and potassium.
image The major target organ is the heart, with induction of cardiac arrhythmias.

image Treatment of cardiac glycoside toxicity

image Prevention of absorption

• Activated charcoal. Cardiac glycosides are well adsorbed by activated charcoal.
• Gastric lavage has been suggested but has not proven to be of benefit.
• Bile acid binding resins are given orally to sequester cardiac glycosides in the gut lumen.

image Manipulation of distribution or enhancement of elimination

• Immune antibody fragments (Fab fragments) are derived from proteolytic processing of antibodies against digitalis glycosides, one form of cardiac glycoside. These antibody fragments also bind other cardiac glycosides.
• Antibody fragments exhibit reduced immunogenicity and are less likely to provoke hypersensitivity reactions.
• Antibody fragments bind cardiac glycosides in plasma and prevent distribution to site of action.
• Antibody-bound cardiac glycosides are rapidly cleared by the kidney.
• Fab fragments are considered an effective antidote to poisoning with cardiac glycosides.

Pesticides

image Many pesticides act as inhibitors of acetylcholinesterase, the endogenous enzyme responsible for the degradation of acetylcholine.
image Organophosphates (e.g., malathion, parathion) are time-dependent irreversible inhibitors of acetylcholinesterase. Organophosphates form a broad group of agents used extensively as insecticides throughout the world and as nerve gas agents.
image Carbamates (e.g., carbaryl, carbofuran) are reversible inhibitors of acetyl cholinesterase used primarily as insecticides.
image Toxicity of organophosphate and carbamate pesticides

image The primary mechanism of action of these agents is inhibition of acetylcholinesterase, the enzyme responsible for degrading acetylcholine into choline and acetate, with the resultant accumulation of acetylcholine (ACh) in neuroeffector junctions. Overstimulation of cholinergic receptors is responsible for the signs and symptoms and toxicity of organophosphate and carbamate poisoning (Figure 7-8).
image Excess acetylcholine results in overstimulation of cholinergic muscarinic and nicotinic receptors in various tissues.

• Excess stimulation of muscarinic receptors results in:

image Increased salivation and bronchial secretions
image Bronchoconstriction
image Bradycardia

• Excess stimulation of nicotinic receptors results in:

image Muscle tremors
image Muscle weakness and paralysis

• Respiratory compromise is the major cause of morbidity and mortality.

image Treatment of organophosphate and carbamate pesticide toxicity

• Pharmacological antagonists

image Atropine, a muscarinic receptor antagonist, is used to reverse the excess muscarinic stimulation resulting from accumulation of acetylcholine.

• Enzyme activators—oximes such as pralidoxime [2-PAM]

image 2-PAM disrupts a phophoryl-ester bond (-P- in Figure 7-8) between the organophosphate molecule and acetylcholinesterase to release the organophosphate from enzyme.
image This reactivates acetylcholinesterase and reverses the effects of cholinesterase inhibitors.
image Organophosphate inhibitors undergo a time-dependent process (called aging) that strengthens the bonds between the inhibitor and enzyme. This results in irreversibility of the inhibition. Once aging has occurred, 2-PAM and other oximes are unable to break the bonds between inhibitor and enzyme. Consequently, after aging, oximes are not able to reactivate acetylcholinesterase.
image Oximes must be given before aging has occurred, generally within a few to 24 hours after exposure depending on the type of organophosphate agent. Thus, early recognition and treatment of organophosphate poisoning are critical.

image

Figure 7-8 Toxicodynamics of organophosphate poisoning.

Calcium Channel Blockers and β-Blockers

image Calcium channel blockers are prescribed for a number of cardiovascular conditions (e.g., angina, hypertension, tachycardia).
image β-Blockers are also used extensively for cardiovascular applications (hypertension, heart failure, angina).
image The widespread use of these drugs has led to an increase in toxicity from overdose, particularly in children, who may become symptomatic with ingestion of a single tablet.
image Toxicity of calcium channel blockers and β-blockers

image Toxicity is a direct extension of the pharmacologic activity of these agents.
image Calcium channel blockers decrease calcium entry into:

• Blood vessels—excessive blockade of calcium entry results in hypotension that may progress to shock
• Cardiac cells—resulting in decreased force of contraction and conduction of the cardiac impulse

image β-Blockers reduce stimulation of β-adrenergic receptors, resulting in reduced generation of the second messenger cAMP and reduced function of calcium channels.
image β-Blocker overdose primarily affects the heart via:

• Decreased calcium entry
• Decreased force of contraction
• Decreased conduction of the cardiac impulse

image Treatment of calcium channel blocker and β-blocker toxicity

image Prevention of absorption

• These drugs are frequently administered as extended-release preparations.
• Strategies to reduce absorption may have beneficial effects because of continued release of drug in the GI tract.

image Activated charcoal (especially MDAC)
image Whole bowel irrigation

image Physiologic treatments

• Calcium channel blocker toxicity

image Supraphysiologic doses of calcium are infused to promote the entry of calcium into cells and reverse the effects of calcium channel blockers.
image Direct vasoconstrictor agents (e.g., norepinephrine) are used to counteract peripheral vasodilation and raise blood pressure.

• β-Blocker toxicity

image Glucagon infusion is used to stimulate cAMP production via a non–β-adrenergic receptor pathway.
image Increased cAMP generation improves cardiac pumping and cardiac conduction.

• Insulin-euglycemic clamp has been used to treat both calcium channel blocker and β-adrenergic blocker overdose.
image Insulin and dextrose are infused simultaneously to produce hyperinsulinemia but maintain blood glucose level.
image Precise mechanism is unclear, but it improves cardiac pumping and cardiac conduction.

Websites

American Association of Poison Control Centers. www.aapcc.org

Canadian Association of Poison Control Centres. www.capcc.ca/resources/resources.php

Glossary of toxicologic terms Glossary of toxicologic terms. http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html

National Library of Medicine (U.S.). www.toxnet.nlm.nih.gov

National Toxicology Program (U.S.). http://cerhr.niehs.nih.gov/reports/index.html

World Health Organization. www.who.int/ipcs/poisons/centre/directory/en/index.html

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