Pharmacology - An Illustrated Review

35. Toxicology and Poisoning

Toxic reactions to drugs and other agents can occur with acute exposure to a high dose of an agent, either accidentally or intentionally administered. Chronic toxicities can be observed with long-term exposure to an agent at lower doses. These reactions may be local, following skin contact or lung inhalation, or systemic, following absorption of the toxin. In some cases, the toxicity only develops following biotransformation of the absorbed substance to toxic metabolites. The resulting toxicities may be short or long term, they may appear immediately or be delayed, and they may be reversible or irreversible.

Toxicities to specific agents have largely been dealt with along with the discussion of their pharmacological properties, but some of the more common toxic substances and poisonings are discussed in this chapter.

Emergency treatment of the poisoned patient

The procedure for the emergency treatment of the poisoned patient is as follows: (1) check respiratory function, cardiovascular function, and central nervous system (CNS) involvement; (2) stabilize the patient; (3) attempt to determine the identity and quantity of poison ingested and the time of exposure; and (4) treat with the appropriate antidote.

 

35.1 Nonspecific Antidotes

In cases of acute poisoning, the main goal is to minimize further exposure and enhance elimination of the toxin. Several procedures are used when specific antidotes are not available, and these are discussed below.

Gastric Lavage with Saline

Mechanism of action. Gastric lavage (stomach pumping) involves fluid, usually saline, being sequentially administered and withdrawn via an orogastric or nasogastric tube.

Pharmacokinetics

– Given orally as a suspension in doses of up to 100 g

Note: During this procedure, the patient's airway is protected by an endotracheal tube to prevent aspiration of the ingested substances into the lung.

Activated Charcoal

Mechanism of action. Activated charcoal adsorbs a large number of organic and inorganic compounds and prevents their absorption from the gastrointestinal (GI) tract.

Pharmacokinetics

– Given orally or via gastric tube as a suspension in doses of up to 100 g

Syrup of Ipecac

Mechanism of action. This is an emetic agent. Emesis used to be primary therapy but is now becoming secondary to other therapies.

Pharmacokinetics. One ounce orally usually produces emesis within 30 minutes.

Contraindications. Emesis is contraindicated when there is a risk of perforation of the esophagus or stomach (corrosive agents), when ingested agents may be aspirated into the lung (e.g., if the patient is comatose), or if emesis is likely to induce seizures (strychnine or CNS stimulants).

Hemodialysis

Mechanism of action. Hemodialysis involves the use of a machine to filter waste products (e.g., creatinine and urea), salts, fluids, or drugs from the blood in kidney failure. The blood flows in the opposite direction to dialysis fluid that are separated by a semipermeable membrane. This allows substances to be cleared down their concentration gradient.

Uses. Hemodialysis is not useful for poisons with large volumes of distribution or poisons that bind tightly to plasma proteins. It is generally reserved for extreme, life-threatening poisoning with alcohol, aspirin, or CNS-active drugs.

35.2 Specific Antidotes

When the identity of the toxic substances is known or strongly suspected, it may be desirable to treat with specific antidotes.

Metal Chelating Agents

These agents are used to treat heavy metal poisoning.

Dimercaprol (British antilewisite)

Mechanism of action. Dimercaprol, or British antilewisite (BAL), protects essential enzymes by forming a stable complex with circulating metallic poison. It promotes excretion of metal in a stable complex form (Fig. 35.1).

Pharmacokinetics

– Given intramuscularly

Uses. Dimercaprol is an effective treatment following poisoning by mercury, arsenic, and some other less common metals, but it is not very effective for lead poisoning.

Side effects

– Increased blood pressure and heart rate, weakness, nausea, and pain at the injection site.

Mercury poisoning

The greatest danger with mercury poisoning is damage of the GI mucosa and kidneys. Fluid loss leads to shock and death. This tends to occur with acute intoxication. Symptoms of chronic intoxication include stomatitis, excessive salivation, blue gum line, renal toxicity, and CNS symptoms (depression, weakness, headache, insomnia, irritability, and hallucinations). This is treated by giving dimercaprol.

 

Calcium Disodium Edetate

Mechanism of action. Calcium disodium edetate (or ethylenediamine tetraacetic acid (CaNa2 EDTA) promotes the excretion of the lead chelate.

Pharmacokinetics

– Given by intravenous (IV) infusion, as it is not effective orally

Uses

– Especially effective in lead poisoning, but may also be useful to chelate other less common metallic poisons

Side effects

– Renal damage and hypersensitivity reactions

Lead poisoning

Acute intoxication with lead is rare. Symptoms of chronic intoxication include spasm and hypermotility of the GI tract, which causes intense cramping and lead encephalopathy (primarily a problem in children), the early symptoms of which are nonspecific and may include decreased appetite, irritability, fatigue, abdominal pain, and vomiting, followed by drowsiness, stupor, convulsions, and coma. This may lead to mental retardation and cerebral palsies, as well as myopathy, fatigue, weakness, wrist drop, foot drop, and involvement of extraocular muscles. Other results are anemia due to impaired heme biosynthesis, porphyrinuria, basophilic stippling of erythrocytes, and gingival lead line. Blood vessel constriction causes pallor and hypertension. Initial treatment is edetate administration. Penicillamine and dimercaprol (limited effectiveness) may also be used.

 

Penicillamine

Penicillamine is a derivative of penicillin.

Mechanism of action. Penicillamine chelates copper, mercury, and lead and promotes their excretion.

Pharmacokinetics

– Administered orally

Uses

– Used to remove copper in hepatolenticular degeneration (Wilson disease)

– Used in combination, usually following EDTA, for lead poisoning

– Also useful in the treatment of rheumatoid arthritis (see Chapter 33)

Fig. 35.1 image Chelators.

Dimercaprol is given by intramuscular injection to chelate various metal ions. A related compound, dimercaptopropane sulfonate (DMPS), is suitable for oral administration. Deferoxamine is highly effective at chelating iron but does not extract iron from hemoglobin or cytochromes.

image

Side effects

– Hypersensitivity reactions

– Rashes

– Arthralgia

– Nephrotic syndrome

Trientine

Uses. Trientine is an alternative copper chelating agent for patients who are hypersensitive to penicillamine.

Wilson disease

Wilson disease is an autosomal recessive disease that results in the accumulation of copper (that is ingested) in the liver and brain, causing cirrhosis and basal ganglia destruction. It may present in a child or young adult with neurologic signs such as tremor, seizures, mental deterioration, and weakness; or there may be signs of cirrhosis, such as jaundice, hepatomegaly (swelling of the liver), edema, and fatigue. Treatment with penicillamine is effective if given early.

 

Deferoxamine

Mechanism of action. Deferoxamine specifically chelates iron (ferric ions and ferrous ions) and promotes its excretion. It binds free and loosely bound iron, for example, from hemosiderin and ferritin, but does not chelate iron bound to hemoglobin or cytochromes.

Pharmacokinetics. This agent is orally effective in preventing iron absorption. It is given intramuscularly or IV for systemic toxicity.

Uses

– Acute iron toxicity and iron storage diseases (e.g., hemochromatosis)

Side effects

– Hypertension, rashes, and GI upset

Iron poisoning

Iron poisoning is the most common metallic poison, due to overdosage with oral supplements, multiple transfusions, or iron storage diseases. Acute symptoms of iron poisoning include vomiting (often bloody), gastric pain, and diarrhea. Chronic symptoms include metabolic acidosis, lethargy, which may progress to cardiovascular collapse, liver damage, and organ failure. Permanent scarring of the GI tract may occur with severe poisoning. Treatment is by desferoxamine.

 

Succimer

Pharmacokinetics

– Orally effective

Uses. Succimer is indicated for lead poisoning in children. It may also be effective for mercury or arsenic.

Table 35.1 summarizes other poisons and their antidotes.

  Table 35.1 image Other Poisons and Their Antidotes

Poison

Antidote

Mechanism of Action of Antidote

Belladonna (atropine)

Physostigmine (p. 47)

Anticholinesterase action

Carbon monoxide

Hyperbaric O2

Hyperbaric O2 increases both O2 delivery to tissue and CO elimination.

Coumarin derivatives (e.g., warfarin)

Phytonadione (Vitamin K1)

Vitamin K promotes hepatic synthesis of factors II, VII, IX, and X, which are needed for coagulation of the blood.

Cyanide

Sodium thiosulfate

Amyl nitrite and sodium nitrite

Sodium thiosulfate increases cyanide metabolism.

Amyl nitrite and sodium nitrite produce methemoglobin, which binds cyanide.

Ethylene glycol and other glycols

Ethanol (pp. 119, 120)

Ethanol is preferentially metabolized by alcohol dehydrogenase and prevents the occurrence of acidosis.

Methanol

Ethanol (pp. 121, 122)

Ethanol is preferentially metabolized by alcohol dehydrogenase and decreases the formation of both formaldehyde and formic acid from methanol.

Iodine

Starch

Starch binds iodine.

Opiates

Naloxone (p. 108)

Naloxone is a narcotic antagonist.

Nitrites

Methylene blue

Narcotic antagonist

Organophosphate

Pralidoxime

Pralidoxime is a cholinesterase reactivator.

Insecticides

Atropine (p. 49)

Atropine is an anticholinergic agent.

Carbon monoxide poisoning

Carbon monoxide (CO) is a colorless, odorless, tasteless, nonirritant toxic gas that is produced from the incomplete burning of fossil fuels. It binds to hemoglobin, forming carboxyhemoglobin, and in doing so, it displaces oxygen. This results in a functional anemia. Symptoms of CO poisoning include headache, dizziness, weakness, confusion, lethargy, nausea, vomiting, seizures, and, at very high concentrations, coma and death. CO poisoning is the most common cause of death from poisoning. Treatment involves removing the source of CO, 100% oxygen therapy, and hyperbaric oxygen therapy (if severe).

 

Electron transport chain

The electron transport chain consists of a group of complexes (CI–CV) that are located in the inner membrane of the mitochondria. It is the mechanism by which the energy needed to drive the oxidative phosphorylation of adenosine triphosphate (ATP) is generated. NADH (the reduced form of nicotinamide adenine dinucleotide) and FADH2 (or 1,5-dihydro-FAD [flavin adenine dinucleotide]), derived from carbohydrate and fatty acid catabolism, are electron donors. As electrons are passed along the chain of complexes, protons (H+ ions) are pumped into the intermembrane space at certain points (CI, CIII, and CIV). These protons cause an electrochemical gradient to form. They flow back into the mitochondrial matrix through complex V (ATP synthase), which generates ATP from adenosine diphosphate (ADP) and Pi. The electron transport chain is disrupted by toxic substances such as cyanide and CO, thus decreasing the capacity for aerobic metabolism.

 

Hemoperfusion

Hemoperfusion is a technique in which large volumes of the patient's blood are passed over an adsorbent substance, e.g., resins or activated carbon, which attracts and removes toxic substances from the blood. It is used to treat overdoses of barbiturates, theophylline, digitalis, carbamazepine, methotrexate, acetaminophen, meprobamate, glutethimide, ethchlorvynol, and paraquat poisoning. Hemoperfusion may also be used to remove waste products in kidney disease and to provide supportive treatment before and after liver transplantation.

 

Organophosphate poisoning

Organophosphates are commonly used insecticides and are one of the most common causes of poisoning worldwide. Organophosphates inhibit the action of acetylcholinesterase in nerve cells which results in excess acetylcholine. Signs and symptoms of organophosphate poisoning include salivation, lacrimation, sweating, vomiting, incontinence of urine and feces, convulsions, cyanosis, bradycardia, and hypotension. Treatment of organophosphate poisoning is with pralidoxime, a cholinesterase reactivator.

 

Arsenic poisoning

Arsenic is considered to be a heavy metal and therefore has many toxic characteristics in common with lead and mercury. Signs and symptoms of arsenic poisoning include headache, confusion, drowsiness, abdominal pain, diarrhea, vomiting, convulsions, coma, and death. Treatment of acute arsenic poisoning is supportive and chelation therapy with dimercaprol is used to bind the arsenic and hasten excretion in all symptomatic patients.

 

35.3 Vitamin Poisoning and Treatment

Vitamins are essential for many processes in the body, but some are highly toxic when ingested in excessive amounts. Table 35.2 lists the toxic effects of some vitamins and the treatment that may be given.

  Table 35.2 image Toxic Effects of Vitamins and Treatment

Vitamin

Toxic Effects

Treatment of Toxic Effects

Vitamin A (retinol)

Acute toxicity: dizziness, vomiting, erythema, and desquamation.

Chronic toxicity: skin and hair changes, liver damage (in infants and children). Can cause pseudotumor cerebri (increased CSF fluid pressure)

Symptomatic and supportive (i.e., treatment is given to prevent, control, or relieve complications and side effects)

Vitamin D (ergocalciferol D2, cholecalciferol D2)

Hypercalcemia, and both mental and physical retardation

Terminate exposure to vitamin D. Initiate a low-calcium diet.

Monitor urine volume, sodium, and potassium and replace lost fluids, sodium, and potassium by IV infusions.

Vitamin E (tocopherol)

Nausea, muscular weakness, fatigue, headache, blurred vision, and GI upset

None

Vitamin K

Hemolytic anemia and hyperbilirubinemia may occur in newborns and persons with glucose-6-phosphate dehydrogenase deficiency

None

Niacin (vitamin B3, nicotinic acid, nicotinamide)

Flushing, headache, pruritus, GI irritation

Symptomatic and supportive

Pyridoxine (B6)

Sensory neuropathy, and interference with levodopa therapy

There is no known treatment for the sensory neuropathy produced by high doses of pyridoxine. Spontaneous recovery usually occurs slowly over several months or years.

Ascorbic acid (vitamin C)

Kidney stones and rebound scurvy (seen only with huge amounts ingested)

None

Note: The vitamins that are not included here have no known toxicity.

Abbreviations: CSF, cerebrospinal fluid; GI, gastrointestinal; IV, intravenous.