PHARMACOTHERAPY OF DRUG POISONING AND EMERGENCY STATES. RADIOPROTECTORS

                                                                                                           

treatment of poisonings

Drugs used to counteract drug overdosage are considered under the appropriate headings, e.g., physostigmine with atropine; naloxone with opioids; flumazenil with benzodiazepines; antibody (Fab fragments) with digitalis; and N-acetyl-cysteine with acetaminophen intoxication. Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, “inactivate” heavy metal ions. Chelates (from Greek: chele = claw [of crayfish]) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high affinity, chelating agents “attract” metal ions present in the organism. The chelates are non-toxic, are excreted predominantly via the kidney, maintain a tight organometallic bond also in the concentrated, usually acidic, milieu of tubular urine and thus promote

the elimination of metal ions.

Na2Ca-EDTA is used to treat lead poisoning. This antidote cannot penetrate cell membranes and must be given parenterally. Because of its high binding affinity, the lead ion displaces Ca2+ from its bond. The lead-containing chelate is eliminated renally. Nephrotoxicity predominates among the unwanted effects.

Na3Ca-Pentetate is a complex of diethylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other  metal intoxications.Dimercaprol (BAL, British Anti-Lewisite) was developed in World War II as an antidote against vesicant organic

arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is dimercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions

are potential adverse effects. Deferoxamine derives from the bacterium Streptomyces pilosus. The substance possesses a very high ironbinding capacity, but does not withdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is

indicated only if enteral absorption of iron is to be curtailed.

Unwanted effects include allergic reactions. It should be noted that blood letting is the most effective means of removing iron from the body; however, this method is unsuitable for treating conditions of iron overload associated with anemia. D-penicillamine can promote the elimination of copper (e.g., in Wilson’s disease) and of lead ions. It can be given orally. Two additional uses are cystinuria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine  that is readily soluble. In the latter, penicillamine can be used as a basal  egimen. The therapeutic effect  may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are: cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances. Antidotes for cyanide poisoning

(A). Cyanide ions (CN-) enter the organism in the form of hydrocyanic acid (HCN); the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract. The lethal dose of HCN can be as low as 50 mg. CN- binds with high affinity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. An internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red). In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN-) by hepatic “rhodanese” or sulfur transferase. As a therapeutic measure, thiosulfate can be given i.v. to promote formation of thiocyanate, which is eliminated in urine. However,

this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methemoglobin- forming agent 4-dimethylaminophenol, which rapidly generates trivalent from divalent iron in hemoglobin.

Competition between methemoglobin and cytochrome oxidase for CN- ions favors the formation of cyanmethemoglobin. Hydroxocobalamin is an alternative, very effective antidote central cobalt atom binds CN- with high  affinity to generate cyanocobalamin.Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. Tolonium chloride is a redox dye that can be given i.v. to reduce methemoglobin. Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type. Phosphorylation of acetylcholinesterase causes an irreversible inhibition of acetylcholine   because its breakdown and hence flooding of the organism with the transmitter. Possible sequelae are exaggerated parasympathomimetic activity, blockade of ganglionic and neuromuscular transmission, and respiratory paralysis. Therapeutic measures include: 1.

administration of atropine in high dosage to shield muscarinic acetylcholine receptors; and 2. reactivation of acetylcholinesterase by obidoxime, which successively binds to the enzyme, captures the phosphate residue by a nucleophilic attack, and then dissociates

from the active center to release the enzyme from inhibition. Ferric Ferrocyanide (“Berlin Blue,” B) is used to treat poisoning with thallium salts (e.g., in rat poison), the

initial symptoms of which are gastrointestinal disturbances, followed by nerve and brain damage, as well as hair loss. Thallium ions present in the organism are secreted into the gut but undergo reabsorption. The insoluble, nonabsorbable colloidal Berlin Blue binds thallium ions. It is given orally to prevent absorption of acutely ingested thallium or to

promote clearance from the organism by intercepting thallium that is secreted into the intestines.

Management of the Poisoned Patient

Over a million cases of acute poisoning occur in the USA each year, although only a small fraction are fatal. Most deaths are due to intentional suicidal overdose by an adolescent or adult. Childhood deaths due to accidental ingestion of a drug or toxic household product have been markedly reduced in the past 30 years as a result of safety packaging and effective poisoning prevention education. Even with a serious exposure, poisoning is rarely fatal if the victim receives prompt medical attention and good supportive care. Careful management of respiratory failure, hypotension, seizures, and thermoregulatory disturbances has resulted in improved survival of patients who reach

the hospital alive.

Initial Management of the Poisoned Patient

The initial management of a patient with coma, seizures, or otherwise altered mental status should follow the same approach regardless of the poison involved. Attempting to make a specific toxicologic diagnosis only delays the application of supportive measures that form the basis of poisoning treatment.First, the airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. For many patients, simple positioning in the lateral decubitus position is sufficient to move the flaccid tongue out of the airway. Breathing should be assessed by observation and oximetry and, if in doubt, by measuring arterial blood gases. Patients with respiratory insufficiency should be intubated and mechanically ventilated. The circulation should

be assessed by continuous monitoring of pulse rate, blood pressure, urinary output, and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determinations. At this point, every patient with altered mental status should receive a challenge with concentrated dextrose, unless a rapid bedside blood sugar test demonstrates that the patient is not hypoglycemic. Adults are given 25 g (50 mL of 50% dextrose solution) intravenously, children 0.5 g/kg (2 mL/kg of 25% dextrose). Hypoglycemic patients may appear to be intoxicated, and there is no  rapid and reliable way to distinguish them from poisoned patients. Alcoholic or malnourished patients should also receive 100 mg of thiamine intramuscularly or in the intravenous infusion solution at this time to prevent Wernicke’s syndrome. The opioid antagonist naloxone may be given in a dose of 0.4–2 mg intravenously. Naloxone will reverse respiratory and CNS depression due to all varieties of opioid drugs. It is useful to remember that these drugs cause death primarily by respiratory depression; therefore, if airway and breathing assistance have already been instituted, naloxone may not be necessary. Larger doses of naloxone may be needed for patients with overdose

involving propoxyphene, codeine, and some other opioids. The benzodiazepine antagonist flumazenil may be of value in patients with suspected benzodiazepine overdose, but it should not be used if there is a history of tricyclic antidepressant overdose or a seizure disorder, as it can induce convulsions in such patients. 

Methods of Enhancing Elimination of Toxins

After appropriate diagnostic and decontamination procedures and administration of antidotes, it is important to consider whether measures for enhancing elimination, such as hemodialysis or urinary alkalinization, can improve clinical outcome. Table  lists intoxications requiring immediate dialysis, those in which it is used only if supportive measures fail, and those for which dialysis is not indicated. Dialysis Procedures

Peritoneal Dialysis This is a relatively simple and available technique but is inefficient in removing most drugs. Hemodialysis Hemodialysis is more efficient than peritoneal dialysis and has been well studied. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (eg, formate in methanol poisoning, oxalate and glycolate in ethylene glycol poisoning). The efficiency of both peritoneal dialysis and hemodialysis is a function of the molecular weight, water

solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin. Hemodialysis is especially useful in overdose cases in which fluid and electrolyte imbalances are present (eg, salicylate intoxication).

Hemoperfusion Blood is pumped from the patient via a venous catheter through a column of adsorbent material and then recirculated to the patient. Hemoperfusion does not improve fluid and electrolyte balance. However, it does remove many high-molecular-weight toxins that have poor water solubility because the perfusion cartridge has a large surface area for adsorption that is directly perfused with the blood and is not impeded by a membrane. The rate-limiting factors in removal of toxins by hemoperfusion are the affinity of the charcoal or adsorbent resin for the drug, the rate of blood flow through the cartridge, and the rate of equilibration of the drug from the peripheral tissues to the blood. Hemoperfusion may enhance whole body clearance of salicylate, phenytoin, ethchlorvynol, phenobarbital, theophylline, and carbamazepine.

Forced Diuresis and Urinary pH Manipulation Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication.

 

 Pharmacotherapy of drug poisoning and extremam state. Radioprotectors. Common pharmacology

Pharmacotherapy of drug poisoning and extremam state

treatment of poisonings

Drugs used to counteract drug overdosage are considered under the appropriate headings, e.g., physostigmine with atropine; naloxone with opioids; flumazenil with benzodiazepines; antibody (Fab fragments) with digitalis; and N-acetyl-cysteine with acetaminophen intoxication.

Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, “inactivate” heavy metal ions. Chelates (from Greek: chele = claw [of crayfish]) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high affinity, chelating agents “attract” metal ions present in the organism. The chelates are non-toxic, are excreted predominantly via the kidney, maintain a tight organometallic bond also in the concentrated, usually acidic, milieu of tubular urine and thus promote the elimination of metal ions.

Na2Ca-EDTA is used to treat lead poisoning. This antidote cannot penetrate cell membranes and must be given parenterally. Because of its high binding affinity, the lead ion displaces Ca2+ from its bond. The lead-containing chelate is eliminated renally. Nephrotoxicity predominates among the unwanted effects.

Na3Ca-Pentetate is a complex of diethylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other  metal intoxications.Dimercaprol (BAL, British Anti-Lewisite) was developed in World War II as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is dimercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects.

Deferoxamine derives from the bacterium Streptomyces pilosus. The substance possesses a very high ironbinding capacity, but does not withdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is indicated only if enteral absorption of iron is to be curtailed.

Unwanted effects include allergic reactions. It should be noted that blood letting is the most effective means of removing iron from the body; however, this method is unsuitable for treating conditions of iron overload associated with anemia. D-penicillamine can promote the elimination of copper (e.g., in Wilson’s disease) and of lead ions. It can be given orally. Two additional uses are cystinuria and rheumatoid arthritis. In the former, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine  that is readily soluble. In the latter, penicillamine can be used as a basal  egimen. The therapeutic effect  may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are: cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters), nephrotoxicity, bone marrow depression, and taste disturbances.

Management guidelines for blood lead levels in adults differ significantly from management guidelines for blood lead levels in children. In adults, a blood lead level greater than or equal to 25 µg/dL (micrograms per deciliter) is considered elevated. However, the majority of adults have blood lead levels less than 3 µg/dL. In children, any blood lead level at or above 10 µg/dL is considered elevated. The difference in elevated levels between children and adults is largely attributed to the fact that children are still growing and developing and a small amount of lead that may have little effect on an adult can be detrimental to a child’s health.

Blood Lead (µg/dL)	Action Necessary
<10	No actioeeded
10-24	Identify and minimize lead exposure
25-49	Remove from exposure if symptomatic Monitor blood lead and zinc protoporphyrin
50-79	Remove from work with lead. Immediate medical evaluation indicated. Chelatioot indicated unless significant symptoms due to lead poisoning
>=80	Same as above. Chelation may be indicated if symptomatic. Important to consult on individual case basis

Management guidelines adopted from the California Department of Health Services, Childhood Lead Poisoning Prevention Branch & Occupational Lead Poisoning Prevention Program

What should I do if I have anelevated blood lead level?

A portion of lead is excreted from the body through body fluids. The remainder is stored in the bones and is virtually impossible to remove once it has settled in the skeletal system. There are a number of methods available to increase the portion of lead excreted from the body through body fluids.

• Eat small frequent meals rather than three large meals each day. A full stomach makes it difficult to absorb lead.

• Eat a diet high in calcium and iron and low in fat. Some recommended foods that meet this requirement are:

 

Antidotes for cyanide poisoning

(A). Cyanide ions (CN-) enter the organism in the form of hydrocyanic acid (HCN); the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract. The lethal dose of HCN can be as low as 50 mg. CN- binds with high affinity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. An internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red). In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN-) by hepatic “rhodanese” or sulfur transferase. As a therapeutic measure, thiosulfate can be given i.v. to promote formation of thiocyanate, which is eliminated in urine. However, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methemoglobin- forming agent 4-dimethylaminophenol, which rapidly generates trivalent from divalent iron in hemoglobin.

Competition between methemoglobin and cytochrome oxidase for CN- ions favors the formation of cyanmethemoglobin. Hydroxocobalamin is an alternative, very effective antidote central cobalt atom binds CN- with high  affinity to generate cyanocobalamin.Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. Tolonium chloride is a redox dye that can be given i.v. to reduce methemoglobin. Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type. Phosphorylation of acetylcholinesterase causes an irreversible inhibition of acetylcholine   because its breakdown and hence flooding of the organism with the transmitter. Possible sequelae are exaggerated parasympathomimetic activity, blockade of ganglionic and neuromuscular transmission, and respiratory paralysis. Therapeutic measures include: 1.

administration of atropine in high dosage to shield muscarinic acetylcholine receptors; and 2. reactivation of acetylcholinesterase by obidoxime, which successively binds to the enzyme, captures the phosphate residue by a nucleophilic attack, and then dissociates

from the active center to release the enzyme from inhibition. Ferric Ferrocyanide (“Berlin Blue,” B) is used to treat poisoning with thallium salts (e.g., in rat poison), the initial symptoms of which are gastrointestinal disturbances, followed by nerve and brain damage, as well as hair loss. Thallium ions present in the organism are secreted into the gut but undergo reabsorption. The insoluble, nonabsorbable colloidal Berlin Blue binds thallium ions. It is given orally to prevent absorption of acutely ingested thallium or to promote clearance from the organism by intercepting thallium that is secreted into the intestines.

Management of the Poisoned Patient

Over a million cases of acute poisoning occur in the USA each year, although only a small fraction are fatal. Most deaths are due to intentional suicidal overdose by an adolescent or adult. Childhood deaths due to accidental ingestion of a drug or toxic household product have been markedly reduced in the past 30 years as a result of safety packaging and effective poisoning prevention education. Even with a serious exposure, poisoning is rarely fatal if the victim receives prompt medical attention and good supportive care. Careful management of respiratory failure, hypotension, seizures, and thermoregulatory disturbances has resulted in improved survival of patients who reach the hospital alive.

Initial Management of the Poisoned Patient

The initial management of a patient with coma, seizures, or otherwise altered mental status should follow the same approach regardless of the poison involved. Attempting to make a specific toxicologic diagnosis only delays the application of supportive measures that form the basis of poisoning treatment.First, the airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. For many patients, simple positioning in the lateral decubitus position is sufficient to move the flaccid tongue out of the airway.

Breathing should be assessed by observation and oximetry and, if in doubt, by measuring arterial blood gases. Patients with respiratory insufficiency should be intubated and mechanically ventilated. The circulation should be assessed by continuous monitoring of pulse rate, blood pressure, urinary output, and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determinations. At this point, every patient with altered mental status should receive a challenge with concentrated dextrose, unless a rapid bedside blood sugar test demonstrates that the patient is not hypoglycemic.

Adults are given 25 g (50 mL of 50% dextrose solution) intravenously, children 0.5 g/kg (2 mL/kg of 25% dextrose). Hypoglycemic patients may appear to be intoxicated, and there is no  rapid and reliable way to distinguish them from poisoned patients. Alcoholic or malnourished patients should also receive 100 mg of thiamine intramuscularly or in the intravenous infusion solution at this time to prevent Wernicke’s syndrome. The opioid antagonist naloxone may be given in a dose of 0.4–2 mg intravenously. Naloxone will reverse respiratory and CNS depression due to all varieties of opioid drugs. It is useful to remember that these drugs cause death primarily by respiratory depression; therefore, if airway and breathing assistance have already been instituted, naloxone may not be necessary.

Larger doses of naloxone may be needed for patients with overdose involving propoxyphene, codeine, and some other opioids. The benzodiazepine antagonist flumazenil may be of value in patients with suspected benzodiazepine overdose, but it should not be used if there is a history of tricyclic antidepressant overdose or a seizure disorder, as it can induce convulsions in such patients.

Methods of Enhancing Elimination of Toxins

After appropriate diagnostic and decontamination procedures and administration of antidotes, it is important to consider whether measures for enhancing elimination, such as hemodialysis or urinary alkalinization, can improve clinical outcome. Table  lists intoxications requiring immediate dialysis, those in which it is used only if supportive measures fail, and those for which dialysis is not indicated. Dialysis Procedures

Peritoneal Dialysis This is a relatively simple and available technique but is inefficient in removing most drugs.

Hemodialysis is more efficient than peritoneal dialysis and has been well studied. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (eg, formate in methanol poisoning, oxalate and glycolate in ethylene glycol poisoning). The efficiency of both peritoneal dialysis and hemodialysis is a function of the molecular weight, water solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin.

Hemodialysis is especially useful in overdose cases in which fluid and electrolyte imbalances are present (eg, salicylate intoxication).

Hemoperfusion Blood is pumped from the patient via a venous catheter through a column of adsorbent material and then recirculated to the patient. Hemoperfusion does not improve fluid and electrolyte balance. However, it does remove many high-molecular-weight toxins that have poor water solubility because the perfusion cartridge has a large surface area for adsorption that is directly perfused with the blood and is not impeded by a membrane. The rate-limiting factors in removal of toxins by hemoperfusion are the affinity of the charcoal or adsorbent resin for the drug, the rate of blood flow through the cartridge, and the rate of equilibration of the drug from the peripheral tissues to the blood. Hemoperfusion may enhance whole body clearance of salicylate, phenytoin, ethchlorvynol, phenobarbital, theophylline, and carbamazepine.

Forced Diuresis and Urinary pH Manipulation Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication.

 

Carbon monoxide

 

is a product of incomplete combustion of natural or petroleum gas. Common sources in the home include faulty central heating systems, gas appliances and fires. Blocked flues and chimneys mean the gas can’t escape and is inhaled by the unsuspecting individual. In the UK, about 50 people die each year in their homes from accidental carbon monoxide poisoning.

Car exhausts are also a common source of carbon monoxide. A lethal level of carbon monoxide in the blood can develop within ten minutes inside a closed garage.

Symptoms

Inhaling carbon monoxide reduces the blood’s ability to carry oxygen

Inhaling carbon monoxide reduces the blood’s ability to carry oxygen, leaving the body’s organs and cells starved of oxygen.

The symptoms of mild carbon monoxide poisoning may be non-specific and similar to those of viral cold infections: headache, nausea, dizziness, sore throat and dry cough. In children, the symptoms are similar to those of a stomach upset, with nausea and vomiting.

More severe poisoning can result in a fast and irregular heart rate, over-breathing (hyperventilation), confusion, drowsiness and difficulty breathing. Seizures and loss of consciousness may also occur.

Symptoms can occur a few days or even months after exposure to carbon monoxide. Such symptoms include confusion, loss of memory and problems with coordination.

Warning signs

It’s important to consider that carbon monoxide poisoning may be a possibility if:

other people in the home or place of work suffer similar symptoms  symptoms tends to disappear when someone goes away (for example, on holiday) and they’re no longer exposed to the carbon monoxide gas  symptoms tend to be seasonal (for example, headaches during the winter when indoor heating is used more often)

 

Diagnosis and treatment

Carbon monoxide poisoning can be confirmed by finding high levels in the blood. Treatment includes making sure the patient is away from any source of the gas, providing basic life support as appropriate and giving oxygen before transferring the patient to hospital.

Those people who suffer mild poisoning invariably make a full recovery. Between 10 and 50 per cent of those with severe poisoning may suffer long-term problems.

Prevention

Carbon monoxide poisoning is preventable, so it’s important to be aware of what may cause it and how to minimise the risk of exposure by putting these safety tips into practice:

have chimneys and flues checked regularly

make sure gas appliances and heating systems are inspected every year

for extra protection, fit carbon monoxide alarms – available from DIY stores

never run cars, motorbikes or lawnmowers in a closed garage

Heavy Metal Intoxication

Some metals such as iron are essential for life, while others such as lead are present in all organisms but serve no useful biologic purpose. Some of the oldest diseases of humans can be traced to heavy metal poisoning associated with metal mining, refining, and use. Even with the present recognition of the hazards of heavy metals, the incidence of intoxication remains significant and the need for preventive strategies and effective therapy remains high. When intoxication occurs, chelator molecules (from chela “claw”) may be used to bind the metal and facilitate its excretion from the body. Chelator drugs are discussed in the second part of this chapter.

Toxicology of Heavy Metals

  

Lead poisoning is one of the oldest occupational and environmental diseases in the world. Despite its recognized hazards, lead continues to have widespread commercial application. Environmental lead exposure, ubiquitous by virtue of the anthropogenic distribution of lead to air, water, and food, has declined considerably in the past 2 decades as a result of diminished use of lead in gasoline and other applications. While these public health measures, together with improved workplace conditions, have decreased the incidence of serious overt lead poisoning, there remains considerable concern over the effects of low-level lead exposure. Extensive evidence indicates that lead may have subtle subclinical adverse effects oeurocognitive function and on blood pressure at blood lead concentrations once considered “normal” or “safe.” Lead serves no useful purpose in the human body. In key target organs such as the developing central nervous system, no safe threshold of lead exposure has been established.

Pharmacokinetics

Inorganic lead is slowly but consistently absorbed via the respiratory and gastrointestinal tracts.

Inorganic lead is poorly absorbed through the skin, but organic lead compounds, eg, leaded antiknock gasoline, are well absorbed by this route. Absorption of lead dust via the respiratory tract is the most common cause of industrial poisoning. The intestinal tract is the primary route of entry in nonindustrial exposure (Table 58–1). Absorption via the gastrointestinal tract varies with the nature of the lead compound, but in general, adults absorb about 10% of the ingested amount while young children absorb up to 50%. Low dietary calcium, iron deficiency, and ingestion on an empty stomach have all been associated with increased lead absorption.

Once absorbed from the respiratory or gastrointestinal tract, lead is bound to erythrocytes and widely distributed initially to soft tissues such as the bone marrow, brain, kidney, liver, muscle, and gonads; then to the subperiosteal surface of bone; and later to bone matrix. Lead also crosses the placenta and poses a potential hazard to the fetus. The kinetics of lead clearance from the body follows a multi-compartment model, composed predominantly of the blood and soft tissues, with a half-life of 1–2 months; and the skeleton, with a half-life of years to decades. Approximately 70% of the lead that is eliminated appears in the urine, with lesser amounts excreted through the bile, skin, hair, nails, sweat, and breast milk. The fractioot undergoing prompt excretion, approximately half of the absorbed lead, may be incorporated into the skeleton, the repository of more than 90% of the body lead burden in most adults. In patients with high bone lead burdens, slow release from the skeleton may elevate blood lead concentrations for years after exposure ceases; and pathologic high bone turnover states such as hyperthyroidism or prolonged immobilization may result in frank lead intoxication. The lead burden in bone has been quantitated using noninvasive x-ray fluorescence, a technique that may provide the best measure of long-term, cumulative lead absorption.

Pharmacodynamics

Lead exerts multisystemic toxic effects through at least three mechanisms: by inhibiting enzyme activity, sometimes as a consequence of binding to sulfhydryl groups; by interfering with the action of essential cations, particularly calcium, iron, and zinc; and by altering the structure of cell membranes and receptors.

Nervous System

The developing central nervous system of the fetus and young child is the most sensitive target organ for lead’s toxic effect. Epidemiologic studies suggest that blood lead concentrations less than 5 g/dL may result in subclinical deficits ieurocognitive function in lead-exposed young children, with no demonstrable threshold for a “no effect” level (Canfield et al, 2003). Hearing acuity may also be diminished. Adults are less sensitive to the CNS effects of lead, but at blood lead concentrations in excess of 30 g/dL, behavioral, constitutional, and neurocognitive effects may gradually emerge, producing signs and symptoms such as irritability, fatigue, decreased libido, anorexia, sleep disturbance, impaired visual-motor coordination, and slowed reaction time.

Headache, arthralgias, and myalgias are also frequent complaints. Tremor occurs but is less common. Lead encephalopathy, usually occurring at blood lead concentrations in excess of 100 g/dL, is typically accompanied by increased intracranial pressure and may produce ataxia, stupor, coma, convulsions, and death. There is wide interindividual variation in the magnitude of lead exposure required to cause overt lead-related signs and symptoms.

Peripheral neuropathy may appear after chronic high-dose lead exposure, usually following months to years of blood lead concentrations in excess of 100 g/dL. Predominantly motor in character, the neuropathy may present clinically with painless weakness of the extensors, particularly in the upper extremity, resulting in classic wrist-drop. Preclinical signs of lead-induced peripheral nerve dysfunction may be detectable by electrodiagnostic testing.

Blood

Lead can induce an anemia that may be either normocytic or microcytic and hypochromic. Lead interferes with heme synthesis by blocking the incorporation of iron into protoporphyrin IX and by inhibiting the function of enzymes in the heme synthesis pathway, including aminolevulinic acid dehydratase and ferrochelatase. Within 2–8 weeks after an elevation in blood lead concentration (generally to 30–50 g/dL or greater), increases in heme precursors, notably free erythrocyte protoporphyrin or its zinc chelate, zinc protoporphyrin, may be detectable in whole blood. Lead also contributes to anemia by increasing erythrocyte membrane fragility and decreasing red cell survival time. Frank hemolysis may occur with high exposure. The presence of basophilic stippling on the peripheral blood smear, thought to be a consequence of lead inhibition of the enzyme 3′,5′- pyrimidine nucleotidase, is sometimes a suggestive—albeit insensitive and nonspecific—diagnostic clue to the presence of lead intoxication.

Kidneys

Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations in excess of 80 g/dL, may result in renal interstitial fibrosis and nephrosclerosis.

Lead nephropathy may have a latency period of years. Lead may alter uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis (“saturnine gout”). Acute high-dose lead exposure sometimes produces transient azotemia, possibly as a consequence of intrarenal vasoconstriction.

Reproductive Organs

High-dose lead exposure is a recognized risk factor for stillbirth or spontaneous abortion. Epidemiologic studies of the impact of low-level lead exposure on reproductive outcome such as low birth weight, preterm delivery, or spontaneous abortion have yielded mixed results. However, a well-designed nested case-control study recently detected an odds ratio for spontaneous abortion of 1.8 (95% CI 1.1–3.1) for every 5 g/dL increase in maternal blood lead across an approximate range of 5–20 g/dL (Borja-Aburto et al, 1999). In males, blood lead concentrations in excess of 40 g/dL have been associated with diminished or aberrant sperm production.

Gastrointestinal Tract

Moderate lead poisoning may cause loss of appetite, constipation, and, less commonly, diarrhea. At high dosage, intermittent bouts of severe colicky abdominal pain (“lead colic”) may occur. The mechanism of lead colic is unclear but is believed to involve spasmodic contraction of the smooth muscles of the intestinal wall. In heavily exposed individuals with poor dental hygiene, the reaction of circulating lead with sulfur ions released by microbial action may produce dark deposits of lead sulfide at the gingival margin (“gingival lead lines”). Although frequently mentioned as a diagnostic clue, this is a far from universal sign of lead exposure.

Cardiovascular System

Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in susceptible individuals. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure.

Studies of middle-aged and elderly men and women have identified cumulative lead exposure to be an independent risk factor for hypertension (Korrick et al, 1999). Lead can also elevate blood pressure in experimental animals, an effect that may be caused by interaction with calciummediated constriction of vascular smooth muscle.

Opiates (heroin, morphine, meperidine, codeine, others)

Addictive drugs, usually taken by needle (except codeine; intravenous or skin-popping; there are ways of inhaling “the dragon” heroin). Your lecturer is not impressed with the adverse personality or health consequences of opiate use itself (well, it’s constipating and bad for the libido). However, the stuff is addictive, expensive, and illegal (which causes some of the problems) and overdose (even in an addict with marvelous tolerance) is very lethal.

 

Unlike cocaine, heroin is not known to have any direct tissue toxicities. There are maybe 4000 deaths from heroin overdose in the US each year. Those dying of heroin overdose either (1) stopped breathing from medullary depression, or (2) got pulmonary edema (nobody knows why opiates can do this, but it’s likely that it’s neurally-mediated, because of tolerance and because brain injury itself can produce similar edema). Of course, there are plenty of heroin-related deaths due to lifestyle and/or unsanitary injection practices.

It’s commonplace for an “accidental” overdose to have been preceded by a critical life-event, and many of these “unfortunate tragic accidents” are probably suicides (Forens. Sci. Int. 62: 129, 1993).

* Confusingly, there is an illness seen only in people who snort cooked heroin, and that much be due to a poison generated in this way. It looks clinically and anatomically like prion disease, but some patients recover; it’s called “heroin spongiform encephalopathy” and is recognizable now on MRI scans: For. Sci. Int. 113: 435, 2000.

Methadone maintenance keeps drug addiction, which is a relapsing problem, under partial control with great savings to society. There are about 100,000 people on methadone maintenance in the US, and only about 500 deaths per year. Most deaths result from increasing the initial dose too rapidly.

You’ll review the various molecules in “Pharm”. Don’t try too hard to interpret a post-mortem morphine level, either to decide whether “it’s enough to kill the person”, or how much of the drug was taken. Tolerance varies tremendously, and attempts to second-guess tolerance by high-tech assays of brain receptors have been non-helpful: For. Sci. Int. 113: 423, 2000. During life, 98% of a dose of opiate is in the tissues; as the body decomposes, much of it will return to the bloodstream. New review J. For. Sci. 46: 1138, 2001. Redistribution is less of a problem than for other drugs: J. For. Sci. 45: 843, 2000.

* Future medical examiners: The S-enantiomer of methadone is inert but is measured by some of the toxicology techniques.

* Don’t forget to look for pupa cases from the maggots that fed on the body. Morphine can be analyzed from here: For. Sci. Int. 120: 127, 2001.

“Big Robbins’s” statement that a third of heroin addicts had diluted their drug with water from the toilet comes as no surprise to this physician. Heroin may be cut with Baby’s talcum powder (stays in the lungs forever), quinine (rough on the heart), or whatever else is handy (who knows?) Heroin addicts seldom use sterile technique, and abscesses and endocarditis (notably on the tricuspid valve, notably staphylococcal) are commonplace, as is the bad retrovirus. “Heroin nephropathy” is usually FSGS (also amyloidosis A, from the abscesses.)

It’s worth remembering that tolerance to opiates is lost VERY fast. One common scenario is a fatal overdose after a 2-3 day stay in jail; the addict simply took the customary dose and died as a result. Savvy medical examiners are now estimating these people’s tolerance history using hair samples

 

Major Forms of Lead Intoxication

Acute

Acute inorganic lead poisoning is uncommon today. It usually results from industrial inhalation of large quantities of lead oxide fumes or, in small children, from ingestion of a large oral dose of lead in lead-based paints or contaminated food or drink. The onset of severe symptoms usually requires several days or weeks of recurrent exposure and presents with signs and symptoms of encephalopathy or colic. Evidence of hemolytic anemia (or anemia with basophilic stippling if exposure has been subacute) and elevated hepatic aminotransferases may be present. The diagnosis of acute inorganic lead poisoning may be difficult, and depending on the presenting symptoms, the condition has sometimes been mistaken for appendicitis, peptic ulcer, pancreatitis, or infectious meningitis. Subacute presentation, featuring headache, fatigue, intermittent abdominal cramps, myalgias, and arthralgias, has often been mistaken for a flu-like viral illness and may not come to medical attention. When there has been recent ingestion of lead-containing paint chips, glazes, or weights, radiopacities may be visible on abdominal radiographs.

Chronic

The patient with chronic lead intoxication usually presents with multisystemic findings, including constitutional complaints of anorexia, fatigue, and malaise; neurologic complaints, including headache, difficulty in concentrating, irritability or depressed mood; weakness, arthralgias or myalgias; and gastrointestinal symptoms. Lead poisoning should be strongly suspected in any patient presenting with headache, abdominal pain, and anemia; and less commonly with motor neuropathy, gout, and renal insufficiency. Chronic lead intoxication should be considered in any child with neurocognitive deficits, growth retardation, or developmental delay.

The diagnosis is best confirmed by measuring lead in whole blood. Although this test reflects lead currently circulating in blood and soft tissues and is not a reliable marker of either recent or cumulative lead exposure, most patients with lead-related disease will have blood lead concentrations above the normal range. Average background blood lead concentrations in North America and Europe have declined considerably in recent decades, and the geometric mean blood lead concentration in the United States in 1999–2000 was estimated to be 1.66 g/dL (CDC, 2003).

Although predominantly a research tool, the concentration of lead in bone assessed by noninvasive K x-ray fluorescence measurement of lead in bone has been correlated with long-term cumulative lead exposure, and its relationship to numerous lead-related disorders is a subject of ongoing investigation. Measurement of lead excretion in the urine following a single dose of a chelating agent (sometimes called a “chelation challenge test”) primarily reflects the lead content of soft tissues and may not be a reliable marker of long-term lead exposure, remote past exposure, or skeletal lead burden.

Organolead Poisoning

Poisoning from organolead compounds is now very rare, in large part due to the worldwide phaseout of tetraethyl and tetramethyl lead as antiknock additives in gasoline. However, organolead compounds such as lead stearate or lead naphthenate are still used in certain commercial processes.

Because of their volatility or lipid solubility, organolead compounds tend to be well absorbed through either the respiratory tract or the skin. Organolead compounds predominantly target the central nervous system, producing dose-dependent effects that may include neurocognitive deficits, insomnia, delirium, hallucinations, tremor, convulsions, and death.

Treatment

Inorganic Lead Poisoning

Treatment of inorganic lead poisoning involves immediate termination of exposure, supportive care, and the judicious use of chelation therapy. (Chelation is discussed further later in this chapter.) Lead encephalopathy is a medical emergency that requires intensive supportive care. Cerebral edema may improve with corticosteroids and mannitol, and anticonvulsants may be required to treat seizures. Radiopacities on abdominal radiographs may suggest the presence of retained lead objects requiring gastrointestinal decontamination. Adequate urine flow should be maintained, but overhydration should be avoided. Intravenous edetate calcium disodium (CaNa2EDTA) is administered at a dosage of 1000–1500 mg/m2/d (approximately 30–50 mg/kg/d) by continuous infusion for up to 5 days. Some clinicians advocate that chelation treatment for lead encephalopathy be initiated with an intramuscular injection of dimercaprol, followed in 4 hours by concurrent administration of dimercaprol and EDTA. Parenteral chelation is limited to 5 or fewer days, at which time oral treatment with another chelator, succimer, may be instituted. In symptomatic lead intoxication without encephalopathy, treatment may sometimes be initiated with succimer. The end point for chelation is usually resolution of symptoms or return of the blood lead concentration to the premorbid range. In patients with chronic exposure, cessation of chelation may be followed by an upward rebound in blood lead concentration as the lead reequilibrates from bone lead stores.

While most clinicians support chelation for symptomatic patients with elevated blood lead concentrations, the decision to chelate asymptomatic subjects is more controversial. Since 1991, the CDC has recommended chelation for all children with blood lead concentrations of 45 g/dL or greater. However, a recent randomized, double-blind, placebo-controlled clinical trial of succimer in children with blood lead concentrations between 25 g/dL and 44 g/dL found no benefit oeurocognitive function or long-term blood lead reduction (Rogan et al, 2001).

Prophylactic use of chelating agents in the workplace should never be a substitute for reduction or prevention of excessive exposure.

Organic Lead Poisoning

Initial treatment consists of decontaminating the skin and preventing further exposure. Treatment of seizures requires appropriate use of anticonvulsants. Empiric chelation may be attempted if high blood lead concentrations are present.

Arsenic

Arsenic is a naturally occurring element in the earth’s crust with a long history of use as a constituent of commercial and industrial products, as a component in pharmaceuticals, and as an agent of deliberate poisoning. Recent commercial applications of arsenic include its use in the manufacture of semiconductors, wood preservatives, herbicides, cotton desiccants, nonferrous alloys, glass, insecticides, and veterinary pharmaceuticals. In some regions of the world, groundwater may contain high levels of arsenic that has leached from natural mineral deposits.

Arsenic in drinking water in the Ganges delta of India and Bangladesh is now recognized as one of the world’s most pressing environmental health problems. Arsine, a hydride gas with potent hemolytic effects, is manufactured predominantly for use in the semiconductor industry but may also be generated accidentally when arsenic-containing ores come in contact with acidic solutions.

It is of historical interest that Fowler’s solution, which contains 1% potassium arsenite, was widely used as a medicine for many conditions from the eighteenth century through the mid twentieth century. Organic arsenicals were the first pharmaceutical antibiotics* and were widely used for the first half of the twentieth century until supplanted by penicillin and other more effective and less toxic agents.

* Paul Ehrlich’s “magic bullet” for syphilis (arsphenamine; Salvarsan) was an arsenical. Other organoarsenicals, most notably lewisite (dichloro[2-chlorovinyl]arsine), were developed in the early twentieth century as chemical warfare agents. Arsenic trioxide was reintroduced into the United States Pharmacopeia in 2000 as an orphan drug for the treatment of relapsed acute promyelocytic leukemia.

Pharmacokinetics

Soluble arsenic compounds are well absorbed through the respiratory and gastrointestinal tracts (Table 58–1). Percutaneous absorption is limited but may be clinically significant after heavy exposure to concentrated arsenic reagents. Most of the absorbed inorganic arsenic undergoes methylation, mainly in the liver, to monomethylarsonic acid and dimethylarsinic acid, which are excreted, along with residual inorganic arsenic, in the urine. When chronic daily absorption is less than 1000 g of soluble inorganic arsenic, approximately two thirds of the absorbed dose is excreted in the urine. After massive ingestions, the elimination half-life is prolonged. Inhalation of arsenic compounds of low solubility may result in prolonged retention in the lung and may not be reflected by urinary arsenic excretion. Arsenic binds to sulfhydryl groups present in keratinized tissue, and following cessation of exposure, hair, nails, and skin may contain elevated levels after urine values have returned to normal. However, arsenic present in hair and nails as a result of external deposition may be indistinguishable from that incorporated after internal absorption.

Pharmacodynamics

Arsenic compounds are believed to exert their toxic effects by several modes of action. Interference with enzymatic function may result from sulfhydryl group binding by trivalent arsenic or by substitution for phosphate. Inorganic arsenic or its metabolites may induce oxidative stress, alter gene expression, and interfere with cell signal transduction. Although on a molar basis trivalent arsenic (As3+, arsenite) is generally two to ten times more acutely toxic than pentavalent arsenic (As5+, arsenate), in vivo interconversion is known to occur, and the full spectrum of arsenic toxicity has occurred after sufficient exposure to either form. Arsine gas is oxidized in vivo and exerts a potent hemolytic effect associated with alteration of ion flux across the erythrocyte membrane; however, it also disrupts cellular respiration in other tissues.

Arsenic is a recognized human carcinogen and has been associated with cancer of the lung, skin, and bladder (National Research Council, 2001). Marine organisms may contain large amounts of a well-absorbed trimethylated organoarsenic, arsenobetaine, as well as a variety of arsenosugars. Arsenobetaine exerts no known toxic effects when ingested by mammals and is excreted in the urine unchanged; arsenosugars are partially metabolized to dimethylarsinic acid.

Major Forms of Arsenic Intoxication

Acute Inorganic Arsenic Poisoning

Within minutes to hours after exposure to high doses (tens to hundreds of milligrams) of soluble inorganic arsenic compounds, many systems are affected. Initial gastrointestinal signs and symptoms include nausea, vomiting, diarrhea, and abdominal pain. Diffuse capillary leak, combined with gastrointestinal fluid loss, may result in hypotension, shock, and death. Cardiopulmonary toxicity, including congestive cardiomyopathy, cardiogenic or noncardiogenic pulmonary edema, and ventricular arrhythmias, may occur promptly or after a delay of several days.

Pancytopenia usually develops within a week, and basophilic stippling of erythrocytes may be present soon after.

Central nervous system effects, including delirium, encephalopathy, and coma, may occur within the first few days of intoxication. An ascending sensorimotor peripheral neuropathy may begin to develop after a delay of 2–6 weeks. This neuropathy may ultimately involve the proximal musculature and result ieuromuscular respiratory failure. Months after an episode of acute poisoning, transverse white striae (Aldrich-Mees lines) may be visible in the nails.

Acute inorganic arsenic poisoning should be considered in an individual presenting with abrupt onset of gastroenteritis in combination with hypotension and metabolic acidosis. The diagnosis may be confirmed by demonstration of elevated amounts of inorganic arsenic and its metabolites in the urine (typically in the range of several thousand micrograms in the first 2–3 days following acute symptomatic poisoning). Arsenic disappears rapidly from the blood, and except in anuric patients, blood arsenic levels should not be used for diagnostic purposes.

Treatment is based on appropriate gut decontamination, intensive supportive care, and prompt chelation with unithiol, 3–5 mg/kg intravenously every 4–6 hours, or dimercaprol, 3–5 mg/kg intramuscularly every 4–6 hours. In animal studies, the efficacy of chelation has been highest when it is administered within minutes to hours after arsenic exposure; therefore, if diagnostic suspicion is high, treatment should not be withheld for the several days to weeks often required to obtain laboratory confirmation. Succimer has also been effective in animal models and has a higher therapeutic index than dimercaprol.

However, because it is available in the United States only for oral administration, its use may not be advisable in the initial treatment of acute arsenic poisoning, when severe gastroenteritis and splanchnic edema may limit absorption by this route.

Chronic Inorganic Arsenic Poisoning

Chronic inorganic arsenic poisoning also results in multisystemic signs and symptoms. Overt noncarcinogenic effects may be evident after chronic absorption of more than 500–1000 g/d. The time to appearance of symptoms will vary with dose and interindividual tolerances. Constitutional symptoms of fatigue, weight loss, and weakness may be present, along with anemia, nonspecific gastrointestinal complaints, and a sensorimotor peripheral neuropathy, particularly featuring a stocking-glove pattern of dysesthesia. Skin changes—among the most characteristic effects— typically develop after years of exposure and include a “raindrop” pattern of hyperpigmentation, and hyperkeratoses involving the palms and soles. Peripheral vascular disease and noncirrhotic portal hypertension may also occur. Epidemiologic studies suggest a possible link to hypertension and diabetes. Cancer of the lung, skin, bladder, and possibly other sites, may appear years after exposure to doses of arsenic that are not high enough to elicit other acute or chronic effects.

The diagnosis of chronic arsenic poisoning involves integration of the clinical findings with confirmation of exposure. Urinary levels of total arsenic, usually less than 50 g/24 h, may return to normal within days to weeks after exposure ceases. Because it may contain large amounts of nontoxic organoarsenic, all seafood should be avoided for at least 3 days prior to submission of a urine sample for diagnostic purposes. The arsenic content of hair and nails (normally less than 1 ppm) may sometimes reveal past elevated exposure, but results should be interpreted cautiously in view of the potential for external contamination.

Arsine Gas Poisoning

Arsine gas poisoning produces a distinctive pattern of intoxication dominated by profound hemolytic effects. After a latent period that may range from 2 hours to 24 hours postinhalation (depending on the magnitude of exposure), massive intravascular hemolysis may occur. Initial symptoms may include malaise, headache, dyspnea, weakness, nausea, vomiting, abdominal pain, jaundice, and hemoglobinuria. Oliguric renal failure, a consequence of hemoglobin deposition in the renal tubules, often appears within 1–3 days. In massive exposures, lethal effects on cellular respiration may occur before renal failure develops. Urinary arsenic levels are elevated but will seldom be available to confirm the diagnosis during the critical period of illness. Intensive supportive care—including exchange transfusion, vigorous hydration, and, in the case of acute renal failure, hemodialysis—is the mainstay of therapy. Currently available chelating agents have not been demonstrated to be of clinical value in arsine poisoning.

Mercury

Metallic mercury as “quicksilver”—the only metal that is liquid under ordinary conditions—has attracted scholarly and scientific interest from antiquity. In early times it was recognized that the mining of mercury was hazardous to health. As industrial use of mercury became common during the past 200 years, new forms of toxicity were recognized that were found to be associated with various transformations of the metal. In the early 1950s, a mysterious epidemic of birth defects and neurologic disease occurred in the Japanese fishing village of Minamata. The causative agent was determined to be methylmercury in contaminated seafood, traced to industrial discharges into the bay from a nearby factory. In addition to elemental mercury and alkylmercury (including methylmercury), other key mercurials include inorganic mercury salts and aryl mercury compounds, each of which exerts a relatively unique pattern of clinical toxicity.

Mercury is mined predominantly as HgS in cinnabar ore and is then converted commercially to a variety of chemical forms. Key industrial and commercial applications of mercury are found in the electrolytic production of chlorine and caustic soda; the manufacture of electrical equipment, thermometers, and other instruments; paint and pigment production; dental amalgam; and gold refining. Use in pharmaceuticals and in biocides has declined substantially in recent years, but occasional use in antiseptics and folk medicines is still encountered. Environmental exposure to mercury from the burning of fossil fuels—or the bioaccumulation of methylmercury in fish— remains a concern in some regions of the world. Low-level exposure to mercury released from dental amalgam fillings occurs, but no evidence of toxicity from this source has been demonstrated.

Pharmacokinetics

The absorption of mercury varies considerably depending on the chemical form of the metal.

Elemental mercury is quite volatile and can be absorbed from the lungs (Table 58–1). It is poorly absorbed from the intact gastrointestinal tract. Inhaled mercury is the primary source of occupational exposure. Organic short-chain alkylmercury compounds are volatile and potentially harmful by inhalation as well as by ingestion. Percutaneous absorption of all types of mercurials is limited but may be of clinical concern when there is heavy exposure. After absorption, mercury is distributed to the tissues within a few hours, with the highest concentration occurring in the kidney.

Inorganic mercury is excreted through the urine and the feces. Excretion of inorganic mercury follows a multicomponent model: most is excreted within days to weeks, but a fraction may be retained in the kidneys and brain for years. Methylmercury undergoes biliary excretion and enterohepatic circulation, with 90% eventually excreted in the feces. Mercury binds to sulfhydryl groups in keratinized tissue, and, as with lead and arsenic, traces appear in the hair and nails.

Major Forms of Mercury Intoxication

Mercury interacts with sulfhydryl groups in vivo, inhibiting enzymes and altering cell membranes.

The pattern of clinical intoxication from mercury depends to a great extent on the chemical form of the metal and the route and severity of exposure.

Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (see below) may also ensue. Acute ingestion of inorganic mercury salts, such as mercuric chloride, can result in a corrosive, potentially life-threatening hemorrhagic gastroenteritis followed within hours to days by acute tubular necrosis and oliguric renal failure.

Chronic poisoning from inhalation of mercury vapor results in a classic triad of tremor, neuropsychiatric disturbance, and gingivostomatitis. The tremor usually begins as a fine intention tremor of the hands, but the face may also be involved, and progression to choreiform movements of the limbs may occur. Neuropsychiatric manifestations, including memory loss, fatigue, insomnia, and anorexia, are common. There may be an insidious change in mood to shyness, withdrawal, and depression along with explosive anger or blushing (a behavioral pattern referred to as erethism).

Recent studies suggest that low-dose exposure may produce subclinical neurologic effects.

Gingivostomatitis, sometimes accompanied by loosening of the teeth, may be reported after highdose exposure. Evidence of peripheral nerve damage may be detected on electrodiagnostic testing, but overt peripheral neuropathy is rare. Acrodynia is an uncommon idiosyncratic reaction to subacute or chronic mercury exposure and occurs mainly in children. It is characterized by painful erythema of the extremities and may be associated with hypertension, diaphoresis, anorexia, insomnia, irritability or apathy, and a miliarial rash.

Methylmercury intoxication affects mainly the central nervous system and results in paresthesias, ataxia, hearing impairment, dysarthria, and progressive constriction of the visual fields. Signs and symptoms may first appear several weeks or months after exposure begins. Methylmercury is a reproductive toxin. High-dose prenatal exposure to methylmercury may produce mental retardation and a cerebral palsy-like syndrome in the offspring. Low-level prenatal exposures have beenassociated with a risk of subclinical neurodevelopmental deficits (National Research Council, 2000). Dimethylmercury is a rarely encountered but extremely neurotoxic form of organomercury that may be lethal in small quantities.

The diagnosis of mercury intoxication involves integration of the history and physical findings with confirmatory laboratory testing or other evidence of exposure. In the absence of occupational exposure, the urine mercury concentration is usually less than 5 g/L, and whole blood mercury is less than 5 g/L (CDC, 2003). In 1990, the Biological Exposure Index (BEI) Committee of the American Conference of Governmental Industrial Hygienists (ACGIH) recommended that workplace exposures should result in urinary mercury concentrations less than 35 g per gram of creatinine and end-of-workweek whole blood mercury concentrations less than 15 g/L.

Treatment

Acute Exposure

In addition to intensive supportive care, prompt chelation with oral or intravenous unithiol, intramuscular dimercaprol, or oral succimer may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. Vigorous hydration may help to maintain urine output, but if acute renal failure ensues, days to weeks of hemodialysis may be necessary. Because the efficacy of chelation declines with time since exposure, treatment should not be delayed until the onset of oliguria or other major systemic effects.

Chronic Exposure

Unithiol and succimer increase urine mercury excretion following acute or chronic elemental mercury inhalation, but the impact of such treatment on clinical outcome is unknown. Dimercaprol has been shown to redistribute mercury to the central nervous system from other tissue sites, and since the brain is a key target organ, dimercaprol should not be used in treatment of exposure to elemental or organic mercury. Limited data suggest that succimer, unithiol, and N-acetyl-L-cysteine (NAC) may enhance body clearance of methylmercury.

Pharmacology of Chelators

Chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to accelerate the elimination of the metal from the body.

Chelating agents are usually flexible molecules with two or more electronegative groups that form stable coordinate-covalent bonds with a cationic metal atom. In some cases, eg, succimer, the parent compound may require in vivo biotransformation to become an active complexing agent. The chelator-metal complexes formed are excreted by the body. Edetate (ethylenediaminetetraacetate, Figure 58–1) is an important example.

The efficiency of the chelator is partly determined by the number of ligands available for metal binding. The greater the number of these ligands, the more stable the metal-chelator complex. Depending on the number of metal-ligand bonds, the complex may be referred to as mono-, bi-, or polydentate. The chelating ligands include functional groups such as –OH, –SH, and –NH, which can donate electrons for coordination with the metal. Such bonding effectively prevents interaction of the metal with similar functional groups of enzymes or other proteins, coenzymes, cellular nucleophiles, and membranes.

In addition to removing the target metal that is exerting toxic effects on the body, some chelating agents (such as calcium EDTA used for lead intoxication) may enhance the excretion of essential cations such as zinc or copper. However, this side effect is seldom of clinical significance during the limited time frame that characterizes most courses of therapeutic chelation.

In some cases, the metal-mobilizing effect of a therapeutic chelating agent may not only enhance that metal’s excretion—a desired effect—but may also redistribute some of the metal to other vital organs. This has been demonstrated for dimercaprol, which redistributes mercury and arsenic to brain while also enhancing urinary mercury and arsenic excretion. Although several chelating agents have the capacity to mobilize cadmium, their tendency to redistribute cadmium to the kidney and increase nephrotoxicity has negated their therapeutic value in cadmium intoxication.

In most cases, the capacity of chelating agents to prevent or reduce the adverse effects of toxic metals appears to be greatest when they are administered very soon after an acute metal exposure.

Use of chelating agents days to weeks after an acute metal exposure ends—or their use in the treatment of chronic metal intoxication—may still be associated with increased metal excretion.

However, at that point, the capacity of such enhanced excretion to mitigate the pathologic effect of the metal exposure may be reduced.

The most important chelating agents currently in use in the United States are described below.

Dimercaprol (2,3-Dimercaptopropanol, BAL)

Dimercaprol (Figure 58–2), an oily, colorless liquid with a strong mercaptan-like odor, was developed in Great Britain during World War II as a therapeutic antidote against poisoning by the arsenic-containing warfare agent lewisite. It thus became known as British anti-Lewisite, or BAL.

Because aqueous solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in peanut oil and must be administered by intramuscular injection, which is often painf animals, dimercaprol may redistribute arsenic and mercury to the central nervous system, and it is not advocated for treatment of chronic poisoning. Water-soluble analogs of dimercaprol—unithiol and succimer—have higher therapeutic indices and have replaced dimercaprol in many settings.

Succimer (Dimercaptosuccinic Acid, DMSA)

Succimer is a water-soluble analog of dimercaprol, and like that agent it has been shown in animal studies to prevent and reverse metal-induced inhibition of sulfhydryl-containing enzymes and to protect against the acute lethal effects of arsenic. In humans, treatment with succimer is associated with an increase in urinary lead excretion and a decrease in blood lead concentration. It may also decrease the mercury content of the kidney, a key target organ of inorganic mercury salts. In the United States, succimer is formulated exclusively for oral use, but intravenous formulations have been used successfully elsewhere. It is absorbed rapidly but somewhat variably after oral administration. Peak blood levels occur at approximately 3 hours. The drug binds in vivo to the amino acid cysteine to form 1:1 and 1:2 mixed disulfides, possibly in the kidney, and it may be these complexes that are the active chelating moieties. The elimination half-time of transformed succimer is approximately 2–4 hours.

Indications & Toxicity

Succimer is currently FDA-approved for the treatment of children with blood lead concentrations greater than 45 g/dL, but it is also commonly used in adults. The usual dosage is 10 mg/kg orally three times a day. Oral administration of succimer is comparable to parenteral EDTA in reducing blood lead concentration and has supplanted EDTA in outpatient treatment of patients capable of absorbing the oral drug. However, despite the demonstrated capacity of both succimer and EDTA to enhance lead elimination, their value in reversing established lead toxicity or in otherwise improving therapeutic outcome has yet to be established by a placebo-controlled clinical trial.

Based on its protective effects against arsenic in animals and its ability to mobilize mercury from the kidney, succimer has also been used in the treatment of arsenic and mercury poisoning.

Succimer has been well tolerated in limited clinical trials. It has a negligible impact on body stores of calcium, iron, and magnesium. It induces a mild increase in urinary excretion of zinc that is of minor or no clinical significance. Gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea, are the most common side effects, occurring in less than 10% of patients.

Rashes, sometimes requiring discontinuation of the medication, have been reported in less than 5% of patients. Mild, reversible increases in liver aminotransferases have beeoted in 6–10% of patients, and isolated cases of mild to moderate neutropenia have been reported.

Edetate Calcium Disodium (Ethylenediaminetetraacetic Acid [EDTA])

Ethylenediaminetetraacetic acid (Figure 58–1) is an efficient chelator of many divalent and trivalent metals in vitro. The drug is administered as a calcium disodium salt to prevent potentially lifethreatening depletion of calcium.

EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular metal ions much more effectively than intracellular ions.

The highly polar ionic character of EDTA limits its oral absorption. Moreover, oral administration may increase lead absorption from the gut. Consequently, EDTA should be administered by intravenous infusion. In patients with normal renal function, EDTA is rapidly excreted by glomerular filtration, with 50% of an injected dose appearing in the urine within 1 hour. EDTA mobilizes lead from soft tissues, causing a marked increase in urinary lead excretion and a corresponding decline in blood lead concentration. In patients with renal insufficiency, excretion of the drug—and its metal-mobilizing effects—may be delayed.

Indications & Toxicity

Edetate calcium disodium is indicated chiefly for the chelation of lead, but it may also have utility in poisoning by zinc, manganese, and certain heavy radionuclides. In spite of repeated claims in the alternative medicine literature, EDTA has no demonstrated utility in the treatment of atherosclerotic cardiovascular disease.

Because the drug and the mobilized metals are excreted via the urine, the drug is contraindicated in anuric patients. Nephrotoxicity from EDTA has been reported, but in most cases this can be prevented by maintenance of adequate urine flow, avoidance of excessive doses, and limitation of a treatment course to 5 or fewer consecutive days. EDTA may result in temporary zinc depletion that is of uncertain clinical significance. An experimental analog of EDTA, calcium disodium diethylenetriaminepentaacetic acid (DTPA), has been used for removal (“decorporation”) of uranium, plutonium, and other heavy radioisotopes from the body.

Unithiol (Dimercaptopropanesulfonic Acid, DMPS)

Unithiol, a dimercapto chelating agent that is a water-soluble analog of dimercaprol, has been available in the official formularies of Russia and other former Soviet countries since 1958 and in Germany since 1976. It has been legally available from compounding pharmacists in the United States since 1999. Unithiol can be administered orally and intravenously. Bioavailability by the oral route is approximately 50%, with peak blood levels occurring in approximately 3.7 hours.

Over 80% of an intravenous dose is excreted in the urine, mainly as cyclic DMPS sulfides. The elimination half-time for total unithiol (parent drug and its transformation products) is approximately 20 hours. Unithiol exhibits protective effects against the toxic action of mercury and arsenic in animal models, and it increases the excretion of mercury, arsenic, and lead in humans.

Indications & Toxicity

Unithiol has no FDA-approved indications, but experimental studies and its pharmacologic and pharmacodynamic profile suggest that intravenous unithiol offers advantages over intramuscular dimercaprol or oral succimer in the initial treatment of severe acute poisoning by inorganic mercury or arsenic. Aqueous preparations of unithiol (usually 50 mg/mL in sterile water) can be administered at a dose of 3–5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes.

If a few days of treatment are accompanied by stabilization of the patient’s cardiovascular and gastrointestinal status, it may be possible to change to oral administration at a dose of 4–8 mg/kg every 6–8 hours. Oral unithiol may also be considered as an alternative to oral succimer in the treatment of lead intoxication.

Unithiol has been reported to have a low overall incidence of adverse effects (< 4%). Self-limited dermatologic reactions (drug exanthems or urticaria) are the most commonly reported adverse effects, though isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. Because rapid intravenous infusion may cause vasodilation and hypotension, unithiol should be infused slowly over an interval of 15–20 minutes.

Penicillamine (D-Dimethylcysteine)

Penicillamine is a white crystalline, water-soluble derivative of penicillin. DPenicillamine is less toxic than the L isomer and consequently is the preferred therapeutic form.

Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation.

Indications & Toxicity

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson’s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout). Its ability to increase urinary excretion of lead and mercury had occasioned its use as outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower side effect profile, has generally replaced penicillamine for these purposes.

Adverse effects have been seen in up to one third of patients receiving penicillamine.

Hypersensitivity reactions include rash, pruritus, and drug fever, and the drug should be used with extreme caution, if at all, in patients with a history of penicillin allergy. Nephrotoxicity with proteinuria has also been reported, and protracted use of the drug may result in renal insufficiency.

Pancytopenia has been associated with prolonged drug intake. Pyridoxine deficiency is a frequent toxic effect of other forms of the drug but is rarely seen with the D form. An acetylated derivative, N-acetylpenicillamine, has been used experimentally in mercury poisoning and may have superior metal-mobilizing capacity, but it is not commercially available.

Preparations Available

Deferoxamine (Desferal)

Parenteral: Powder to reconstitute, 500 mg/vial

Dimercaprol (BAL in Oil)

Parenteral: 100 mg/mL for IM injection

Edetate calcium [calcium EDTA] (Calcium Dis odium Versenate)

Parenteral: 200 mg/mL for injection

Penicillamine (Cuprimine, Depen)

Oral: 125, 250 mg capsules; 250 mg tablets

Succimer (Chemet)

Oral: 100 mg capsules

Unithiol (Dimaval)

Bulk powder available for compounding as oral capsules, or for infusion (50 mg/mL).

Antidotes

Some poisons have specific antidotes:

Poison/Drug	Antidote
Anticholinergics	Cholinergics (and vice-versa)
Antipsychotics such as haldol and/or risperidone	Ropinirole or Bromocryptine (and vice-versa)
Atropine and/or scopolamine	Physostigmine
benzodiazepines and barbiturates	flumazenil
Beta-Blockers (Propranolol, Sotalol, etc.)	Calcium Gluconate and/or Glucagon. Salbutamol is also used (and vice-versa)
Caffeine and other Xanthines	Adenosine (and vice-versa)
Calcium Channel Blockers (Verapamil, Diltiazem)	Calcium Gluconate
Cyanide	amyl nitrite/sodium nitrite/sodium thiosulfate or hydroxocobalamin
ethylene glycol	ethanol or fomepizole, and thiamine
Hydrofluoric acid	Calcium Gluconate
Iron (and other heavy metals)	desferrioxamine, Deferasirox or Deferiprone
Isoniazid	Pyridoxine
Magnesium	Calcium Gluconate
methanol	ethanol or fomepizole, and folinic acid
Nicotine	Bupropion and other ganglion blockers
opioids	naloxone
Organophosphates	Atropine and Pralidoxime
paracetamol (acetaminophen)	N-acetylcysteine
Thallium	Prussian blue
vitamin K anticoagulants, e.g. warfarin	vitamin K

 

Classification Of Poisons

The poisons most commonly met with may be divided into three classes – viz., animal, vegetable, and mineral; of these the two latter ar more numerous, or at all events more commonly met with than the former.

Animal Poisons

In the first class is poisoning from certain shellfish, such as mussels, lobsters, etc., the eating of which is sometimes followed by an eruption of nettle-rash over the whole body, which causes it to have a bloated swollen appearance, and produces difficulty of breathing, accompanied with giddiness, nausea, stomachache, and great thirst.

Treatment

If commenced within two or three hours after the appearance of the symptoms, an emetic of mustard, salt, and warm water, should be given. The emetic should be compounded thus: –

Mustard, I teaspoonful.

Common salt, I teaspoonful.

Warm water, a tumblerful. Mix, and take as a draught.

Should, however, a longer time have elapsed, purgatives, such as a tablespoonful of castor oil, or half an ounce of Epsom salts, should be administered and repeated until full action is obtained. Stimulants, such as salvolatile, or aromatic spirits of ammonia, and ether, may also be administered if there be much depression.

The following form would be a useful draught: – Take of Nitrous spirits of ether, 30 minims.

Spirits of salvolatile, 30 minims.

Water, to make up 1 1/2 ounces. Repeat the dose every two or three hours until the system rallies.

Vegetable Poisons

Of these the most commonly met with are the aconite or monkshood, belladonna or deadly nightshade; the hellebore, hemlock, henbane, foxglove, laburnum, yew, colchicum or meadow saffron, and mushrooms, all of which are indigenous to this country. Others, such as opium, Indian hemp, nux vomica, and gamboge, are not native here.

Among vegetable poisons should be included oxalic acid, and that most deadly of all poisons, prussic acid, which is found in undiluted “almond flavouring” used for culinary pur-Doses.

Symptoms

Vegetable poisons have many features in common, thus they are strongly acrid and narcotic, or depressing; causing drowsiness, feebleness of pulse, vomiting, purging, and griping.

Under the following enumeration, the symptoms peculiar to each will be found, together with their appropriate treatment.

In order to assist the reader in the detection of vegetable poisons, we have appended a plate giving representations of some of the poisonous plants most commonly met with in temperate climates, and which are most likely to be mistaken for harmless plants by children and others.

 

1. Green Hellebore.                                                      2. Monk’s Hood.                                       3. Yew.

 

4.Deadly Nightshade.

Alropa Belladonna.

Symptoms

These generally are sudden in their occurrence. As in criminal or accidental poisoning the quantity of the poison is usually large, the symptoms are both sudden and severe. In criminal poisoning, however, as is well known from many notorious instances that have been made public, the dose sometimes given is small and continued for a long interval so as to give the symptoms the characters of disease. Villany often succeeds in this attempt, but happily more frequently fails. It is in these cases that the true nature of the symptoms becomes difficult of detection, and calls for the closest vigilance. The circumstances attending the large and clumsy doses of the first mentioned class of cases are for the most part so obvious that a little investigation leads to discovery. Another feature attends these, that is the suddenness and severity of the attack not unfrequently induces a suspicion of poisoning where truly disease alone is the cause of death or illness. Further investigation will generally lead to a correct conclusion.

The symptoms of the most common poisons now to be related will be found of assistance in the formation of an opinion m either instance.

Circumstances Modifying Action Of Poisons

There are certain conditions of the body which modify the action of poisons. Sleep or intoxication for example which retards, or debilitated states of the body which accelerate their action. Different diseases also have very different influence over the action of poisons, some accelerating and others retarding them.

Distinctive Symptoms

Then again, the symptoms of poisoning will generally occur after a meal or medicines have been taken, manifesting themselves within an hour after the poison has been introduced into the system. Strong presumptive evidence of poisoning may also be assumed when a number of people, who have been partaking of the same food, are all seized with similar symptoms. In such a case it is very advisable to cause a strict investigation to be made into the articles of food of which the sufferers have partaken, and not only this, but all the culinary utensils, in which the food has been prepared, should also be examined.

Diseases Resembling Poisoning

Great caution should, however, be observed before arriving at the conclusion that poisons have been administered, and it should be borne in mind that there are many diseases the symptoms of which offer a close resemblance to those of poisoning; among these are those particularly affecting the nervous system, such as apoplexy, lockjaw, epilepsy, etc. The symptoms of cholera are often very sudden, and have been mistaken for those of poisoning, as have also colic or perforations, resulting from ulceration of either the stomach or intestines. The diseases of the heart also frequently cause the sudden appearance of alarming symptoms, which, if the existence of disease were not suspected, might easily be mistaken for those of poisoning.

Gaseous Poisons These poisons are present in the gaseous state and if inhaled, destroy the capability of the blood as a carrier of oxygen and irritate or destroy the tissues of the air passages and lungs. When in con- tact with the skin and mucous membranes, gaseous poisons produce lacrimation, vesication, inflammation, and congestion. Examples are car- bon monoxide, carbon dioxide, hydrogen sulfide, sulfur dioxide, ammonia gas, chlorine gas, and chemical warfare agents Inorganic Poisons Inorganic poisons fall into two classes: (a) Corrosives, which are substances that rapidly destroy or decompose the body tissues at point of contact. Some examples are hydrochloric, nitric, and sulfuric acids; phenol; sodium hydrox- ide; and iodine. (b) Metals and their salts, which are corrosive and irritate locally, but whose chief action occurs after absorption when they damage internal organs, especially those of excretion. Some examples are arsenic, antimony, copper, iron, lead, mercury, radioactive substances, and tin. Alkaloidal Poisons These poisons are nitrogenous plant principles that produce their chief effect on some part of the central nervous system. Some examples are atropine, cocaine, morphine, and strychnine. Nonalkaloidal Poisons These poisons include various chemical com- pounds, some obtained from plants, having hyp- notic, neurotic, and systemic effects. Some examples are barbiturates, salicylates, digoxin, and turpentine.

Drug overdose

 

Drug overdose
Classification and external resources
Activated carbon is a commonly used agent for decontamination of the gastrointestinal tract in overdoses.
ICD–10	T36–T50
ICD–9	960–979
DiseasesDB	3971
MeSH	D015537

The term drug overdose (or simply overdose or OD) describes the ingestion or application of a drug or other substance in quantities greater than are recommended^[1] or generally practiced.^[2] An overdose may result in a toxic state or death.^[2]

Classification

The word “overdose” implies that there is a common safe dosage and usage for the drug; therefore, the term is commonly only applied to drugs, not poisons, though even certain poisons are harmless at a low enough dosage.

Drug overdoses are sometimes caused intentionally to commit suicide or as self-harm, but many drug overdoses are accidental, the result of intentional or unintentional misuse of medication. Unintentional misuse leading to overdose can include using prescribed or unprescribed drugs in excessive quantities in an attempt to produce euphoria.

Usage of illicit drugs of unexpected purity, in large quantities, or after a period of drug abstinence can also induce overdose. Cocaine users who inject intravenously can easily overdose accidentally, as the margin between a pleasurable drug sensation and an overdose is small.^[3]

Unintentional misuse can include errors in dosage caused by failure to read or understand product labels. Accidental overdoses may also be the result of over-prescription, failure to recognize a drug’s active ingredient, or unwitting ingestion by children^[4] A common unintentional overdose in young children involves multi-vitamins containing iron. Iron is a component of the hemoglobin molecule in blood, used to transport oxygen to living cells. When taken in small amounts, iron allows the body to replenish hemoglobin, but in large amounts it causes severe pH imbalances in the body. If this overdose is not treated with chelation therapy, it can lead to death or permanent coma.

The term ‘overdose’ is often misused as a descriptor for adverse drug reactions or negative drug interactions due to mixing multiple drugs simultaneously.

 Signs and symptoms

Toxidrome[5]
Symptoms	BP	HR	RR	Temp	Pupils	bowel sounds	diaphoresis
anticholinergic	~	up	~	up	up	down	down
cholinergic	~	~	unchanged	unchanged	down	up	up
opioid	down	down	down	down	down	down	down
sympathomimetic	up	up	up	up	up	up	up
sedative-hypnotic	down	down	down	down	~	down	down

Signs and symptoms of an overdose varies depending on the drug or toxin exposure. The symptoms can often be divided into differing toxidromes. This can help one determine what class of drug or toxin is causing the difficulties.

Symptoms of opioid overdoses include slow breathing, heart rate and pulse.^[6] Opioid overdoses can also cause pinpoint pupils, and blue lips and nails due to low levels of oxygen in the blood. A person experiencing an opioid overdose might also have muscle spasms, seizures and decreased consciousness. A person experiencing an opiate overdose usually will not wake up even if their name is called or if they are shaken vigorously.

Drug poisoning

Introduction

Poisoning can result from an overdose of either prescribed drugs or drugs that are bought over the counter. It can also be caused by drug abuse or drug interaction.

The effects vary depending on the type of drug and how it is taken (see table below). When you call the emergency services, give as much information as possible. While waiting for help to arrive, look for containers that might help you to identify the drug.

Recognition features

Category	Drug	Effects of poisioning
Painkillers	Asprin (swallowed)	·        upper abdominal pain ·        nausea & vomiting ·        ringing in the ears ·        ‘sighing’ when breathing ·        confusion and delirium ·        dizziness.
	Paracetamol (swallowed)	·        little effect at first, but abdominal pain, nausea and vomiting may develop ·        irreversible liver damage may occur within 3 days (malnourishment and alcohol increase the risk).
Nervous system depressants and tranquillisers	Barbiturates and benzodiazepines(swallowed)	·        lethargy and sleepiness, leading to unconsciousness ·        shallow breathing ·        weak, irregular, or abnormally slow or fast pulse.
Stimulants and hallucinogens	Amphetamines (including Ectasy) and LSD(swallowed); cocaine(inhaled)	·        excitable, hyperactive behaviour, wildness and frenzy ·        sweating ·        tremor of the hands ·        hallucinations.
Narcotics	Morphine, heroin (commonly injected)	·        small pupils ·        sluggishness and confusion, possibly leading to unconsciousness ·        slow, shallow breathing which may stop altogether ·        needle marks, which may be infected.
Solvents	Glue, lighter fuel (inhaled)	·        nausea and vomiting ·        headaches ·        hallucinations ·        possibly, unconsciousness ·        rarely, cardiac arrest.

Treatment

Your aims:

·      To maintain breathing and circulation

·      To arrange removal to hospital.

If the casualty is conscious:

·      Help them into a comfortable position

·      Ask them what they have taken

·      Reassure them while you talk to them

·      Dial 999 for an ambulance

·      Monitor and record vital signs – level of response, pulse and breathing – until medical help arrives

·      Look for evidence that might help to identify the drug, such as empty containers. Give these samples and containers to the paramedic or ambulance crew.

If the casualty becomes unconscious:

·      open the airway and check breathing

·      be prepared to give chest compressions and rescue breaths if necessary

·      place them into the recovery position if the casualty is unconscious but breathing normally

·      dial 999 for an ambulance.

 

Antimycobacterial Drugs: Introduction

Most antibiotics are more effective against rapidly growing organisms than against slowly growing ones. Because mycobacteria are very slowly growing organisms, they are relatively resistant to antibiotics. Mycobacterial cells can also be dormant and thus completely resistant to many drugs— or killed only very slowly by the few drugs that are active. The lipid-rich mycobacterial cell wall is impermeable to many agents. A substantial proportion of mycobacterial organisms are intracellular, residing within macrophages, and inaccessible to drugs that penetrate poorly. Finally, mycobacteria are notorious for their ability to develop resistance to any single drug. Combinations of drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years depending on which drugs are used. The various drugs used to treat tuberculosis, which is caused by Mycobacterium tuberculosis and the closely related M bovis, atypical mycobacterial infections, and leprosy, which is caused by M leprae, are described in thischapter.

Drugs Used in Tuberculosis

Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis (Table 47–1). Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47–2).

In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they do provide additional coverage should the isolate prove to be resistant to isoniazid, rifampin, or both. Unfortunately, such resistance occurs in up to 10% of cases in the United States. Most patients with tuberculosis can be treated entirely as outpatients, with hospitalization being required only for those who are seriously ill or who require diagnostic evaluation.

Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.

It is a small (MW 137), simple molecule freely soluble in water. The structural similarity to pyridoxine is shown below.

In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.2 g/mL or less and is bactericidal for actively growing tubercle bacilli. Isoniazid is less effective against atypical mycobacterial species. Isoniazid is able to penetrate into phagocytic cells and thus is active against both extracellular and intracellular organisms.

Isoniazid (INH)

Mechanism of Action & Basis of Resistance

Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.

The activated form of isoniazid exerts its lethal effect by forming a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis. Resistance to isoniazid has been associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of katG; promoter mutations resulting in overexpression of ahpC, a putative virulence gene involved in protection of the cell from oxidative stress; and mutations in kasA.

Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and are usually not cross-resistant to ethionamide. Resistant mutants occur in susceptible mycobacterial populations with a frequency of about 1 bacillus in 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected out if isoniazid is given as the sole drug. However, addition of a second independently acting drug, to which resistance also emerges at a frequency of 1 in 106 to 1 in 108, is effective. The odds that a bacillus is resistant to both drugs are approximately 1 in 106 x 106, or 1 in 1012, which is several orders of magnitude more than the number of infecting organisms. Single- drug therapy with isoniazid and failure to use isoniazid plus at least one other drug to which the infecting strain is susceptible (which is tantamount to single-drug therapy) has led to the 10–20% prevalence of isoniazid resistance in clinical isolates from the Caribbean and Southeast Asia. Currently, about 8–10% of primary clinical isolates in the United States are isoniazid-resistant.

Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract. The administration of a 300-mg oral dose (5 mg/kg in children) results in peak plasma concentrations of 3–5 g/mL within 1–2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations.

Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined. The average concentration of isoniazid in the plasma of rapid acetylators is about one third to one half of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this has not been proved. More rapid clearance of isoniazid by rapid acetylators is of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose.

Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. The dose need not be adjusted in renal failure, but one third to one half of the normal dose is recommended in severe hepatic insufficiency.

Clinical Uses

The usual dosage of isoniazid is 5 mg/kg/d, with a typical adult dose being 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin 600 mg). Pyridoxine, 25–50 mg/d is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage.

Isoniazid as a single agent is also indicated for treatment of latent tuberculosis, which is usually determined by a positive tuberculin skin test.

Isoniazid is routinely recommended for individuals who are at greatest risk for developing active disease after being infected such as very young children, persons who test positive within 2 years after a documented negative skin test (ie, recent converters), and immunocompromised individuals, especially HIV-infected and AIDS patients.

Isoniazid is also indicated for prevention of tuberculosis in close contacts of active cases of pulmonary tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.

Adverse Reactions

The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.

Allergic Reactions

Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.

Direct Toxicity

Isoniazid-induced hepatitis is the most frequent major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal) seen in 10–20% of patients, who usually are asymptomatic. Such increases do not require cessation of the drug. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those aged 21–35, 1.2% of those aged 36–50, and 2.3% for those aged 50 and above. The risk of hepatitis is greater in alcoholics and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug. Peripheral neuropathy is observed in 10–20% of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose. It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine.

Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort.

Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity.

Rifampin

Rifampin is a large (MW 823), complex semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gramnegative cocci, some enteric bacteria, mycobacteria, and chlamydia.

Susceptible organisms are inhibited by less than 1 g/mL, but resistant mutants are present in all microbial populations at a frequency of approximately 1:106. Administration of rifampin as a single drug selects for these highly resistant organisms. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin.

Antimycobacterial Activity, Resistance, & Pharmacokinetics

Rifampin binds strongly to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.

Resistance results from one of several possible point mutations in rpoB, the gene for the beta subunit of RNA polymerase. These mutations prevent binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal insufficiency is not necessary.

Usual doses result in serum levels of 5–7 g/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, but adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Clinical Uses

Mycobacterial Infections

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, is administered together with isoniazid, ethambutol, or another antituberculous drug in order to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in some atypical mycobacterial infections and in leprosy when used together with a sulfone. Rifampin is an alternative to isoniazid prophylaxis for patients who are unable to take isoniazid or who have had close contact with a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

Other Indications

Rifampin is used in a variety of other clinical situations. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis. Rifampin has been recommended also for use in combination with ceftriaxone or vancomycin in treatment of meningitis caused by highly penicillin-resistant strains of pneumococci.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis.

Rifampin commonly causes light chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, thrombocytopenia, and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, some anticonvulsants, protease inhibitors, and contraceptives. Likewise, administration of rifampin with ketoconazole, cyclosporine, or chloramphenicol results in significantly lower serum levels of these drugs.

Ketoconazole in turn may reduce rifampin serum concentrations by interfering with absorption.

Ethambutol

Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro- isomer of the structure

shown below, dispensed as the dihydrochloride salt.

Susceptible strains of M tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1–5 g/mL. Ethambutol is an inhibitor of mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene.

Ethambutol is well absorbed from the gut. Following ingestion of 25 mg/kg, a blood level peak of 2–5 g/mL is reached in 2–4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. Ethambutol crosses the blood-brain barrier only if the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation. As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs.

Clinical Use

Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose in combination with isoniazid or rifampin. The higher dose is recommended for treatment of tuberculous meningitis. The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used.

Adverse Reactions

Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red-green color blindness. This dose-related side effect is more likely to occur at a dosage of 25 mg/kg/d continued for several months. With dosages of 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used.

 Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

Pyrazinamide

Pyrazinamide (PZA) is a relative of nicotinamide, stable, slightly soluble in water, and quite inexpensive. At neutral pH, it is inactive in vitro, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 g/mL. Drug is taken up by macrophages and exerts its activity against intracellular organisms residing within this acidic environment. Pyrazinamide is converted to pyrazinoic acid, the active form of the drug, by mycobacterial pyrazinamidase, which is encoded by pncA. The drug target and mechanism of action are unknown. Resistance is due to mutations in pncA that impair conversion of pyrazinamide to its active form. Impaired uptake of pyrazinamide may also contribute to resistance.

C

Clinical Use

Serum concentrations of 30–50 g/mL at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8–11 hours. A 50–70 mg/kg dose is used for twice-weekly or thrice-weekly treatment regimens.

Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6- month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse.

Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs.

Adverse Reactions

Major adverse effects of pyrazinamide include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis.

Streptomycin

Most tubercle bacilli are inhibited by streptomycin, 1–10 g/mL, in vitro. Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 g/mL.

Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or rrs, encoding 16S ribosomal rRNA, that alters the ribosomal binding site.

Streptomycin penetrates into cells poorly, and consequently it is active mainly against extracellular tubercle bacilli.

Additional drugs are needed to eliminate intracellular organisms, which constitute a significant proportion of the total mycobacterial burden. Streptomycin crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges.

Clinical Use in Tuberculosis

Streptomycin sulfate remains an important drug in the treatment of tuberculosis. It is employed when an injectable drug is needed or desirable, principally in individuals with severe, possibly lifethreatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d, not to exceed 1–1.5 g, for children) for several weeks, followed by 1–1.5 g two or three times weekly for several months.

Serum concentrations of approximately 40 g/mL are achieved 30–60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given simultaneously to prevent emergence of resistance.

Adverse Reactions

Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common side effects and may be permanent.

Toxicity is dose-related, and the risk is increased in the elderly. Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.

 

Alternative Second-Line Drugs for Tuberculosis

The alternative drugs listed below are usually considered only (1) in the case of resistance to the drugs of first choice (which occurs with increasing frequency); (2) in case of failure of clinical response to conventional therapy; and (3) when expert guidance is available to deal with the toxic effects.

For many of the second-line drugs listed below, the dosage, emergence of resistance, and long-term toxicity have not been fully established.

Ethionamide

Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids.

It is poorly water soluble and available only in oral form. It is metabolized by the liver.

Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 g/mL, or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 g/mL. Serum concentrations in plasma and tissues of approximately 20 g/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. A 1 g/d dosage, although effective in the treatment of tuberculosis, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur.

Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.

Ethionamide is administered at an initial dosage of 250 mg once daily, which is increased in 250 mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d) if possible. The 1 g/d dosage, although theoretically desirable, is seldom tolerated, and one often must settle for a total daily dose of 500–750 mg.

Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be lowlevel cross-resistance between isoniazid and ethionamide.

Capreomycin

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 g/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.

Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis.

Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation.

Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may occur. Dosing of capreomycin is the same as streptomycin.

Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule.

Antibiotics & Other Inhibitors of Cell Wall Synthesis.

Concentrations of 15–20 g/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided doses.

Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions.

Pyridoxine 150 mg/d should be given with cycloserine as this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses.

Side effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 g/mL.

Aminosalicylic Acid (PAS)

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis..

Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 g/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 g/mL or more after a 4

g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid.

Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.

Aminosalicylic acid, formerly a first-line agent for treatment of tuberculosis, is used infrequently now because other oral drugs are better-tolerated. Gastrointestinal symptoms often accompany full doses of aminosalicylic acid.

Anorexia, nausea, diarrhea, and epigastric pain and burning may be diminished by giving aminosalicylic acid with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia, often occur after 3–8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently.

Kanamycin & Amikacin

Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) have rendered it obsolete.

 The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis.

Prevalence of amikacin-resistant strains is low (less than 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 g/mL or less.

Amikacin is also active against atypical mycobacteria.

There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30–50 g/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases.

The recommended dosage is 15 mg/kg/d intramuscularly or intravenously daily for 5 days a week for the first 2 months of therapy and then 1–1.5 g two or three times weekly to complete a 6-month course.

Ciprofloxacin & Levofloxacin

In addition to their activity against many gram-positive and gram-negative bacteria, ciprofloxacin and levofloxacin inhibit strains of M tuberculosis at concentrations less than 2 g/mL. They are also active against atypical mycobacteria.

Ofloxacin was used in the past, but levofloxacin is preferred because it is the L-isomer of ofloxacin (a racemic mixture of D- and L-stereoisomers), the active antibacterial component of ofloxacin, and it can be administered once daily.

Levofloxacin tends to be slightly more active in vitro than ciprofloxacin against M tuberculosis; ciprofloxacin is slightly more active against atypical mycobacteria. Serum concentrations of 2–4 g/mL and 4–8 g/mL are achieved with standard oral doses of ciprofloxacin and levofloxacin, respectively.

Fluoroquinolones are an important recent addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents.

The standard dosage of ciprofloxacin is 750 mg orally twice a day. That of levofloxacin is 500–750 mg as a single daily dose.

Rifabutin (Ansamycin)

This antibiotic is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs which also are cytochrome P450 substrates. The usual dose of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dose should be reduced to 150 mg/d. If efavirenz (also a P450 inducer) is used, the recommended dose of rifabutin is 450 mg/d. (See Havlir 1999, and Centers 1998, for details.)

Rifabutin is effective in prevention and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4 counts below 50/ L. It is also effective for preventive therapy of tuberculosis, either alone in a 6-month regimen or with pyrazinamide in a 2-month regimen.

Rifapentine

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and M avium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine is indicated for treatment of tuberculosis caused by rifampin-susceptible strains. The dose is 600 mg once or twice weekly. Whether rifapentine is as effective as rifampin has not been established, and rifampin therefore remains the rifamycin of choice for treatment of tuberculosis.

Drugs Active Against Atypical Mycobacteria

About 10% of mycobacterial infections seen in clinical practice in the USA are caused not by M tuberculosis or M leprae but by nontuberculous or so-called “atypical” mycobacteria. These organisms have distinctive laboratory characteristics, occur in the environment, and are not communicable from person to person. Disease caused by these organisms is often less severe than tuberculosis. As a general rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents such as erythromycin, sulfonamides, or tetracycline, which are not effective against M tuberculosis, may be effective against atypical strains. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol but relatively resistant to isoniazid and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection. A few representative pathogens, with the clinical presentation and the drugs to which they are often susceptible, are given in Table 47–3.

M avium complex (MAC), which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/ L).

Mycobacterium avium complex is much less susceptible than M tuberculosis to most antituberculous drugs. Combinations of agents are required to suppress the disease. Disseminated MAC is incurable and therapy is life-long if CD4 counts are below 200/ L. The need for multidrug therapy frequently leads to side effects that can be difficult to manage. Azithromycin, 500 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d, is an effective and welltolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, such as ciprofloxacin 750 mg twice daily or rifabutin, 300 mg once daily. Other agents that may be useful are listed in Table 47–3. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of M avium complex bacteremia in AIDS patients with CD4 < 200/ L but may not offer a survival advantage. Clarithromycin also effectively prevents MAC bacteremia in AIDS patients, but if breakthrough bacteremia occurs, the isolate often is resistant to both clarithromycin and azithromycin, precluding the use of the most effective drugs for treatment.

Rifampin

This drug (see Rifapentine) in a dosage of 600 mg daily can be strikingly effective in lepromatous leprosy. Because of the probable risk of emergence of rifampin-resistant M leprae, the drug is given in combination with dapsone or another antileprosy drug. A single monthly dose of 600 mg may be beneficial in combination therapy.

Clofazimine

Clofazimine is a phenazine dye that can be used as an alternative to dapsone. Its mechanism of action is unknown but may involve DNA binding.

Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released, so that the serum half-life may be 2 months.

Clofazimine is given for sulfone-resistant leprosy or when patients are intolerant to sulfone. A common dosage is 100 mg/d orally. The most prominent untoward effect is skin discoloration

ranging from red-brown to nearly black. Gastrointestinal intolerance occurs occasionally.

Antimycobacterial Drugs >

Preparations Available

Drugs Used in Tuberculosis

Aminosalicylate sodium (Paser)

Oral: 4 g delayed release granules

Capreomycin(Capastat Sulfate)

Parenteral: 1 g powder to reconstitute for injection

Cycloserine(Seromycin Pulvules)

Oral: 250 mg capsules

Ethambutol(Myambutol)

Oral: 100, 400 mg tablets

Ethionamide(Trecator-SC)

Oral: 250 mg tablets

Isoniazid (generic)

Oral: 50, 100, 300 mg tablets; syrup, 50 mg/5 mL

Parenteral: 100 mg/mL for injection

Pyrazinamide (generic)

Oral: 500 mg tablets

Rifabutin(Mycobutin)

Oral: 150 mg capsules

Rifampin(generic, Rifadin, Rimactane)

Oral: 150, 300 mg capsules

Parenteral: 600 mg powder for IV injection

Rifapentine (Priftin)

Oral: 150 mg tablets

Streptomycin (generic)

Parenteral: 1 g lyophilized for IM injection

Drugs Used in Leprosy

Clofazimine(Lamprene)

Oral: 50 mg capsules

Dapsone(generic)

Oral: 25, 100 mg tablets

 

 

 

1.     http://www.medicinethroughtime.co.uk/Medicine_worksheets/videos.htm

2.     http://www.youtube.com/watch?v=Btqlf6Rs_Ek&feature=related

3.     http://www.youtube.com/watch?v=Lt0BjNwF6IU&feature=related

4.     http://www.youtube.com/watch?v=07Tr__R_koE&feature=related

5.     http://www.youtube.com/watch?v=8zYIEiXvSZY&feature=related

6.     http://www.youtube.com/watch?v=2uehdqZzKEM&feature=related

7.     http://www.youtube.com/watch?v=0qGNuAUy–Dc&feature=related

8.     http://www.youtube.com/watch?v=xiuWdJYyIKs

9.     http://www.apchute.com/moa.htm