Toxicology A Case-Oriented Approach - part 9 pps

taken on a chronic basis, gastric mucosal erosions occur. Many coffee drinkers experience heartburn and this symptom arises from a reduction in the tone of the lower esophageal sphincter that, in turn, leads to acid reflux. In common with the other methylxanthines, caffeine has a potent effect on the cardiovascular system. With large ingestions tachycardia, dysrhythmias, and extra- systoles are noted. The observed increase in heart rate is believed to be associated with small increases in blood pressure, force of contraction, and cardiac output. Caffeine toxicity is also manifested by many symptoms. The term “caffeinism” has been applied to a syndrome of long-term excessive caffeine use. Patients with this condition exhibit headache, delirium, palpitations, and tachycardia. Often, there are gastrointestinal complaints, muscle twitches, psychomotor agitation, and possible arrhythmias. The lethal dose of caffeine is highly variable but 3 g was reported as a cause of death in at least one case. The commonly published lethal dose is 150 to 200 mg/kg (about 15 g for a 150-lb. man). Blood levels greater than 25 µ g/mL also are regarded as in the toxic range, but a good correlation between blood level and toxicity does not exist. Although the major exposure of most people to caffeine is in the form of beverage coffee, caffeine also has at least two medical applications. It is available over-the- counter as an aid for the prevention of sleep and has been employed for this purpose by generations of students. Vivarin™ and No-Doz™ are two such products. Some neonatalogists employ it in the treatment of apnea of prematurity. It is superior to theophylline in some ways, i.e., a much greater half-life that allows for less frequent dosing. Caffeine also has a wider therapeutic window; for example, there is a larger gap between doses that provide therapeutic benefit vs. those associated with toxicity. Blood levels are of some value in this application and the following guidelines are recommended: Caffeine is also sold in many over-the-counter diet pills. What, if any, value it has in this context has been the object of substantial controversy. T HEOPHYLLINE Theophylline is a methylxanthine that finds its most common medical application in asthma therapy. It was once thought that it worked by inhibiting cyclic AMP phosphodiesterase activity. This theory was disproven when it was demonstrated that the concentrations of drug required to achieve this purpose were not attainable in vivo . Further, more potent phosphodiesterase inhibitors have been shown to be ineffective in asthma treatment. In overdoses, however, part of theophylline’s actions probably are due to phosphodiesterase inhibition. Currently, the mechanism of action of theophylline is believed to be antagonism of the activity of adenosine. Because Therapeutic 8–14 µ g/mL Toxic >30 µ g/mL Fatal >80 µ g/mL 0371 ch22 frame Page 433 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC adenosine modulates histamine release and, therefore, causes constriction of respi- ratory smooth muscle (bronchoconstriction), theophylline, by antagonizing adenos- ine, causes a bronchial muscle relaxation. Theophylline also causes a release of catecholamines. Epinephrine and norepinephrine are, therefore, quite elevated in overdoses with theophylline. Normal metabolism of theophylline consists of oxidation to 1,3 dimethyluric acid and/or demethylation to 3-methylxanthine or 1-methyluric acid. A small percent is eliminated as theophylline. In very young babies theophylline is partly metabolized to caffeine, a reaction that does not occur in older children or adults. Because of this, it is advisable to perform analyses for both theophylline and caffeine when conducting drug monitoring of the very young who are being treated with theophyl- line. The reactions of theophylline metabolism involve the cytochrome P 450 mixed- function oxidase system. Therefore, many factors alter theophylline clearance by changing the available quantities of these enzymes. Cigarette smoking or barbiturates may shorten theophylline half-life by 50%, whereas some medicines such as eryth- romycin, ciprofloxacin, and propranolol inhibit theophylline metabolism. The toxicity of methylxanthines is mainly in association with an excess of their normal therapeutic actions. Their stimulatory actions can reach the extreme, causing cardiac and/or respiratory arrest. Theophylline also has a notorious GI irritation believed to reside in its direct stimulation of the chemoreceptor trigger zone. Thus, nausea and vomiting are common findings in any level of theophylline overdose. Restlessness, excitation, and insomnia are symptoms of mild overdose with the methylxanthines. Perceptual distortions, such as seeing lights or hearing noises, may be experienced. Headache and dizziness are often reported in overdose. At the cardiovascular level, tachycardia may progress to ventricular fibrillation and car- diopulmonary arrest. These are due to the aforementioned excess secretion of cate- cholamines by theophylline. The catecholamines stimulate the myocardium and this effect is aggravated by hypokalemia, hypercalcemia, hypophosphatemia, or meta- bolic acidosis. Convulsions and coma may precede death. One of the unusual characteristics of theophylline overdose is that major symptoms may be the first indication of the overdose. Often, nausea and vomiting are the first signs but, on occasion, generalized seizures occur without any other sign of overdose. Theophylline overdose is clearly a life-threatening emergency and therapy must be initiated as promptly and energetically as possible. Ipecac should not be used, but lavage must be attempted for ingestions that happened during the previous hour. Activated charcoal with cathartic is usually desirable. Hypotension can be treated with intravenous fluids. Seizures can be treated with diazepam or phenobarbital. Lidocaine may be required for arrhythmias. In serious overdoses, hemodialysis is helpful in enhancing elimination, but charcoal hemoperfusion is three times faster in reducing the body burden of theophylline. The pharmacokinetics of hemoperfu- sion are described in a case at the end of this chapter. Blood levels are helpful in the evaluation and treatment of theophylline overdose. They should be run every 2 hours until a decrease is observed and then every 4 hours until a level of 20 µ g/mL is achieved. Interpretation of levels is based on the fact that patients with acute exposures usually tolerate up to 90 µ g/mL whereas those with chronic overdose experience toxicity at lower levels (greater than 40 µ g/mL). The fact that many 0371 ch22 frame Page 434 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC patients appear to be quite stable mandates the need for blood testing. It indicates that the patient may be in serious jeopardy despite appearances to the contrary. A 5-year study of 300 patients showed that blood concentration above 80 µ g/mL is predictive of major toxicity and suggests that charcoal hemoperfusion should be started. Another study refined this value and concluded that if theophylline goes above 60 µ g/mL or clinical status is deteriorating, then hemoperfusion should be started while the patient is stable. Supportive therapy must usually be extensive. A rough correlation exists between blood level and toxicity for the methylxanthines. For caffeine, blood levels below 15 µ g/mL usually are not associated with toxicity. Fatal levels have been reported in the range of 1600 µ g/mL. For theophylline, physicians are advised to medicate the patient so that blood concentrations equal 10 to 20 µ g/mL. Some patients are toxic at these concentrations, so recently this therapeutic range has been adjusted and 5 to 15 µ g/mL is now regarded as the appropriate range for the control of asthma. Theophylline is employed for asthma therapy because it dilates the bronchi. This effect is presumed to be due to its ability to relax smooth muscle. C AMPHOR Camphor is a compound with stimulant properties on the cerebral cortex. It is found in many pharmaceutical products (Table 22.4) because of the many additional prop- erties that it possesses. Among its uses are as a preservative, antipruritic, topical rubifacient, cold remedy, and antiseptic. Camphor is not highly toxic and has a minimum lethal dose of approximately 50 mg/kg. However, because it is widespread in the consumer market, present in large quantities, and can be absorbed through intact skin, a significant number of poisonings are found. Nausea and vomiting are the usual first findings in camphor overdose. From there the customary findings in stimulant overdose are noted. These include confusion, restlessness, delirium, and possible hallucinations. Muscular excitability proceeds to TABLE 22.4 Some Compounds Containing Camphor Product % Camphor Absorbine Pain Lotion 10 Ben Gay Children’s Rub 5 Campho-Phenique Liquid 10.85 Heet 3 Mustarole 4 Vick’s VapoRub 4.75 Vick’s Vaposteam 6.2 Sloan’s Liniment 5 Note: The U.S. FDA ruled in 1983 that medicinal products may not contain more than 11% of camphor. 0371 ch22 frame Page 435 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC tremors and then epileptic-type seizures. Seizure onset can be sudden, without any previous signs that seizures are imminent. They can be followed by depression after the seizure and then coma. If there is a fatal outcome, it is usually due to respiratory depression. Patients who have been poisoned by camphor can be diagnosed partly on the basis of the customary signs of stimulant exposure. History may be helpful if parents or others report an unusual exposure to a pharmaceutical product. Because such exposures normally are large in amount, the odor of camphor is usually detect- able in urine or on the breath. This odor has been described as organic and pungent in nature. If blood testing is conducted, a level of 14.5 mg/L is ominous and suggests the danger of imminent seizures. Camphor exposures should be treated with lavage and activated charcoal. Sup- portive care should include benzodiazepines or barbiturates for seizures. If they are refractory, then pentobarbital may be effective. Hemodialysis has been shown to be ineffective in decreasing blood levels; however, hemoperfusion with resins has been successful in enhancing the rate of camphor elimination. Questions 1. What are the advantages and disadvantages of treating obesity with sym- pathomimetic amines? 2. Discuss the use of methylphenidate as treatment for attention deficit disorder. How can a drug classified as a stimulant cause a depression of hyperactivity in children? 3. Contrast the use of caffeine and theophylline as treatments for pulmonary problems in infants. What toxicity is associated with each and how can laboratory data be helpful in avoiding toxicity? 4. What are the toxic features of camphor and where is this compound found medically? Case Study 1: The Hazards of Dieting An 18-year-old woman ingested eight over-the-counter diet pills. Two hours later she felt ill and went to an emergency department for evaluation of a headache and generalized malaise. Her BP was 140/90 and pulse 52. No neu- rological abnormalities were noted. Because of her history of the diet pill ingestion, gastric lavage was attempted. She was discharged only to return soon after with generalized convulsions. She was lethargic but awake and aware of herself and her surroundings. She was admitted to the hospital and 1 day later she abruptly lost all brain stem reflexes. A spinal tap revealed that her CSF was grossly bloody. Evaluation by electroencephalogram resulted in an isoelectric profile. Carotid angiography revealed that her intracranial vessels were not filling with blood in a normal manner. She was placed on respiratory support but, after a long interval of flat brain waves, that support was withdrawn and she was pronounced dead. 0371 ch22 frame Page 436 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC What is a possible identification for the diet pills? a) Phenylpropanolamine b) Diethylpropionate c) Thyroxine d) Fenfluramine All of the suggested answers are marketed alone or in combination with other agents as diet medicines. Diethylpropionate and fenfluramine, however, were never sold in the United States as over-the-counter drugs. Because they have a modest abuse potential, both required a prescription. Fenfluramine was removed from the market in 1997 when a number of patients were found to have cardiac injury that appeared to be related to use of fenfluramine. Thyroxine is not a diet drug although it has been used in that manner by some persons. This is a great mistake because of thyroxine’s high potency and the fact that any weight loss it provokes is mainly lean body mass. Thyroxine also requires a prescription. Phenylpropanolamine is available as an over-the-counter appetite suppres- sant. It is fairly effective for this purpose but has many side effects including rapid tolerance, insomnia, and occasional irregularities of cardiac rhythm. On rare occasions it causes major toxicity as related in the present case. Questions Q1. What adverse effects have been reported for phenylpropanolamine? a) CNS stimulation b) Hypertension c) Abuse potential d) All of the above Q2. How does phenylpropanolamine resemble amphetamine? a) Pharmacologically similar but structurally in a different class. b) Stereoisomers of each other. c) Optical isomers of each other. d) Phenylpropanolamine is a hydroxylated form of amphetamine. Q3. Which of the following items of evidence helps to rule in a drug as the cause of this patient’s symptoms? a) Absence of signs of chronic hypertension on autopsy. b) Brain evaluation did not show a bleeding source such as an aneurysm or an atrioventricular malformation. c) Relation of drug use to appearance of symptoms in time. d) All of the above. Answers and Discussion Q1. (Answer = d) Phenylpropanolamine is classified as a sympathomimetic amine. This is a large class of compounds that includes drugs with very high abuse potential such as amphetamine and methamphetamine as well 0371 ch22 frame Page 437 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC as numerous analogs of these compounds. They have the classical phar- macological properties of stimulants. All of the features listed here are common to this class of drugs. Q2. (Answer = d) Phenylpropanolamine is very similar to amphetamine and differs from it merely by the presence of a hydroxyl group on the carbon adjacent to the benzene ring. However, it does not have the same molecular formula as amphetamine and is not an isomer of it. (See the structures of sympathomimetic amines in this text.) Q3. (Answer = d) It is rare for this particular response to occur in sympath- omimetic amine usage. Cerebrovascular accidents are usually associated with hypertension, cerebral malformations, or chronic degenerative dis- ease in the central nervous system. Therefore, among the probable causes of this patient’s stroke, phenylpropanolamine overdose is far down the list. Nevertheless, her death was eventually attributed to phenylpropano- lamine exposure because no other proximate cause could be determined and her drug use was close in time to the occurrence of this catastrophic event. In addition, there are a number of other published cases of stroke arising from moderate consumption of sympathomimetic amines. Reference McDowell, J. and LeBlanc, H., Phenylpropanolamine and cerebral hemorrhage, West. J. Med., 142, 688–691, 1985. Case Study 2: The Excitable Baby A 4-month-old baby girl who weighed 10 lbs. was brought to a hospital by her distraught parents who found the child with an empty bottle of an over-the- counter medication. The bottle had contained about 30 Tri-Aqua pills. On evaluation, the child was found to be irritable with elevated breathing and heart rate. Physical exam revealed hyperresponsiveness to any stimulation with increased muscle tone and hyperactive deep tendon reflexes. Therapy was started with the administration of Ipecac. Upon receipt of this emetic the child vomited coffee ground emesis. Laboratory studies were immediately initiated and they revealed the following: pCO 2 18 mm pH 7.45 K 2.6 HCO 3 – 13 Glucose 323 Theophylline 31 Chest X-ray Normal 0371 ch22 frame Page 438 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC The child was provided IV fluids, NG suction, antacids, and benzodiazepines for her hyperstimulation status. Dialysis for the elevated theophylline was con- sidered but was eventually deemed to be unnecessary because it was only modestly above the therapeutic range. All of the patient’s aberrant laboratory findings normalized over the following 6 days of hospitalization, although the hyperexcitability and tachycardia persisted for over 2 days past the time of the ingestion. Which of the following drugs was probably in the Tri-Aqua pills? a) Caffeine b) Aspirin c) Morphine d) Theophylline The bottle of Tri-Aqua contained caffeine pills each of which contained 98 mg of caffeine. The symptoms of caffeine overdose are very consistent with the hyperactive appearance of this patient. Morphine is not possible because it is not an over-the-counter medication nor does it provoke signs of hyperstimula- tion. Aspirin does cause some of this child’s findings but the overall picture is, in many respects, different from aspirin. Theophylline seems to be a likely suspect because it is a stimulant and the patient had a high theophylline level. The theophylline level is, however, not impressive and serum concentrations greater than 40 mg/L or higher would be expected for this degree of hyperstim- ulation. The observed theophylline arose as a metabolite of caffeine. During her hospitalization both caffeine and theophylline drug levels were frequently measured in this patient. Because her physicians were mainly con- cerned about possible theophylline toxicity, they ordered that theophylline be tested serially and, if possible, that it be confirmed by a second test method. The laboratory, accordingly, ran both enzyme immunoassay and high-perfor- mance liquid chromatography methods. The following data were recorded: In view of the marked discrepancy between these two methods a third, different HPLC method was attempted and recovery experiments were run in an effort to unravel this mystery. The third method gave results of 6.7 and 9.1 mg/L for specimens 2 and 3, respectively. It was eventually determined that the first two methods were erroneous and the third method, which gave the lowest answers, was correct. Specimen Enzyme Immunoassay HPLC Number (mg/L) (mg/L) 1 9.2 12.4 2 13.6 31 3 13.4 32 4 10.7 24 0371 ch22 frame Page 439 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC Questions Q1. An erroneously high HPLC result would most likely result from a) A problem with the instrument detector b) An interference from a metabolite of the analyte c) An improperly labeled standard d) Another medicinal taken at the same time Q2. What is the best HPLC method modification to prevent co-elution? a) Change the flow rate b) Change the type of detector c) Change the mobile phase d) Change the column Q3. Are theophylline and caffeine concentrations valuable in caffeine overdose? a) Both are critical. b) Neither is valuable. c) Only theophylline is needed because it is a more toxic drug. d) Only caffeine is needed because it is present in larger amounts. Q4. How did this child’s ingestion compare with a lethal dose of approximately 100 mg/kg? a) Far below a fatal dose b) Almost a fatal dose c) Just above a fatal dose d) Manyfold greater than the estimated fatal dose Answers and Discussion Q1. (Answer = b) Any of these possible answers are feasible but interference from a metabolite is most likely. Metabolites are structurally similar to the drug being tested and it is entirely possible, sometimes probable, that they will react in a manner similar to the test substance. In the case being discussed, paraxanthine, a metabolite of caffeine, co-eluted with theophyl- line and contributed to the area under the curve (Figure 22.3). The instru- ment’s result was effectively equal to paraxanthine plus theophylline. Also, as a result of its structural similarity, paraxanthine cross-reacted in the immunoassay with the anti-theophylline antibody. It is quite unusual, however, for two test methods to be affected to such a large degree. The erratic HPLC method gave results that were up to 500% too high while the enzyme immunoassay had errors of up to 380%. Q2. (Answer = c) Neither the detector nor the flow rate will have any signif- icant effect on the co-elution of these two compounds. If the column were changed, it would probably separate the two compounds. Although this step could be taken, it would be easier to change the mobile phase. In this case, conversion to a more acidic mobile phase led to a separation of theophylline from caffeine. Q3. (Answer = b) Neither serum concentration is of much clinical value. The correlation between concentration and clinical symptoms is extremely 0371 ch22 frame Page 440 Monday, August 27, 2001 1:53 PM © 2002 by CRC Press LLC © 2002 by CRC Press LLC Anticholinergic Drugs CONTENTS Introduction Anticholinergic Activity Antihistamines Chemistry Toxicity Treatment Antidepressants Amine Theory of Depression Therapy for Depressive Illness Tricyclic Antidepressants (TCA) Toxicity Laboratory Testing Therapeutic Monitoring Testing for Suspected Overdose Second-Generation Antidepressants Toxicity Third-Generation Antidepressants Toxicity Monoamine Oxidase Inhibitors (MAOI) Toxicity Antipsychotic Drugs Terminology History Mechanism of Psychosis Side-Effects Toxicity Autonomic Nervous System Cardiovascular Central Nervous System Treatment of Overdose Laboratory Testing Questions INTRODUCTION This chapter is devoted to drugs that have anticholinergic properties (Table 23.1). This is a large group of compounds with many pharmaceutical applications. Thus, included 23 © 2002 by CRC Press LLC Anticholinergic Drugs CONTENTS Introduction Anticholinergic Activity Antihistamines Chemistry Toxicity Treatment Antidepressants Amine Theory of Depression Therapy for Depressive Illness Tricyclic Antidepressants (TCA) Toxicity Laboratory Testing Therapeutic Monitoring Testing for Suspected Overdose Second-Generation Antidepressants Toxicity Third-Generation Antidepressants Toxicity Monoamine Oxidase Inhibitors (MAOI) Toxicity Antipsychotic Drugs Terminology History Mechanism of Psychosis Side-Effects Toxicity Autonomic Nervous System Cardiovascular Central Nervous System Treatment of Overdose Laboratory Testing Questions INTRODUCTION This chapter is devoted to drugs that have anticholinergic properties (Table 23.1). This is a large group of compounds with many pharmaceutical applications. Thus, included 23 . She was lethargic but awake and aware of herself and her surroundings. She was admitted to the hospital and 1 day later she abruptly lost all brain stem reflexes. A spinal tap revealed that her. theophylline. The catecholamines stimulate the myocardium and this effect is aggravated by hypokalemia, hypercalcemia, hypophosphatemia, or meta- bolic acidosis. Convulsions and coma may precede death. One. primarily stimulants that have some hallucinatory character. They are also discussed separately, in the chapter on stimulants. Those discussed here are primarily hallucinatory. Various names have