Cases of Two Chemical Criminals: Drug-Induced Hypertension and Respiratory Paralysis Two Ironic Examples of How Chemicals Have Been Used To Harm and To Help Dominick A. Labianca Brooklyn College of The City University of New York, Brooklyn, New York 11210
"n
Certain individuals in our society have severely abused some of the positive acCH2CHNH$ CH&HNHg complishments of modern chemistry, I Tyrmiwa wmmiasethereby adding a chilling dimension to their criminal pursuits. They have hurt Ho cm Tetrah@mbiopferin HO people with chemicals whose legitimate Tymsine Dopa applications have been obscured by the adHoncH~cH~NH3+ verse publicity generated by their destrucDopa Decalbaxylase Dopanine-p-Hydmxylase tive use. Fyidoxal Phosphate Wctefe Numerous instances of such chemical asHO Dopamine saults have been documented in the press in recent sears, including the deaths of two women in Washington state in February, 1991 after they consumed cyanide-laced Sudafed 12-Hour Capsules (I). Several other instances of poisonings have also Epinephrine (Q been described in this Journal. These involved nitroglycerin (2),cyanide (31,scopolNorepinephrine (NQ and thallium (5). amine (4). This article addresses two cases in which Figure 1. The biosynthesis of norepinephrine (NE) and epinephrine (E). Participating enused prescription zymes are named above the arrows, and the associated coenzymes are written in italics drugs harm being below the arrows. The participating amino acids and amines are shown in their respective detected-r even suspected-for a consid-d,,i,,.i-, ,, ,,t,-, ..,-. erable amount of tim; Because many students currently taking undergraduate sodic and severe (91, a pattern similar to that exhibited by chemistry and biochemistry courses are enrolled in prePortioli and Valcavi's patient. professional programs geared toward health-related caHowever, clinical evaluation of the patient was inconsisreers, the chemistry and circumstances of these cases tent with the physicians' preliminary diagnosis. A pheomerit their consideration. chromocytoma was ruled out by conclusive tests, and both A Case of Acute Hypertension urinary and blood concentrations of NE and E were found to be within acceptable limits. Yet the patient continued to In 1981, physicians Italo Portioli and Roberto Valcavi of have acute hypertensive attacks. Fortunately for him, his Reggio Emilia, Italy, reported the perplexing story of a n physicians were able to arrest them via chemical means. individual who experienced periodic bouts of severe hyperAs described below, the nature of the patient's treatment tension (6,7). The patient was a 37-year-old male who sold and the nature of his problem were both related to the mineral water and other beverages. He had been in excelbody's production of NE and E. lent health before the onset of this condition. During the hypertensive attacks, which occurred once or twice daily Biochemica'Considerations and lasted one or two hours. his arterial blood messure a serireadings were as high as 240h20 mm Hg and Biosynthesis of the Hormones ous threat to his survival. NE and E are the two principal hormones of the adrenal medulla (10-12). The outline oftheir biosynthesis is shown Difficulties in Diagnosis in Fieure 1. The physicians suspected that their patient had a pheoThe first step is generally regarded as the rate-limiting chromocytoma. This is a tumor of the adrenal medulla, a step of the sequence: key component of each of the body's two adrenal glands, the hydroxylation of tyrosine, an L-a-aminoacid which are located one on top of each kidney (8,9). The tumor causes hypersecretion, into the circulation, of two This oxidation reaction is catalyzed by tyrosine hydroxcatecholamines: ylase. This enzyme is classified as a monooxygenase because it facilitates the addition of one atom of molecular noradrenaline, also called norepinephrine (NE) oxygen (omitted in the diagram) to tyrosine to form the adrenaline, also called epinephrine (El major product, dopa. The other oxygen atom appears in Aconsequence of this action is an increase in the heart rate water (also omitted) (13). The coenzyme, and constriction of the blood vessels, thus producing a rise tetrahydrobiopterin, is the reducing agent that activates in blood pressure. The resulting hypertension may be epi: the molecular oxygen.
a
1.
---
0
16
Journal of Chemical Education
The second step involves
Discovering the Source of the Condition
Effects of the Hormones
The ultimate therapeutic measure, however, was finally implemented by the patient himself. He effected a cure when he realized that the onset of his condition, which persisted for five months, always coincided with his consumption of the mineral water that his wife, a nurse, periodically brought him from his store. So he stopped drinking the water, and the hypertensive attacks ceased. His wife was convicted of attempted homicide aRer analysis of a sample of the water revealed the presence of a dangerously high concentration (400 mg/Lj of metaraminol(2). This is a sympathomimetic amine that stimulates the release of NE. I t is used therapeutically for patients with severe hmotension (16).As noted above. the clinical analvses conducted on the ;ictim3s blood and ukne had failed to detect any abnormality in catecholamine levels; perhaps the hlood and urine samples were taken after the patient had been stabilized and the levels had returned to normal.
NE and E are classified a s svm~athomimetic(10): thev produce effects that mimic thoie a'ssociated withth; sGath he tic division of the autonomic (involuntaw) nervous system. They thus account for the body's "figk-or-flight" response to stressful situations because, under such conditions, the adrenal medulla increases its output of these hormones. As noted above, this is accompanied by a rise in hlood pressure. Other changes also occur.
A Case of Fatal Respiratory Paralysis Genene Jones was a licensed vocational nurse convicted of murder and &en a 99-vear sentence in Februaw. ". 1984 for committinga particuiarly heinous and tragic crime. The victim, Chelsea McClellan. had been a healthv 14month-old girl who died aRer receiving a routine ch&knp in September, 1982 a t a pediatrics clinic in Kerrville, TX, where Jones h a d been employed since the preceding
sthe pmduction of dopamne, the first catecholamine in the
sequence, via decarboxylation of dopa This requires catalysis by dopa decarboxylase and the participation of the coenzyme pyridoxal phosphate, a derivative of pyridoxine (vitamin Be). The final two steps of the sequence involve the hydmxylation of dopamine to NE-with the coenzyme asexbate (vitamin C) functioning as the nducing agent in a reaction catalyzed by dopamine-P-hydroxylase the methylation of NE to give E The latter hormone (El comprises about 80% of all the catecholamines ~ r o d u c e dbv the adrenal medulla. and NE constitutes most of the remainder (14).
The rate of respiration is accelerated. Respiratory passages a n dilated. T h e rate of digestion is decreased. Blood sugar levels are increased. The etliciency of muscular contractions is increased. Cellular metabolism is stimulated. Normally, the body has control mechanisms that dissipate these effects when the stressful condition ceases to exist. However, when NE and E are produced in excess in response to a n abnormal physiological stimulus, a s suspected in the case a t hand, then external controls must be Therapeutic Regimen
Although the cause of their patient's condition continued to elude them, Drs. Portioli and Valcavi successfully treated him with a drug commonly used to counteract the hypertensive effects of a pheochromocytoma. The drug was phentolamine (11,a n imidazoline. Phentolamine is classified as a n adrenergic antagonist, a term that denotes its ability to bond to the active sites of the adrenergic receptors on the surfaces of the membranes of cells that normally respond to NE and E. (Adrenergic receptors are protein receptor molecules.) Thus, phentolm i n e blocks the action of these catecholamines (9, 15). Using this drug, the physicians were able to effectively reduce their patient's hlood pressure to normal levels whenever he presented with one of his attacks.
.......-...
The girl had been given a lethal injection of ~ucrinylcholine W h , eq 21, a neuromuscular hlocking agent used legtimately, in the form of it; chloride salt, as an ad~uvantto surgical anesthesia t171. In this capacity, SCh eltccts relaxation of skeletal muscle, and it is used to facilitate uprratlve manipulations, such a s insertion of a breathing tube. However. when dosuae and administration i f SCh are nor carefull~monitored,&occurred with Chelsea McClellan, then fatal r e s ~ i r a t o w~ a r a l ~ sisi slikelv. Adding to the tragedy of ehelsea ~k!lellan's death was the fact that Jones was also sus~ectedof havine murdered a number of other babies i n the Pediatric 1ntcnsive Care Unit (PICU) of San Antonio's Medical Center Hospital, about 60 miles southeast of Kerrville. She had been employed there from October, 1978 to March, 1982. The crime against Chelsea McLellan attracted considerable attention nationwide (18, 19) and became the subject of a popular book, Deadly Medicine (201, which was adapted a s a television drama of the same title, telecasted in New York on November 11, 1991. The book not only details the case but also examines a possible motive for Jones' behavior. The district attorney who prosecuted her held the opinion t h a t she deliberately created medical emergencies with the intention of resolving them. She produced life-threatening circumstances surreptitiously and then intervened triumphantly and dramatically, thereby portraying herself a s a type of "super nurse". If this were true, then Jones' selection of method was poor indeed, given the high risk involved. Perhaps she was not fully aware of the potentially hazardous nature of SCh, whose mechanism of action is described below. ~
~
Interruption of Neuromuscular Nerve lmpulse Transmission
The action of SCh is linked to that of acetylcholine (ACh, eq 11, which is a chemical agent or neurotransmitter that is essential to the functioning of the autonomic newous system. The Activity ofACh One function of ACh is to facilitate contractions of muscle fibers, which occur when individual muscle cells are stimulated by nerve impulses transmitted to them by Volume 71 Number 1 January 1994
17
nerve cells called motor neurons. Thcsc impulses are clcctr~calsienals ecncrated from the flow of ions. notablv Na* and Kt,across neuronal membranes. The junctions between motor neurons and muscle fibers are called neuromuscular junctions. When each nerve impulse arrives a t a neummuscularjunction, AChis released from the motor neuron and transmits the impulse across the junction to the muscle fiber, thereby stimulating a contraction. This process involves the binding of ACh to the cholinergic polypeptide receptor molecules of the postjunctional membrane of each muscle cell. Once nerve impulse transmission is completed, relaxation of the contracting muscle occurs because ACh is hydrolyzed to acetate (A) and choline (Ch) in a reaction catalyzed by t h e enzyme acetylcholinesterase (AChE), a s depicted in eq 1.This sets the stage for the transmission of another impulse. The regeneration of the requisite ACh proceeds via the transfer of a n acetyl group to Ch from acetyl coenzyme A (CoA), a key molecular participant in body metabolism. The latter reaction is catalyzed by the enzyme choline acetyltransferase.
-
-
H3C,
+
H,C-NCH,CH,OOCCH, /
H3C
+ H,O
AChE
(ACh)
CH3COO- 1 (A)
' 4 4+
H,C7NCH,CH20H H3C
+ Ht (1)
(Ch)
The Chemical Evidence Ultimately, Genene Jones' crime was detected because her actions were subjected to the scrutiny of modern analytical techniques. Although much of the case against her was circumstantial, solid incriminating evidence was obtained through chemical analysis. Tissue samples from the exhumed body of Chelsea McClellan were analyzed according to a method developed by Forney et al. (24). The Analytical Technique SCh was extracted from embalmed tissue and then identified and quantified by G C N S analysis. The technique entailed conversion of the isolated SCh to the corresponding demethylated compound (dm-SCh, eq 3), which lacks the bis-quaternary ammonium character of SCh and thus has the enhanced volatility that facilitates this type of analysis. The reaction involved methylation of the nucleophilic benzenethiolate ion (PhS-) by each of two methyl groups cleaved from the quaternary ammonium moieties of SCh (25). The neutral dm-SCh so obtained was then identified by its GC retention time and its MS analysis in the electron-impact mode.
The Activity of SCh SCh (eq 2) is structurally similar to ACh. Consequently, when i t is given to a patient, SCh effectively competes with ACh for the cholinergic receptors of muscle cells. (SCh is usually given by p a r e n t e d administration, and intravenous infusion is used more often than intramuscular introduction.) Because SCh is hydrolyzed quite slowly by AChE, the preferential binding of the drug to cholinergic receptors effectively interrupts nerve impulse transmission between motor neurons and muscle fibers. This produces muscular relaxation of extended duration. For example, after a single intravenous dose of 10 to 30 mg of SCh, the following occurs. Muscular relaxation usually occurs within 1min 'The effectpeaks within 2 min. 'The effectgenerally disappears within 5 min. Transient apnea (cessation of respiration) usually occurs a t the time of peak relaxation. In the controlled clinical situation, however, this condition poses no problem for clinicians and anesthesiologists because the patient is carefully monitored near the facilities needed for rapid respiratory and cardiovascular resuscitation. Moreover, t h e desired degree of relaxation is easily obtained and controlled by regulating dosage levels of SCh and the associated rate of its administration. The effects of SCh dissipate rapidly once its administration ends, a s seen from the data cited above for a single intravenous dose of the drug. This is due to the facile hydrolysis of SCh to Ch and succinate (S), according to eq 2. The reaction is catalyzed by the enzyme butyrylcholinesterase (BuChE),which occurs in liver and olasma. I t is also k n o n~ a s cholinestervsc I ChE , swum csterase, or plt!udoChF 117.21-23,.
18
Journal of Chemical Education
. did not exhibit a molecular The mass s ~ e c t r u mwhich ion peak, wa; consistent with the production of the fragment ions shown in Fleurc 2. with the hase oeak at d z 58. Not shown are the resonance structures a'ssociated with
-
+
CH-N
p
3
\
m/z 58
CH3
F gure 2. Slr~cluresof maor fragment ions conssten1 wlth the mass spectr~mof demetnylafea s~ccmylcnolne ,dm-SCh, ,24)
