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Therapy of Acute Poisoning
therapy of acute poisoning by H. Douglas Johnson f reports of acciden tal poisonings in the United States were to be considered as cases of a hypothetioal disease, the malady might be described as-
I
The disease strikes one in 2,500 of the U.S. population each year, with its greatest incidence in children under the age of five. In young children, when properly treated, recovery can be expected in most cases. While less frequent in older individuals, the disease takes a more serious form, with a larger percentage of the cases terminating fatally.
Accidental poisoning, of course, is not a disease. It is a health problem, however, and its impact on our society is essentially that described above. 0 It isa problem about which all of the health-oriented professions are concerned. For many years the pharmacist has played an active part in the control of accidental poisoning. He has had an educational role in reducing its occurrence ,a nd an advisory role in obtaining prompt treatment. As in his other professional activities, the pharmacist's understanding should 'go beyond the requirements for immediate performance. Specifically, this is an area of professional activity for which the pharmacist should have a basic understanding of the nature of poisons and the principles of poisoning therapy. nature of poisons, poisonings
The sciences of pharmacology and toxicology are based upon the fact that foreign chemicals can induce alterations in biological systems. This is a phenomenon that is essentially true for all chemicals, for at sufficiently high concentrations all chemicals induce biological effects. o Of 83,704 accidental ingestions reported in 1967, 86.8 percent were in children under five. Fewer deaths are consistently reported for this age group however. (Bulletin of the National Clearinghouse for Poison Control Centers, September-October 1968.)
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If we limit consideration to chemicals that are biologically active at concentrations likely to be applied in realistic situations, we find them classined as foods, drugs or poisons depending upon the nature of the effects induced. Of the enormous spectrum of chemicals available, only a limited number are useful as foods or drugs. A much larger number induce undesirable or damaging effects and are basically poisonous. Many of the chemicals present in contemporary commercial products fall into this category and provide a constant potential for accidental poisoning.
Specifically acting and reversible poi· sons also are possible-e.g., carbon monoxide-but note that specific ac· tion need not necessarily be reversible -e.g., organic phosphate insecticides. (c) Chemicals with high reactivity are likely to react nons electively and nonreversibly with many structures within a biological system. So many physiologic disruptions occur that specific actions can not be singled out. Since reactions may be nonreversible, the biological system recovery might require repairs and replacements. Few drugs but many poisons are in this category. Moderately reactive substances that damage tissues and in· toxic mechanisms duce inflammation-e.g., tear gasesare referred to as "irritants." More Chemicals induce biological effects highly reactive poisons that cause tis· by their presence in biological syssue death-e.g., heavy metals, formal· tems and it is interesting to note that dehyde-are "protoplasmic poisons." they may do so regardless of their Very highly reactive substances-e.g., potential for chemical reaction. The strong acids and bases-that cause both following cases and mechanisms may tissue death and disintegration are be consideredcalled "corrosives." (a) Nonreactive (inert) chemicals The reactivity of a chemical is in· may induce biological effects by alterherent in its structure but also is reo ing the properties of the solvent syslated to its concentration. Greater reo tems in which they are dissolved. A activity occurs with higher concentrafew drugs and poisons appear to opertions. A poison that only irritates and ate by this mechanism but in general induces inflammation at low concen· the number of such chemicals is small. trations may be protoplasmic poison As an example, some inert organic at higher concentrations. Similarly, solvents are speculated to induce CNS a drug with specific actions when dis· depression by altering the spatial ortributed throughout the body may be ganization of cellular water molecules. , irritating at its administration site (b) Chemicals with low reactivity where it is more highly concentrated. may react selectively with only a few exposure routes chemicals (receptors) within a biological system. If these receptors are The common routes for accidental directly involved in the physiologic exposure to poisons are topical conprocesses of the system then the chemtact, oral ingestion and inhalation. All ical induces specific physiologic of them require absorption across liveffects, one or several of which may ing cells for entry into systemic circube predominant. Low reactivity often lation. In addition to systemic tox· confers reversibility as well, in which icities, exposure by any of the routes case the biological system recovers unmay result in local damage as well. damaged upon removal of the foreign Most nonphysiologic chemicals are chemical. absorbed by passive, rather than aCMost drugs fall into this category tive, transport 'across cell 'm embranes. and induce relatively specific, reversExcept for very small molecules which ible, therapeutically useful effects.
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
may penetrate membrane pores along with water, most chemicals are passively absorbed by dissolution in the lipids of the cell membranes. Lipidsolubility is necessary as well as watersolubility in the adjacent 'aqueous phases and the ratio between the two will determine relative capacity for absorption. In the case of ionizable compounds, the nonionized form (being more lipid-soluble) is the more readily absorbed. The skin is not primarily an absorbing organ. Its dead cornified outer surface impedes the approach of chemicals to the living inner layers. However, when the inner layers are exposed, lipid-soluble substances are absorbed. Still the amount reaching systemic circulation will likely be small unless the contaminated skin area is large, the skin is damaged-e.g., abraded, bumed-or the solvent involved promotes penetration. Topical absorption can be reduced by prompt decontamination. The skin is susceptible to varying degrees of local damage. Mildly reactive substances may affect the dead surface only. More reactive substances may cause irritation of deeper layers. Highly reactive substances cause corrosion, often before decontamination can be accomplished. Oral ingestion exposes poisons to me mucous membranes of the gastrointestinal tract through which substances can be rapidly absorbed into systemic circulation. Absorption rates will vary with the solubility and ionization properties of the poison at the pH's encountered. Other factors being equal, weak acids are more rapidly absorbed in the stomach where they are less ionized (and more lipid-soluble) 'at the acid pH and weak bases are more rapidly absorbed in the intestinal tract where they are less ionized at the basic pH. As for local effects, ingested irritants induce nausea and vomiting and more reactive compounds may cause necrosis and corrosion. Inhaled gases reach the alveoli of the lungs where they are very rapidly absorbed into circulation. Dusts, unless of very small particle size, tend to be deposited in the upper respiratory passages. Mildly irritating substances may be deeply inhaled. More severe irritants are not because they induce reflex brea th-holding. Depending upon site, local damage may take the fonn of tracheitis, bronchitis, and/or pneumonitis. termination of exposure
The elimination of absorbed poisons is accomplished by mechanisms that remove unneeded foreign substances
from the body. The two basic patterns are (a) excretion unchanged and (b) biot,ransformation followed by excretion. The relative utilization of these patterns depends upon the physical and chemical properties of the particular poison. In the mechanics of urine formation, all except the macromole.cular constituents of plasma filter into the kidney tubules. Reabsorption of various substances then occurs and the residue is excreted las urine. In general, essential m'etalbolites are reabsorbed and retained individually by active processes, and lipid-soluble substances 'a re passively reabsorbed and retained as a class. It follows that poisons of low lipid-solubility are poorly reabsorbed and are excreted unchanged by the kidneys. Many of the retained lipid-soluble substances undergo biotransformation. The changes that occur increase water/lipid solubility ratio to the point that urinary or biliary excretion is possible. Most often water solubility is increased by introduction of hydroxyl radicals, reduction of molecular size or linkage (conjugation) with a highly water-soluble compound such as glucuronic acid. Most biotransformation of foreign substances occurs in the liver. The group of hepatic enzymes commonly involved are those of the endoplasmic reticulum. These enzymes are often referred to as the hepatic microsomal enzymes. Since the liver and kidneys are the organs primarily involved in the metabolism and elimination of poisons and since reactive substances in contact with tissues can cause local damage, it is not surprising that liver and kidney damage are common ,consequences of systemic poisonings. emptying the stomach
induction of emesis Indications-Emesis can be employed in all situations e~cept those in which the violent physical activity m,a y be dangerous. Such contraindications include ( a ) unconsciousness-aspiration of vomitus may occur, (b) kerosene ingestion-effects of 'aspiration are particularly dangerous, ( c ) corrosive damage to the esophagus and associated structures-perforation m'a yoccur and ( d) health conditions that may be adversely affected-cardiac disease, pregnancy, etc. PhYsiology-Vomiting is a complex activity coordinated by the vomiting center located in the reticular formation of the medulla. The vomiting center can be activated-and vomiting induced-in several ways. Irritation
of the upper GI tract initiates impulses that activate it and so does chemical stimulation of the chemoreceptor trigger zone (CTZ) located nearby in the brain. With these two mechanisms, a chemical may induce vomiting both before and after absorption from the GI tract. Regardless of the inducing mechanism, however, .vomiting does not occur if the vomiting center is depressed, either selectively by drugs or as ,a consequence of 'generalized central nervous system depression. Also CTZmediated vomiting does not occur if the CTZ is blocked by drugs such as chlorpromazine. Therapeutic induction- ( 1) Many poisons automatically induce vomiting, either by GI irritation or by stimulation of the CTZ after some absorption has occurred. (2) Gagging will induce vomiting and this may be accomplished by tickling the back of the throat with a finger or spoon handle. Vomiting induced in this manner tends not to be persistent, however, because the stimulus cannot be continued once the vomiting starts. Consequently, gaginduced vomiting may not be effective in 'emptying the stomach completely. Gag-induced vomiting is more effective when an irritant is present in the stom'ach to synergize the action. This might be the poison itself or the prior administration of a mild irritant solution such as warm salt water, warm soapy water or warm mustard water. However, in the event that such a solution is administered and vomiting does not occur, the dilution of the poison that occurs m'ay be undesirable. Although dilution reduces the concentration gradient for absorption, the increased volume coupled with th·e great surface area of the GI tract may result in faster absorption. (3) Ipecac syrup may be administered orally to induce vomiting. The usual dose is 15 ml. Ipecac contains emetine and other principles that irritate the GI tract locally and stimulate the CTZ after absorption. Ipecac induces vomiting persistent enough to empty the stomach. Its chief disadvantage is that its action is delayed. Average induction time is about 20 minutes, which means that it is even longer in some cases. This is a significant delay when a potent poison has been ingested. ( 4) Apomorphine's most prominent action is direct stimulation of the CTZ and it is a potent emetic provided the CTZ is not blocked or the vomiting center depressed. It is not suitable for home medicine chests since it must be administered parenterally. As conventionally used (5 mg subcutaneously for adults) , apomorVol. NS9. No.5, May 1969
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H. Douglas Johnson is associate professor of
pharmacology at the University of Georgia school of pharmacy. He earned his BS, MS and PhD from the University of Florida and has been employed in the area of pharmaceutical education since earning his PhD. Active in many capacities within the university community, Johnson has published several scientific and professional articles and developed professional exhibits at the University of Georgia school of pharmacy. APhA life-member Johnson also is a member of AIHP, Georgia Pharmaceutical Association, Rho .chi, Kappa Psi and Sigma Xi.
phine does not induce ideal emesis. Its .a ction is delayed five to ten minutes and it persists for some time and may exhaust the patient. A morphine antagonist (e.g., nalophine, levallorphan) may be used to terminate prolonged vomiting or a smaller dose of apomorphine ma y be given intravenously. Doses of 1-30 mcg/ Kg IV .i nduce almost immediate vomiting that lasts for only one to two minutes. ( 5) Substances such as copper sulfate and antimony potassium tartrate -tartar emetic-should not be used as emetics as they are inherently toxic themselves. Should vomiting not occur, they would be retained and contribute to the toxic syndrome.
gastric lavage Indications-In general, gastric lavage is worthwhile during the first three hours after ingestion of a poison. Its benefits, however, decrease with the passage of time and the systemic absorption of the poison. Lavage may be of value for a somewhat longer period if there is reason to expect delayed stomach emptying. Irritation-and therefore an irritant poison-delays emptying, as do fat or protein solutions that may be administered for this purpose. Comparison to emesis- (1) Lavage requires special equipment and technic and generally can be carried out only by professional personnel in medical treatment centers. (2) Lavage is considered by some to be more effective than emesis since fluids are introduced to wash the stomach and because the process can be repeated as long as necessary. Lavage is undoubtedly effective for removing suspensions 'a nd substances in solution. However, it is not as effective as emesis for removing larger solids as partially dissolved capsules. Neither will it completely remove 216
finely divided solids-as shown by x-rays after barium sulfate ingestion. ( 3) Lavage has fewer ·c ontraindications than emesis since there is less chance for 'a spiration and less physical activity. Lavage can be performed with the unconscious, after kerosene, and in the debilitated where emesis would be dangerous. Lavage is still contraindicated after corrosive poisons since it, too, could cause perforation. It also is contraindicated ,a fter central nervous system stimulants, in which case the manipulation might induce convulsions. Operative principles- With proper technic, a lavage tube is introduced into the stomach of the patient. The patient may be conscious or anesthetized. If anesthetized, the use of an endotracheal tube will further insure against aspiration. The lavage fluid is then injected, the patient turned to allow mixing and the fluid withdrawn. The procedure is repeated until the washings are clear. Water may be used as the lavage fluid. However, if the identity of the poison is known, a neutralizing solution or a poorly absorbed solvent for
the poison may be used to better advantage. Since the lavage fluid is not left in the body, the range of neutralizing chemicals that may be safely used is greater than it would be otherwise. A number of neutralizing solutions and solvents are listed in table 1. When lavage is complete, any indicated drugs may be administered through the tube before it is withdrawn. administration of adsorbents
activated charcoal Indications-Activated charcoal has a good capacity for adsorbing a wide variety of chemicals and is the best therapeutic adsorbent available. Its activity is not unlimited however. Not all chemicals are equally well adsorbed and a few-cyanides, for example-are very poorly adsorbed. Nevertheless, the administration of activated charcoal is considered to be a routinely useful procedure. In view of the delayed emetic action of ipecac syrup, there is a growing speculation that activated charcoal may be of more real value in the home medicine chest as an emergency treatment for acciden tal poisoning. Adsorption properties-In the adsorption process, nonionized chemical is deposited on the charcoal surface. Ionizable poisons are adsorbed more readily under pH conditions that inhibit ionization. In the stomach, weak acids are more rapidly adsorbed than weak bases. Bases are adsorbed, however, for there is always some nonionized form in equilibrium with the ionized. Adsorption is reversible 'a nd poisons so bound are withheld only temporarily from systemic absorption. The charcoal-poison complex must therefore be removed from the body for permanent poison control. Removal may be speeded by emesis, lavage or catharsis. However, even if left to
table I lavage solutions and solvents toxic agent
lavage fluid
organic poisonsalkaloids organic acids, oxalates oxidizable substances phenol
tannic acid, 4 percent lime water; calcium lactate, 1-3 percent potassium permanganate, 1:5000 vegetable oil
inorganic poisonsheavy metal salts iron, copper salts lead, barium salts mercury salts thallium salts yellow phosphorus cyanides, hypochlorites iodides fluorides
protein solutions potassium ferrocyanide, 0.1 percent sodium sulfate, magnesium sulfate solution sodium formaldehyde sulfoxalate, 5 percent sodium iodide, potassium iodide, 1 perce nt mineral oil; copper sulfate, 0.2 percent sodium thiosulfate, 5 percent starch solution lime water; calcium lactate, 1-3 percen t
(Adapted from Gleason, M.N., et ~/. : Clinic~1 Toxicology of Commerci~1 Products, second ed it ion, Williams and Wilkins Company, Baltimore, 1963.)
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
normal gastrointestinal elimination cIharcoal admin!stration is still useful: t slows systemIC absorption and since s~stemic elimination processes are con~muous the peak poison level reached III the body is reduced. . A~tivated charcoal makes no distmctIon between food, drug or poison?~s chemicals and all are in competItIon for its 'a dsorptive capacity. !hus the presence of other substances m the stomach may interfer'e with its adsorption of poisons. Similarly, the presence of adsorbed indigenous chemicals in plain charcoal and burnt toast makes these virtually useless as adsorbents. Use with emetics-Orally administe~ed e~etics given simultaneously ~Ith 'a ctIvated charcoal are antagonistIc. The emetic is adsorbed onto the charcoal, losing its emetic potency and reducing the adsorptive capacity of the charcoal. ~n oral emetic (with emesis) is a SUItable procedure before activated charcoal; administered afterwards it may not induce emesis. Parent~ral emetics are of course active after charcoal.
universal antidote Rationale-Universal antidote usually contains two parts activated charcoal, one part tannic acid and one part magnesium oxide. The tannic acid is intended to precipitate plant principles and the magnesium oxide to neutralize stomach acid so as to reduce solubilization of metallic salts. The chief value of the product, however, lies in the adsorbent properties of the activated charcoal. Comparison with activated charcoal - Recent studies have shown that activated charcoal alone is more effective than universal antidote, even when the dose of the antidote is such that an equal amount .of activated charcoal is administered. This is because the other ingredients of universal antidote adsorb onto its activated charcoal and reduce adsorptive capacity. speeding intestinal elimination
catharsis Indications-Catharsis speeds passage of materials through the intestinal tract and decreases the time available for their systemic absorption. The reduction in time is not significant in the case of rapidly absorbed substances, but it is beneficial when poison absorption is slow, either innately so or as the result of prior administration of activated charcoal. Catharsis is also useful in the removal of conjugated poisons excreted into the bile. The conjugates are usually slowly absorbable substances. Ca-
table II
potential liver microsomal enzyme IndUCing drugs* pharmacologic category
drug
sedative·hypnotics
ba r qitu rates glutethimide (Doriden) methaprylon (Noludar)
anticonvulsants
diphenylhydantoin (Dilantin) mephenytoin (Mesantoin) paramethadione (Paradione)
tranquilizers
chlordiazepoxide (Librium) meprobamate (Equanil, Miltown) phenaglycodol (Ultran) chlorpromazine (Thorazine) promazine (Sparine)
muscle relaxants
carisoprodol (Rela, Soma) orphenadrine (Norflex)
hypoglycem ics
tolbutamide (Orinase)
antihistamines
diphenhydramine (8enadryl) chlorcyclizine
a nti-infla m matories
phenylbutazone (Butazolidin) cortisone prednisolone
androgens
testosterone
progestins
norethynodrel
(Adapted from Conney, A.H., Pharm~col , Rev., 19. 317,1967.) * Note-There has, been n
tharsis is contraindicated in the case of irritant poisons. Choice of cathartic-Sodium sulfate is a suitable cathartic for the elimination of unabsorbed poisons. The goal is to maintain high bulk and fast flow rate throughout the entire intestinal tract and saline cathartics do this more effectively than other types of cathartics. Furthermore, sodium sulfate is nontoxic if absorbed. systemic poison level reduction
At present, alteration of biotransformation is largely of theoretical consideration in the treatment of acute poisoning.
liver microsomal enzyme induction A number of drugs induce synthesis of the liver microsomal enzymes that metabolize lipophyllic foreign chemicals and speed their elimination from the body. Such an approach to acute poisoning therapy is 'Of little value, however, because the induction process is so slow. Typically, several hours pass after administration of an inducer before induction begins and several days pass before maximum effects are achieved. To be useful during the acute period, induction therapy would have to be begun before poisoning occurred-a logistically impossible situation. Incidental microsomal enzyme induction, on the other hand, may play a role in recovery from acute poisoning. If the patient previously has been
taking an inducer drug for some other purpose-sedative doses of phenobarbital, for example-he will be in a better position to eliminate metabo~1any commonly lizable poisons. used drugs are potential liver microsnmal enzyme inducers (see table II).
liver microsomal enzyme inhibition A different relationship exists for poisons that are inactive as ingested and are metabolized to their toxic forms. Enzyme induction enhances their acute toxicity, and theoretically enzyme inhibition should reduce their toxicity. A number of microsomal enzyme inhibitors are known. However, at present they appear to be of little therapeutic. value. Although they retard the appearance of the toxic form, they also prolong its duration by inh1biting further degradation and elimination. acceleration of elimination
speeding kidney excretion Indications-Hydrophilic poisons are readily excreted by the kidneys because they are poorly reabsorbed passively in the renal tubules. Lipophyllic poisons, on the other hand-because they are weII reabsorbed passivelyare slowly excreted and it is for these poisons that accelerated elimination is needed. Not surprisingly, accelerated excretion of lipophyllic poisons can be achieved by inhibiting passive reabsorption. Either or both of the following technics may be used. Vol. NS9, No.5, May 1969
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Reduction of concentration gradient -The gradient for passive tubule reabsorption is usually high since the renal filtrate is concentrated as it passes down the tubules. Retention of water in the filtrate will reduce this gradient and can be accomplished by the 'administration of an osmotic diuretic. Of the various types of diuretics, the osmotic diuretics-e.g., urea, mannitol-are the best suited. They are active throughout the length of the renal tubule ( while water diuresis alters distal tubule dynamics chiefly). Since they do not affect active reabsorption, they are less likely than other diuretics to induce serious electrolyte disturbances. The excretion of all passively reabsorbed poisons can be accelerated by osmotic diuresis. Such therapy may reduce the body half-life of a poison to 50 percent of its original value. Ionic trapping-In the case of ionizable poisons, passive reabsorption can be reduced by adjusting the pH of the tubule filtrate 'So that the poison is ionized. Normal urine, being acid, is already so suited for excretion of weak bases. Such excretion can be enhanced by making the urine strongly acid. However, the greater therapeutic opportunity arises with acid poisons, in which case the urine can be alkalinized. Alkalinization of the urine can be accomplished by oral or parenteral administration of a systemic antacid such
as sodium lactate, sodium bicarbonate, etc. Alkalinization significantly increases the excretion rate of weakly acid poisons.
hemodialysis 1ndications-In hemodialysis, unwanted solutes in the blood are allowed to diffuse across a semipermeable membrane into a solution (dialysate) provided by the therapist. This procedure can be used to remove a wide variety of poisons from the body, particularly in situations where the . physiologic removal rate is inadequate. Such situ'ations may include renal failure, poisons with innately slow excretion rates and severe poisonings in which large amounts of poison are present. Generally, hemodialysis is not needed for poisons that are rapidly metabolized or excreted and it is not very effective for poisons that ,are intensively bound to plasma proteins. General procedures-In peritoneal dialysis, the membranes of the abdominal cavity and organs serve as the dialysis membrane, and the dialysate is provided by instilling 'a suitable solution into the cavity -a nd exchanging it every one to two hours. This is a relatively simple procedure and is roughly equivalent to osmotic diuresis in speeding poison removal. In extracorporeal hemodialysis, the patient's blood is circulated through a machine-'artiflcial kidney-in which the blood and dialysate are separated
table III specific systemic antidotes toxic agent
antidote
(1) Antidotes that reduce the level of the toxic substance-
arsenic, mercury copper lead, plutonium, uranium strontium, radium bromide cyanide fluoroacetate methanol drug overdosages-heparln
dimercaprol (BAL in Oil)" penicillamine (Cuprimine)a caNa2 EDTA (CaNa2 Versenate)a calcium saltsd chlorides d sodium nitrite a and sodium thiosulfateo monacetin; actatesb ethanolb protamine sulfatea
(2) Antidotes that protect or restore receptors-
carbon monoxide cholinesterase inhibitors (e.g., parathion, malathion) drug overdosagescoumarin-type anticoagulants curare derivatives narcotics
oxygene pralidoxime (Protopam)f phytonadione (Mephyton, etc.)e edrophonium (Tensilon): neostigmine (Prostigmin)e nalorphine (Nalline); levallorphan (Lorfan)e
(3) Antidotes that repair or bypass the biochemical lesion-
methemoglobin inducers (e.g., aniline) drug overdosages5·fluorouracil 6-mercaptopurine (Purinethol) methotrexate (Amethopterin)
methylene blue' thymidine h adenine, hypoxanthineh folinic acid (Leucovorin)h
(a) reacts with toxic agent (d) promotes excretion (nitrites induce methemoglobin which reacts (e) competes for receptors with cyanide) (f) restores receptors (b) inhibits metabolic activation (g) repairs biochemical lesion (c) enhances metabolic inactivation (h) bypasses biochemical lesion (Adapted from Goldstein, A., d .,1., Principles of Drug Action, Hoeber Medical Division, Harper and Row, New York, 1968.)
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Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
by a semipenneablecellophane membrane. Specialized equipment and technics are required. The process is highly efficient and the body half-life of a poison may be reduced to 25 percent of its original value. The passage of a solute across a dialysis membrane occurs passively, with the solute moving when there is a concentration gradient. The dialysate then must contain the normal plasma solutes so that these do not leave the body and its poison concentration must be kept low so that the poison will dialyse effectively. The dialysate must be replaced regularly, either continuously as in extracorporeal hemodialysis or intermittently as in peritoneal dialysis. Measures to increase effi,ciencyProcedures that trap the poison in the dialysate and prevent back-diffusion increase efficiency. Many poisons bind to proteins to some extent and their dialysis can be enhanced by adding nve percent albwnin to the dialysate. Also, since substances dialyse in nonionized form, back-diffusion can be reduced by adjusting dialysate pH so that the poison is ionized. The pH·s required for maximum efficiency are nonphysiologic. Consequently this latter procedure is limited to extracorporeal hemodialysis. Back-diffusion of lipophyllic poisons also may be reduced by the use of a lipid dialysate. systemic antidotes
lndications-Systemic antidotes reduce the toxic effects of absorbed poisons. They are indicated when systemic absorption cannot be prevented and they may be used in conjunction with general measures to promote poison removal. Systemic antidotes can be administered only ( a ) when the identity of the poison is known 'a nd (b) when an antidote for it exists. Of these two qualifications, antidote existence is the more restrictive. Only a relatively few poisons have systemic antidotes (see tables III, below left and W on opposite page) . Specific vs. nonspecific antidotesSystemic antidotal mechanisms can be classified as specmc or nonspecific, depending upon whether they actually alter some element of the toxic mechanism or only oppose the toxic symptoms produced. Specific antidotesi.e., those that act upon the poisons, its receptors or the resulting biochemical lesion-are the more effective. Nonspecific antidotes are essentially no more than symptomatic treabnent. specific antidotes
Mechanisms-A number of specific antidotes reduce the effective level of
the toxic substance in the body. Some ~eact with ,a nd inactivate the poison ltself-for example, dimercaprol complexes ·w ith arsenic or mercury. Others alter the metabolism of the poison, either inhibiting its toxic activation as ethanol does in methanol poisoning or accelerating its inactivation as sodium thiosuHate does in cy'a nide poisoning. In some cases excretion of the poison may be increased, as strontium excretion is enhanced by calcium administration. Antidotes that reduce poison levels are basically protective rather than restorative. However, if the poisonreceptor reaction is reversible, subsequent re-establishment of equilibrium will free previously bound receptors and a degree of restoration is introduced.. Some specific antidotes react with body receptors rather than with the poison. Most of them give competitive protection by virtue of their greater affinity for the receptors. Again, if the poison-receptor reaction is reversible, the benefits may be restorative as well. This is true in nalorphine reversal of morphine action for example. Few antidotes can disrupt nonreversible poison-receptor complexes. One important case, however, is pralidoxime, the antidote for the cholinesterase inhibitor insecticides. Pralidoxime reacts with the poison-receptor complex, displaces the insecticide and then frees the cholinesterase. Finally, a few antidotes repair or bypass the toxic biochemical lesion to give restorative action. As examples, methylene blue reduces methemoglobin back to hemoglobin in aniline poisoning and folinic ,acid bypasses the effects of overdosage with folic acid antagonists. nonspecific antidotes
M echanisms-If no specific antidote exists or·if none is available, then administration of a nonspecific antagonistmay be worthwhile. Such antidotes oppose only the symptoms of a poison and although the toxic mechanism still occurs, its effects may be minimized. Nonspecific 'antagonism can be accomplished either by inducing opposite symptoms or by blocking response of the symptom-producing mechanism. As examples, CNS stimulants induce opposing symptoms in poisoning with eNS depressants and atropine blocks response to the aocumulated acetylcholine in poisoning with cholinesterase inhibitors. . supportive treatment
Indications-Specific antidotes are not known for many poisons. Even
when an antidote is lavailable, rarely can all toxicities be reversed without some residual effects-either of the poison or of the antidote. Recovery in such cases will depend upon the ability of the body to withstand the toxic eHects until the poison is eliminated and repair instituted. Organs and systems that are fully adequate for nonnal physiologic dem'a nds may not be adequate to meet the demands of -a toxic situation. Supportive therapy, then, consists of measures to maintain vital functions during the critical period so that recovery can occur. Supportive treatment is indicated in all symptomatic poisonings and it is equal in importance to proper antidotal therapy.
the patient's head tilted far back to give a good airway and his nose pinched shut, ·t he operator takes a deep breath, seals his mouth over the patient's mouth and inHates the patient's lungs. Such direct contact is suitable except when a very potent poison has been ingested orally. In this event, 'a gauze pad or mechanical airway will protect the operator from exposure. Respiration of an adult requires insuffiations of about twice normal tidal volume 12 times per minute. Children require smaller, more frequent insuffiations. If the stomach becomes inflated, gentle epigastric compression will eliminate the distention.
respiratory system
Circulatory shock-Some poisons cause circulatory shock. Shock occurs when vascular volume exceeds blood volume-either as a result of vasomotor failure (neurogenic shock) or asa result of blood loss (hypovolemic shock). The blood pools in peripheral vessels and cardiac return is reduced. Cardiac output likewise is reduced and becomes inadequate for body needs. Poisons cause neurogenic shock by depressing, over stimulating and fatiguing the vasomotor center or by inducing severe pain which inhibits the center reflexly. Poisons cause hypovolemic shock largely by damaging capillaries so that plasma leakage occurs. Supportive treatment consists of eleva tion of the feet to increase cardiac return, plus appropriate drug therapy. In neurogenic shock, a sympathomimetic vasoconstrictor-e.g., levarterenol, metaraminol-will support vascular tone. In hypovolemic shock, a plasma volume expander (e.g., dextran, human serum albumin) is indicated. Congestive heart failure-Poisons
Inflammatory obstruction-Inflammation of the upper respiratory tract by irritants or corrosives causes secretion and swelling that interfere with adequate ventilation of the lungs. The entire airway may be e~posed to toxiceHects by inhalation of irritants; the nasopharynx is exposed to ingested irritants. Supportive measures include tilting the patient's head back to give the best airway possible, removal of secretions and, if necessary, endotracheal intubation or tr~cheot omy to bypass the obstruction. Pulmonary edema-Exposure of the alveoli to irritants causes pneumonitis with exudation of fluids into alveolar and interstitial spaces. This interferes with gaseous exchange. Supportive treatment consists of rest in a vertical position to reduce oxygen demand and to increase vital capacity, oxygen therapy and, perhaps, administration of a bronchodilator to provide a better airway. Alveolar exposure may be by inhalation of gases, aspiration of liquids or by pulmonary excretion of volatile substances absorbed elsewhere. Respiratory failure-Respiratory failure may be caused by poisons that depress, overstimulate and fatigue the respiratory center or that paralyze the respiratory muscles. Prompt institution of artificial respiration is essential as oxygen deprivation exceeding three to five minutes causes brain damage or death. This is best accomplished with a mechanical respirator when such is available. Oxygen therapy also may be useful, especially when full respiratory movement is not possible, when obstruction cannot be elimina ted or when there is impairment of alveolar exchange, circulatory transport or tissue utilization of oxygen. Of the emergency methods of artificial respiration direct mouth-tomouth insuffiation is preferred. With
cardiovascular system
table IV nonspecific systemiC antidotes toxic agent
antidote
(1) Antidotes that induce opposing symptomspicrotoxin; eNS depressants pentyle netetrazol (e.g., barbiturate (Metrazol); overdosage) bemegride ' (Megimide); etc.amobarbital (Amytal); eNS stimulants pentobarbital (e.g., strychnine (Nembutal); etc. poisoning) (2) Antidotes that block symptom occurrencecholinesterase atropine sulfate inhibitors (e.g., parathion, malathion) (a) Other therapy for eNS depression preferred. See text.
Vol. NS9, No.5, May 1969
219
that dam'age the myocardium weaken its contractile force and induce congestive heart failure. This can be treated by rest to reduce circulatory requirements, treatment of pulmonary edema, administration of a digitalis glycoside-e.g., digoxin-to increase myocardial -contractile force and a thiazide diuretic to mobilize retained fluids. Cardiac arrhythmias-Arrhythmias occur when the initiation and conduction of electrical impulses in the heart become disordered. Halogenated hydrocarbons sensitize the myocardium so that sympathetic stimulaOther tion triggers arrhythmias. types of poison-induced derangements also occur, however. Since acute poisoning is a condition of limited duration, nonfatal arrhythmias may not require treatment. Auricular arrhythmias, in general, are of this type. Ventricular arrhythmias are more dangerous and require treatment. Ventricular tachycardia of supraventricular origin can be suppressed by parasympathetic stimulation induced by carotid sinus pressure or by a parasympathomimetic drug-e.g., methacholine, neostigmine. Bradycardia of supraventricular origin can be suppressed with a parasympathetic blocking drug-e.g., atropine. In ventricular _bradyca~dia due to AV blockage, a sympathomimetic drug-e.g., epinephrine, isoproterenol-will speed ventricular pacemaker activity, or an artificial pacemaker can be used. Ventricular nbrillation can be treated prophylactically with a myocardial depressant-e.g., quinidine-or acutely by electrical defibrillation. Cardiac arrest-In cardiac arrest, external cardiac massage-or more accurately, external cardiac compression .....,must be hegun immediately to maintain circulation until cardiac function can be restored. With the patient lying on a firm surface, the operator (preferrably an experienced individual) compresses the lower sternum with both hands, one above the other, 60 times per minute. A second operator administers mouth-to-mouth respiration, or if a second operator is not available, the single operator stops cardiac compression every 15 seconds to give two respiratory insuffiations. Measures to restore cardiac function include administration of a sympathomimetic drug-e.g., epinephrine, isoproterenol-to 'activate a quiescent heart, or electrical stimulation to arrest Rbrillation. central nervous system
The central nervous system is susceptible to several toxic mechanisms. Poisons may derange cerebral metabo222
lism-with varying degrees of selectivity and potency. Mild derangement induces delirium. More severe der.angementcauses overt functional depression. A lesser number of poisons are stimulants causing convulsions or irritants causing cerebral edema. Delirium-Delirium can be combatted by correcting contributing disturbances of oxygenation, fluid-electrolyte balance, acid-bas-e balance and by accommodation of the patient so as to minimize the eHects of his mental impairment. The latter include a distraction-free environment, personal reassurance and, if necessary, a sedative-e.g., paraldehyde, chloral hydrate. In general however; drugs are avoided. CNS depression-The chief dangers of sever-e eNS depression are respiratory and vasomotor failure. These vital functions can be maintained with mechanical support of respiration and sympathomimetic support (e.g., levarterenol, metaraminol) of blood pressure. The measur-es should be accompanied by nursing care to prevent complications of prolonged coma and immobility. Although not preferred therapy today, an analeptic-e.g., bemegride, picrotoxin-is sometimes used to stimulate the respiratory and vasomotor -centers, especially ' when other therapy is unavailable. CNS stimulation-Convulsions induced .by eNS stimulation m,ay cause physical injury due to uncontrolled motor activity, and respiratory depression and anoxia due to exhaustion of the respiratory center or to spastic paralysis during the attack. During the attack, prevention of injury is the prime consideration. Keeping the patient on the floor or on 'a bed will prevent falls. A side position with head down, if possible to maintain, will minimize aspira tion of saliva or vomitus. A firm object-e.g., a knotted handkerchief-between the teeth will prevent tongue biting. If necessary, initiate respiration after the attack. After the attack, a specific 'antidote for the poison or a nonspecific antidote for CNS stimulation-e.g., a short- or in termediate-acting barbitura te-can be administered. Cerebral edema-In oerebral edema, tissue swelling and elevated intracranial pressure compress the cerebI1al vasculature to cause cerebral anoxia, and depress the vital centers to cause respira tory depression and secondary respiratory acidosis. Intravenous infusion of a hypertonic solution-e.g., urea, mannitolwill temporarily ,mohilize fluid from the brain osmotically. Hypothermia will reduce oxygen demand and forced
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
respiration will combat the acidosis. In severe cases cerebrospinal fluid may be withdrawn from the lateral ventricles. kidneys
N ephrosis- Renal tubule degeneration may be caused by direct toxic action or by renal ischemia secondary to circulatory shock. Directly nephrotoxic poisons-e.g., heavy metalstypically da·mage the proximal tubules, causing first, cessation of absorptive function and polyuria, and then in rapid succession, tubular obstruction and oliguria or anuria. Polyuria occurs again during recovery as tubule patency is restored before absorptive function. In acute nephrosis with severe oliguria, compensation for lack of renal homeostatic control is necessary. This requires careful regulation of salt and water intake to replace only the amounts lost and control of potassium accumulation from diet and intracellular turnover. The latter can be accomplished by a low potassium diet, administration of a potassium-trapping ion-exchange resin-e.g., sodium polystyrene sulfonate-and, if necessary, peritoneal or hemodialysis. In mild nephrosis, less -rigid regulation is necessary and an osmotic diuretic-,-e.g., mannitol-may be used to maintain urine How. In any case, drugs must be used cautiously since kidney excretion of them and their metabolites is impaired. liver
Toxic hepatitis-Toxic hepatitis may result from directly hepatotoxic poisons -e.g., halogenated hydrocarbons, heavy metals-or in some cases from allergic reactions. Directly toxic poisons produce their effects consistently and these may be severe. Because of the large functional reserve of the liver,mild to moderate liver damage may be asymptomatic. . Supportive treatment consists of rest to reduce metabolic requirements; a high carbohydrate, high protein diet to support liver resistance to further damage; regulation of electrolyte disturbances, and in severe cases, therapy to counteract the metabolic consequences of inadequate liver function. Drugs that require liver detoxication for their removal must be used cautiouslY·1 In partial biliary obstruction, administration of cholestyramine resin will reduce bilirubin accumulation. In hepatic coma, ammonia accumulation may be controlled by a low protein diet along with intestinal sterilization to reduce bacterial breakdown of amino acids as 'a n ammonia source and (continued on page 231)
I
The disease strikes one in 2,500 of the U.S. population each year, with its greatest incidence in children under the age of five. In young children, when properly treated, recovery can be expected in most cases. While less frequent in older individuals, the disease takes a more serious form, with a larger percentage of the cases terminating fatally.
Accidental poisoning, of course, is not a disease. It is a health problem, however, and its impact on our society is essentially that described above. 0 It isa problem about which all of the health-oriented professions are concerned. For many years the pharmacist has played an active part in the control of accidental poisoning. He has had an educational role in reducing its occurrence ,a nd an advisory role in obtaining prompt treatment. As in his other professional activities, the pharmacist's understanding should 'go beyond the requirements for immediate performance. Specifically, this is an area of professional activity for which the pharmacist should have a basic understanding of the nature of poisons and the principles of poisoning therapy. nature of poisons, poisonings
The sciences of pharmacology and toxicology are based upon the fact that foreign chemicals can induce alterations in biological systems. This is a phenomenon that is essentially true for all chemicals, for at sufficiently high concentrations all chemicals induce biological effects. o Of 83,704 accidental ingestions reported in 1967, 86.8 percent were in children under five. Fewer deaths are consistently reported for this age group however. (Bulletin of the National Clearinghouse for Poison Control Centers, September-October 1968.)
214
If we limit consideration to chemicals that are biologically active at concentrations likely to be applied in realistic situations, we find them classined as foods, drugs or poisons depending upon the nature of the effects induced. Of the enormous spectrum of chemicals available, only a limited number are useful as foods or drugs. A much larger number induce undesirable or damaging effects and are basically poisonous. Many of the chemicals present in contemporary commercial products fall into this category and provide a constant potential for accidental poisoning.
Specifically acting and reversible poi· sons also are possible-e.g., carbon monoxide-but note that specific ac· tion need not necessarily be reversible -e.g., organic phosphate insecticides. (c) Chemicals with high reactivity are likely to react nons electively and nonreversibly with many structures within a biological system. So many physiologic disruptions occur that specific actions can not be singled out. Since reactions may be nonreversible, the biological system recovery might require repairs and replacements. Few drugs but many poisons are in this category. Moderately reactive substances that damage tissues and in· toxic mechanisms duce inflammation-e.g., tear gasesare referred to as "irritants." More Chemicals induce biological effects highly reactive poisons that cause tis· by their presence in biological syssue death-e.g., heavy metals, formal· tems and it is interesting to note that dehyde-are "protoplasmic poisons." they may do so regardless of their Very highly reactive substances-e.g., potential for chemical reaction. The strong acids and bases-that cause both following cases and mechanisms may tissue death and disintegration are be consideredcalled "corrosives." (a) Nonreactive (inert) chemicals The reactivity of a chemical is in· may induce biological effects by alterherent in its structure but also is reo ing the properties of the solvent syslated to its concentration. Greater reo tems in which they are dissolved. A activity occurs with higher concentrafew drugs and poisons appear to opertions. A poison that only irritates and ate by this mechanism but in general induces inflammation at low concen· the number of such chemicals is small. trations may be protoplasmic poison As an example, some inert organic at higher concentrations. Similarly, solvents are speculated to induce CNS a drug with specific actions when dis· depression by altering the spatial ortributed throughout the body may be ganization of cellular water molecules. , irritating at its administration site (b) Chemicals with low reactivity where it is more highly concentrated. may react selectively with only a few exposure routes chemicals (receptors) within a biological system. If these receptors are The common routes for accidental directly involved in the physiologic exposure to poisons are topical conprocesses of the system then the chemtact, oral ingestion and inhalation. All ical induces specific physiologic of them require absorption across liveffects, one or several of which may ing cells for entry into systemic circube predominant. Low reactivity often lation. In addition to systemic tox· confers reversibility as well, in which icities, exposure by any of the routes case the biological system recovers unmay result in local damage as well. damaged upon removal of the foreign Most nonphysiologic chemicals are chemical. absorbed by passive, rather than aCMost drugs fall into this category tive, transport 'across cell 'm embranes. and induce relatively specific, reversExcept for very small molecules which ible, therapeutically useful effects.
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
may penetrate membrane pores along with water, most chemicals are passively absorbed by dissolution in the lipids of the cell membranes. Lipidsolubility is necessary as well as watersolubility in the adjacent 'aqueous phases and the ratio between the two will determine relative capacity for absorption. In the case of ionizable compounds, the nonionized form (being more lipid-soluble) is the more readily absorbed. The skin is not primarily an absorbing organ. Its dead cornified outer surface impedes the approach of chemicals to the living inner layers. However, when the inner layers are exposed, lipid-soluble substances are absorbed. Still the amount reaching systemic circulation will likely be small unless the contaminated skin area is large, the skin is damaged-e.g., abraded, bumed-or the solvent involved promotes penetration. Topical absorption can be reduced by prompt decontamination. The skin is susceptible to varying degrees of local damage. Mildly reactive substances may affect the dead surface only. More reactive substances may cause irritation of deeper layers. Highly reactive substances cause corrosion, often before decontamination can be accomplished. Oral ingestion exposes poisons to me mucous membranes of the gastrointestinal tract through which substances can be rapidly absorbed into systemic circulation. Absorption rates will vary with the solubility and ionization properties of the poison at the pH's encountered. Other factors being equal, weak acids are more rapidly absorbed in the stomach where they are less ionized (and more lipid-soluble) 'at the acid pH and weak bases are more rapidly absorbed in the intestinal tract where they are less ionized at the basic pH. As for local effects, ingested irritants induce nausea and vomiting and more reactive compounds may cause necrosis and corrosion. Inhaled gases reach the alveoli of the lungs where they are very rapidly absorbed into circulation. Dusts, unless of very small particle size, tend to be deposited in the upper respiratory passages. Mildly irritating substances may be deeply inhaled. More severe irritants are not because they induce reflex brea th-holding. Depending upon site, local damage may take the fonn of tracheitis, bronchitis, and/or pneumonitis. termination of exposure
The elimination of absorbed poisons is accomplished by mechanisms that remove unneeded foreign substances
from the body. The two basic patterns are (a) excretion unchanged and (b) biot,ransformation followed by excretion. The relative utilization of these patterns depends upon the physical and chemical properties of the particular poison. In the mechanics of urine formation, all except the macromole.cular constituents of plasma filter into the kidney tubules. Reabsorption of various substances then occurs and the residue is excreted las urine. In general, essential m'etalbolites are reabsorbed and retained individually by active processes, and lipid-soluble substances 'a re passively reabsorbed and retained as a class. It follows that poisons of low lipid-solubility are poorly reabsorbed and are excreted unchanged by the kidneys. Many of the retained lipid-soluble substances undergo biotransformation. The changes that occur increase water/lipid solubility ratio to the point that urinary or biliary excretion is possible. Most often water solubility is increased by introduction of hydroxyl radicals, reduction of molecular size or linkage (conjugation) with a highly water-soluble compound such as glucuronic acid. Most biotransformation of foreign substances occurs in the liver. The group of hepatic enzymes commonly involved are those of the endoplasmic reticulum. These enzymes are often referred to as the hepatic microsomal enzymes. Since the liver and kidneys are the organs primarily involved in the metabolism and elimination of poisons and since reactive substances in contact with tissues can cause local damage, it is not surprising that liver and kidney damage are common ,consequences of systemic poisonings. emptying the stomach
induction of emesis Indications-Emesis can be employed in all situations e~cept those in which the violent physical activity m,a y be dangerous. Such contraindications include ( a ) unconsciousness-aspiration of vomitus may occur, (b) kerosene ingestion-effects of 'aspiration are particularly dangerous, ( c ) corrosive damage to the esophagus and associated structures-perforation m'a yoccur and ( d) health conditions that may be adversely affected-cardiac disease, pregnancy, etc. PhYsiology-Vomiting is a complex activity coordinated by the vomiting center located in the reticular formation of the medulla. The vomiting center can be activated-and vomiting induced-in several ways. Irritation
of the upper GI tract initiates impulses that activate it and so does chemical stimulation of the chemoreceptor trigger zone (CTZ) located nearby in the brain. With these two mechanisms, a chemical may induce vomiting both before and after absorption from the GI tract. Regardless of the inducing mechanism, however, .vomiting does not occur if the vomiting center is depressed, either selectively by drugs or as ,a consequence of 'generalized central nervous system depression. Also CTZmediated vomiting does not occur if the CTZ is blocked by drugs such as chlorpromazine. Therapeutic induction- ( 1) Many poisons automatically induce vomiting, either by GI irritation or by stimulation of the CTZ after some absorption has occurred. (2) Gagging will induce vomiting and this may be accomplished by tickling the back of the throat with a finger or spoon handle. Vomiting induced in this manner tends not to be persistent, however, because the stimulus cannot be continued once the vomiting starts. Consequently, gaginduced vomiting may not be effective in 'emptying the stomach completely. Gag-induced vomiting is more effective when an irritant is present in the stom'ach to synergize the action. This might be the poison itself or the prior administration of a mild irritant solution such as warm salt water, warm soapy water or warm mustard water. However, in the event that such a solution is administered and vomiting does not occur, the dilution of the poison that occurs m'ay be undesirable. Although dilution reduces the concentration gradient for absorption, the increased volume coupled with th·e great surface area of the GI tract may result in faster absorption. (3) Ipecac syrup may be administered orally to induce vomiting. The usual dose is 15 ml. Ipecac contains emetine and other principles that irritate the GI tract locally and stimulate the CTZ after absorption. Ipecac induces vomiting persistent enough to empty the stomach. Its chief disadvantage is that its action is delayed. Average induction time is about 20 minutes, which means that it is even longer in some cases. This is a significant delay when a potent poison has been ingested. ( 4) Apomorphine's most prominent action is direct stimulation of the CTZ and it is a potent emetic provided the CTZ is not blocked or the vomiting center depressed. It is not suitable for home medicine chests since it must be administered parenterally. As conventionally used (5 mg subcutaneously for adults) , apomorVol. NS9. No.5, May 1969
215
H. Douglas Johnson is associate professor of
pharmacology at the University of Georgia school of pharmacy. He earned his BS, MS and PhD from the University of Florida and has been employed in the area of pharmaceutical education since earning his PhD. Active in many capacities within the university community, Johnson has published several scientific and professional articles and developed professional exhibits at the University of Georgia school of pharmacy. APhA life-member Johnson also is a member of AIHP, Georgia Pharmaceutical Association, Rho .chi, Kappa Psi and Sigma Xi.
phine does not induce ideal emesis. Its .a ction is delayed five to ten minutes and it persists for some time and may exhaust the patient. A morphine antagonist (e.g., nalophine, levallorphan) may be used to terminate prolonged vomiting or a smaller dose of apomorphine ma y be given intravenously. Doses of 1-30 mcg/ Kg IV .i nduce almost immediate vomiting that lasts for only one to two minutes. ( 5) Substances such as copper sulfate and antimony potassium tartrate -tartar emetic-should not be used as emetics as they are inherently toxic themselves. Should vomiting not occur, they would be retained and contribute to the toxic syndrome.
gastric lavage Indications-In general, gastric lavage is worthwhile during the first three hours after ingestion of a poison. Its benefits, however, decrease with the passage of time and the systemic absorption of the poison. Lavage may be of value for a somewhat longer period if there is reason to expect delayed stomach emptying. Irritation-and therefore an irritant poison-delays emptying, as do fat or protein solutions that may be administered for this purpose. Comparison to emesis- (1) Lavage requires special equipment and technic and generally can be carried out only by professional personnel in medical treatment centers. (2) Lavage is considered by some to be more effective than emesis since fluids are introduced to wash the stomach and because the process can be repeated as long as necessary. Lavage is undoubtedly effective for removing suspensions 'a nd substances in solution. However, it is not as effective as emesis for removing larger solids as partially dissolved capsules. Neither will it completely remove 216
finely divided solids-as shown by x-rays after barium sulfate ingestion. ( 3) Lavage has fewer ·c ontraindications than emesis since there is less chance for 'a spiration and less physical activity. Lavage can be performed with the unconscious, after kerosene, and in the debilitated where emesis would be dangerous. Lavage is still contraindicated after corrosive poisons since it, too, could cause perforation. It also is contraindicated ,a fter central nervous system stimulants, in which case the manipulation might induce convulsions. Operative principles- With proper technic, a lavage tube is introduced into the stomach of the patient. The patient may be conscious or anesthetized. If anesthetized, the use of an endotracheal tube will further insure against aspiration. The lavage fluid is then injected, the patient turned to allow mixing and the fluid withdrawn. The procedure is repeated until the washings are clear. Water may be used as the lavage fluid. However, if the identity of the poison is known, a neutralizing solution or a poorly absorbed solvent for
the poison may be used to better advantage. Since the lavage fluid is not left in the body, the range of neutralizing chemicals that may be safely used is greater than it would be otherwise. A number of neutralizing solutions and solvents are listed in table 1. When lavage is complete, any indicated drugs may be administered through the tube before it is withdrawn. administration of adsorbents
activated charcoal Indications-Activated charcoal has a good capacity for adsorbing a wide variety of chemicals and is the best therapeutic adsorbent available. Its activity is not unlimited however. Not all chemicals are equally well adsorbed and a few-cyanides, for example-are very poorly adsorbed. Nevertheless, the administration of activated charcoal is considered to be a routinely useful procedure. In view of the delayed emetic action of ipecac syrup, there is a growing speculation that activated charcoal may be of more real value in the home medicine chest as an emergency treatment for acciden tal poisoning. Adsorption properties-In the adsorption process, nonionized chemical is deposited on the charcoal surface. Ionizable poisons are adsorbed more readily under pH conditions that inhibit ionization. In the stomach, weak acids are more rapidly adsorbed than weak bases. Bases are adsorbed, however, for there is always some nonionized form in equilibrium with the ionized. Adsorption is reversible 'a nd poisons so bound are withheld only temporarily from systemic absorption. The charcoal-poison complex must therefore be removed from the body for permanent poison control. Removal may be speeded by emesis, lavage or catharsis. However, even if left to
table I lavage solutions and solvents toxic agent
lavage fluid
organic poisonsalkaloids organic acids, oxalates oxidizable substances phenol
tannic acid, 4 percent lime water; calcium lactate, 1-3 percent potassium permanganate, 1:5000 vegetable oil
inorganic poisonsheavy metal salts iron, copper salts lead, barium salts mercury salts thallium salts yellow phosphorus cyanides, hypochlorites iodides fluorides
protein solutions potassium ferrocyanide, 0.1 percent sodium sulfate, magnesium sulfate solution sodium formaldehyde sulfoxalate, 5 percent sodium iodide, potassium iodide, 1 perce nt mineral oil; copper sulfate, 0.2 percent sodium thiosulfate, 5 percent starch solution lime water; calcium lactate, 1-3 percen t
(Adapted from Gleason, M.N., et ~/. : Clinic~1 Toxicology of Commerci~1 Products, second ed it ion, Williams and Wilkins Company, Baltimore, 1963.)
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
normal gastrointestinal elimination cIharcoal admin!stration is still useful: t slows systemIC absorption and since s~stemic elimination processes are con~muous the peak poison level reached III the body is reduced. . A~tivated charcoal makes no distmctIon between food, drug or poison?~s chemicals and all are in competItIon for its 'a dsorptive capacity. !hus the presence of other substances m the stomach may interfer'e with its adsorption of poisons. Similarly, the presence of adsorbed indigenous chemicals in plain charcoal and burnt toast makes these virtually useless as adsorbents. Use with emetics-Orally administe~ed e~etics given simultaneously ~Ith 'a ctIvated charcoal are antagonistIc. The emetic is adsorbed onto the charcoal, losing its emetic potency and reducing the adsorptive capacity of the charcoal. ~n oral emetic (with emesis) is a SUItable procedure before activated charcoal; administered afterwards it may not induce emesis. Parent~ral emetics are of course active after charcoal.
universal antidote Rationale-Universal antidote usually contains two parts activated charcoal, one part tannic acid and one part magnesium oxide. The tannic acid is intended to precipitate plant principles and the magnesium oxide to neutralize stomach acid so as to reduce solubilization of metallic salts. The chief value of the product, however, lies in the adsorbent properties of the activated charcoal. Comparison with activated charcoal - Recent studies have shown that activated charcoal alone is more effective than universal antidote, even when the dose of the antidote is such that an equal amount .of activated charcoal is administered. This is because the other ingredients of universal antidote adsorb onto its activated charcoal and reduce adsorptive capacity. speeding intestinal elimination
catharsis Indications-Catharsis speeds passage of materials through the intestinal tract and decreases the time available for their systemic absorption. The reduction in time is not significant in the case of rapidly absorbed substances, but it is beneficial when poison absorption is slow, either innately so or as the result of prior administration of activated charcoal. Catharsis is also useful in the removal of conjugated poisons excreted into the bile. The conjugates are usually slowly absorbable substances. Ca-
table II
potential liver microsomal enzyme IndUCing drugs* pharmacologic category
drug
sedative·hypnotics
ba r qitu rates glutethimide (Doriden) methaprylon (Noludar)
anticonvulsants
diphenylhydantoin (Dilantin) mephenytoin (Mesantoin) paramethadione (Paradione)
tranquilizers
chlordiazepoxide (Librium) meprobamate (Equanil, Miltown) phenaglycodol (Ultran) chlorpromazine (Thorazine) promazine (Sparine)
muscle relaxants
carisoprodol (Rela, Soma) orphenadrine (Norflex)
hypoglycem ics
tolbutamide (Orinase)
antihistamines
diphenhydramine (8enadryl) chlorcyclizine
a nti-infla m matories
phenylbutazone (Butazolidin) cortisone prednisolone
androgens
testosterone
progestins
norethynodrel
(Adapted from Conney, A.H., Pharm~col , Rev., 19. 317,1967.) * Note-There has, been n
tharsis is contraindicated in the case of irritant poisons. Choice of cathartic-Sodium sulfate is a suitable cathartic for the elimination of unabsorbed poisons. The goal is to maintain high bulk and fast flow rate throughout the entire intestinal tract and saline cathartics do this more effectively than other types of cathartics. Furthermore, sodium sulfate is nontoxic if absorbed. systemic poison level reduction
At present, alteration of biotransformation is largely of theoretical consideration in the treatment of acute poisoning.
liver microsomal enzyme induction A number of drugs induce synthesis of the liver microsomal enzymes that metabolize lipophyllic foreign chemicals and speed their elimination from the body. Such an approach to acute poisoning therapy is 'Of little value, however, because the induction process is so slow. Typically, several hours pass after administration of an inducer before induction begins and several days pass before maximum effects are achieved. To be useful during the acute period, induction therapy would have to be begun before poisoning occurred-a logistically impossible situation. Incidental microsomal enzyme induction, on the other hand, may play a role in recovery from acute poisoning. If the patient previously has been
taking an inducer drug for some other purpose-sedative doses of phenobarbital, for example-he will be in a better position to eliminate metabo~1any commonly lizable poisons. used drugs are potential liver microsnmal enzyme inducers (see table II).
liver microsomal enzyme inhibition A different relationship exists for poisons that are inactive as ingested and are metabolized to their toxic forms. Enzyme induction enhances their acute toxicity, and theoretically enzyme inhibition should reduce their toxicity. A number of microsomal enzyme inhibitors are known. However, at present they appear to be of little therapeutic. value. Although they retard the appearance of the toxic form, they also prolong its duration by inh1biting further degradation and elimination. acceleration of elimination
speeding kidney excretion Indications-Hydrophilic poisons are readily excreted by the kidneys because they are poorly reabsorbed passively in the renal tubules. Lipophyllic poisons, on the other hand-because they are weII reabsorbed passivelyare slowly excreted and it is for these poisons that accelerated elimination is needed. Not surprisingly, accelerated excretion of lipophyllic poisons can be achieved by inhibiting passive reabsorption. Either or both of the following technics may be used. Vol. NS9, No.5, May 1969
217
Reduction of concentration gradient -The gradient for passive tubule reabsorption is usually high since the renal filtrate is concentrated as it passes down the tubules. Retention of water in the filtrate will reduce this gradient and can be accomplished by the 'administration of an osmotic diuretic. Of the various types of diuretics, the osmotic diuretics-e.g., urea, mannitol-are the best suited. They are active throughout the length of the renal tubule ( while water diuresis alters distal tubule dynamics chiefly). Since they do not affect active reabsorption, they are less likely than other diuretics to induce serious electrolyte disturbances. The excretion of all passively reabsorbed poisons can be accelerated by osmotic diuresis. Such therapy may reduce the body half-life of a poison to 50 percent of its original value. Ionic trapping-In the case of ionizable poisons, passive reabsorption can be reduced by adjusting the pH of the tubule filtrate 'So that the poison is ionized. Normal urine, being acid, is already so suited for excretion of weak bases. Such excretion can be enhanced by making the urine strongly acid. However, the greater therapeutic opportunity arises with acid poisons, in which case the urine can be alkalinized. Alkalinization of the urine can be accomplished by oral or parenteral administration of a systemic antacid such
as sodium lactate, sodium bicarbonate, etc. Alkalinization significantly increases the excretion rate of weakly acid poisons.
hemodialysis 1ndications-In hemodialysis, unwanted solutes in the blood are allowed to diffuse across a semipermeable membrane into a solution (dialysate) provided by the therapist. This procedure can be used to remove a wide variety of poisons from the body, particularly in situations where the . physiologic removal rate is inadequate. Such situ'ations may include renal failure, poisons with innately slow excretion rates and severe poisonings in which large amounts of poison are present. Generally, hemodialysis is not needed for poisons that are rapidly metabolized or excreted and it is not very effective for poisons that ,are intensively bound to plasma proteins. General procedures-In peritoneal dialysis, the membranes of the abdominal cavity and organs serve as the dialysis membrane, and the dialysate is provided by instilling 'a suitable solution into the cavity -a nd exchanging it every one to two hours. This is a relatively simple procedure and is roughly equivalent to osmotic diuresis in speeding poison removal. In extracorporeal hemodialysis, the patient's blood is circulated through a machine-'artiflcial kidney-in which the blood and dialysate are separated
table III specific systemic antidotes toxic agent
antidote
(1) Antidotes that reduce the level of the toxic substance-
arsenic, mercury copper lead, plutonium, uranium strontium, radium bromide cyanide fluoroacetate methanol drug overdosages-heparln
dimercaprol (BAL in Oil)" penicillamine (Cuprimine)a caNa2 EDTA (CaNa2 Versenate)a calcium saltsd chlorides d sodium nitrite a and sodium thiosulfateo monacetin; actatesb ethanolb protamine sulfatea
(2) Antidotes that protect or restore receptors-
carbon monoxide cholinesterase inhibitors (e.g., parathion, malathion) drug overdosagescoumarin-type anticoagulants curare derivatives narcotics
oxygene pralidoxime (Protopam)f phytonadione (Mephyton, etc.)e edrophonium (Tensilon): neostigmine (Prostigmin)e nalorphine (Nalline); levallorphan (Lorfan)e
(3) Antidotes that repair or bypass the biochemical lesion-
methemoglobin inducers (e.g., aniline) drug overdosages5·fluorouracil 6-mercaptopurine (Purinethol) methotrexate (Amethopterin)
methylene blue' thymidine h adenine, hypoxanthineh folinic acid (Leucovorin)h
(a) reacts with toxic agent (d) promotes excretion (nitrites induce methemoglobin which reacts (e) competes for receptors with cyanide) (f) restores receptors (b) inhibits metabolic activation (g) repairs biochemical lesion (c) enhances metabolic inactivation (h) bypasses biochemical lesion (Adapted from Goldstein, A., d .,1., Principles of Drug Action, Hoeber Medical Division, Harper and Row, New York, 1968.)
218
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
by a semipenneablecellophane membrane. Specialized equipment and technics are required. The process is highly efficient and the body half-life of a poison may be reduced to 25 percent of its original value. The passage of a solute across a dialysis membrane occurs passively, with the solute moving when there is a concentration gradient. The dialysate then must contain the normal plasma solutes so that these do not leave the body and its poison concentration must be kept low so that the poison will dialyse effectively. The dialysate must be replaced regularly, either continuously as in extracorporeal hemodialysis or intermittently as in peritoneal dialysis. Measures to increase effi,ciencyProcedures that trap the poison in the dialysate and prevent back-diffusion increase efficiency. Many poisons bind to proteins to some extent and their dialysis can be enhanced by adding nve percent albwnin to the dialysate. Also, since substances dialyse in nonionized form, back-diffusion can be reduced by adjusting dialysate pH so that the poison is ionized. The pH·s required for maximum efficiency are nonphysiologic. Consequently this latter procedure is limited to extracorporeal hemodialysis. Back-diffusion of lipophyllic poisons also may be reduced by the use of a lipid dialysate. systemic antidotes
lndications-Systemic antidotes reduce the toxic effects of absorbed poisons. They are indicated when systemic absorption cannot be prevented and they may be used in conjunction with general measures to promote poison removal. Systemic antidotes can be administered only ( a ) when the identity of the poison is known 'a nd (b) when an antidote for it exists. Of these two qualifications, antidote existence is the more restrictive. Only a relatively few poisons have systemic antidotes (see tables III, below left and W on opposite page) . Specific vs. nonspecific antidotesSystemic antidotal mechanisms can be classified as specmc or nonspecific, depending upon whether they actually alter some element of the toxic mechanism or only oppose the toxic symptoms produced. Specific antidotesi.e., those that act upon the poisons, its receptors or the resulting biochemical lesion-are the more effective. Nonspecific antidotes are essentially no more than symptomatic treabnent. specific antidotes
Mechanisms-A number of specific antidotes reduce the effective level of
the toxic substance in the body. Some ~eact with ,a nd inactivate the poison ltself-for example, dimercaprol complexes ·w ith arsenic or mercury. Others alter the metabolism of the poison, either inhibiting its toxic activation as ethanol does in methanol poisoning or accelerating its inactivation as sodium thiosuHate does in cy'a nide poisoning. In some cases excretion of the poison may be increased, as strontium excretion is enhanced by calcium administration. Antidotes that reduce poison levels are basically protective rather than restorative. However, if the poisonreceptor reaction is reversible, subsequent re-establishment of equilibrium will free previously bound receptors and a degree of restoration is introduced.. Some specific antidotes react with body receptors rather than with the poison. Most of them give competitive protection by virtue of their greater affinity for the receptors. Again, if the poison-receptor reaction is reversible, the benefits may be restorative as well. This is true in nalorphine reversal of morphine action for example. Few antidotes can disrupt nonreversible poison-receptor complexes. One important case, however, is pralidoxime, the antidote for the cholinesterase inhibitor insecticides. Pralidoxime reacts with the poison-receptor complex, displaces the insecticide and then frees the cholinesterase. Finally, a few antidotes repair or bypass the toxic biochemical lesion to give restorative action. As examples, methylene blue reduces methemoglobin back to hemoglobin in aniline poisoning and folinic ,acid bypasses the effects of overdosage with folic acid antagonists. nonspecific antidotes
M echanisms-If no specific antidote exists or·if none is available, then administration of a nonspecific antagonistmay be worthwhile. Such antidotes oppose only the symptoms of a poison and although the toxic mechanism still occurs, its effects may be minimized. Nonspecific 'antagonism can be accomplished either by inducing opposite symptoms or by blocking response of the symptom-producing mechanism. As examples, CNS stimulants induce opposing symptoms in poisoning with eNS depressants and atropine blocks response to the aocumulated acetylcholine in poisoning with cholinesterase inhibitors. . supportive treatment
Indications-Specific antidotes are not known for many poisons. Even
when an antidote is lavailable, rarely can all toxicities be reversed without some residual effects-either of the poison or of the antidote. Recovery in such cases will depend upon the ability of the body to withstand the toxic eHects until the poison is eliminated and repair instituted. Organs and systems that are fully adequate for nonnal physiologic dem'a nds may not be adequate to meet the demands of -a toxic situation. Supportive therapy, then, consists of measures to maintain vital functions during the critical period so that recovery can occur. Supportive treatment is indicated in all symptomatic poisonings and it is equal in importance to proper antidotal therapy.
the patient's head tilted far back to give a good airway and his nose pinched shut, ·t he operator takes a deep breath, seals his mouth over the patient's mouth and inHates the patient's lungs. Such direct contact is suitable except when a very potent poison has been ingested orally. In this event, 'a gauze pad or mechanical airway will protect the operator from exposure. Respiration of an adult requires insuffiations of about twice normal tidal volume 12 times per minute. Children require smaller, more frequent insuffiations. If the stomach becomes inflated, gentle epigastric compression will eliminate the distention.
respiratory system
Circulatory shock-Some poisons cause circulatory shock. Shock occurs when vascular volume exceeds blood volume-either as a result of vasomotor failure (neurogenic shock) or asa result of blood loss (hypovolemic shock). The blood pools in peripheral vessels and cardiac return is reduced. Cardiac output likewise is reduced and becomes inadequate for body needs. Poisons cause neurogenic shock by depressing, over stimulating and fatiguing the vasomotor center or by inducing severe pain which inhibits the center reflexly. Poisons cause hypovolemic shock largely by damaging capillaries so that plasma leakage occurs. Supportive treatment consists of eleva tion of the feet to increase cardiac return, plus appropriate drug therapy. In neurogenic shock, a sympathomimetic vasoconstrictor-e.g., levarterenol, metaraminol-will support vascular tone. In hypovolemic shock, a plasma volume expander (e.g., dextran, human serum albumin) is indicated. Congestive heart failure-Poisons
Inflammatory obstruction-Inflammation of the upper respiratory tract by irritants or corrosives causes secretion and swelling that interfere with adequate ventilation of the lungs. The entire airway may be e~posed to toxiceHects by inhalation of irritants; the nasopharynx is exposed to ingested irritants. Supportive measures include tilting the patient's head back to give the best airway possible, removal of secretions and, if necessary, endotracheal intubation or tr~cheot omy to bypass the obstruction. Pulmonary edema-Exposure of the alveoli to irritants causes pneumonitis with exudation of fluids into alveolar and interstitial spaces. This interferes with gaseous exchange. Supportive treatment consists of rest in a vertical position to reduce oxygen demand and to increase vital capacity, oxygen therapy and, perhaps, administration of a bronchodilator to provide a better airway. Alveolar exposure may be by inhalation of gases, aspiration of liquids or by pulmonary excretion of volatile substances absorbed elsewhere. Respiratory failure-Respiratory failure may be caused by poisons that depress, overstimulate and fatigue the respiratory center or that paralyze the respiratory muscles. Prompt institution of artificial respiration is essential as oxygen deprivation exceeding three to five minutes causes brain damage or death. This is best accomplished with a mechanical respirator when such is available. Oxygen therapy also may be useful, especially when full respiratory movement is not possible, when obstruction cannot be elimina ted or when there is impairment of alveolar exchange, circulatory transport or tissue utilization of oxygen. Of the emergency methods of artificial respiration direct mouth-tomouth insuffiation is preferred. With
cardiovascular system
table IV nonspecific systemiC antidotes toxic agent
antidote
(1) Antidotes that induce opposing symptomspicrotoxin; eNS depressants pentyle netetrazol (e.g., barbiturate (Metrazol); overdosage) bemegride ' (Megimide); etc.amobarbital (Amytal); eNS stimulants pentobarbital (e.g., strychnine (Nembutal); etc. poisoning) (2) Antidotes that block symptom occurrencecholinesterase atropine sulfate inhibitors (e.g., parathion, malathion) (a) Other therapy for eNS depression preferred. See text.
Vol. NS9, No.5, May 1969
219
that dam'age the myocardium weaken its contractile force and induce congestive heart failure. This can be treated by rest to reduce circulatory requirements, treatment of pulmonary edema, administration of a digitalis glycoside-e.g., digoxin-to increase myocardial -contractile force and a thiazide diuretic to mobilize retained fluids. Cardiac arrhythmias-Arrhythmias occur when the initiation and conduction of electrical impulses in the heart become disordered. Halogenated hydrocarbons sensitize the myocardium so that sympathetic stimulaOther tion triggers arrhythmias. types of poison-induced derangements also occur, however. Since acute poisoning is a condition of limited duration, nonfatal arrhythmias may not require treatment. Auricular arrhythmias, in general, are of this type. Ventricular arrhythmias are more dangerous and require treatment. Ventricular tachycardia of supraventricular origin can be suppressed by parasympathetic stimulation induced by carotid sinus pressure or by a parasympathomimetic drug-e.g., methacholine, neostigmine. Bradycardia of supraventricular origin can be suppressed with a parasympathetic blocking drug-e.g., atropine. In ventricular _bradyca~dia due to AV blockage, a sympathomimetic drug-e.g., epinephrine, isoproterenol-will speed ventricular pacemaker activity, or an artificial pacemaker can be used. Ventricular nbrillation can be treated prophylactically with a myocardial depressant-e.g., quinidine-or acutely by electrical defibrillation. Cardiac arrest-In cardiac arrest, external cardiac massage-or more accurately, external cardiac compression .....,must be hegun immediately to maintain circulation until cardiac function can be restored. With the patient lying on a firm surface, the operator (preferrably an experienced individual) compresses the lower sternum with both hands, one above the other, 60 times per minute. A second operator administers mouth-to-mouth respiration, or if a second operator is not available, the single operator stops cardiac compression every 15 seconds to give two respiratory insuffiations. Measures to restore cardiac function include administration of a sympathomimetic drug-e.g., epinephrine, isoproterenol-to 'activate a quiescent heart, or electrical stimulation to arrest Rbrillation. central nervous system
The central nervous system is susceptible to several toxic mechanisms. Poisons may derange cerebral metabo222
lism-with varying degrees of selectivity and potency. Mild derangement induces delirium. More severe der.angementcauses overt functional depression. A lesser number of poisons are stimulants causing convulsions or irritants causing cerebral edema. Delirium-Delirium can be combatted by correcting contributing disturbances of oxygenation, fluid-electrolyte balance, acid-bas-e balance and by accommodation of the patient so as to minimize the eHects of his mental impairment. The latter include a distraction-free environment, personal reassurance and, if necessary, a sedative-e.g., paraldehyde, chloral hydrate. In general however; drugs are avoided. CNS depression-The chief dangers of sever-e eNS depression are respiratory and vasomotor failure. These vital functions can be maintained with mechanical support of respiration and sympathomimetic support (e.g., levarterenol, metaraminol) of blood pressure. The measur-es should be accompanied by nursing care to prevent complications of prolonged coma and immobility. Although not preferred therapy today, an analeptic-e.g., bemegride, picrotoxin-is sometimes used to stimulate the respiratory and vasomotor -centers, especially ' when other therapy is unavailable. CNS stimulation-Convulsions induced .by eNS stimulation m,ay cause physical injury due to uncontrolled motor activity, and respiratory depression and anoxia due to exhaustion of the respiratory center or to spastic paralysis during the attack. During the attack, prevention of injury is the prime consideration. Keeping the patient on the floor or on 'a bed will prevent falls. A side position with head down, if possible to maintain, will minimize aspira tion of saliva or vomitus. A firm object-e.g., a knotted handkerchief-between the teeth will prevent tongue biting. If necessary, initiate respiration after the attack. After the attack, a specific 'antidote for the poison or a nonspecific antidote for CNS stimulation-e.g., a short- or in termediate-acting barbitura te-can be administered. Cerebral edema-In oerebral edema, tissue swelling and elevated intracranial pressure compress the cerebI1al vasculature to cause cerebral anoxia, and depress the vital centers to cause respira tory depression and secondary respiratory acidosis. Intravenous infusion of a hypertonic solution-e.g., urea, mannitolwill temporarily ,mohilize fluid from the brain osmotically. Hypothermia will reduce oxygen demand and forced
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
respiration will combat the acidosis. In severe cases cerebrospinal fluid may be withdrawn from the lateral ventricles. kidneys
N ephrosis- Renal tubule degeneration may be caused by direct toxic action or by renal ischemia secondary to circulatory shock. Directly nephrotoxic poisons-e.g., heavy metalstypically da·mage the proximal tubules, causing first, cessation of absorptive function and polyuria, and then in rapid succession, tubular obstruction and oliguria or anuria. Polyuria occurs again during recovery as tubule patency is restored before absorptive function. In acute nephrosis with severe oliguria, compensation for lack of renal homeostatic control is necessary. This requires careful regulation of salt and water intake to replace only the amounts lost and control of potassium accumulation from diet and intracellular turnover. The latter can be accomplished by a low potassium diet, administration of a potassium-trapping ion-exchange resin-e.g., sodium polystyrene sulfonate-and, if necessary, peritoneal or hemodialysis. In mild nephrosis, less -rigid regulation is necessary and an osmotic diuretic-,-e.g., mannitol-may be used to maintain urine How. In any case, drugs must be used cautiously since kidney excretion of them and their metabolites is impaired. liver
Toxic hepatitis-Toxic hepatitis may result from directly hepatotoxic poisons -e.g., halogenated hydrocarbons, heavy metals-or in some cases from allergic reactions. Directly toxic poisons produce their effects consistently and these may be severe. Because of the large functional reserve of the liver,mild to moderate liver damage may be asymptomatic. . Supportive treatment consists of rest to reduce metabolic requirements; a high carbohydrate, high protein diet to support liver resistance to further damage; regulation of electrolyte disturbances, and in severe cases, therapy to counteract the metabolic consequences of inadequate liver function. Drugs that require liver detoxication for their removal must be used cautiouslY·1 In partial biliary obstruction, administration of cholestyramine resin will reduce bilirubin accumulation. In hepatic coma, ammonia accumulation may be controlled by a low protein diet along with intestinal sterilization to reduce bacterial breakdown of amino acids as 'a n ammonia source and (continued on page 231)