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“Reversible” Carbamate Inhibitors
Therapeutically useful drugs of this class of interest are shown in Figure 8–2; the essential moiety of physostigmine is a methylcarbamate of an amine-substituted phenol. An increase in anti-ChE potency and duration of action results from the linking of two quaternary ammonium moieties.
One such example is the miotic agent demecarium (2 neostigmine molecules connected by a series of 10 methylene groups). The second quaternary group confers additional stability to the drug-AChE interaction. Carbamoylating inhibitors with high lipid solubilities (e.g., rivastigmine), which readily cross the blood–brain barrier and have longer durations of action, are approved or in clinical trial for the treatment of Alzheimer’s disease (see Chapter 20).
The carbamate insecticides carbaryl (SEVIN),propoxur (BAYGON), and aldicarb (TEMIK), which are used extensively as garden insecticides, inhibit ChE in a fashion identical with other car-bamoylating inhibitors.
Organophosphorus Compounds
The prototypic compound is DFP, which produces virtually irreversible inactivation of AChE and other esterases by alkylphosphorylation. Its high lipid solubility, low molecular weight, and volatility facilitate inhalation, transdermal absorption, and penetration into the CNS. After desul-furation, the insecticides in current use form the dimethoxy or diethoxyphosphoryl enzyme.
Malathion, parathion, and methylparathion have been popular insecticides. Acute and chronic toxicity has limited the use of parathion and methylparathion, and potentially less hazardous compounds have replaced them. The parent compounds are inactive in inhibiting AChE in vitro;
they must be activated in vivo via a phosphoryl oxygen for sulfur substitution (phosphothioate to FIGURE 8–1 Steps in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of AChE. Only the three residues of the catalytic triad are depicted. The associations and reactions shown are: A. Acetyl-choline (ACh) catalysis: binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by edrophonium. C. Neostigmine reaction with and inhibition of acetylcholinesterase (AChE): reversible bind-ing of neostigmine, formation of the dimethyl carbamoyl enzyme, slow hydrolysis of the dimethyl carbamoyl enzyme.
D. Diisopropyl fluorophosphate (DFP) reaction and inhibition of AChE: reversible binding of DFP, formation of the diisopropyl phosphoryl enzyme, formation of the aged monoisopropyl phosphoryl enzyme. Hydrolysis of the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl phosphoryl enzyme is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state of ACh hydrolysis resembles the conjugates formed by the tetrahedral phosphate inhibitors and accounts for their potency. Amide bond hydrogens from Gly 121 and 122 stabilize the carbonyl and phorphoryl oxygens. E. Reactivation of the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack of the phosphorus on the phosphorylated enzyme will form a phospho-oxime with regeneration of active enzyme.
phosphate), a conversion carried out predominantly by hepatic CYPs. This reaction also occurs in the insect, typically with more efficiency. Other insecticides possessing the phosphorothioate structure have been widely employed, including diazinon (SPECTRACIDE, others) and chlorpyrifos (DURSBAN,LORSBAN). Chlorpyrifos recently has been placed under restricted use because of evi-dence of chronic toxicity in the newborn animal. For the same reason, diazinon has been banned in the U.S.
i-C3H7O
i-C3H7O P
O
F
CH3O
CH3O P
O
S CHCOOC2H5 CH2COOC2H5
CH3O
CH3O P
S
S CHCOOC2H5 CH2COOC2H5 FIGURE 8–2 Representative “reversible” anticholinesterase agents employed clinically.
DFP Malathion Malaoxon
Malathion (CHEMATHION,MALA-SPRAY) requires conversion to malaoxon (replacement of a sulfur atom with oxygen in vivo, conferring resistance to mammalian species). Malathion can be detox-ified by hydrolysis of the carboxyl ester linkage by plasma carboxylesterases, and plasma car-boxylesterase activity dictates species resistance to malathion. The detoxification reaction is much more rapid in mammals and birds than in insects. Malathion has been employed in aerial spray-ing of relatively populous areas for control of Mediterranean fruit flies and mosquitoes that harbor and transmit viruses harmful to human beings (e.g., West Nile encephalitis virus). Evi-dence of acute toxicity from malathion arises only with suicide attempts or deliberate poisoning.
(diisopropyl fluorophosphate)
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The lethal dose in mammals is ∼1 g/kg. Exposure to the skin results in a small fraction (<10%) of systemic absorption. Malathion is used topically in the treatment of pediculosis (lice) infestations.
Among the quaternary ammonium organophosphorus compounds, only echothiophate is useful clinically (limited to ophthalmic administration). It is not volatile and does not readily pen-etrate the skin.
PHARMACOLOGICAL PROPERTIES
The pharmacological properties of anti-ChE agents can be predicted by knowing where ACh is released physiologically by nerve impulses, the degree of nerve impulse activity, and the responses of the corresponding effector organs to ACh (see Chapter 6). The anti-ChE agents potentially can produce all the following effects: (1) stimulation of muscarinic receptor responses at autonomic effector organs; (2) stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions); and (3) stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS.
In general, compounds containing a quaternary ammonium group do not penetrate cell mem-branes readily; hence, anti-ChE agents in this category are absorbed poorly from the gastrointesti-nal (GI) tract or across the skin and are excluded from the CNS by the blood–brain barrier after moderate doses. On the other hand, such compounds act preferentially at the neuromuscular junc-tions of skeletal muscle, exerting their action both as anti-ChE agents and as direct agonists. They have comparatively less effect at autonomic effector sites and ganglia.
The more lipid-soluble agents are well absorbed after oral administration, have ubiquitous effects at both peripheral and central cholinergic sites, and may be sequestered in lipids for long periods of time. Lipid-soluble organophosphorus agents also are well absorbed through the skin, and the volatile agents are transferred readily across the alveolar membrane.
The therapeutically important sites of action of anti-ChE agents are the CNS, eye, intestine, and the neuromuscular junction of skeletal muscle; other actions are of toxicological consequence.
EYE When applied locally to the conjunctiva, anti-ChE agents cause conjunctival hyperemia and constriction of the pupillary sphincter muscle around the pupillary margin of the iris (miosis) and the ciliary muscle (block of accommodation reflex with resultant focusing to near vision).
Miosis is apparent in a few minutes and can last several hours to days. The block of accommoda-tion generally disappears before terminaaccommoda-tion of miosis. Intraocular pressure, when elevated, usu-ally falls as the result of facilitation of outflow of the aqueous humor (see Chapter 63).
GASTROINTESTINAL TRACT Neostigmine enhances gastric contractions, increases the secretion of gastric acid, and stimulates the lower potion of the esophagus. In patients with marked achalasia and dilation of the esophagus, the drug can cause a salutary increase in tone and peristalsis.
Neostigmine augments GI motor activity; the colon is particularly stimulated. Propulsive waves are increased in amplitude and frequency, and movement of intestinal contents is thus promoted.
The effect of anti-ChE agents on intestinal motility probably represents a combination of actions at the ganglion cells of Auerbach’s plexus and at the smooth muscle fibers (see Chapter 37).
NEUROMUSCULAR JUNCTION Most of the effects of potent anti-ChE drugs on skeletal muscle can be explained by their inhibition of AChE at neuromuscular junctions. However, there is good evidence for an accessory direct action of neostigmine and other quaternary ammonium anti-ChE agents on skeletal muscle.
The lifetime of free ACh in the nerve-muscle synapse (∼200 µsec) is normally shorter than the decay of the end-plate potential or the refractory period of the muscle. After inhibition of AChE, the residence time of ACh in the synapse increases, allowing for lateral diffusion and rebinding of the transmitter to multiple receptors and a prolongation of the decay time of the endplate potential. Asynchronous excitation and fasciculations of muscle fibers occur. With sufficient inhibition of AChE, depolarization of the endplate predominates, and blockade owing to depolarization ensues (see Chapter 9). The anti-ChE agents will reverse the antago-nism caused by competitive neuromuscular blocking agents but not that caused by depolariz-ing agents (e.g., succinylcholine), whose depolarization will be further enhanced by AChE inhibition (see Chapter 9).
ACTIONS AT OTHER SITES Secretory glands that are innervated by postganglionic cholin-ergic fibers include the bronchial, lacrimal, sweat, salivary, gastric (antral G cells and parietal cells), intestinal, and pancreatic acinar glands. Low doses of anti-ChE agents augment secretory responses to nerve stimulation; higher doses actually produce an increase in the resting rate of secretion.
Anti-ChE agents increase contraction of smooth muscle fibers of the bronchioles and ureters. The cardiovascular actions of anti-ChE agents are complex, since they reflect both ganglionic and postganglionic effects of accumulated ACh on the heart and blood vessels and actions in the CNS.
The predominant effect on the heart from the peripheral action of accumulated ACh is bradycar-dia, resulting in a fall in cardiac output. Higher doses usually cause a fall in blood pressure, often due to effects of anti-ChE agents on medullary vasomotor centers of the CNS. Anti-ChE agents augment vagal influences on the heart. At the ganglia, accumulating ACh initially is excitatory on nicotinic receptors, but at higher concentrations, ganglionic blockade ensues as a result of per-sistent depolarization. Excitation of parasympathetic ganglion cells reinforces diminished cardiac function, whereas enhanced function results from the action of ACh on sympathetic ganglion cells.
Excitation followed by inhibition also is elicited by ACh at the central medullary vasomotor and cardiac centers. These effects are complicated further by the hypoxemia resulting from the bron-choconstrictor and secretory actions of increased ACh on the respiratory system; hypoxemia, in turn, can reinforce both sympathetic tone and ACh-induced discharge of epinephrine from the adrenal medulla. Hence, it is not surprising that an increase in heart rate is seen with severe ChE inhibitor poisoning. Hypoxemia probably is a major factor in the CNS depression that appears after large doses of anti-ChE agents. Atropine antagonizes CNS-stimulant effects, although not as completely as muscarinic effects at peripheral autonomic effector sites.
ABSORPTION, FATE, AND EXCRETION Physostigmine is absorbed readily from the GI tract, subcutaneous tissues, and mucous membranes. The conjunctival instillation of solutions of the drug may result in systemic effects if measures (e.g., pressure on the inner canthus) are not taken to prevent absorption from the nasal mucosa. Parenterally administered physostigmine is largely destroyed within 2 hours, mainly by hydrolytic cleavage by plasma esterases; renal excre-tion plays only a minor role in its eliminaexcre-tion.
Neostigmine and pyridostigmine are absorbed poorly after oral administration, such that much larger doses are needed than by the parenteral route (effective parenteral dose of neostigmine, 0.5–2 mg; equivalent oral dose, 15–30 mg or more). Neostigmine and pyridostigmine are destroyed by plasma esterases, with half-lives of 1–2 hours.
Organophosphorus anti-ChE agents with the highest risk of toxicity are highly lipid-soluble liq-uids; many have high vapor pressures. Agents used as agricultural insecticides (e.g., diazinon, malathion) generally are dispersed as aerosols or dusts that are absorbed rapidly through the skin and mucous membranes following contact with moisture, by the lungs after inhalation, and by the GI tract after ingestion. Absorbed organophosphorus compounds are hydrolyzed by plasma and liver esterases to the corresponding phosphoric and phosphonic acids, which are excreted in the urine. Young animals are deficient in these esterases (carboxylesterases and paraoxonases), which could contribute to toxicity in neonates and children.
TOXICOLOGY
ACUTE INTOXICATION
Acute intoxication by anti-ChE agents causes muscarinic and nicotinic signs and symptoms, and, except for compounds of extremely low lipid solubility, affects the CNS. Systemic effects appear within minutes after inhalation of vapors or aerosols. The onset of symptoms is delayed after GI and percutaneous absorption. Duration of effects is determined largely by the properties of the compound: lipid solubility, whether it must be activated to the oxon, stability of the organophos-phorus-AChE bond, and whether “aging” of phosphorylated enzyme has occurred.
After local exposure to vapors or aerosols or after their inhalation, ocular and respiratory effects generally appear first. Ocular manifestations include marked miosis, ocular pain, con-junctival congestion, diminished vision, ciliary spasm, and brow ache. With acute systemic absorption, miosis may not be evident due to sympathetic discharge in response to hypotension.
In addition to rhinorrhea and hyperemia of the upper respiratory tract, respiratory effects include tightness in the chest and wheezing due to bronchoconstriction and increased bronchial secretion.
GI symptoms occur earliest after ingestion and include anorexia, nausea and vomiting, abdomi-nal cramps, and diarrhea. With percutaneous absorption of liquid, localized sweating and muscle fasciculations in the immediate vicinity are generally the earliest symptoms. Severe intoxication is manifested by extreme salivation, involuntary defecation and urination, sweating, lacrimation, penile erection, bradycardia, and hypotension.
Nicotinic actions at the neuromuscular junctions of skeletal muscle usually consist of fatiga-bility and generalized weakness, involuntary twitchings, scattered fasciculations, and eventually severe weakness and paralysis. The most serious consequence is paralysis of the respiratory muscles.
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The broad spectrum of effects of acute AChE inhibition on the CNS includes confusion, ataxia, slurred speech, loss of reflexes, Cheyne-Stokes respiration, generalized convulsions, coma, and central respiratory paralysis. Actions on the vasomotor and other cardiovascular centers in the medulla oblongata lead to hypotension.
The time of death after a single acute exposure may range from <5 minutes to nearly 24 hours, depending on the dose, route, agent, and other factors. The cause of death primarily is respiratory failure, usually accompanied by a secondary cardiovascular component. Peripheral muscarinic and nicotinic as well as central actions all contribute to respiratory compromise; effects include laryngospasm, bronchoconstriction, increased tracheobronchial and salivary secretions, compro-mised voluntary control of the diaphragm and intercostal muscles, and central respiratory depres-sion. Blood pressure may fall to alarmingly low levels and cardiac arrhythmias intervene. These effects usually result from hypoxemia and often are reversed by assisted pulmonary ventilation.
Delayed symptoms appearing after 1–4 days and marked by persistent low blood ChE and severe muscle weakness are termed the intermediate syndrome. A delayed neurotoxicity also may be evident after severe intoxication (see below).
Diagnosis and Treatment
The diagnosis of severe, acute anti-ChE intoxication is made readily from the history of exposure and the characteristic signs and symptoms. In suspected cases of milder, acute, or chronic intox-ication, determination of the ChE activities in erythrocytes and plasma generally will establish the diagnosis. Although these values vary considerably in the normal population, they usually are depressed well below the normal range before symptoms are evident.
Atropine in sufficient dosage effectively antagonizes the actions at muscarinic receptor sites, and to a moderate extent, at peripheral ganglionic and central sites. Atropine should be given in doses sufficient to cross the blood–brain barrier. Following an initial injection of 2–4 mg (intra-venously if possible, otherwise intramuscularly), 2 mg should be given every 5–10 minutes until muscarinic symptoms disappear, if they reappear, or until signs of atropine toxicity appear. More than 200 mg may be required on the first day. A mild degree of atropine block should then be maintained for as long as symptoms are evident. Atropine is virtually without effect against the peripheral neuromuscular compromise, which may be reversed by pralidoxime (2-PAM), a cholinesterase reactivator. AChE reactivators are beneficial in the therapy of organophospho-rus anti-ChE intoxication, but their use is supplemental to the administration of atropine.
In moderate or severe intoxication with an organophosphorus anti-ChE agent, the recom-mended adult dose of pralidoxime is 1–2 g, infused intravenously over not less than 5 minutes. If weakness is not relieved or if it recurs after 20–60 minutes, the dose should be repeated. Early treatment is very important to assure that the oxime reaches the phosphorylated AChE while the latter still can be reactivated. Many of the alkylphosphates are extremely lipid soluble, and if extensive partitioning into body fat has occurred and desulfuration is required for inhibition of AChE, toxicity will persist and symptoms may recur after initial treatment. With severe toxicities from the lipid-soluble agents, it is necessary to continue treatment with atropine and pralidoxime for a week or longer.
General supportive measures are important, including: (1) termination of exposure, by removal of the patient or application of a gas mask if the atmosphere remains contaminated, removal and destruction of contaminated clothing, copious washing of contaminated skin or mucous membranes with water, or gastric lavage; (2) maintenance of a patent airway; (3) artifi-cial respiration, if required; (4) administration of oxygen; (5) alleviation of persistent convulsions withdiazepam (5–10 mg, intravenously); and (6) treatment of shock.
CHOLINESTERASE REACTIVATORS Although the phosphorylated esteratic site of AChE undergoes hydrolytic regeneration at a slow or negligible rate, nucleophilic agents, such as hydroxylamine (NH2OH), hydroxamic acids (RCONH–OH), and oximes (RCH=NOH), reactivate the enzyme more rapidly than does spontaneous hydrolysis. Reactivation with pralidoxime (Figure 8–1E) occurs at a million times the rate of that with hydroxylamine. Several bis-quaternary oximes are even more potent as reactivators for insecticide and nerve gas poisoning (e.g., HI-6, used in Europe as an antidote).
PHARMACOLOGY, TOXICOLOGY, AND DISPOSITION The reactivating action of oximes in vivo is most marked at the skeletal neuromuscular junction. Following a dose of an organophosphorus compound that produces total blockade of transmission, the intravenous injec-tion of an oxime restores responsiveness of the motor nerve to stimulainjec-tion within minutes. Antido-tal effects are less striking at autonomic effector sites, and the quaternary ammonium group restricts entry into the CNS.
Although high doses or accumulation of oximes can inhibit AChE and cause neuromuscular blockade, they should be given until one can be assured of clearance of the offending organophos-phate. Many organophosphates partition into lipid and are released slowly as the active entity.
Current antidotal therapy for organophosphate exposure resulting from warfare or terrorism includes parenteral atropine, an oxime (2-PAM or HI-6), and a benzodiazepine as an anticonvul-sant. Oximes and their metabolites are readily eliminated by the kidney.
THERAPEUTIC USES
AVAILABLE THERAPEUTIC AGENTS
The compounds described here are those commonly used as anti-ChE drugs and ChE reactivators in the U.S. Ophthalmic preparations are described in Chapter 63. Conventional dosages and routes of administration are given in the discussion of therapeutic applications.
Physostigmine salicylate (ANTILIRIUM), for injection. Physostigmine sulfate ophthalmic oint-ment; physostigmine salicylate ophthalmic solution. Pyridostigmine bromide, for oral (MESTINON) or parenteral (REGONOL,MESTINON) use. Neostigmine bromide (PROSTIGMIN), for oral use. Neostig-mine methylsulfate (PROSTIGMIN), for parenteral use. Ambenonium chloride (MYTELASE), for oral use. Tacrine (COGNEX), donepezil (ARICEPT), rivastigmine (EXELON), and galantamine (REMINYL), approved for the treatment of Alzheimer’s disease.
Pralidoxime chloride (PROTOPAM CHLORIDE), the only AChE reactivator currently available in the U.S., available in a parenteral formulation. The AChE reactivator HI-6 is available in several European and Near Eastern countries.
PARALYTIC ILEUS AND ATONY OF THE URINARY BLADDER
In the treatment of both these conditions, neostigmine generally is preferred among the anti-ChE agents. The direct parasympathomimetic agents (Chapter 7) are employed for the same purposes.
The usual subcutaneous dose of neostigmine methylsulfate for postoperative paralytic ileus is 0.5 mg, given as needed. Peristaltic activity commences 10–30 minutes after parenteral administra-tion, whereas 2–4 hours are required after oral administration of neostigmine bromide (15–30 mg).
It may be necessary to assist evacuation with a small low enema or gas with a rectal tube.
A similar dose of neostigmine is used for the treatment of atony of the detrusor muscle of the urinary bladder.
Neostigmine should not be used when the intestine or urinary bladder is obstructed, when peritonitis is present, when the viability of the bowel is doubtful, or when bowel dysfunction results from inflammatory bowel disease.
GLAUCOMA AND OTHER OPHTHALMOLOGIC INDICATIONS
For a complete account of the pharmacotherapy of glaucoma and the roles of anti-ChE agents in ocular therapy, see Chapter 63.
MYASTHENIA GRAVIS
Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigabil-ity of skeletal muscle; exacerbations and partial remissions occur frequently. The defect in myas-thenia gravis is in synaptic transmission at the neuromuscular junction, such that mechanical responses to nerve stimulation are not well sustained. Myasthenia gravis is caused by an autoim-mune response primarily to the ACh receptor at the postjunctional endplate. These antibodies reduce the number of receptors detectable by receptor-binding assays and electrophysiological measurements of ACh sensitivity. The similarity of the symptoms of myasthenia gravis and curare poisoning suggested that physostigmine might be of therapeutic value; 40 years elapsed before this suggestion was tried, successfully.
In a subset of ∼10% of patients with myasthenic syndrome, muscle weakness has a congenital rather than an autoimmune basis, with mutations in the ACh receptor that affect ligand-binding and channel-opening kinetics, or in a form of AChE tethered by a collagen-like tail. Administra-tion of anti-ChE agents does not result in subjective improvement in most congenital myasthenic patients.
Diagnosis
Although the diagnosis of autoimmune myasthenia gravis usually can be made from the history, signs, and symptoms, its differentiation from certain neurasthenic, infectious, endocrine, congen-ital, neoplastic, and degenerative neuromuscular diseases can be challenging. Myasthenia gravis is the only condition in which the muscular weakness can be improved dramatically by anti-ChE medication. The edrophonium test for evaluation of possible myasthenia gravis is performed by rapid intravenous injection of 2 mg of edrophonium chloride, followed 45 seconds later by an
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additional 8 mg if the first dose is without effect; a positive response consists of brief improvement in strength, unaccompanied by lingual fasciculation (which generally occurs in nonmyasthenic patients). An excessive dose of an anti-ChE drug results in a cholinergic crisis, characterized by skeletal muscle weakness (due to depolarization blockade of nicotinic receptors at the neuromus-cular junction) and other features (see above) from excess ACh at muscarinic receptors. The dis-tinction between the weakness of cholinergic crisis/anti-AChE overdose and myasthenic weakness is of practical importance: the former is treated by withholding, and the latter by administering, the anti-ChE agent. When the edrophonium test is performed cautiously (limiting the dose to 2 mg and with facilities for respiratory resuscitation available) a further decrease in strength indicates cholinergic crisis, while improvement signifies myasthenic weakness. Atropine sulfate, 0.4–0.6 mg or more intravenously, should be given immediately if a severe muscarinic reaction ensues. Detec-tion of antireceptor antibodies in muscle biopsies or plasma is now widely employed to establish the diagnosis.
Treatment
Pyridostigmine, neostigmine, and ambenonium are the standard anti-ChE drugs used in the symp-tomatic treatment of myasthenia gravis. All can increase the response of myasthenic muscle to repetitive nerve impulses, primarily by the preservation of endogenous ACh. The optimal single oral dose of an anti-ChE agent is determined empirically. Baseline recordings are made for grip strength, vital capacity, and a number of signs and symptoms that reflect the strength of various muscle groups. The patient then is given an oral dose of pyridostigmine (30–60 mg), neostigmine (7.5–15 mg), or ambenonium (2.5–5 mg). The improvement in muscle strength and changes in other signs and symptoms are noted at frequent intervals until there is a return to the basal state.
After an hour or longer in the basal state, the drug is readministered at 1.5 times the initial amount, and the functional observations are repeated. This sequence is continued, with increas-ing increments of one-half the initial dose, until an optimal response is obtained.
The interval between oral doses required to maintain a reasonably even level of strength usu-ally is 2–4 hours for neostigmine, 3–6 hours for pyridostigmine, and 3–8 hours for ambenonium.
However, the required dose may vary from day to day; physical and emotional stress, infections, and menstruation usually necessitate an increase in the frequency or size of the dose. In addition, unpredictable exacerbations and remissions of the myasthenic state may require adjustment of dosage. Patients can be taught to modify their dosage regimens according to their changing requirements.
Pyridostigmine is available in sustained-release tablets containing a total of 180 mg, of which 60 mg is released immediately and 120 mg over several hours; this preparation is of value in maintaining patients for 6–8-hour periods but should be limited to use at bedtime. Muscarinic cardiovascular and GI side effects of anti-ChE agents generally can be controlled by atropine or other anticholinergic drugs (see Chapter 7), remembering that anticholinergic drugs mask many side effects of an excessive dose of an anti-ChE agent. In most patients, tolerance develops even-tually to the muscarinic effects, so that anticholinergic medication is not necessary.
A number of drugs, including curariform agents and certain antibiotics and general anesthet-ics, interfere with neuromuscular transmission (see Chapter 9); their administration to patients with myasthenia gravis is hazardous without proper adjustment of anti-ChE dosage and other appropriate precautions. Glucocorticoids and immunosuppressant therapies are also used in the treatment of myasthenia gravis.
INTOXICATION BY ANTICHOLINERGIC DRUGS
In addition to atropine and other muscarinic agents, phenothiazines, antihistamines, and tricyclic antidepressants have central and peripheral anticholinergic activity. The effectiveness of physostigmine in reversing the anticholinergic effects of these agents has been documented. How-ever, other toxic effects of the tricyclic antidepressants and phenothiazines (see Chapters 17 and 18), such as intraventricular conduction deficits and ventricular arrhythmias, are not reversed by physostigmine. In addition, physostigmine may precipitate seizures; hence, its usually small potential benefit must be weighed against this risk. The initial intravenous or intramuscular dose of physostigmine is 2 mg, with additional doses given as necessary. Physostigmine, a tertiary amine, crosses the blood–brain barrier, in contrast to the quaternary anti-AChE drugs.
ALZHEIMER’S DISEASE
A deficiency of intact cholinergic neurons, particularly those extending from subcortical areas such as the nucleus basalis of Meynert, has been observed in patients with progressive dementia of the Alzheimer type. Using a rationale similar to that in other CNS degenerative diseases, ther-apy for enhancing concentrations of cholinergic neurotransmitters in the CNS has been used in