CHOLINESTERASE INHIBITORS
3. A. Excessive administration of pilocarpine can cause it to enter the circulatory system, activate
en-dothelial muscarinic receptors, and produce a fall in blood pressure. This will activate sympathetic
re-flexes that increase the heart rate. Higher levels of pilocarpine would be required to stimulate mus-carinic receptors on the heart that can decrease the heart rate. Although pilocarpine can enter the CNS and produce confusion in older patients, this also requires higher doses. Pilocarpine will constrict the pupil at therapeutically appropriate doses.
4. C. Glaucoma as a preexisting condition does not contraindicate an AChE inhibitor. The other preex-isting conditions preclude the administration of AChE inhibitors. Potentiation of parasympathetic stimulation can constrict airway smooth muscle and aggravate asthma, further weaken A-V conduction, and risk perforation of the bowel if an obstruction is present.
5. B. Hypotension, which can be life threatening, can be avoided by preventing the entry of directly act-ing cholinomimetics into the circulatory system.
Bradycardia and sweating are also avoided by the same precaution, but they are less significant.
Delirium is not an issue for choline esters, since they do not enter the CNS.
S U P P L E M E N TA L R E A D I N G
Abou-Donia M and Lapadula DM. Mechanisms of organophosphorus ester-induced delayed neurotoxi-city: Type I and type II. Annu Rev Pharmacol Toxicol 1990;30:405–440.
Evoli A, Batocchi AP, and Tonali P. A practical guide to the recognition and management of myasthenia gravis. Drugs 1996;52:662–670.
Farlow MR. Pharmacokinetic profiles of current thera-pies for Alzheimer’s disease: implications for switching to galanthamine. Clin Ther
2001;23:A13–A24.
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Hoyng PF and van Beek LM. Pharmacological therapy for glaucoma: a review. Drugs 2000;411–34.
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Medical applications of neurochemical principles. J Neurochem 1995 64:1909–1918.
Schneider LS. Treatment of Alzheimer’s disease with cholinesterase inhibitors. Clin Geriatr Med 2001;17:337–358.
Treatment of nerve gas poisoning. Med Lett 1995;37:43–44.
132 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM
12 Directly and Indirectly Acting Cholinomimetics 133
C a s e
S t u d y
Will you give 2-PAM to Pam?A
young woman named Pam has been brought to the emergency department. She is sweating profusely, vomiting, and having difficulty breathing.She cannot walk without assistance, and she has a pulse of 30. She is delirious and unable to explain her condition. The friend who brought her in said that the woman had threatened suicide 2 hours ear-lier. What should you do?
ANSWER:It is very likely that Pam has ingested an AChE inhibitor, most likely an insecticide. An addi-tional diagnostic test would be to examine the size of the pupils and test for pupillary reflexes. If it is an anti-AChE overdose, the pupils will be constricted, and they will open only slightly (if at all) when the eye is darkened. The easy decision is to administer atropine, a treatment that typically presents rela-tively little risk. This will reduce or eliminate many symptoms, including the bradycardia, nausea, hy-potension, sweating, and the component of the res-piratory difficulty resulting from bronchoconstric-tion. A more difficult decision is whether to give an oxime (2-pralidoxime) to reactivate the AChE. It appears that the ingestion occurred in the past 2
hours, so reactivation by an oxime is still possible.
The more difficult question is whether oxime treat-ment is necessary. Insecticides can include re-versible carbamate AChE inhibitors or irrere-versible phosphorylating compounds. Unfortunately, you don’t know which she has ingested. Certainly a quick inquiry to see if the product can be identified would be worth the effort. Oximes are effective in reactivating AChE inhibited by carbamates as well as phosphorylating inhibitors. However, oxime treatment does present some risk of its own, and it is not typically used for carbamate poisoning, since the life-threatening stage should pass within a few hours. You should immediately prepare for ventila-tory support, as paralysis of the muscles of respira-tion is the primary cause of death. So there is no de-finitive answer to whether to administer an oxime.
If there is reason to suspect a phosphorylating in-hibitor was ingested or the patient is descending further into severe respiratory distress, treatment with an oxime might be warranted. However, if the patient’s condition appears to be stable and ade-quate ventilatory support is available, it might be better to treat the patient symptomatically.
134
Muscarinic blocking drugs are compounds that se-lectively antagonize the responses to acetylcholine (ACh) and other parasympathomimetics that are medi-ated by activation of muscarinic receptors. These agents are also referred to as muscarinic antagonists, antimus-carinic drugs, and anticholinergics. The belladonna alka-loids, such as atropine, are the oldest known muscarinic blocking compounds, and their medicinal use preceded the concept of neurochemical transmission.
CHEMISTRY
The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopol-amine (Scopolscopol-amine). They are tertiary scopol-amines that con-tain an ester linkage. Atropine is a racemic mixture of
DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active. Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural sim-ilarity to the belladonna alkaloids are also in use. All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group.
The control of access to muscarinic receptors in the cen-tral nervous system (CNS) by a tertiary amine versus quaternary ammonium group is fundamentally impor-tant in selecting among antimuscarinic agents.
MECHANISM OF ACTION
Antimuscarinic drugs are competitive antagonists of the binding of ACh to muscarinic receptors. The seven trans-membrane helices of these receptors have a ringlike or-ganization in the cell membrane that forms a narrow central cleft where ACh binds. At least seven amino acids from four transmembrane helices have been im-plicated in agonist binding to the muscarinic receptors.
Some of these residues, particularly a negatively charged aspartate, interact electrostatically with the positively charged quaternary ammonium moiety of ACh, whereas other residues are required for binding to the ester moiety. Although the tertiary amine and qua-ternary ammonium groups of antimuscarinic drugs bind to the same anionic site on the receptor that agonists occupy, these drugs do not fit into the narrow cleft and consequently cannot activate the receptor.
D R U G L I S T
Muscarinic Blocking Drugs
William F. Wonderlin
13 13
GENERIC NAME PAGE
Atropine 136
Cyclopentolate 137
Dicyclomine 137
Glycopyrrolate 137
Ipratropium 138
GENERIC NAME PAGE
Oxybutynin 137
Propantheline 137
Scopolamine 136
Tolterodine 137
Tropicamide 137
13 Muscarinic Blocking Drugs 135
Dicyclomine (Bentyl), oxybutynin (Ditropan), and tolterodine (Detrol) are nonselective smooth muscle re-laxants that produce relatively little antagonism of mus-carinic receptors at therapeutic concentrations. The mechanism of relaxation is not known. Finally, some other classes of drugs can act in part as muscarinic an-tagonists. For example, the antipsychotics and antide-pressants produce antimuscarinic side effects (e.g., dry mouth).