CHOLINERGIC MECHANISMS AND USES In this section of autonomic pharmacology, we are going to look at the mechanisms of action, effects on selected organ systems and some of the more important uses of cholinergic agents. Agents that interact with the cholinergic system can be divided into 3 classes: a. Muscarinics b. Nicotinics c. Anticholinesterases. The anticholinesterases are included since the results of a blockade of the catabolizing enzyme would amplify cholinergic response. In the first 2 classes there are agents which mimic and other agents which block or inhibit the endogenous response. Think about the following, considering the function of the parasympathetic system which is the maintenance of day-to-body functions. 1. As you know, there are two types of cholinergic receptors. They are muscarinic and _________. Good. No, The answer is nicotinic. 2. Parasympathomimetic agents act directly on exocrine glands where they ________ secretions. increase decrease Good. No, The answer is A. Digestion, for example, is under parasympathetic control. These compounds stimulate secretion of pancreatic enzymes, HCl and pepsin. Also, gall bladder and bronchial secretions are increased. 3. Parasympathomimetic agents can act directly on smooth muscle to Contract Relax O.K. Not generally. The answer is A. Smooth muscle innervated by the PNS is generally stimulated by the parasympathomimetic agents, e.g. intestinal smooth muscle, bronchial smooth muscle, ciliary muscle of the eye and smooth muscle found in the bladder (the sphincters in the bladder and G.I. tract are relaxed, however). 4. Parasympathomimetic agents act directly on the heart to _______ rate. Increase Decrease Very good. No, I think you have missed a most important point, The answer is B. The parasympathetic system includes the VAGUS NERVE and therefore when stimulated would produce a vagal response - bradycardia. 5. What do you think would happen if an agent which blocks the parasympathic system were administered? Bradycardia Tachycardia No change in heart rate. Yes. No, The answer is B. By blocking the parasympathetic system, tachycardia would indeed develop. By the way, this tachycardia usually develops when the antimuscarinic ATROPINE (an antidote to many poisonings) is administered. 6. Under parasympathetic stimulation, there is a(n) ________ in the force of contraction in the atria. Increase Decrease Correct. Incorrect. The answer is B. The FORCE of contraction in the atria is definitely DECREASED. Be sure and remember also that other areas of the heart (bundle of His and A-V node) show a DECREASED CONDUCTION with these agents. A-V block (2:1 or 3:1) may even be produced. Let's try to correlate therapeutic use and action of some muscarinic agents which include Carbachol, Methacholine and Bethanechol. 7. These agents may be used to promote G.I. motility in post-operative atony. True False Fine. No, The answer is True. These agents mimic the parasympathetic nervous system which tends to control the day-to-day body functions including defecation. Thus these agents may be used to treat post-op atony in the G.I. tract. Let's try to correlate therapeutic use and action of some muscarinic agents which include: Carbachol, Methacholine and Bethanechol. 8. The muscarinic agents listed may be used to treat post-op urinary retention. O.K. No, The answer is A. Look back at the previous discussion and remember the effect on smooth muscle and sphincters of the bladder. Let's try to correlate therapeutic use and action of some muscarinic agents which include: Carbachol, Methacholine and Bethanechol. 9. These agents produce miosis and this may be used in treating glaucoma. Very good. No, The answer is true. The cholinergic response is indeed a contraction of the CIRCULAR MUSCLE of the iris producing MIOSIS thus increasing the release of intraocular fluid through the canal of schlemm. The ciliary muscle is also contracted permitting accommodation. 10. Now, what about structures? Carbachol, methacholine and bethanechol are structurally grouped into which of the following classes? Alkaloids Choline esters Carbamic esters Organophosphates Good. No, however, some alkaloids (e.g. muscarine, pilocarpine) are muscarinic agonists. No. Carbanic esters are REVERSIBLE ANTICHOLINESTERASE agents. No. Organophosphates are IRREVERSIBLE ANTICHOLINESTERASE agents. 11. Which one(s) of the following is (are) hydrolyzed by cholinesterases? Methacholine Carbachol Bethanechol All are hydrolyzed by cholinesterases B and C only Very good. No. The answer is A. METHACHOLINE in this group is susceptible to hydrolysis by CHOLINESTERASES (principally acetyl- cholinesterase) and thus has more TRANSIENT effects than either of the other agents. 12. Which has (have) the most nicotine-like activity? Methacholine Carbachol Bethanechol Not bad. No, The second foil is correct! CARBACHOL may act at least in part by releasing endogenous ACh. Now, there is a second class of muscarinic agents. These compounds are nitrogen containing substances derived from plants and are termed ALKALOIDS. 13. Which of the following is a muscarinic alkaloid? Nicotine Neostigmine Pilocarpine Atropine None of the above Fine. No. Nicotine is classified as a nicotinic NOT a muscarinic. No. Neostigmine is NOT a muscarinic agent its actions include inhibition of acetylcholinesterase and direct stimulation at the neuromuscular junction. It has nicotinic actions, but by inhibiting AChE other parasympathomimetic effects may be produced. No. ATROPINE is an ANTIDOTE for poisoning from muscarinic agents. The muscarinic alkaloids include: 1. Pilocarpine 2. Muscarine 3. Arecoline. To treat poisoning by any one of these agents a specific muscarinic blocking agent is used. 14. Which one of the following would be the best treatment for muscarine poisoning? Scopolamine Atropine Nicotine Large amounts of ACh. Good. Not really You're kidding No. ATROPINE is the best agent to treat muscarinic poisoning since it blocks only the muscarinic sites and has no effect at the neuromuscular junction or the ganglia. SCOPOLAMINE is another muscarinic blocking agent, but it has more pronounced effects on the CNS ranging from drowsiness to confusion and amnesia. In some people a low dose of scopolamine may cause CNS excitement, hallucinations and delirium. Scopolamine, administered in small amounts, is used in treating motion sickness. Some of the more important side effects of the antimuscarinics include: 1. tachycardia 2. dry mouth 3. mydrasis 4. drowsiness. 15. The effect of atropine on G.I. motility increase decrease no change Yes. No. The answer is B (decrease). The muscarinic action is to stimulate G.I. motility. The antimuscarinic (or atropine-like) action is to decrease motility. 16. The effect of atropine on respiratory tract secretion Increase Decrease No change Yes. No, The answer is B. Respiratory tract secretions are DECREASED and this effect can be useful in pre-op procedures. 17. The effect of atropine on heart rate O.K. No, The answer is A. The heart rate is INCREASED since the action of ACh released from the vagus nerve is blocked. 18. The action of atropine on acid and pepsin secretion in the stomach Yes. No, The answer is B. Atropine DECREASES acid and pepsin secretion and for this reason it has been, used in the past for treatment of peptic ulcers. NICOTINIC compounds produce a stimulating action on the autonomic ganglia and the neuromuscular junction and include: A. Nicotine B. 1,1-dimethyl-4-phenylpiperazinium (DMPP) iodide. It is true that these agents stimulate the ganglia and are nicotinic compounds but they may also produce a subsequent blockade at the same sites. 19. Which agents is most likely to produce a blockade of the autonomic ganglia nicotine 1,1-dimethyl -4-phenylpiperazinium (DMPP) iodide Yes. No, the answer is A In high doses both agents listed produce a persistent depolarizing blockade of the autonomic ganglia. But, nicotine is most effective and DMPP is least effective. In contrast to the above agents which stimulate then block (i.e. depolarizing blockade) the autonomic ganglia, there are compounds which: a. compete with ACh for the receptor sites (competitive blockade) b. stabilize post-synaptic membranes against the actions of ACh thus producing blockade without stimulation. 20. Which one of the agents listed below blocks the ganglia by occupying the receptor sites of ACh without first causing stimulation? Neostigmine Nicotine Trimethaphan Diisopropylfluourophosphate (DFP) Very good. No. Neostigmine blocks the hydrolysis of ACh by binding to acetylcholinesterase. Remember also, that it directly stimulates at the neuromuscular junction. No. Nicotine always stimulate first. No. This is a little premature but this compound is an "organophosphate" and combines irreversibly with acetyl- cholinesterase. Trimethaphan is an agent which blocks (competitively) the ganglionic nicotinic ACh receptor without stimulating it. Other drugs in this class include: A. Hexamethonium (the prototypic ganglionic blocker) B. Mecamylamine (orally active but rarely used) 21. Which one of the following is not a compound containing a quaternary nitrogen? Hexamethonium Trimethaphan Mecamylamine Very good. No, The answer is C. Of the compounds listed only mecamylamine is a non-quaternary agent. At one time this compound was given to treat hypertension but as you might expect, it crosses fairly easily into the CNS (since it is a non-quarternary compound) resulting in tremors, mental confusion, seizures and mania or depression. As our last group of cholinergic agents, let's discuss those which inhibit the hydrolysis of ACH by binding to the esterase (AChE inhibitors). There are two types: 1. Those that bind REVERSIBLY 2. Those that bind IRREVERSIBLY. 22. Which one of the following reversible inhibitors at cholinesterase also has direct cholinergic action? Physostigmine Neostigmine Edrophonium Good. No. The answer is B. Neostigmine has both an indirect activity (increase in ACH by inhibition of ACH esterase) AND a direct action on the cholinergic receptor at the muscular junction. 23. Which one is not a substrate of ACH esterase but binds only to the anionic site and not the esteratic site of the enzyme? physostigmine neostigmine edrophonium Good. No. The answer is C. Both neostigmine and physostigmine are substrates of the enzyme and are slowly hydrolized thus inhibiting ACH hydrolysis. EDROPHONIUM is NOT a substrate, is NOT hydrolyzed and binds only at the anionic site. Both neostigmine and physostigmine are short acting agents (3-6 hrs.) Edrophonium, however, has an even shorter onset and duration of action, lasting less than 30 minutes. 24. Which of the following "irreversible" cholinesterase inhibitors is active only after biotransformation? DFP Soman Parathion All inorganic phosphates mentioned are active only after biotransformation Correct No. The answer is C. Most inorganic phosphates are active in their original form: the phosphorus forming a stable covalent bond with the esteratic site. Parathion, (a widely used pesticide) however, must be converted to Paraoxon which is a true cholinesterase inhibitor. This last agent has probably been responsible for more cases of accidental poisoning and death than any other organophosphorus compound! Let's look briefly at the therapeutic uses of these anti-CHE agents. AChE inhibitors show some superiority to other drugs in 3 areas: 1. atony of the smooth muscle of the intestinal tract and urinary bladder 2. glaucoma 3. myasthenia gravis. 25. Which of the following agents do you think would be useful in treating urinary retention? Bethanechol DMPP Neostigmine All of the above A and C only. Good. Partly. Partly No, The answer is E. Both muscarinic agonists (i.e. Bethechol) and anticholinesterases (i.e. Neostigmine) are useful in treating post-operative atony in the G.I. tract and bladder. Neostigmine is generally preferred to physostigmine since PHYSOSTIGMINE is a non-quaternary compound and produces serious CNS side effects especially in larger doses. These CNS effects include confusion, ataxia, slurred speech, loss of reflexes, coma, convulsions and central respiratory paralysis. 26. Physostigmine is a non-quarternary, reversible cholinesterase inhibitor and _________ is a non-quarternary, non-stimulating ganglionic blocker. Good. No, the answer is mecamylamine. Both physiostigmine and mecamylamine are non-quarternary compounds and therefore enter the CNS easily. You should also remember that both muscarinic compounds and the anticholinesterase agents or a combination of both are used to treat glaucoma - other than the congenital type which rarely responds to other than surgical treatment. An attack of acute congestive glaucoma (produced by a variety of factors that cause pupillary dilation or engorgement of intraocular vessels) is a medical emergency and combi- nation therapy of NEOSTIGMINE and METHACHOLINE should be employed in such cases. 27. What class of cholinergic agents does methacholine belong to? Fine. No, The answer is muscarinic. Methacholine is a muscarinic agent. 28. What class of cholinergics does neostigmine belong to? AChE inhibitor Alkaloid Choline ester Yes No, The answer is AChE inhibitor. 29. Is neostigmine reversible or irreversible? reversible irreversible yes No, The answer is reversible. It is a reversible cholinesterase inhibitor. We come now to myasthenia gravis, our third use of the anti-ChE compounds. The disease is characterized by weakness and rapid fatigue of skeletal muscle. This condition is often caused by an autoimmune response directed against the postjunctional end-plate. 30. Which of the following compounds has been employed to treat myasthenia but is too short acting (3-6 hrs.) to be a good choice, with problems arising in maintaining a reasonable degree of muscular strength? Nicotine Physostigmine Neostigmine DFP Good. No, The second and third foils are correct! Both neostigmine and physostigmine fit this description. 31. Which compound is a blocker at nicotinic sites? Fine. Nicotine first stimulates then produces a depolarizing blockade. No, The answer is A. Nicotine first stimulates then produces a depolarizing blockade. 32. Which one produces severe side effects in the CNS? The extremely long duration of action complicates adjustment of dosage to daily fluctuations in requirement as necessary in myasthenia. Also it is prone to precipitate episodes of cholinergic crisis from cumulative overdosage. Yes. No, The answer is DFP (an organophosphate). You could have answered correctly by a process of elimination. Currently ambenomium, an analog of neostigmine with a moderately longer duration of action, offers more satisfactory control over myasthenia gravis than does neostigmine. Once myasthenia has been diagnosed and treatment begun, you will be faced with the problem of distinguishing underdosage from overdosage since they both can show the same symptom which is muscle weakness. 33. Edrophonium, a very short acting cholinesterase inhibitor administered in cholinergic crisis (overdosage) should improve the patient's condition worsen the patient's condition have no effect. Of course. Absolutely not. Edrophonium administered to a patient who has been over-dosed with an anti-CHE usually causes an increase in the cholingergic crisis while a patient who is underdosed will show improvement. Edrophonium may also be employed to help in diagnosing myasthenia, but this test may be dangerous to the patient and should be conducted only in a controlled environment. So much for cholinergic mechanisms and uses. The patient usually gets worse. Edrophonium administered to a patient who has been over-dosed with an anti-CHE usually causes an increase in the cholingergic crisis while a patient who is underdosed will show improvement. Edrophonium may also be employed to help in diagnosing myasthenia, but this test may be dangerous to the patient and should be conducted only in a controlled environmnet. So much for cholinergic mechanisms and uses.