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DRUGS ACTING AT SYNAPTIC AND NEUROEFFECTOR JUNCTIONAL SITES - AUTONOMIC AND NEUROMUSCULAR PHARMACOLOGY (11) Subcommittee: W.W. Fleming (West Virginia)(Chairman) William J. Cooke (Eastern Virginia Med. School) James W. Gibb (Utah) Joseph J. Krzanowski (Univ. So. Florida) Robert J. Theobold (Kirksville Coll. Osteo. Med.) 1. In general, medical students come to us with a sound background in the anatomy of the ANS but a somewhat inadequate grasp of its physiology. Therefore, we need to spend considerable time on the latter and little time on the former in ANS pharmacology. 2. The importance of autonomic pharmacology is greater than that of its collective therapeutic agents. It is the foundation for understanding other areas such as cardiovascular pharmacology and pharmacology of the central nervous system. Autonomic nerves and/or their effector cells are the site of action responsible for the side effects of many drugs whose primary sites of action are elsewhere. 1. Introduction to autonomic N.S. (1) History - know the anatomical relationships of the two- neuron systems for both of the portions of the autonomic nervous system. Know the relevance to the development of the concept of neurotransmitters and end-organ receptor specificity. 1) Define words containing the suffixes, -ergic,-mimetic, -lytic and -ceptive. 2) Understand homeostasis, fight-or-fight (as proposed by Cannon) and rest-and-repair with regard to sympathetic and parasympathetic activity. 3) Central control reflexes. 4) Dual innervation-recognize that sympathetic and parasympathetic innervations are not balanced in all organs. 5) Predominant tone. 2. Cholinergic systems and related drugs (1) 1) Know the kinetics of the formation, storage, release and inactivation of ACETYLCHOLINE. Be aware of receptor subtypes (e.g., M1, M2). 2) Acetylcholine-muscarinic and nicotinic receptor sites a) know the locations and differences between muscarinic and nicotinic receptor sites. b) muscarinic agonists (mimic muscarine) may be used to treat the following conditions: paralytic ileus, nonobstructive atony of the bladder and glaucoma. Less important are paroxysmal supraventricular tachycardia, intoxication with antimuscarinic agents (including tricyclic antidepressants which may cause glaucoma). i) undesirable effects include salivation, sweating, colic, defecation, headache and loss of accommodation. ii) some esters may be potentiated by the presence of anticholinesterase agents. iii) contraindications include peptic ulcer, asthma, coronary insufficiency and hyperthyroidism. iv) drugs to be considered: ACETYLCHOLINE (prototype-not used clinically), BETHANECHOL, pilocarpine and MUSCARINE for historical interest. 3. Anticholinesterases (1) a) Principles and knowledge objectives to be considered. The student should be able to: i) Compare the two major cholinesterases- acetylcholinesterase (ACHE) and butyrylcholinesterase (BUCHE) as to anatomical locations, sites of synthesis and function. ii) Explain the chemical makeup of the active site of ACHE (anionic and esteratic) as to attraction, attachment and rates of breakdown of various substrates and inhibitors. iii) Relate the site and onset of action of anticholinesterases and routes of administration; also the duration of action of anticholinesterases with sites and type of attachment to the enzyme. iv) State and explain why anticholinesterases are reversible or irreversible. v) Relate the direct effects as being due to quaternary ammonium nitrogen and the indirect effects as being due to anticholinesterase activity. vi) Describe the effects of accumulated acetylcholine at muscarinic sites (cardiac muscle, vascular system, respiratory systems, glands, g.i. and g.u. and eye structures), nicotinic sites (ganglia and NMJ) as well as effects on central nervous system. vii) Indicate therapeutic uses for anticholinesterases such as glaucoma, gastrointestinal or urinary tract atony, myasthenia gravis and treatment of atropine poisoning. viii) Describe adverse or toxic effects of anticholinesterases as being due to accumulation or excess acetylcholine and overstimulation of muscarinic and nicotinic receptors. ix) Distinguish and characterize antidoting agents that reactivate phosphorylated ACHE (pralidoxime) and agents that block effects of excess acetylcholine at muscarinic receptors (atropine). Recognize the role of enzyme aging in the enzyme- inhibitor interaction. b. Drugs to be considered: i) Recall all prototypical drugs such as: PHYSOSTIGMINE, NEOSTIGMINE, EDROPHONIUM and ISOFLUROPHATE. ii) Be familiar with anticholinesterase insecticides: malathion, sarin, parathion and the nerve gases, SOMAN and VX series. Know that malathion and parathion must be biotransformed. Know that poisoning with soman is not treatable with PRALIDOXIME. iii) Consider effect of age on muscarinic sites [heart and cholinergic sites in the brain (Alzheimer's disease) - use of choline derivatives.] 4. Antagonists at muscarinic receptor sites (1) a) Act as competitive antagonists. b) Uses: gastric or intestinal hypersensitivity or secretion, excessive salivation, motion sickness, to product mydriasis and cycloplegia, or an an adjunct prior to general anesthesia. c) Undesirable effects include xerostomia, blurred vision, photophobia, tachycardia, anhidrosis, difficulty in micturition, hyperthermia, glaucoma and mental confusion in the elderly. d) Contraindications: glaucoma, obstructive disease of the gastrointestinal tract or urinary tract, intestinal atony. e) Drugs to be considered: ATROPINE, scopolamine and ipratropium. 5. Drugs acting at autonomic ganglia (1) a) NICOTINE i) Agonist and antagonist properties. ii) Not used clinically, except as a smoking deterrent. iii) Historical, social and toxicological significance. b) Antagonists acting at ganglionic nicotinic receptor sites. i) Pharmacological effects and the role of predominant tone. ii) Use: hypertension, autonomic hyperreflexia. iii) Use severely limited by side effects: loss of accommodation, xerostomia, urinary hesitancy and retention, impotence, constipation, anorexia, eructation and orthostatic hypotension. iv) Example: trimethaphan, HEXAMETHONIUM 6. Antagonists at nicotinic receptor sites in the skeletal neuromuscular junction (NMJ) (1) a) Know that selectivity of drugs between ganglionic and neuromuscular nicotinic receptors is only relative and the resulting clinical implications. b) Physiology and Pathophysiology of transmission at NMJ. c) Classes of neuromuscular antagonists: i) Depolarizing agents - e.g. SUCCINYLCHOLINE. (a) know characteristics of phases I and II of blockade and interactions with anticholinesterases (b) metabolism (atypical cholinesterases) and titration of effect (c) toxicity ii) Competitive antagonists at NMJ. (a) prototypical drugs: atracurium, TUBOCURARINE, PANCURONIUM, vecuronium, gallamine (b) interaction with anticholinesterase (c) metabolism (d) histamine release and toxicity iii) Drugs with secondary actions as NMJ antagonists: peptide and aminoglycoside antibiotics, magnesium, and some general anesthetics (ether). d) Know order of paralysis of muscles. 7. Sympathetic systems, the adrenal medulla and related drugs (5) 1) Know the steps and processes involved in sympathetic transmission and release from adrenal medulla. a) biosynthetic pathway and enzymes, including short (feedback inhibition) and long term (enzyme induction) control. b) storage of norepinephrine and epinephrine c) release of norepinephrine and epinephrine d) concept of biophase and location of receptors e) removal of NE from biophase i) metabolism, including locations, characteristics and roles of COMT and MAO ii) neuronal uptake [distinguish from vesicular uptake (changes with age; increases in heart, decreases in blood vessels, increase in brain)] iii) extraneuronal uptake iv) escape into and fate in blood 2) Know examples of drugs which interfere with specific steps in noradrenergic transmission (METHYLDOPA, RESERPINE, COCAINE, GUANETHIDINE, bretylium) and important drug interactions with these drugs. 3) Know the classification of adrenoceptors (alpha 1, alpha 2, beta 1, beta 2) and important locations of each receptor type. 4) Alpha 1 agonists are used to treat the following conditions: nasal congestion, hypotension, paroxysmal atrial tachycardia and to cause mydriasis or to cause vasoconstriction with local anesthetics. a) undesirable effects include hypertension, headache, restlessness and excitability. b) drug interactions may occur with halogenated hydrocarbon anesthetics such as halothane, oxytocic drugs and monamine oxidase inhibitors. c) contraindications include severe hypertension or cardiac disease. d) drugs: EPINEPHRINE, norepinephrine, PHENYLEPHRINE, phenylpropanolamine and methoxamine (note norepinephrine has no selectivity among alpha 1 ,alpha 2, beta 1 receptors; epinephrine has no selectivity. 5) alpha 2 agonists are used to treat hypertension a) central site of action b) undesirable side effects include xerostomia, drowsiness, sedation, constipation, dizziness, headache and profound hypotension. c) cannot be given intravenously due to effects on peripheral postjunctional alpha 1 & alpha 2 receptors which will cause hypertension. d) CLONIDINE and alpha methylnorepinephrine (metabolite of alpha methyldopa) 6) Nonselective alpha 1 - alpha 2 antagonists. a) prototype: phentolamine (reversible) b) formerly used for hypertension c) understand limitations of excessive tachycardia 7) alpha 1 selective antagonists are used to treat hypertension a) understand value of relative selectivity b) undesirable side effects include dizziness, headache, drowsiness, weakness, postural hypotension, tachycardia. c) drug interactions may include synergism with diuretics or other antihypertensive drugs d) drugs: PRAZOSIN (reversible), phenoxybenzamine (irreversible). 8) alpha 2 selective antagonists - no therapeutic use (example is yohimbine). 9) Indirectly acting sympathomimetics. a) understand mechanism of action and clarify that some agents have mixed (direct/indirect) action. b) interaction with monoamine oxidase inhibitors (e.g., pargyline) c) prototypical drugs i) TYRAMINE - not used therapeutically but present in some cheeses, wines and beers ii) EPHEDRINE and pseudoephedrine - greater central action than many other sympathomimetics iii) AMPHETAMINE - predominant central actions, use and limitations in appetite suppression, importance as a drug of abuse 10) Nonselective beta 1 and beta 2 agonists. a) EPINEPHRINE i) no selectivity among alpha 1, alpha 2 and beta 1 and beta 2 receptors ii) effective for bronchodilation but use limited by cardiovascular effects. iii) use in improving cardiac conduction, in treatment of anaphylactic shock, as an adjunct to local anesthetics b) ISOPROTERENOL i) selective for beta 1 and beta 2 receptors ii) effective for bronchodilation (alpha 2) but usefulness limited by cardiac stimulation (beta 1) peripheral vasodilation (beta 2) 11) Beta 1 selective agonists are used for the short treatment of cardiac decompensation. a) undesirable side effects include tachycardia, hypertension (residual alpha 1 effect) and arrhythmias b) contraindicated in idiopathic hypertrophic subaortic stenosis c) drugs: dobutamine 12) Beta 2 agonists are used to treat asthma, bronchospasm and emphysema. a) undesirable side effects include nervousness, headache, tachycardia, palpitations, sweating, muscle cramps, (note selectivity for beta 1 over beta 2 receptors is only relative) b) drugs: terbutaline, ALBUTEROL c) effective orally and by inhalation d) longer acting than ISOPROTERENOL e) have made the use of isoproterenol (by inhalation) and ephedrine (oral) for relief of bronchospasm obsolete f) Reduction in both beta 1 and beta 2 agonists response in older organisms (e.g., trachea, heart, blood vessels) 13) Nonselective beta 1 and beta 2 antagonists. a) prototypical drugs - 1-PROPRANOLOL, nadolol, timolol and pindolol b) uses: hypertension, angina, arrhythmias c) limitation: bronchoconstriction due to antagonism of beta 2 receptors 14) Beta 1 antagonists are used to treat hypertension. a) Undesirable side effects include tiredness, dizziness, shortness of breath, bradycardia, congestive heart failure, diarrhea, flatulence and heartburn. b) Generally contrainindicated in sinus bradycardia, heart block, cardiogenic shock and overt cardiac failure, careful in asthmatics-relative selectivity. c) drugs: e.g. METOPROLOL, ATENOLOL 15) DOPAMINE a) Dopamine receptors b) Established role of dopamine as a transmitter in CNS; effect of age on dopaminergic receptors: decline in nigrostriatal areas. c) Use as a renal vascular dilator 16) Labetolol a) Discuss as an example of a drug which block both alpha 1 and beta 1, beta 2 adrenoceptors b) Consider its use in hypertension. -------------------------------------------------- Minimum list of drugs in autonomic and neuromuscular pharmacology ACETYLCHOLINE +ALBUTEROL AMPHETAMINE +ATENOLOL atracurium +ATROPINE BETHANECHOL bretylium CLONIDINE COCAINE dobutamine DOPAMINE EDROPHONIUM EPHEDRINE EPINEPHRINE gallamine GUANETHIDINE HEXAMETHONIUM +ipratropium ISOFLUROPHRATE ISOPROTERENOL +labetalol malathion methoxamine +METHYLDOPA +METOPROLOL MUSCARINE +nadolol NEOSTIGMINE +NICOTINE NOREPINEPHRINE PANCURONIUM PARATHION PARGYLINE PHENOXYBENZAMINE +PHENYLPROPANOL- AMINE PHENTOLAMINE +phenylephrine physostigmine pilocarpine pindolol +pseudoephedrine PRALIDOXIME +PRAZOSIN +PROPRANOLOL RESERPINE scopolamine SOMAN SUCCINYLCHOLINE terbutaline +timolol trimethaphan TUBOCURARINE TYRAMINE vecuronium PRIMARY DRUGS - All capital letters SECONDARY DRUGS - small letters +Indicates that drug is listed in the 200 most commonly prescribed drugs in 1989 (National Prescription Audit). All of the first 100 and most of the second 100 of the top 200 drugs prescribed are included in this document.