By K. Inog. Eastern Nazarene College.
Carbamates like substances consists of an enliven- (neostigmine 10 mg amitriptyline free shipping, pyridostigmine cheap amitriptyline 50 mg amex, physos- ing proven 10 mg amitriptyline, mild stimulation that is probably tigmine) and organophosphates (para- the effect desired in betel chewing order amitriptyline 10 mg mastercard, a oxon, ecothiopate) can also be applied widespread habit in South Asia. Of this locally to the eye in the treatment of group, only pilocarpine enjoys thera- glaucoma; however, their long-term use peutic use, which is limited to local ap- leads to cataract formation. Although they possess high acute toxic- AChE can be inhibited selectively, with ity in humans, they are more rapidly de- the result that ACh released by nerve graded than is DDT following their impulses will accumulate at cholinergic emission into the environment. Inhibitors of only with the choline-binding site of AChE are, therefore, indirect parasym- AChE. Their action is evident toms of dementia in some subtypes of at all cholinergic synapses. Members of both groups react like ACh with AChE and can be considered false substrates. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus permitting a high turnover rate and activity of AChE. Decarbaminoyla- tion following hydrolysis of a carba- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Drugs Acting on the Parasympathetic Nervous System 103 Carbachol Arecoline Direct parasympatho- mimetics Arecoline = ingredient of betel nut: betel Acetylcholine chewing AChE ACh AChE Physostigmine Inhibitors of acetylcholinesterase (AChE) Indirect Neostigmine parasympathomimetics Paraoxon (E 600) Acetylcholine Nitrostigmine = + Acetyl Parathion = AChE E 605 ms Choline Deacetylation Neostigmine + Carbaminoyl AChE Hours to days Decarbaminoylation Paraoxon + Phosphoryl AChE Dephosphorylation impossible A. Direct and indirect parasympathomimetics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Relaxation of smooth musculature Bronchodilation can be achieved by the Excitation of the parasympathetic divi- use of ipratropium in conditions of in- sion of the autonomic nervous system creased airway resistance (chronic ob- causes release of acetylcholine at neuro- structive bronchitis, bronchial asth- effector junctions in different target or- ma). The major effects are summarized this quaternary compound has little ef- in A (blue arrows). Some of these effects fect on other organs because of its low have therapeutic applications, as indi- rate of systemic absorption. Be- Substances acting antagonistically cause of its quaternary nitrogen, this at the M-cholinoceptor are designated drug does not enter the brain and re- parasympatholytics (prototype: the al- quires parenteral administration. Its kaloid atropine; actions shown in red in spasmolytic action is especially marked the panels). Therapeutic use of these because of additional ganglionic block- agents is complicated by their low organ ing and direct muscle-relaxant actions. Possibilities for a targeted Lowering of pupillary sphincter to- action include: nus and pupillary dilation by local ad- • local application ministration of homatropine or tropic- • selection of drugs with either good or amide (mydriatics) allows observation poor membrane penetrability as the of the ocular fundus. For diagnostic us- situation demands es, only short-term pupillary dilation is • administration of drugs possessing needed. Inhibition of exocrine glands AV-block, respectively, to raise heart Bronchial secretion. Premedication rate and to facilitate cardiac impulse with atropine before inhalation anes- conduction. As a quaternary substance, thesia prevents a possible hypersecre- it does not penetrate into the brain, tion of bronchial mucus, which cannot which greatly reduces the risk of CNS be expectorated by coughing during in- disturbances (see below). M1-receptors have also been demonstrated in the brain; how- ever, these cannot be reached by piren- zepine because its lipophilicity is too low to permit penetration of the blood- brain barrier. Pirenzepine was formerly used in the treatment of gastric and du- odenal ulcers (p. Effects of parasympathetic stimulation and blockade Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. CNS-dampening effects exchange through increased cutaneous Scopolamine is effective in the prophy- blood flow. Decreased peristaltic activ- laxis of kinetosis (motion sickness, sea ity of the intestines leads to constipa- sickness, see p. Elderly subjects are more tion is present in the neutral, mem- sensitive to such central effects. Unlike atropine, scopol- pressants, neuroleptics, antihista- amine exerts a calming and amnesio- mines, antiarrhythmics, antiparkinso- genic action that can be used to advan- nian agents. Apart from symptomatic, general Symptomatic treatment in parkin- measures (gastric lavage, cooling with sonism for the purpose of restoring a ice water), therapy of severe atropine dopaminergic-cholinergic balance in intoxication includes the administra- the corpus striatum. Antiparkinsonian tion of the indirect parasympathomi- agents, such as benzatropine (p.
Blockade of cholinergic sites in the Tropicamide vestibular nuclei and reticular formation may account Muscle relaxants Orphenadrine for the effectiveness of this agent discount 10 mg amitriptyline with mastercard. When the motion is Cyclobenzaprine less stressful and lasts longer buy amitriptyline 50 mg with mastercard, the antihistamines (H1- Source: Modified from L buy 75mg amitriptyline otc. Elderly pa- employed if the patient has any disorder that might be tients are especially sensitive to antimuscarinic effects aggravated by the cholinergic stimulation resulting in the CNS proven 75mg amitriptyline, such as impairment of memory. Anti- muscarinics should not be given to patients with gas- CONTRAINDICATIONS AND CAUTIONS trointestinal infections because the drug will slow gas- Muscarinic blocking agents are contraindicated in tric motility and cause the patient to retain the angle-closure glaucoma. You most likely to be different in an elderly versus a proceed to ask questions that might provide a clue young patient? However, she also exhibits cardiovascular and gastrointestinal signs of ANSWERS excessive vagal tone, which you would like to block 1. Which of the following risk factors in heart decreases with age, which is typically accom- prescribing atropine is most important to you? However, it can prevent the detection administering tropicamide, it would be most impor- of early signs of an overdose of neostigmine, which tant to know can quickly progress to a depolarizing block of (A) If the patient has angle-closure glaucoma skeletal muscle and paralysis of the respiratory (B) If the patient has open-angle glaucoma muscles. Dry mouth, ocular disturbances, and tachy- (C) If the patient is taking a cholinomimetic miotic cardia are common side effects of atropine given drug alone, but these effects are less likely to occur with 4. In which of the following conditions would atropine competition between atropine and the increase in be the least likely to increase blood pressure? Application of tropicamide to the eye of a pa- hibitor tient with narrow-angle (angle-closure) glaucoma is (C) A patient being treated with bethanechol a very serious risk, because the peripheral move- 5. A patient has come to you complaining of feeling ment of the relaxed iris can block the outflow of drowsy and finding it hard to concentrate. Clinical aspects of inhaled anticholiner- the absence of a circulating muscarinic agonist be- gic therapy. Case Study The Risks of Treating Peptic Ulcers with Antimuscarinic Drugs 55-year-old man who works in the furnace that do not enter the CNS, such as glycopyrrolate, Aroom at a steel foundry has developed chronic can be prescribed for blocking gastric acid secre- peptic ulcer disease that has not responded to treat- tion, thereby avoiding central side effects. You the most important risk factor for this worker is his are considering giving him an antimuscarinic drug exposure to a hot workplace. This worker is prob- peptic ulcer disease today because of their many ably required to do heavy physical labor, which will side effects, but they still can play a useful role as add to the hyperthermia and cardiac stimulation. Unfortunately, high concentra- Compensatory feedback via the vagus nerve to slow tions are required to block gastric acid secretion, the heart rate will be blocked by a peripherally act- which means that many side effects are difficult to ing muscarinic antagonist, and this could lead to avoid. Overall, antimuscarinic therapy would not be a Although CNS depression and loss of concentration good choice for this worker unless he can be moved is a concern with tertiary amine muscarinic antago- to a safer work environment. Westfall DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Mecamylamine 146 Trimethaphan 145 Nicotine 147 GANGLIONIC TRANSMISSION carinic, are present on the cell bodies of the postgan- glionic neurons. Stimulation of the preganglionic neuron Transmission through autonomic ganglia is more com- results in the release of acetylcholine (ACh) from the plex than neurotransmission at the neuromuscular and preganglionic nerve terminal, which in turn activates postganglionic neuroeffector junctions and is subject to postganglionic cholinergic receptors and leads ulti- numerous pharmacological and physiological influ- mately to the formation of a propagated action potential ences. At the more complicated parasympathetic ganglia, there is a simple presynaptic synapses, the release of ACh from preganglionic neurons to postsynaptic cell relationship; in others, the presyn- results in the appearance of complex postsynaptic po- aptic to postsynaptic cell relationship may involve neu- tential changes consisting of several temporally ar- rons interposed between the presynaptic and postsy- ranged components. At There is considerable diversity among nicotinic some autonomic ganglia, the SIF cell is a true interneu- acetylcholine receptors, and at least one source of this ron, receiving afferent innervation from preganglionic diversity is the multiplicity of acetylcholine receptor cholinergic neurons and forming efferent synapses with genes. At other autonomic ganglia, its cle are different from those in autonomic ganglia and function is not completely understood, but the SIF cell the central nervous system. Excitatory and Inhibitory Potentials Unlike the receptors at postganglionic neuroeffector junctions or at skeletal neuromuscular junctions, both The interaction of ACh with the postsynaptic nicotinic types of cholinergic receptors, that is, nicotinic and mus- receptor results in depolarization of the membrane, an 141 142 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM influx of Na and Ca through a neuronal nicotinic re- existence of these receptors provides a wide variety of ceptor channel, and the generation of the fast EPSP. Agonists This change in postsynaptic potential is principally re- for these receptors most likely reach the ganglia through sponsible for the generation of the propagated action the circulation. For simplic- eral presynaptic terminals innervate a single ganglion ity, the figure has been divided into a type A synapse, cell, and several preganglionic axon terminals must which includes SIF cells, and a type B synapse, which fire simultaneously for transmission to take place. The drugs the type of receptor mediating the response, and the pri- either interact with the nicotinic–cholinergic receptor mary transmitter or mediator that activates the receptor. Interaction of ACh with the postsynaptic ganglionic cell muscarinic receptor is responsible for slowly devel- GANGLIONIC STIMULANTS oping depolarization, the slow EPSP, which has a longer latency than the fast EPSP and a duration of 30 to 60 A variety of agents, including nicotine, lobeline, and di- seconds. The slow EPSP is due to inhibition of a voltage- methylphenyl piperazinium (DMPP), can stimulate gan- dependent K current called the M current, and inhibi- glionic nicotinic receptors.
Several variables play a role in a success of a medical decision support system and it is important to address these to move ahead from where we stand now buy 75mg amitriptyline fast delivery. Issues like physician reluctance generic amitriptyline 75mg online, intimidating systems discount 50 mg amitriptyline with mastercard, proprietary interests generic amitriptyline 75mg free shipping, local practice, technological factors, and outdated knowledgebase are all limiting factors for the growth and acceptance of computer-based decision support Copyright © 2005, Idea Group Inc. Copying or distributing in print or electronic forms without written permission of Idea Group Inc. In addition to these limitations, the decision making functions are no longer limited to the physicians. The patients, healthcare administrators, insurance carriers, healthcare professionals, policy makers, risk analysts, and the government at large are all stakeholders in this medical decision making process. It will be extremely limiting to tie down these requirements to local proprietary computer systems. While the field of medicine pioneered the knowledge sharing techniques among decision support systems, the introduction of several sharing standards segmented market as a net result defeated the purpose of such standard. The growth, availability, and acces- sibility of the Internet opened the door for development of a new model for sharing medical knowledge and decision support systems across networks. Internet-based decision support systems with focus on a particular medical domain will be prevalent in the future. For example, several medical guideline modeling languages are using a common interface for knowledge acquisition purposes. Protégé is the most commonly used tool to acquire the knowledge and then formulate the output in various modeling languages. This converg- ing trend will begin to happen at the knowledge representation and knowledge execution modules as well. This will give raise to a true acceptance of a common knowledge sharing technique. The next key area of medical decision support systems is the unique characteristics of its users. Most users get intimidated by the complexities and challenges posed by the user interface. While medical decision making is not a simple process, the decision support systems should help reducing the complexity and not increasing them. Past studies indicate that the complexity of customizing the knowledge or a simple rule forces the physicians to refrain form using the system. Training clinicians in usage of complex decision support process is a worthy investment. The benefits of the usage of medical decision support systems outweigh the costs incurred in development, implementation, and maintenance of such products. Chapter Summary Medical decision support systems, when used along with the clinical information systems at the point of care can improve the quality of care provided. Despite evidence of the benefits of decision support, and despite endorsement by a national patient safety panel (Kohn, Corrigan & Donaldson, 2000), computerized clinical decision support has not achieved wide diffusion. A recent survey found that such systems were used in less than five percent of all healthcare facilities (Wong, Legnini, Whitmore, & Taylor, 2000). When the user interface, availability, and accessibility issues of the medical decision support systems are properly addressed, the usage of the systems will grow multi fold! When such medical decision support systems are blended into the day-to-day practice workflow, then these systems are destined to succeed! Copying or distributing in print or electronic forms without written permission of Idea Group Inc. Medical Decision Support Systems and Knowledge Sharing Standards 215 References Beatty, P. User attitudes to computer-based decision support in anesthesia and critical care: A preliminary survey. Rule-based expert systems: The MYCIN experiments of the Stanford heuristic programming project. Management science: Modeling, analysis and interpretation, Cincinnati, OH: South-Western.