Autonomic Nervous System-2-1.pptx

1. Autonomic NervousSystem Gvantsa Kvariani

2. Tuesday, February 2, 20XX Sample Footer Text 2 The autonomic nervous system (ANS) is part of the peripheral nervous system and regulates involuntary, visceral body functions in different organ systems (e.g., the cardiovascular, gastrointestinal, genitourinary systems). It is divided into the sympathetic and parasympathetic ne rvous systems.

3. Tuesday, February 2, 20XX Sample Footer Text 3 The sympathetic nervous system has a thoracolumbar outflow and is activated during fight or flight response, while the parasympathetic nervous system has a craniosacral outflow and is activated during digestion and rest. The sympathetic and parasympathetic nervous systems consist of preganglionic and postganglionic neurons. The preganglionic fibers of both ANS divisions and the postganglionic fibers of the parasympathetic division are cholinergic fibers (release acetylcholine) that act on cholinergic receptors (nicotinic or muscarinic). All postganglionic fibers of the sympathetic division are adrenergic fibers (release norepinephrine) that act on adrenergic alpha or beta receptors for neurotransmission, with the exception of the fibers innervating the sweat glands, which are cholinergic.

4. Tuesday, February 2, 20XX Sample Footer Text 4 The adrenal medulla does not have a postsynaptic neuron. The sympathetic preganglionic fibe rs stimulate the chromaffin cells of the adrenal medulla directly via acetylcholine on nicotinic receptors, which results in the release of norepinephrine and epinephrin e mediating the fight or flight response.

5. Tuesday, February 2, 20XX Sample Footer Text 5 The sympathetic and parasympathetic nervous systems have antagonistic effects in some organ systems. The effects of the sympathetic nervous system on target organs include mydriasis, increased heart rate, contractility, and conduction velocity, bronchodilation, sweat secretion, decreased intestinal motility, and increased renin release. The effect of the parasympathetic nervous system on target organs include miosis, decreased heart rate, contractility, and conduction velocity; increased intestinal motility; and bronchoconstriction. In addition to the sympathetic and parasympathetic nervous systems, there is the enteric nervous system, which consists of enteric ganglia, the myenteric (Auerbach) and the submucosal (Meissner) plexuses, and the interstitial cells of Cajal. The enteric nervous system controls gastrointestinal motility and secretion. Autonomic function can be affected by medications (e.g., selective serotonin reuptake inhibitors, anticholinergics) as well as diseases (e.g., diabetes mellitus, Parkinson disease, multiple system atrophy).

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11. Tuesday, February 2, 20XX Sample Footer Text 11 1.Efferent neurons: The ANS carries nerve impulses from the CNS to the effector organs through two types of efferent neurons: the preganglionic neurons and the postganglionic neurons. The cell body of the first nerve cell, the preganglionic neuron, is located within the CNS. The preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous system). The ganglia function as relay stations between the preganglionic neuron and the second nerve cell, the postganglionic neuron. The cell body of the postganglionic neuron originates in the ganglion. It is generally nonmyelinated and terminates on effector organs, such as visceral smooth muscle, cardiac muscle, and the exocrine glands.

12. Tuesday, February 2, 20XX Sample Footer Text 12 Afferent neurons: The afferent neurons (fibers) of the ANS are important in the reflex regulation of this system (for example, by sensing pressure in the carotid sinus and aortic arch) and in signaling the CNS to influence the efferent branch of the system to respond.

14. Tuesday, February 2, 20XX Sample Footer Text 14 Sympathetic neurons: • The preganglionic neurons of the sympathetic system come from the thoracic and lumbar regions (T1 to L2) of the spinal cord • They synapse in two cord-like chains of ganglia that run close to and in parallel on each side of the spinal cord. • The preganglionic neurons are short in comparison to the postganglionic ones. The axons of the postganglionic neuron extend from the ganglia to tissues they innervate and regulate. • In most cases, the preganglionic nerve endings of the sympathetic nervous system are highly branched, enabling one preganglionic neuron to interact with many postganglionic neurons. This arrangement enables activation of numerous effector organs at the same time. [Note: The adrenal medulla, like the sympathetic ganglia, receives preganglionic fibers from the sympathetic system. The adrenal medulla, in response to stimulation by the ganglionic neurotransmitter acetylcholine, secretes epinephrine (adrenaline), and lesser amounts of norepinephrine, directly into the blood.]

15. Tuesday, February 2, 20XX Sample Footer Text 15 Parasympathetic neurons: • The parasympathetic preganglionic fibers arise from cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus), as well as from the sacral region (S2 to S4) of the spinal cord and synapse in ganglia near or on the effector organs. • The vagus nerve accounts for 90% of preganglionic parasympathetic fibers. Postganglionic neurons from this nerve innervate most organs in the thoracic and abdominal cavity. • Thus, in contrast to the sympathetic system, the preganglionic fibers are long, and the postganglionic ones are short, with the ganglia close to or within the organ innervated. • In most instances, there is a one-to-one connection between the preganglionic and postganglionic neurons, enabling discrete response of this system.

16. Parasympathetic preganglionic fibers arise from cranial cranial nerves and sacral nerves. • Short postganglionic axons innervate cardiac muscle, bronchial smooth muscle, and • exocrine glands. • Parasympathetic innervation predominates over sympathetic innervation of salivary • glands, lacrimal glands, and erectile tissue.

17. Tuesday, February 2, 20XX Sample Footer Text 17 Enteric neurons: The enteric nervous system is the third division of the ANS. It is a collection of nerve fibers that innervate the gastrointestinal (GI) tract, pancreas, and gallbladder, and it constitutes the “brain of the gut.” This system functions independently of the CNS and controls motility, exocrine and endocrine secretions, and microcirculation of the GI tract. It is modulated by both the sympathetic and the parasympathetic nervous systems.

18. Tuesday, February 2, 20XX Sample Footer Text 18 The effect of sympathetic stimulation is an increase in heart rate and blood pressure, mobilization of energy stores, and increase in blood flow to skeletal muscles and the heart, while diverting flow from the skin and internal organs. Sympathetic stimulation results in dilation of the pupils and bronchioles. reduces GI motility and affects function of the bladder and sexual organs. Fight-or-flight response: These reactions are triggered both by direct sympathetic activation of effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine. Hormones released by the adrenal medulla directly enter the bloodstream and promote responses in effector organs that contain adrenergic receptors The sympathetic nervous system tends to function as a unit and often discharges as a complete system, for example, during severe exercise or in reactions to fear.

19. Tuesday, February 2, 20XX Sample Footer Text 19 Functions of the parasympathetic nervous system The parasympathetic division is involved with maintaining homeostasis within the body. It is required for life, since it maintains essential functions, such as digestion and elimination. The parasympathietic division usually acts to oppose or balance the actions of the sympathetic division and generally predominates the sympathetic system in "rest-and-digest" situations. Unlike the- sympathetic system, the parasympathetic system never discharges as a complete system. If it did, it would produce massive, undesirable, and unpleasant symptoms, such as involuntary urination, defecation. Instead, parasympathetic fibers innervating Specific organs such as the gut, heart, or eye are activated separetely, and the system affects these organs individually.

21. Tuesday, February 2, 20XX Sample Footer Text 21 General information •Exits central nervous system (dorsal motor nucleus) with cranial nerves CN III, CN VII, CN IX, CN X, and the sacral spinal roots(craniosacral outflow) •Preganglionic axons (long, myelinated cholinergic fibers): synapse in ganglia close to end organs •Postganglionic axons (short, cholinergic fibers): leave ganglia and

22. Tuesday, February 2, 20XX Sample Footer Text 22 Sacral outflow •Supplies pelvis via 2nd– 4th sacral spinal nerves •Lateral horn of the sacral segments of S2–S4 → pelvic splanchnic nerves → inferior hypogastric plexus or ganglia within walls of pelvic (e.g., descending and sigmoid colon, rectum, ureter, prostate, blad der, urethra) and genital organs. Cranial outflow The cranial outflow supplies visceral structures of the head, neck and face via CN III, CN VII, CN IX and of the thorax and upper abdomen via CN X. •Four bilateral autonomic ganglia in the head and neck: • Edinger-Westphal nucleus → oculomotor nerve (CN III) → ciliary ganglion → sphincter pupillae (miosis) and ciliary muscle(accommodation) • Superior salivatory nucleus → facial nerve → pterygopalatine ganglion and submandibular ganglion → lacrimal gland, glands of the mucosa of the oral and nasal cavity, pharynx, and sinuses • Inferior salivatory nucleus → glossopharyngeal nerve → otic ganglion → salivation of parotid gland •Dorsal nucleus of the vagus nerve → CN X → several ganglia close to/or within the walls of the gastrointestinal tract and lungs

25. Tuesday, February 2, 20XX Sample Footer Text 25 Dual innervation: Most organs are innervated by both divisions of the ANS. Thus, vagal parasympathetic innervation slows the heart rate and sympathetic innervation increases heart rate. Despite this dual innervation, one system usually predominates in controlling the activity of a given organ. For example, the vagus nerve is the predominant factor for controlling heart rate. The dual innervation of organs is dynamic and fine-tuned continually to maintain homeostasis. Sympathetic innervation: Although most tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic system.

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27. Tuesday, February 2, 20XX Sample Footer Text 27 III. CHEMICAL SIGNALING BETWEEN CELLS Neurotransmission in the ANS is an example of chemical signaling between cells. In addition to neurotransmission, other types of chemical signaling include the secretion of hormones and the release of local mediators 1. Hormones Specialized endocrine cells secrete hormones into the bloodstream, where they travel throughout the body, exerting effects on broadly distributed target cells (see Unit V: Drugs Affecting the Endocrine System). 2. Local mediators Most cells secrete chemicals that act locally on cells in the immediate environment. Because these chemical signals are rapidly destroyed or removed, they do not enter the blood and are not distributed throughout the body. Histamine and prostaglandins are examples of local mediators.

28. Tuesday, February 2, 20XX Sample Footer Text 28 Neurotransmitters The release is triggered by arrival of the action potential at the nerve ending, leading to depolarization. An increase in intracellular Ca2+ initiates fusion of synaptic vesicles with the presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse across the synaptic cleft, or space (synapse), between neurons and combine with specific receptors on the postsynaptic (target) cell. Types of neurotransmitters: Although over 50 signal molecules in the nervous system have been identified, norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin, histamine, glutamate, and γ-aminobutyric acid are most commonly involved in the actions of therapeutically useful drugs. Each of these chemical signals binds to a specific family of receptors. Acetylcholine and norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of neurotransmitters function in the CNS.

29. Tuesday, February 2, 20XX Sample Footer Text 29 Acetylcholine: The autonomic nerve fibers can be divided into two groups based on the type of neurotransmitter released. If transmission is mediated by acetylcholine, the neuron is termed cholinergic. Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. It is the neurotransmitter at the adrenal medulla. Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system, and a few sympathetic system organs, also involves the release of acetylcholine. In the somatic nervous system, transmission at the neuromuscular junction (the junction of nerve fibers and voluntary muscles) is also cholinergic

31. Tuesday, February 2, 20XX Sample Footer Text 31 Norepinephrine and epinephrine: When norepinephrine is the neurotransmitter, the fiber is termed adrenergic. In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effector organs. Epinephrine secreted by the adrenal medulla (not sympathetic neurons) also acts as a chemical messenger in the effector organs.

32. Tuesday, February 2, 20XX Sample Footer Text 32 Dissipation of the transmitter/termination of neurotransmitter action: The action of the neurotransmitter is terminated either by destruction by enzymes (cholinesterase destroys acetyl choline whereas monoamine oxidase [MAO] and catechol-o-methyl- transferase [COMT] destroy noradrenaline) or by reuptake of the neurotransmitter by tissues or axonal terminal (noradrenaline at adrenergic endings).

33. Tuesday, February 2, 20XX Sample Footer Text 33 SIGNAL TRANSDUCTION IN THE EFFECTOR CELL The binding of chemical signals to receptors activates enzymatic processes within the cell membrane that ultimately results in a cellular response, such as the phosphorylation of intracellular proteins or changes in the conductivity of ion channels. A neurotransmitter can be thought of as a signal and a receptor as a signal detector and transducer. The receptors in the ANS effector cells are classified as adrenergic or cholinergic based on the neurotransmitters or hormones that bind to them. Epinephrine and norepinephrine bind to adrenergic receptors, and acetylcholine binds to cholinergic receptors.

34. Tuesday, February 2, 20XX Sample Footer Text 34 Cholinergic receptors are further classified as nicotinic or muscarinic. Some receptors, such as the postsynaptic cholinergic nicotinic receptors in skeletal muscle cells, are directly linked to membrane ion channels and are known as ionotropic receptors. Binding of neurotransmitter to ionotropic receptors directly affects ion permeability. All adrenergic receptors and cholinergic muscarinic receptors are G protein– coupled receptors (metabotropic receptors). Metabotropic receptors mediate the effects of ligands by activating a second messenger system inside the cell. The two most widely recognized second messengers are the adenylyl cyclase system and the calcium/phosphatidylinositol system

35. Tuesday, February 2, 20XX Sample Footer Text 35 Muscarinic receptors Muscarinic receptors belong to the class of G protein– coupled receptors (metabotropic receptors). These receptors, in addition to binding ACh, also recognize muscarine, an alkaloid in certain poisonous mushrooms. By contrast, the muscarinic receptors show only a weak affinity for nicotine, an alkaloid found in tobacco and other plants. There are five subclasses of muscarinic receptors; however, only M1, M2, and M3 receptors have been functionally characterized. These receptors, in addition to binding with acetylcholine, also recognize muscarine. Muscarine is an alkaloid that is present in certain poisonous mushrooms.

36. Tuesday, February 2, 20XX Sample Footer Text 36 1. Which is correct regarding the sympathetic nervous system? 1.It generally mediates body functions in “rest- and-digest” mode. 2.The neurotransmitter at the sympathetic ganglion is norepinephrine (NE). 3.The neurotransmitter at the sympathetic ganglion is acetylcholine (ACh). 4.Sympathetic neurons release ACh in the effector organs.

37. Tuesday, February 2, 20XX Sample Footer Text 37 C. The neurotransmitter at the sympathetic and parasympathetic ganglia is acetylcholine. The sympathetic system generally mediates body functions in “fight-or-flight” mode and the parasympathetic system generally mediates body functions in “rest-and-digest” mode. Sympathetic neurons release NE, and parasympathetic neurons release ACh in the effector cells.

38. Tuesday, February 2, 20XX Sample Footer Text 38 .2. Why does the somatic nervous system enable a faster response compared to the ANS? 1.Somatic motor neurons have ganglia where neurotransmission is mediated by ACh. 2.Somatic motor neurons have ganglia where neurotransmission is mediated by NE. 3.Somatic motor neurons are not myelinated. 4.Somatic motor neurons are myelinated and do not have ganglia.

39. Tuesday, February 2, 20XX Sample Footer Text 39 D. Somatic motor neurons are myelinated and have no ganglia. This enables faster transmission in the somatic neurons.

40. Tuesday, February 2, 20XX Sample Footer Text 40 3. Which physiological change occurs when the parasympathetic system is activated? A. Increase in heart rat B. Inhibition of lacrimation (tears) C. Dilation of the pupil (mydriasis) D. Increase in gastric motility

41. Tuesday, February 2, 20XX Sample Footer Text 41 D. Activation of the parasympathetic system causes an increase in gastric motility, increase in fluid secretions, reduction in heart rate, and constriction of the pupil. In the “rest-and-digest” mode, the parasympathetic system is more active, which helps with digestion.

42. Tuesday, February 2, 20XX Sample Footer Text 42 Which physiological change is expected when the sympathetic system is inhibited using a pharmacological agent? A. Reduction in heart rate B. Increase in blood pressure C. Decrease in fluid secretions D. Constriction of blood vessels

43. Tuesday, February 2, 20XX Sample Footer Text 43 A. Activation of the sympathetic system causes an increase in heart rate, increase in blood pressure, reduction or thickening of fluid secretions, and constriction of blood vessels. Therefore, inhibition of the sympathetic system should theoretically cause a reduction in heart rate, decrease in blood pressure, increase in fluid secretions, and relaxation of blood vessels.

44. Tuesday, February 2, 20XX Sample Footer Text 44 Which is correct regarding activation of receptors on the effector organs in the ANS? A. Acetylcholine activates muscarinic receptors. B. Acetylcholine activates adrenergic receptors. C. Epinephrine activates nicotinic receptors. D. Norepinephrine activates muscarinic receptors.

45. Tuesday, February 2, 20XX Sample Footer Text 45 A. Acetylcholine is the neurotransmitter in the cholinergic system, and it activates both muscarinic and nicotinic cholinergic receptors, not adrenergic receptors. Norepinephrine and epinephrine activate adrenergic receptors, not muscarinic receptors.

46. Tuesday, February 2, 20XX Sample Footer Text 46 Which statement is correct regarding the autonomic nervous system? A. Afferent neurons carry impulses from the central nervous system (CNS) to the effector organs. B. Preganglionic neurons of the sympathetic system arise from the cranial nerves, as well as from the sacral region. C. When there is a sudden drop in blood pressure, the baroreceptors send signals to the brain to activate the parasympathetic system. D. The heart receives both sympathetic and parasympathetic innervation.

47. Tuesday, February 2, 20XX Sample Footer Text 47 D. The heart receives both sympathetic and parasympathetic innervation. Activation of sympathetic neurons increases the heart rate and force of contraction, and activation of parasympathetic neurons reduces the heart rate and force of contraction (slightly). Afferent neurons carry impulses from the periphery to the CNS, and efferent neurons carry signals away from the CNS. Preganglionic neurons of the sympathetic system arise from thoracic and lumbar regions of the spinal cord, whereas the preganglionic neurons of the parasympathetic system arise from cranial nerves and the sacral region. When there is a sudden drop in blood pressure, the sympathetic system is activated, not the parasympathetic system.

48. Tuesday, February 2, 20XX Sample Footer Text 48 Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other on the basis of their different affinities for agents that mimic the action of ACh (cholinomimetic agents).

52. Tuesday, February 2, 20XX Sample Footer Text 52 Where do we use Acetylcholine? THE CHOLINERGIC NEURON The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), postganglionic fibers of the parasympathetic division use ACh as a neurotransmitter

54. Tuesday, February 2, 20XX Sample Footer Text 54 Location of muscarinic receptors: These receptors are found on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands. Although all five subtypes are found on neurons, M1 receptors are also found on gastric parietal cells, M2 receptors on cardiac cells and smooth muscle M3 receptors on the bladder, exocrine glands, and smooth muscle. [Note: Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these tissues, but at high concentration, they may show some activity at nicotinic receptors.]

55. Tuesday, February 2, 20XX Sample Footer Text 55 Muscarinic receptors Muscarinic receptors belong to the class of G protein–coupled receptors (metabotropic receptors). These receptors, in addition to binding ACh, also recognize muscarine, an alkaloid in certain poisonous mushrooms. By contrast, the muscarinic receptors show only a weak affinity for nicotine, an alkaloid found in tobacco and other plants. There are five subclasses of muscarinic receptors; however, only M1, M2, and M3 receptors have been functionally characterized. These receptors, in addition to binding with acetylcholine, also recognize muscarine. Muscarine is an alkaloid that is present in certain poisonous mushrooms.

56. Tuesday, February 2, 20XX Sample Footer Text 56 III. CHOLINERGIC RECEPTORS (CHOLINOCEPTORS) Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other on the basis of their different affinities for agents that mimic the action of ACh (cholinomimetic agents).

57. Tuesday, February 2, 20XX Sample Footer Text 57 Neurotransmission at cholinergic neurons Neurotransmission in cholinergic neurons involves six sequential steps: 1) synthesis of ACh, 2) storage, 3) release, 4) binding of ACh to the receptor, 5) degradation of ACh in the synaptic cleft (the space between the nerve endings and the adjacent receptors on nerves or effector organs) 6) recycling of choline

58. Tuesday, February 2, 20XX Sample Footer Text 58 1.Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium and can be inhibited by the drug hemicholinium.The uptake of choline is the rate- limiting step in ACh synthesis. Choline acetyl- transferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form ACh (an ester) in the cytosol.

59. Tuesday, February 2, 20XX Sample Footer Text 59 2.Storage of acetylcholine in vesicles: ACh is packaged and stored into presynaptic vesicles by an active transport process. The mature vesicle contains not only ACh but also adenosine triphosphate (ATP) and proteoglycan.

60. Tuesday, February 2, 20XX Sample Footer Text 60 Release of acetylcholine: When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of contents into the synaptic space. This release can be blocked by botulinum toxin. In contrast, the toxin in black widow spider venom causes all the ACh stored in synaptic vesicles to empty into the synaptic gap.

61. Tuesday, February 2, 20XX Sample Footer Text 61 Binding to the receptor: ACh released from the synaptic vesicles diffuses across the synaptic space and binds to postsynaptic receptors on the target cell, to presynaptic receptors on the membrane of the neuron that released ACh, or to other targeted presynaptic receptors. The postsynaptic cholinergic receptors on the surface of effector organs are divided into two classes: muscarinic and nicotinic. Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells, as mediated by second messenger molecules.

62. Tuesday, February 2, 20XX Sample Footer Text 62 5.Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly terminated, because acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the synaptic cleft.

63. Tuesday, February 2, 20XX Sample Footer Text 63 6. Recycling of choline: Choline may be recaptured by a sodium- coupled, high-affinity uptake system that transports the molecule back into the neuron. There, it is available to be acetylated into ACh.

64. Tuesday, February 2, 20XX Sample Footer Text 64 Mechanism of acetylcholine signal transduction: A number of different molecular mechanisms transmit the signal generated by ACh occupation of the receptor.

65. Tuesday, February 2, 20XX Sample Footer Text 65 ACh interacts with M1, M3, and M5 muscarinic cholinoceptors to increase phosphatidylinositol (PI) turnover and Ca mobilization (a) By activation of G protein (Gq), the interaction of ACh with M1 and M3 muscarinic cholinoceptors stimulates polyphosphatidylinositol phosphodiesterase (phospholipaseC), which hydrolyzes PI to inositol trisphosphate (IP3) and diacylglycerol (DAG). (b) IP3 mobilizes intracellular Ca+ from the endoplasmic and sarcoplasmic reticula, and activates Ca+-regulated enzymes and cell processes. (c) DAG activates protein kinaseC, which results in phosphorylation of cellular enzymes and other protein substrates and the influx of extracellular calcium that results in activation of contractile elements in smooth muscle.

66. Tuesday, February 2, 20XX Sample Footer Text 66 ACh also interacts with M2 and M4 muscarinic cholinoceptors to activate G proteins (GI), which leads to inhibition of adenylyl cyclase activity with decreased levels of cyclic AMP (cAMP) and to increased K1 conductance with effector cell hyperpolarization.

69. Tuesday, February 2, 20XX Sample Footer Text 69 Nicotinic receptors These receptors, in addition to binding ACh, also recognize nicotine but show only a weak affinity for muscarine. The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel. Binding of two ACh molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell. Nicotine at low concentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor. Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ) in skeletal muscles. Those at the NMJ are sometimes designated NM, and the others, NN. The nicotinic receptors of autonomic ganglia differ from those of the NMJ. For example, ganglionic receptors are selectively blocked by hexamethonium and mecamylamine, whereas NMJ receptors are specifically blocked by tubocurarine and atracurium.

70. Tuesday, February 2, 20XX Sample Footer Text 70 Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptors (muscarinic or nicotinic). These agents may be broadly classified into two groups: 1) choline esters, which include endogenous ACh and synthetic esters of choline, such as carbachol and bethanechol, and 2) naturally occurring alkaloids, such as nicotine and pilocarpine All direct-acting cholinergic drugs have a longer duration of action than ACh. The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness.

71. Tuesday, February 2, 20XX Sample Footer Text 71 Muscarinic agonists: Pilocarpine is a nonselective muscarinic agonist used to treat xerostomia and glaucoma. Attempts are currently underway to develop muscarinic agents that are directed against specific receptor subtypes.

72. Tuesday, February 2, 20XX Sample Footer Text 72 Acetylcholine Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes. Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the cholinesterases. ACh has both muscarinic and nicotinic activity. Its actions include the following: 1. Decrease in heart rate and cardiac output: The actions of ACh on the heart mimic the effects of vagal stimulation. For example, if injected intravenously, ACh produces a brief decrease in cardiac rate (bradycardia) and cardiac output, mainly because of a reduction in the rate of firing at the sinoatrial (SA) node. [Note: Normal vagal activity regulates the heart by the release of ACh at the SA node.] 2. Decrease in blood pressure: Injection of ACh causes vasodilation and lowering of blood pressure by an indirect mechanism of action. ACh activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels. This results in the production of nitric oxide from arginine. Nitric oxide then diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation via phosphodiesterase-3 inhibition. In the absence of administered cholinergic agents, the vascular cholinergic receptors have no known function, because ACh is never released into the blood in significant quantities. Atropine blocks these muscarinic receptors and prevents ACh from producing vasodilation.

73. Tuesday, February 2, 20XX Sample Footer Text 73 Pilocarpine 1.(1) Pilocarpine is occasionally used topically for open-angle glaucoma, either as 2.eyedrops or as a sustained-release ocular insert (Ocusert). - adrenoceptor antagonists and prostaglandin analogs are the drugs of choice to treat open-angle glaucoma. Other drug classes used include  -adrenergic receptor agonists and diuretics. 3.(2) When used before surgery to treat acute narrow-angle glaucoma (a medical emergency), pilocarpine is often given in combination with an indirectly acting muscarinic agonist such as physostigmine. 4.(3) Pilocarpine and cevimeline (Evoxac) increase salivary secretion. They are used to treat Sjögren syndrome-associated dry mouth. 5.(4) Pilocarpine is a tertiary amine that is well absorbed from the GI tract and enters the CNS.

74. Tuesday, February 2, 20XX Sample Footer Text 74 Adverse effects and contraindications 1.The adverse effects associated with direct-acting muscarinic cholinoceptor agonists 2.are extensions of their pharmacologic activity. The most serious include nausea, vom- iting, sweating, salivation, bronchoconstriction, decreased blood pressure, and diarrhea, all of which can be blocked or reversed by atropine. Systemic effects are minimal for drugs applied topically to the eye. 3.These drugs are contraindicated in the presence of peptic ulcer (because they increase acid secretion), asthma, cardiac disease, and Parkinson disease. They are not recommended in hyperthyroidism because they predispose to arrhythmia; they are also not recommended when there is mechanical obstruction of the GI or urinary tract.

76. Tuesday, February 2, 20XX Sample Footer Text 76 In the gastrointestinal (GI) tract, acetylcholine increases salivary secretion increases gastric acid secretion stimulates intestinal secretions motility. Respiratory tract: It also enhances bronchiolar secretions and causes bronchoconstriction. Methacholine, a direct-acting cholinergic agonist, is used to assist in the diagnosis of asthma due to its bronchoconstricting properties. In the genitourinary tract, ACh increases the tone of the detrusor muscle, causing urination. In the eye, ACh is involved in stimulation of ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle, causing miosis (marked constriction of the pupil). ACh (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery.

77. Tuesday, February 2, 20XX Sample Footer Text 77 Bethanechol Bethanechol is an unsubstituted carbamoyl ester, structurally related to ACh. It is not hydrolyzed by AChE due to the esterification of carbamic acid, although it is inactivated through hydrolysis by other esterases. It lacks nicotinic actions (due to addition of the methyl group), but does have strong muscarinic activity. Its major actions are on the smooth musculature of the bladder and GI tract. It has about a 1-hour duration of action. 1.Actions: Bethanechol directly stimulates muscarinic receptors and selectively stimulates urinary and gastrointestinal tract. Its effect on the GI tract causes increased intestinal motility and tone. It also stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter muscles are relaxed. These effects stimulate urination. It has persistent effects because it is resistant to cholinesterases. 2.Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly seen in postpartum or postoperative or with spinal cord injury, and nonobstructive urinary retention to facilitate emptying of the neurogenic bladder. Bethanechol may also be used to treat neurogenic atony as well as megacolon. 3.Adverse effects: Bethanechol can cause generalized cholinergic stimulation, with sweating, salivation, flushing, decreased blood pressure (with reflex tachycardia), nausea, abdominal pain, diarrhea, and bronchospasm. Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent.

78. Tuesday, February 2, 20XX Sample Footer Text 78 Carbachol (carbamylcholine) Carbachol has both muscarinic and nicotinic actions. Like bethanechol, carbachol is an ester of carbamic acid and a poor substrate for AChE. It is biotransformed by other esterases, but at a much slower rate. 1.Actions: Carbachol has profound effects on both the cardiovascular and Gl systems because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems. It can cause release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, it mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction. The vision becomes fixed at some particular distance, making it impossible to focus 2.Therapeutic uses: Because of its high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used. Intraocular use provides miosis for eye surgery and lowers intraocular pressure in the treatment of glaucoma. 3.Adverse effects: With ophthalmologic use, few adverse effects occur due to lack of systemic penetration {quaternary amine}.

79. Tuesday, February 2, 20XX Sample Footer Text 79 Pilocarpine The alkaloid pilocarpine is a tertiary amine and is stable to hydrolysis by AChE Compared with ACh and its derivatives, it is far less potent but is uncharged and can penetrate the CNS at therapeutic doses. Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology. 1.Actions: Applied topically to the eye, pilocarpine produces rapid miosis, contraction of the ciliary muscle, and spasm of accommodation. Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug is beneficial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck. Sjögren syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine tablets and cevimeline, a cholinergic drug that also has the drawback of being nonspecific.

80. Tuesday, February 2, 20XX Sample Footer Text 80 1.Therapeutic use in glaucoma: Pilocarpine is used to treat glaucoma and is the drug of choice for emergency lowering of intraocular pressure of both open- angle and angle-closure glaucoma. Pilocarpine is extremely effective in opening the trabecular meshwork around the Schlemm canal, causing an immediate drop in intraocular pressure because of the increased drainage of aqueous humor. This action occurs within a few minutes, lasts 4 to 8 hours, and can be repeated. [Note: Topical carbonic anhydrase inhibitors, such as dorzolamide and β-adrenergic blockers such as timolol, are effective in treating glaucoma but are not used for emergency lowering of intraocular pressure.] The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine.

81. Tuesday, February 2, 20XX Sample Footer Text 81 Adverse effects: Pilocarpine can cause blurred vision, night blindness, and brow ache. Poisoning with this agent is characterized by exaggeration of various parasympathetic effects, including profuse sweating (diaphoresis) and salivation. The effects are similar to those produced by consumption of mushrooms of the genus Inocybe, which contain muscarine. Parenteral atropine, at doses that can cross the blood–brain barrier, is administered to counteract the toxicity of pilocarpine.

83. Tuesday, February 2, 20XX Sample Footer Text 83 INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASE AGENTS (REVERSIBLE) AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its actions. It is located both pre- and postsynaptically in the nerve terminal where it is membrane bound. Inhibitors of AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide cholinergic action by preventing the degradation of ACh. This results in an accumulation of ACh in the synaptic space. Therefore, these drugs can provoke a response at all cholinoceptors, including both muscarinic and nicotinic receptors of the ANS, as well as at the NMJ and in the brain. Reversible inhibitors are physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, and donepeizil. The reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting agents. All are poorly absorbed from conjunctiva, skin, and lungs except physostigmine which is well absorbed from all sites. The effects are similar to direct-acting cholinergic agonists.

84. Tuesday, February 2, 20XX Sample Footer Text 84 These agents are commonly used in the treatment of: • glaucoma, • myasthenia gravis, • stimulation of gastrointestinal and urinary tract motility (for example, neostigmine)—same effects as with agonists, • reversal of neuromuscular blockade, and • atropine poisoning. Primary target organs of anticholineste ase drugs are eye, skeletal muscle, neuromuscular junctions, gastrointestinal tract, urinary tract, respiratory tract, and heart.

85. Tuesday, February 2, 20XX Sample Footer Text 85 Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by generalized muscle weakness. The pathophysiology of MG involves autoantibodies directed against postsynaptic acetylcholine receptors (AchR), thereby impairing neuromuscular transmission. Women are more frequently affected and about 10–15% of cases are associated with thymoma. The most common initial symptoms are ptosis and/or diplopia due to ocular muscle weakness, with the disease usually progressing to generalized weakness within two years. At that point, patients have difficulties standing up, climbing stairs, and possibly even swallowing and/or chewing. Muscle weakness worsens throughout the day with increased activity and improves after rest.

86. Tuesday, February 2, 20XX Sample Footer Text 86 MG is diagnosed according to patient history, physical examination, antibody testing, and electromyographic evaluation. All patients should be screened for thymomas via CT as they can be surgically removed, allowing for possible curative treatment. The treatment of choice consists of acetylcholinesterase inhibitors, possibly in combination with immunosuppressive drugs if symptoms persist. Acute exacerbations, as seen in myasthenic crisis, should be treated with either IV immunoglobulins or plasma exchange.

87. Tuesday, February 2, 20XX Sample Footer Text 87 Thymus involvement •Muscle-like (myoid) cells in the thymus express AChR → autoreactive targeting by T cells → production of acetylcholine receptor antibodies (AChR antibodies) Acetylcholine receptor antibodies •Responsible for inhibition of signal transduction at the neuromuscular junction (NMJ) •Antibodies target postsynaptic AChRs of normal muscle cells → competitive inhibition of acetylcholine (ACh) → AChR decay through receptor internalization (↓ receptor density at the postsynaptic membrane) and activation of complement (→ muscle cell lysis) → impaired signal transduction at the NMJ → skeletal muscle weakness and fatigue • Seropositive MG (80–90% of cases): positive assays for antibodies (in blood) against the acetylcholine receptor (AChR-Ab) • Seronegative MG (10–20% of cases): negative for AChR antibodies, but may be positive for muscle-specific tyrosine kinase antibodies (MuSK antibodies)

88. Tuesday, February 2, 20XX Sample Footer Text 88 •Symptoms worsen with increased muscle use throughout the day and improve with rest. •Sometimes associated with exacerbating factors, including: • Medications • Muscle relaxants • Beta blockers • Benzodiazepines • Aminoglycosides, fluoroquinolones • Low-potency antipsychotics • Tricyclic antidepressants • D-penicillamine • Pregnancy • Stress • Infection

89. Tuesday, February 2, 20XX Sample Footer Text 89 Clinical manifestations Fatigable weakness of skeletal muscles in which smaller muscles responsible for fine movements (e.g., eye muscles) tend to be affected first, while larger muscles muscles become affected later on. •Eye muscle weakness: most common initial symptom • Triad of: • Ptosis • Diplopia • Blurred vision •Bulbar muscle weakness • Slurred speech • Difficulty chewing and/or swallowing •Proximal limb weakness • Rising from a chair • Climbing stairs • Brushing hair • Deep tendon reflexes are not affected. •Respiratory muscle weakness: causes dyspnea

90. Tuesday, February 2, 20XX Sample Footer Text 90 Physical examination findings •Curtain sign: Lifting the more ptotic eyelid reveals ptosis in the contralateral eyelid. • According to Hering's law of equal innervation, the muscles of both eyelids receive equal innervation. • Manual lifting of the more ptotic eyelid → elimination of the central compensation required to keep the more ptotic eyelidelevated → less innervation to both eyelids → relaxing of the contralateral levator palpebrae superioris → enhancement of ptosis in contralateral eyelid •Cogan lid twitch sign • The patient is asked to gaze downward for 10–20 seconds and then to look straight ahead • The affected upper eyelid briefly twitches •Simpson test • Provocation test used to reproduce eyelid fatigue • Positive if looking upward for > 1 minute (without lifting the head) provokes eyelid fatigue •Ice test: ice pack placed on one eye for 5 minutes → temporary improvement of eyelid fatigue

91. Tuesday, February 2, 20XX Sample Footer Text 91 Approach •Suspected cases of MG are generally confirmed via EMG and AChR antibodies. •Chest CT to rule out thymoma Laboratory studies •AChR antibody test (most specific test) • 80–90% of patients with generalized MG have antibodies • 100% of patients with thymoma have antibodies •Other associated antibodies: anti-MuSK Electrodiagnostics •Electromyography (EMG): shows decremental response following repetitive nerve stimulation Imaging •Chest CT: every newly diagnosed MG patient to rule out thymoma

92. Tuesday, February 2, 20XX Sample Footer Text 92 •Edrophonium test (Tensilon test) • Used to diagnose MG before AChR antibody test became the common method • Symptoms improve rapidly after administration of a short- acting acetylcholinesterase inhibitor • High false positive rate

93. Tuesday, February 2, 20XX Sample Footer Text 93 •First line: cholinesterase inhibitors • Drug of choice: pyridostigmine • Only improve symptoms (no causal treatment) •Supplemental immunosuppressants: if symptoms persist despite anticholinesterase treatment • Glucocorticoids • Alternatives are azathioprine, cyclosporine, mycophenolate mofetil

94. Tuesday, February 2, 20XX Sample Footer Text 94 Edrophonium Edrophonium is the prototype short-acting AChE inhibitor. Edrophonium binds reversibly to the active center of AChE, preventing hydrolysis of ACh. It is rapidly absorbed and has a short duration of action of 10 to 20 minutes due to rapid renal elimination. Edrophonium is a quaternary amine, and its actions are limited to the periphery. It is used in the diagnosis of myasthenia gravis, an autoimmune disease caused by antibodies to the nicotinic receptor at the NMJ. This causes the degradation of the nicotinic receptors, making fewer receptors available for interaction with ACh. Intravenous injection of edrophonium leads to a rapid increase in muscle strength in patients with myasthenia gravis. Care must be taken, because excess drug may provoke a cholinergic crisis (atropine is the antidote). Edrophonium may also be used to assess cholinesterase inhibitor therapy, for differentiating cholinergic and myasthenic crises, and for reversing the effects of nondepolarizing neuromuscular blockers after surgery. Due to the availability of other agents, edrophonium use has become limited.

95. Tuesday, February 2, 20XX Sample Footer Text 95 Edrophonium is also used to diagnose myasthenia gravis.* The Tensilon test uses the short-acting drug edrophonium chloride, which is given intravenously, to assess the adequacy of treatment with AChE inhibitors. Small doses of edrophonium improve weakness, especially in the eye muscles, briefly and temporarily in untreated myasthenia patients or in treated patients in whom AChE inhibition is inadequate. Worsening of muscle weakness indicates that the dose of AChE inhibitor is too high—that is, excessive ACh stimulation at the neuromuscular junction results in a depolarizing blockade). A trial use of oral pyridostigmine bromide is an alternative approach. Tolerance may develop to long-term use of the AChE inhibitors.

96. Tuesday, February 2, 20XX Sample Footer Text 96 Physostigmine Physostigmine is a nitrogenous carbamic acid ester found naturally in plants and is a tertiary amine. It is a substrate for AChE, and it forms a relatively stable carbamoylated intermediate with the enzyme, which then becomes reversibly inactivated. The result is potentiation of cholinergic activity throughout the body. 1. Actions: Physostigmine has a wide range of effects and stimulates not only the muscarinic and nicotinic sites of the ANS, but also the nicotinic receptors of the NMJ. Muscarinic stimulation can cause contraction of gastrointestinal smooth muscles, miosis, bradycardia, and hypotension Nicotinic stimulation can cause skeletal muscle twitches, fasciculations, and skeletal muscle paralysis (at higher doses). Its duration of action is about 30 minutes to 2 hours, and it is considered an intermediate-acting agent. Physostigmine can enter and stimulate the cholinergic sites in the CNS. 2. Therapeutic uses: Physostigmine is used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine and scopolamine, and to reverse the effects of neuromuscular blockers (NMBs). 3. Adverse effects: Physostigmine is well absorbed orally and it enters the CNS. High doses of physostigmine may lead to convulsions. Bradycardia and a fall in cardiac output may also occur. Inhibition of AChE at the NMJ causes the accumulation of ACh and, ultimately through continuous depolarization, results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses.

98. Tuesday, February 2, 20XX Sample Footer Text 98 Neostigmine Neostigmine [nee-oh-STIG-meen] is a synthetic compound that is also a carbamic acid ester, and it reversibly inhibits AChE in a manner similar to physostigmine. 1. Actions: Unlike physostigmine, neostigmine has a quaternary nitrogen. Therefore, it is more polar, is absorbed poorly from the GI tract, and does not enter the CNS. Its effect on skeletal muscle is greater than physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has an intermediate duration of action, usually 30 minutes to 2 hours. 2. Therapeutic uses: Neostigmine is used to stimulate the bladder and GI tract and as an antidote for competitive neuromuscular-blocking agents. It is also used to manage symptoms of myasthenia gravis. 3. Adverse effects: Adverse effects of neostigmine include those of generalized cholinergic stimulation, such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm. Unlike physostigmine, neostigmine is poorly absorbed from the GI tract and has negligible distribution into the CNS; therefore, it does not cause CNS side effects and is not used to overcome toxicity of central-acting antimuscarinic agents such as atropine. Neostigmine is contraindicated when intestinal or urinary bladder obstruction is present.

103. Tuesday, February 2, 20XX Sample Footer Text 103 Direct parasympathomimetics •Local side effects: blurred vision due to miosis when applied to the eyes •Systemic side effects: identical to those of indirect parasympathomimetics •Indirect parasympathomimetics •Cardiovascular symptoms • Bradycardia • Hypotension •Gastrointestinal symptoms • Diarrhea • Nausea • Abdominal pain •Genitourinary symptoms: uncontrolled urination •Exocrine glands • ↑ Sweating • ↑ Salivation • ↑ Gastric secretion •Ocular symptoms • Miosis • Lacrimation •CNS-related symptoms: can culminate in coma • Hypoventilation • Lethargy • Tremor • Restlessness • Anxiety • Ataxia •Musculoskeletal symptoms • Weakness • Paralysis → peripheral neuromuscular respiratory failure • Spasms • Fasciculations

104. Tuesday, February 2, 20XX Sample Footer Text 104 Cholinergic crisis (cholinergic syndrome) •Definition: potentially life-threatening acetylcholine receptor overstimulation •Etiology: poisoning with organophosphates (e.g., parathion) •Pathophysiology: irreversible acetylcholinesterase inhibition •Epidemiology: most commonly seen in farmers, as organophosphates are used as insecticides •Clinical presentation • Muscarinic effects • Excess of secretions, including salivation, sweating, lacrimation, urination, defecation, and emesis • Miosis and blurred vision • Bradycardia • Bronchospasm • Bronchorrhea • Nicotinic effects: blockage at the neuromuscular junction (similar mechanism observed in succinylcholine) • Systemic effects • Hypoventilation • Lethargy • Seizures, coma •Treatment: antimuscarinic agents • Atropine • Pralidoxime DUMBBBELLSS: Diarrhea, Urination, Miosis, Bradycardia, Bronch ospasm, Bronchorrhea, Emesis, Lacrimation, Lethargy, Sweating, and Salivation are the main symptoms of cholinergic crisis.

105. Tuesday, February 2, 20XX Sample Footer Text 105 Botulinum toxin blocks the release of acetylcholine from cholinergic nerve terminals. Which is a possible effect of botulinum toxin? A. Skeletal muscle paralysis B. Improvement of myasthenia gravis symptoms C. Increased salivation D. Reduced heart rate

106. Tuesday, February 2, 20XX Sample Footer Text 106 Correct answer = A. Acetylcholine released by cho-inergic neurons acts on nicotinic receptors in the skeletal muscle cells to cause contraction. Therefore, blockade of ACh release causes skeletal muscle paralysis. Myasthenia gravis is an autoimmune disease where antibodies are produced against nicotinic receptors and inactivate nicotinic receptors. A reduction in ACh release therefore worsens (not improves) the symptoms of this condition. Reduction in ACh release by botulinum toxin causes reduction in secretions including saliva (not increase in salivation) causing dry mouth and an increase (not reduction) in heart rate due to reduced vagal activity.

107. Tuesday, February 2, 20XX Sample Footer Text 107 1.A patient develops urinary retention after an abdominal surgery. Urinary obstruction was ruled out in this patient. Which strategy would be helpful in promoting urination? 2.A. Activating nicotinic receptors B. Inhibiting the release of acetylcholine C. Inhibiting cholinesterase enzyme D. Blocking muscarinic receptors

108. Tuesday, February 2, 20XX Sample Footer Text 108 Correct answer = C. Activation of muscarinic receptors in the detrusor muscles of urinary bladder can promote urination in patients where the tone of detrusor muscle is low. Inhibiting cholinesterase enzyme increases the levels of acetylcholine, and acetylcholine can increase the tone of the detrusor muscle. There are no nicotinic receptors in the detrusor muscles; therefore, activation of nicotinic receptors is not helpful. Inhibiting the release of acetylcholine or blocking muscarinic receptors worsens urinary retention.

109. Tuesday, February 2, 20XX Sample Footer Text 109 Which of the following drugs could theoretically improve asthma symptoms? A. Bethanechol B. Pilocarpine C. Pyridostigmine D. Atropine

110. Tuesday, February 2, 20XX Sample Footer Text 110 Correct answer = D. Muscarinic agonists and drugs that increase acetylcholine levels cause constriction of bronchial smooth muscles and could exacerbate asthma symptoms. Bethanechol and pilocarpine are muscarinic agonists, and pyridostigmine is a cholinesterase inhibitor that increases levels of acetylcholine. Atropine is a muscarinic antagonist and therefore does not exacerbate asthma. Theoretically, it should relieve symptoms of asthma (not used clinically for this purpose).

111. Tuesday, February 2, 20XX Sample Footer Text 111 “A 25-year-old woman presents to the general medicine clinic complaining of vision problems. She has difficulty keeping her eyes open and complains of “seeing double.” Her symptoms fluctuate throughout the day. Her ptosis is more common in the left eye, but will switch over to the right eye. Her symptoms are generally better in the morning and worsen as the day progresses. Her ptosis seems to get better after she rests her eyes. She exercises regularly, but has noticed that over the past 2 months she has struggled to complete her evening run due to fatigue in her hips.You suspect myasthenia gravis and perform an edrophonium (Tensilon) test.The test is positive and therefore the patient is started on mestinon.”

112. Tuesday, February 2, 20XX Sample Footer Text 112 Edrophonium test and diagnosis: An intramuscular or intravenous injection of edrophonium will alleviate ptosis by temporarily increasing the availability of acetylcholine at the synapse, allowing contraction of the levator palpebrae superiorus muscle.This test is very specific for diagnosing myasthenia gravis. Mechanisms of action of edrophonium and mestinon: acetylcholinesterase (AChE) ”

113. Tuesday, February 2, 20XX Sample Footer Text 113 Muscarinic antagonists (antimuscarinic agents) are a group of anticholinergic drugs that competitively inhibit postganglionicmuscarinic receptors. As such, they have a variety of applications that involve the parasympathetic nervous system. Which organ systems are most affected by an antimuscarinic agent depends on the specific characteristics of the agent, particularly its lipophilicity. Lipophilic agents (i.e., atropine or benztropine) are able to cross the blood-brain barrier and therefore affect the central nervous system (CNS) in addition to other organ systems. Less lipophilic agents (i.e., ipratropium or butylscopolamine) are administered if the CNS does not need to be targeted, specifically for respiratory (e.g., asthma), gastrointestinal (e.g., irritable bowel syndrome), or genitourinary applications (e.g., urinary incontinence). Numerous adverse effects have been reported, the most common of which is dry mouth. An overdose can result in anticholinergic syndrome, which manifests in disorientation, hyperthermia, tachycardia, and/or coma.To avoid toxicity, it is especially important to consider the anticholinergic effects of other drug classes before administering muscarinic antagonists.

118. Tuesday, February 2, 20XX Sample Footer Text 118 Anticholinergic syndrome (overdose) •Etiology • Belladonna poisoning • Jimson weed/Angel's trumpet (Datura stramonium) poisoning: The plant contains alkaloids, such as atropine and scopolamine, which lead to anticholinergic intoxication and mydriasis (“gardener's pupil”). • Medications • Anticholinergic agents (e.g., atropine, benztropine, trihexyphenidyl) • Drugs with anticholinergic properties • Tricyclic antidepressives (predominantly doxepin, amitriptyline, imipramine, and trimipramine) • Antipsychotics (e.g., clozapine, quetiapine) • First-generation antihistamines (e.g., promethazine, dimenhydrinate) •Clinical features • Dry mouth, warm, flushed skin, thirst, tachycardia, arrhythmias, mydriasis, confusion, and agitation • Possibly anticholinergic delirium: Excessive use of tricyclic antidepressants (or other medications with significant anticholinergic effects) can cause life-threatening delirium, hallucinations, and psychomotor symptoms. •Treatment: antidote for purely anticholinergic poisoning (e.g. atropine): physostigmine

119. ThankYou Sample Footer Text 119

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