Drugs-Affecting-ANS.pptx Drugs-Affecting-ANS.pptx Drugs-Affecting-ANS.pptx Drugs-Affecting-ANS.pptx

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1. Drugs Acting on the Autonomic Nervous System

2. Autonomic nervous system The autonomic nervous system (ANS) is sometimes called the involuntary or visceral nervous system because it mostly functions with the person having little conscious awareness of its activity. Working closely with the endocrine system the ANS helps to regulate and integrate the body’s internal functions within a relatively narrow range of normal on a minute-to-minute basis. The ANS integrates parts of the central nervous system (CNS) and peripheral nervous system to automatically react to changes in the internal and external environments.

3. Structure and Function of the Autonomic Nervous System The main nerve centers for the ANS are located in the hypothalamus, the medulla, and the spinal cord. Nerve impulses that arise in peripheral structures are carried to these centers by afferent nerve fibers. These integrating centers in the CNS respond by sending out efferent impulses along the autonomic nerve pathways. These impulses adjust the functioning of various internal organs in ways that keep the body’s internal environment constant, or homeostatic.

4. Functions The ANS works to regulate blood pressure, heart rate, respiration, body temperature, water balance, urinary excretion, and digestive functions, among other things. This system exerts minute-to-minute control of body responses, which is balanced by the two divisions of the ANS.

5. Divisions The ANS is divided into two branches: The sympathetic nervous system (SNS) and the parasympathetic nervous system. These two branches differ in three basic ways: (1) the location of the originating cells in the CNS, (2) the location of the nerve ganglia, and (3) the preganglionic and postganglionic neurons

6. Sympathetic Nervous System The SNS is sometimes referred to as the “fight-or-flight” system, or the system responsible for preparing the body to respond to stress. Stress can be either internal, such as cell injury or death, or external, such as a perceived or learned reaction to various external situations or stimuli. For the most part the SNS acts much like an accelerator, speeding things up for action.

7. Structure and Function The SNS is also called the thoracolumbar system because the CNS cells that originate impulses for this system are located in the thoracic and lumbar sections of the spinal cord. These cells send out short preganglionic fibers that synapse or communicate with nerve ganglia located in chains running alongside the spinal cord. Acetylcholine ( ACh ) is the neurotransmitter released by these preganglionic nerves. The nerve ganglia, in turn, send out long postganglionic fibers that synapse with neuroeffectors, using norepinephrine or epinephrine as the neurotransmitter. One of the sympathetic ganglia, on either side of the spinal cord, does not develop postganglionic axons but produces norepinephrine and epinephrine, which are secreted directly into the bloodstream. These ganglia have evolved into the adrenal medullae. When the SNS is stimulated the chromaffin cells of the adrenal medullae secrete epinephrine and norepinephrine directly into the bloodstream.

8. Parasympathetic Nervous System In many areas the parasympathetic nervous system works in opposition to the SNS. This allows the autonomyic system to maintain a fine control over internal homeostasis. For example, the SNS increases heart rate, whereas the parasympathetic system decreases it. Thus, the ANS can influence heart rate by increasing or decreasing sympathetic activity or by increasing or decreasing parasympathetic activity. This is very much like controlling the speed of a car by moving between the accelerator and the brake or combining the two. Whereas the SNS is associated with the stress reaction and expenditure of energy, the parasympathetic system is associated with activities that help the body to store or conserve energy, a “rest-and-digest” response

9. Structure and Function The parasympathetic system is sometimes called the craniosacral system because the CNS neurons that originate parasympathetic impulses are found in the cranium (one of the most important being the vagus or tenth cranial nerve) and in the sacral area of the spinal cord The terms cholinergic, muscarinic, and vagal are often used interchangeably when discussing the parasympathetic system. It has long preganglionic axons that meet in ganglia located close to or within the organ to be affected. The postganglionic axon is very short, going directly to the effector cell. The neurotransmitter sed by both the preganglionic and postganglionic neurons is ACh .

10. Parasympathetic system stimulation results in the following actions: Increased motility and secretions in the GI tract to promote digestion and absorption of nutrients. Decreased heart rate and contractility to conserve energy and provide rest for the heart. Constriction of the bronchi, with increased secretions. Relaxation of the GI and urinary bladder sphincters, allowing evacuation of waste products. Pupillary constriction, which decreases the light entering the eye and decreases timulation of the retina.

11. Adrenergic Agonists

12. ADRENERGIC AGONIST An adrenergic agonist is also called a sympathomimetic drug because it mimics the effects of the sympathetic nervous system (SNS). The therapeutic and adverse effects associated with these drugs are related to their stimulation of adrenergic receptor sites. That stimulation can be either direct, by occupation of the adrenergic receptor, or indirect, by modulation of the release of neurotransmitters from the axon. Some drugs act in both ways. Adrenergic agonists also can affect both the alpha- and beta-receptors, or they can act at specific receptor sites. The use of adrenergic agonists varies from ophthalmic preparations for dilating pupils to systemic preparations used to support individuals experiencing shock. They are used in patients of all ages.

13. Alpha- and Beta-Adrenergic Agonists Drugs that are generally sympathomimetic (Figure 30.2) are called alpha-agonists (stimulate alpha-receptors) and beta-agonists (stimulate beta-receptors). These agonists stimulate all of the adrenergic receptors; that is, they affect both alpha- and beta-receptors. Agents that affect both alpha- and beta-receptor sites include dobutamine (generic), dopamine (generic), ephedrine (generic), epinephrine ( Adrenalin , Adrenaclick ), and norepinephrine ( Levophed ). Some of these drugs are naturally occurring catecholamines.

14. Drugs in Focus: Alpha- and Beta-Adrenergic Agonists

15. Therapeutic Actions and Indications The effects of the sympathomimetic drugs are mediated by the adrenergic receptors in target organs: Heart rate increases with increased myocardial contractility; bronchi dilate and respirations increase in rate and depth; blood vessels constrict, causing an increase in blood pressure; intraocular pressure decreases; glycogenolysis (breakdown of glucose stores so that the glucose can be used as energy) occurs throughout the body; pupils dilate; and sweating can increase. These drugs generally are indicated for the treatment of hypotensive states or shock, bronchospasm, and some types of asthma.

16. DOPAMINE Dopamine, a naturally occurring catecholamine, is the sympathomimetic of choice for the treatment of shock. It stimulates the heart and blood pressure but also causes a renal and splanchnic arteriole dilation that increases blood flow to the kidneys, preventing the diminished renal blood supply and possible renal shutdown that can occur with epinephrine or norepinephrine, which are also naturally occurring catecholamines that interact with both alpha- and beta-adrenergic receptors and are used for the treatment of shock and to stimulate the body after cardiac arrest and for immediate relief of anaphylaxis.

17. Dobutamine and ephedrine Dobutamine and ephedrine are synthetic catecholamines. Dobutamine, although it acts at both receptor sites, has a slight preference for beta1-receptor sites. It is used in the treatment of heart failure because it can increase myocardial contractility without much change in rate and does not increase the oxygen demand of the cardiac muscle, an advantage over all of the other sympathomimetic drugs.

18. Ephedrine stimulates the release of norepinephrine from nerve endings and acts directly on adrenergic receptor sites. Although ephedrine was once used for situations ranging from the treatment of shock to chronic management of asthma and allergic rhinitis, its use in many areas is declining because of the availability of less toxic drugs with more predictable onset and action. Many over-the-counter (OTC) cold products contain ephedrine or pseudoephedrine. These products can be used to produce methamphetamine, an often-abused street drug. By law the sale of these products is now restricted. The products are found behind the counter at pharmacies, not on open shelves, and the amount that can be purchased at any given time is limited.

19. Pharmacokinetics These drugs are generally absorbed rapidly after injection or passage through mucous membranes. They are metabolized in the liver and excreted in the urine. When used in emergency situations, they are given IV to achieve rapid onset of action.

20. Contraindications and Cautions The alpha- and beta-agonists are contraindicated in patients with known hypersensitivity to any component of the drug to prevent hypersensitivity reactions ; pheochromocytoma because the systemic overload of catecholamines could be fatal ; with tachyarrhythmias or ventricular fibrillation because the increased heart rate and oxygen consumption usually caused by these drugs could exacerbate these conditions ; with hypovolemia, for which fluid replacement would be the treatment for the associated hypotension ; and with halogenated hydrocarbon general anesthetics, which sensitize the myocardium to catecholamines and could cause serious cardiac effects. Caution should be used with any kind of peripheral vascular disease (e.g., atherosclerosis, Raynaud disease, diabetic endarteritis), which could be exacerbated by systemic vasoconstriction. Because the sympathomimetic drugs stimulate the SNS, they should be used during pregnancy and lactation only if the benefits to the mother clearly outweigh any potential risks to the fetus or neonate.

21. Common adverse effects associated with adrenergic agonists.

22. Clinically Important Drug–Drug Interactions Increased effects of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) can occur because of the increased norepinephrine levels or increased receptor stimulation that occurs with both drugs. There is an increased risk of hypertension if alpha and beta-adrenergic agonists are given with any other drugs that cause hypertension, including herbal therapies and OTC preparations (Box 30.2). Any adrenergic agonist will lose effectiveness if combined with any adrenergic antagonist. Monitor the patient’s drug regimen for appropriate use of the drugs.

23. Alpha-Specific Adrenergic Agonists Alpha-specific adrenergic agonists , or alpha-agonists, are drugs that bind primarily to alpha-receptors rather than to beta-receptors. Three drugs belong to this class: Clonidine ( Catapres ), midodrine (generic), and phenylephrine ( Neo-Synephrine , and others).

24. Therapeutic Actions and Indications Therapeutic effects of the alpha-specific adrenergic agonists result from the stimulation of alpha-receptors within the SNS. The uses are varied, depending on the specific drug and the route of administration . Phenylephrine , a potent vasoconstrictor and alpha1-agonist with little or no effect on the heart or bronchi, is used in many combination cold and allergy products. Parenterally, it is used to treat shock or shock-like states, to overcome paroxysmal supraventricular tachycardia, to prolong local anesthesia, and to maintain blood pressure during spinal anesthesia. Topically, it is used to treat allergic rhinitis and to relieve the symptoms of otitis media. Ophthalmically , it is used to dilate the pupils for eye examination, before surgery, or to relieve elevated eye pressure associated with glaucoma. Phenylephrine is found in many cold and allergy products because it is so effective in constricting topical vessels and decreasing the swelling, signs, and symptoms of rhinitis.

25. Midodrine Midodrine is an oral drug that is used to treat orthostatic hypotension in patients who do not respond to traditional therapy. It activates alpha1-adrenergic receptors, leading to peripheral vasoconstriction and an increase in vascular tone and blood pressure. This effect can cause a serious supine hypertension. Patients need to be monitored in the standing, sitting, and supine positions to determine whether this will be a problem. CLONIDINE specifically stimulates CNS alpha2-receptors. This leads to decreased sympathetic outflow from the CNS because the alpha2-receptors moderate the release of norepinephrine from the nerve axon. Clonidine is available in oral and transdermal forms for use to control hypertension and as an injection for epidural infusion to control pain in cancer patients. Because of its centrally acting effects, clonidine is associated with many more CNS effects (bad dreams, sedation, drowsiness, fatigue, headache) than other sympathomimetics. It can also cause extreme hypotension, heart failure, and bradycardia due to its decreased effects of the sympathetic outflow from the CNS.

26. Pharmacokinetics These drugs are generally well absorbed from all routes of administration and reach peak levels in a short period—20 to 45 minutes. They are widely distributed in the body, metabolized in the liver, and primarily excreted in the urine. The transdermal form of clonidine is slow release and has a 7-day duration of effects, so it only needs to be replaced once a week. Phenylephrine can be given IM, subcutaneously, IV, orally, and as a nasal or an ophthalmic solution.

27. Contraindications and Cautions The alpha-specific adrenergic agonists are contraindicated in the presence of allergy to the specific drug to avoid hypersensitivity reactions ; severe hypertension or tachycardia because of possible additive effects ; and narrow-angle glaucoma, which could be exacerbated by arterial constriction. There are no adequate studies about use during pregnancy and lactation , so use should be reserved for situations in which the benefit to the mother outweighs any potential risk to the fetus or neonate. They should be used with caution in the presence of CV disease or vasomotor spasm because these conditions could be aggravated by the vascular effects of the drug ; thyrotoxicosis or diabetes because of the thyroid-stimulating and glucose-elevating effects of sympathetic stimulation ; or renal or hepatic impairment, which could interfere with metabolism and excretion of the drug.

28. Adverse Effects Patients receiving these drugs often experience adverse effects that are extensions of the therapeutic effects or other sympathetic stimulatory reactions. CNS effects include feelings of anxiety, restlessness, depression, fatigue, strange dreams, and personality changes. Blurred vision and sensitivity to light may occur because of the pupil dilation that occurs when the sympathetic system is stimulated. CV effects can include arrhythmias, ECG changes, blood pressure changes, and peripheral vascular problems. Nausea, vomiting, and anorexia can occur, related to the depressant effects of the SNS on the GI tract. GU effects can include decreased urinary output, difficulty urinating, dysuria, and changes in sexual function related to the sympathetic stimulation of these systems. These drugs should not be stopped suddenly; adrenergic receptors will be very sensitive to catecholamines, and sudden withdrawal can lead to tachycardia, hypertension, arrhythmias, flushing, and even death. Avoid these effects by tapering the drug over 2 to 4 days when it is being discontinued. As with other sympathomimetics, if phenylephrine is given IV, care should be taken to avoid extravasation. The vasoconstricting effects of the drug can lead to necrosis and cell death in the area of extravasation.

29. Clinically Important Drug–Drug Interactions Phenylephrine combined with MAOIs can cause severe hypertension, headache, and hyperpyrexia; this combination should be avoided. Increased sympathomimetic effects occur when phenylephrine is combined with TCAs; if this combination must be used the patient should be monitored very closely. Clonidine has a decreased antihypertensive effect if taken with TCAs, and a paradoxical hypertension occurs if it is combined with propranolol. If these combinations are used, the patient response should be monitored closely and dose adjustment made as needed. Midodrine can precipitate increased drug effects of digoxin, beta-blockers, and many antipsychotics. Such combinations should be avoided. Any adrenergic agonist will lose effectiveness if combined with any adrenergic antagonist. Monitor the patient’s drug regimen for appropriate use of the drugs.

30. Beta-Specific Adrenergic Agonists Most of the drugs that belong to the class of beta-specific adrenergic agonists, or beta-agonists, are beta2-specific agonists and are used to manage and treat bronchial spasm, asthma, and other obstructive pulmonary conditions. These drugs, including albuterol ( Proventil HFA , Ventolin ), arformoterol ( Brovana ), formoterol ( Foradil , Perforomist ), indacaterol ( Arcapta ), levalbuterol ( Xopenex ), metaproterenol (generic), olodaterol ( Striverdi Respimat ), salmeterol ( Serevent ), and terbutaline (generic), which deals with drugs used to treat obstructive pulmonary diseases. Beta3-agonists act to relax the bladder and are used to help treat overactive bladder as discussed in Chapter 52. This chapter specifically addresses isoproterenol ( Isuprel ), which is used as a sympathomimetic for its overall stimulatory properties.

31. Pharmacokinetics Isoproterenol is rapidly distributed after injection; it is metabolized in the liver and excreted in the urine. The half-life is relatively short—less than 1 hour. Contraindications and Cautions Isoproterenol is contraindicated in the presence of allergy to the drug or any components of the drug to avert hypersensitivity reactions ; with pulmonary hypertension, which could be exacerbated by the effects of the drug ; during anesthesia with halogenated hydrocarbons, which sensitize the myocardium to catecholamines and could cause a severe reaction ; with eclampsia, uterine hemorrhage, and intrauterine death, which could be complicated by uterine relaxation or increased blood pressure ; and during pregnancy and lactation because of potential effects on the fetus or neonate. Caution should be used with diabetes, thyroid disease, vasomotor problems, degenerative heart disease, or history of stroke, all of which could be exacerbated by the sympathomimetic effects of the drug , and with severe renal impairment, which could alter excretion of the drug.

32. Adverse Effects Patients receiving isoproterenol often experience adverse effects related to the stimulation of sympathetic adrenergic receptors. CNS effects include restlessness, anxiety, fear, tremor, fatigue, and headache. CV effects can include tachycardia, angina, myocardial infarction, and palpitations. Pulmonary effects can be severe, ranging from difficulty breathing, coughing, and bronchospasm to severe pulmonary edema. GI upset, nausea, vomiting, and anorexia can occur as a result of the slowing of the GI tract with SNS stimulation. Hypokalemia can occur as a result of the release of aldosterone that occurs with sympathetic stimulation and the resultant loss of potassium. Other anticipated effects can include sweating, pupil dilation, rash, and muscle cramps which occur as a result of the potassium shift.

33. Clinically Important Drug–Drug Interactions Increased sympathomimetic effects can be expected if this drug is taken with other sympathomimetic drugs. Decreased therapeutic effects can occur if this drug is combined with beta-adrenergic blockers.

34. Adrenergic Antagonists

35. Adrenergic antagonists or adrenergic blocking agents are also called sympatholytic drugs because they lyse, or block, the effects of the sympathetic nervous system (SNS). The therapeutic and adverse effects associated with these drugs are related to their adrenergicreceptor - site specificity; that is, the ability to react with specific adrenergic receptor sites without activating them, thus preventing the typical manifestations of SNS activation. By occupying the adrenergic receptor site, they prevent norepinephrine released from the nerve terminal or from the adrenal medulla from activating the receptor, thus blocking the SNS effects

36. Therapeutic Actions and Indications Adrenergic blocking agents competitively block the effects of norepinephrine at alpha-and beta-receptors throughout the SNS. Subsequently, this results in lower blood pressure, slower pulse rate, and increased renal perfusion with decreased renin levels. Most of these drugs are indicated to treat essential hypertension, alone or in combination with diuretics. Labetalol is used IV and orally to treat hypertension. It also can be used with diuretics and has been used to treat hypertension associated with pheochromocytoma (tumor of the chromaffin cells of the adrenal medulla, which periodically releases large amounts of norepinephrine and epinephrine into the system) and clonidine withdrawal. Amiodarone, which is available in oral and IV forms, is saved for serious emergencies and only used as an antiarrhythmic. Carvedilol is only available orally and is used to treat hypertension, as well as heart failure (HF) and left ventricular dysfunction after myocardial infarction (MI).

37. Pharmacokinetics These drugs are well absorbed when given orally and are distributed throughout the body when given IV or orally. They are metabolized in the liver and excreted in feces and urine. The half-life varies with the particular drug and preparation.

38. Contraindications and Cautions The nonselective adrenergic blocking agents are contraindicated in patients with known hypersensitivity to any component of the drug to avoid potentially serious hypersensitivity reactions ; with bradycardia or heart blocks, which could be worsened by the slowed heart rate and conduction ; with asthma, which could be exacerbated by the loss of norepinephrine’s effect of bronchodilation; with shock or HF, which could become worse with the loss of the sympathetic reaction ; and who are lactating because of the potential adverse effects on neonates.

39. Variety of adverse effects and toxicities associated with adrenergic blocking antagonists.

40. Clinically Important Drug–Drug Interactions There is increased risk of excessive hypotension if any of these drugs is combined with volatile liquid general anesthetics such as enflurane, halothane, or isoflurane. The effectiveness of diabetic agents is increased, leading to hypoglycemia when such agents are used with these drugs; patients should be monitored closely and dose adjustments made as needed. In addition, carvedilol has been associated with potentially dangerous conduction system disturbances when combined with verapamil or diltiazem; if this combination is used the patient requires continuous monitoring.

41. Therapeutic Actions and Indications Phentolamine blocks the postsynaptic alpha1-adrenergic receptors, decreasing sympathetic tone in the vasculature and causing vasodilation, which leads to a lowering of blood pressure. It also blocks presynaptic alpha2-receptors, preventing the feedback control of norepinephrine release. The result is an increase in reflex tachycardia that occurs when blood pressure is lowered. Phentolamine is most frequently used to prevent cell death and tissue sloughing after extravasation of intravenous norepinephrine or dopamine, causing a local vasodilation and a return of blood flow to the area

42. Pharmacokinetics Phentolamine is rapidly absorbed after IV or IM injection and is excreted in the urine. There are few data on its metabolism and distribution. Contraindications and Cautions Phentolamine is contraindicated in the presence of allergy to this or similar drugs and in the presence of coronary artery disease or MI because of the potential exacerbation of these conditions ; it should be used cautiously in pregnancy or lactation because of the potential adverse effects on the fetus or neonate.

43. Adverse Effects Patients receiving phentolamine often experience extensions of the therapeutic effects, including hypotension, orthostatic hypotension, angina, MI, cerebrovascular accident, flushing, tachycardia, and arrhythmia— all of which are related to vasodilation and decreased blood pressure. Headache, weakness, and dizziness often occur in response to hypotension. Nausea, vomiting, and diarrhea may also occur. Clinically Important Drug–Drug Interactions Ephedrine and epinephrine may have decreased hypertensive and vasoconstrictive effects if they are taken concomitantly with phentolamine because these agents work in opposing ways in the body. Increased hypotension may occur if this drug is combined with alcohol, which is also a vasodilator.

44. Pharmacokinetics The alpha1-selective adrenergic blocking agents are well absorbed after oral administration and undergo extensive hepatic metabolism. They are excreted in the urine. Contraindications and Cautions The alpha1-selective adrenergic blocking agents are contraindicated in the presence of allergy to any of these drugs to avoid hypersensitivity reactions and also with lactation because the drugs cross into breast milk and could have adverse effects on the neonate. They should be used cautiously in the presence of HF or renal failure because their blood pressure–lowering effects could exacerbate these conditions and with hepatic impairment, which could alter the metabolism of these drugs. Caution also should be used during pregnancy because of the potential for adverse effects on the fetus.

45. Adverse Effects The adverse effects associated with the use of these drugs are usually related to their effects of SNS blockage. CNS effects include headache, dizziness, weakness, fatigue, drowsiness, and depression. Nausea, vomiting, abdominal pain, and diarrhea may occur as a result of direct effects on the GI tract and sympathetic blocking. Anticipated CV effects include arrhythmias, hypotension, edema, HF, and angina. The vasodilation caused by these drugs can also cause flushing, rhinitis, reddened eyes, nasal congestion, and priapism. Clinically Important Drug–Drug Interactions Increased hypotensive effects may occur if these drugs are combined with any other vasodilating or antihypertensive drugs, such as nitrates, calcium-channel blockers, drugs used for erectile dysfunction and angiotensin-converting enzyme inhibitors.

46. Pharmacokinetics These drugs are absorbed from the GI tract after oral administration and undergo hepatic metabolism. Food has been found to increase the bioavailability of propranolol, although this effect was not found with other beta-adrenergic blocking agents. Absorption of sotalol is decreased by the presence of food. Propranolol also crosses the blood–brain barrier, but nadolol, and sotalol do not, making them a better choice if CNS effects occur with propranolol. These drugs are all excreted in the urine. Carteolol and metipranolol are only available in an ophthalmic form and are not usually absorbed systemically.

47. Contraindications and Cautions Nonselective beta-adrenergic blocking agents are contraindicated in the presence of allergy to any of these drugs or any components of the drug being used to avoid hypersensitivity reactions ; with bradycardia or heart blocks, shock, or HF, which could be exacerbated by the cardiac-suppressing effects of these drugs ; with bronchospasm, chronic obstructive pulmonary disease (COPD), or acute asthma, which could worsen due to the blocking of sympathetic bronchodilation ; with pregnancy because teratogenic effects have occurred in animal studies with all of these drugs except sotalol and because neonatal apnea, bradycardia, and hypoglycemia could occur ; and with lactation because of the potential effects on the neonate, which could include slowed heart rate, hypotension, and hypoglycemia. The safety and efficacy for use of these drugs in children have not been established. These drugs should be used cautiously in patients with diabetes and hypoglycemia because of the blocking of the normal signs and symptoms of hypoglycemia and hyperglycemia ; with thyrotoxicosis because of the adrenergic blocking effects on the thyroid gland ; or with renal or hepatic dysfunction, which could interfere with the excretion and metabolism of these drugs.

48. Adverse Effects Patients receiving these drugs often experience adverse effects related to blockage of betareceptors in the SNS. CNS effects include headache, fatigue, dizziness, depression, paresthesias , sleep disturbances, memory loss, and disorientation. CV effects can include bradycardia, heart block, HF, hypotension, and peripheral vascular insufficiency. Pulmonary effects can range from difficulty breathing, coughing, and bronchospasm to severe pulmonary edema and bronchial obstruction. GI upset, nausea, vomiting, diarrhea, gastric pain, and even colitis can occur as a result of unchecked parasympathetic activity and the blocking of the sympathetic receptors. Genitourinary (GU) effects can include decreased libido, impotence, dysuria, and Peyronie disease. Other effects that can occur include decreased exercise tolerance (patients often report that their “get up and go” is gone), hypoglycemia or hyperglycemia, and liver changes. If these drugs are stopped abruptly after long-term use, there is a risk of angina, MI, hypertension, and stroke because the receptor sites become hypersensitive to catecholamines after being blocked by the drugs.

49. Pharmacokinetics The beta1-selective adrenergic blockers are absorbed from the GI tract after oral administration, reach peak levels directly with IV infusion, and are not usually absorbed when given in ophthalmic form. The bioavailability of metoprolol is increased if it is taken in the presence of food. These drugs are metabolized in the liver and excreted in the urine. Metoprolol readily crosses the blood–brain barrier and may cause more CNS effects than acebutolol and atenolol, which do not cross the barrier.

50. Contraindications and Cautions The beta1-selective adrenergic blockers are contraindicated in the presence of allergy to the drug or any components of the drug to avoid hypersensitivity reactions ; with sinus bradycardia, heart block, cardiogenic shock, HF, or hypotension, all of which could be exacerbated by the cardiac-depressing and blood pressure–lowering effects of these drugs ; and with lactation because of the potential adverse effects on the neonate. They should be used with caution in patients with diabetes, thyroid disease, or COPD because of the potential for adverse effects on these diseases with sympathetic blockade ; and in pregnancy because of the potential for adverse effects on the fetus . The safety and efficacy of the use of these drugs in children have not been established.

51. Adverse Effects Patients receiving these drugs often experience adverse effects related to the blocking of beta1- receptors in the SNS. CNS effects include headache, fatigue, dizziness, depression, paresthesias , sleep disturbances, memory loss, and disorientation. CV effects can include bradycardia, heart block, HF, hypotension, and peripheral vascular insufficiency. Pulmonary effects ranging from rhinitis to bronchospasm and dyspnea can occur; these effects are not as likely to occur with these drugs as with the nonselective beta-blockers. GI upset, nausea, vomiting, diarrhea, gastric pain, and even colitis can occur as a result of unchecked parasympathetic activity and the blocking of the sympathetic receptors. GU effects can include decreased libido, impotence, dysuria, and Peyronie disease. Other effects that can occur include decreased exercise tolerance (patients often report that their “get up and go” is gone), hypoglycemia or hyperglycemia, and liver changes that are reflected in increased concentrations of liver enzymes. If these drugs are stopped abruptly after long term use, there is a risk of severe hypertension, angina, MI, and stroke because the receptor sites become hypersensitive to catecholamines after being blocked by the drug.

52. Clinically Important Drug–Drug Interactions A decreased hypertensive effect occurs if these drugs are given with clonidine, NSAIDs, rifampin, or barbiturates. If such a combination is used the patient should be monitored closely and dose adjustment made. There is an initial hypertensive episode followed by bradycardia if these drugs are given with epinephrine. Increased serum levels and increased toxicity of intravenous lidocaine will occur if it is given with these drugs. An increased risk for orthostatic hypotension occurs if these drugs are taken with prazosin. If this combination is used the patient must be monitored closely and safety precautions taken. The selective beta1-blockers have increased effects if they are taken with verapamil, cimetidine, methimazole, or propylthiouracil. The patient should be monitored closely and appropriate dose adjustment made.

53. SUMMARY

54. Cholinergic Agonists

55. Cholinergic agonists act at the same site as the neurotransmitter acetylcholine ( ACh ) and increase the activity of the ACh receptor sites throughout the body. Because these sites are found extensively throughout the parasympathetic nervous system, their stimulation produces a response similar to what is seen when the parasympathetic system is activated. As a result, these drugs are often called parasympathomimetic because their action mimics the action of the parasympathetic nervous system. Because the action of these drugs cannot be limited to a specific site, their effects can be widespread throughout the body, and they are usually associated with many undesirable systemic effects. Cholinergic agonists work either directly or indirectly. Direct-acting cholinergic agonists occupy receptor sites for ACh on the membranes of the effector cells of the postganglionic cholinergic nerves, causing increased stimulation of the cholinergic receptor. In contrast, indirect-acting cholinergic agonists cause increased stimulation of the Ach receptor sites by reacting with the enzyme acetylcholinesterase and preventing it from breaking down the ACh that was released from the nerve. These drugs produce their effects indirectly by producing an increase in the level of ACh in the synaptic cleft, leading to increased stimulation of the cholinergic receptor site (Figure 32.1). See Box 32.1 for use of these drugs across the lifespan .

56. Pharmacokinetics The direct-acting cholinergic agonists are generally well absorbed after oral administration and have relatively short half-lives, ranging from 1 to 6 hours. The metabolism and excretion of these drugs are not known but are believed to occur at the synaptic level using normal processes similar to the way that ACh is handled. Drugs used topically are not generally absorbed systemically.

57. Contraindications and Cautions These drugs are used sparingly because of the potential undesirable systemic effects of parasympathetic stimulation. They are contraindicated with hypersensitivity to any component of the drug to avoid hypersensitivity reaction and in the presence of any condition that would be exacerbated by parasympathetic effects, such as bradycardia, hypotension, vasomotor instability, and coronary artery disease, which could be made worse by the cardiac- and cardiovascular-suppressing effects of the parasympathetic system. Peptic ulcer, intestinal obstruction, or recent GI surgery could be negatively affected by the Gistimulating effects of the parasympathetic nervous system. Asthma could be exacerbated by the increased parasympathetic effect, overriding the protective sympathetic bronchodilation. Bladder obstruction or impaired healing of sites from recent bladder surgery could be aggravated by the stimulatory effects on the bladder. Epilepsy and parkinsonism could be affected by the stimulation of ACh receptors in the brain. Caution should be used during pregnancy and lactation because of the potential adverse effects on the fetus or neonate.

58. Variety of adverse effects and toxicities associated with cholinergic agonists .

59. Clinically Important Drug–Drug Interactions There is an increased risk of cholinergic effects if these drugs are combined or given with acetylcholinesterase inhibitors, such as neostigmine. The patient should be monitored and appropriate dose adjustments made.

60. The cause of the disease is not yet known, but it is known that there is a progressive loss of ACh -producing neurons and their target neurons in the cortex of the brain. These neurons seem to be related to memory and associations between memories that allow connections between thoughts and stimuli (e.g., seeing a face and being able to know that it is a face and to name the person the face belongs to). There are three reversible indirectacting cholinergic agonists available to slow the progression of this disease. These include galantamine ( Razadyne ), rivastigmine ( Exelon ), and donepezil ( Aricept ) (see Table 32.2). Inlate 2003 an N -methyl-D-aspartate (NMDA) receptor antagonist, memantine ( Namenda ),was also approved for use in the treatment of Alzheimer’s disease. This drug works in a unique way to block various receptor sites in the brain and slow the buildup of plaque on the involved axons, which seems to slow the effects of this disease, and is the only drug of its class that is available (Box 32.5). In 2015 a combination of an extended release capsule containing memantine and donepezil ( Namzaric ) was approved for treatment of Alzheimer’s disease, targeting two different sites of action.

61. Pharmacokinetics Anticholinesterase inhibitors are well absorbed after oral administration and distributed throughout the body. The sites of metabolism and excretion for all of these drugs are not known. It is thought that they are metabolized at the nerve synapse or in the tissues. Neostigmine is a synthetic drug that has a strong influence at the neuromuscular junction. Neostigmine has a duration of action of 2 to 4 hours and therefore must be given every few hours, based on patient response, to maintain a therapeutic level. Pyridostigmine has a longer duration of action than neostigmine (3 to 6 hours) and is preferred in some cases for the management of myasthenia gravis because it does not need to be taken as frequently. Pyridostigmine is available in oral and parenteral forms; the latter can be used if the patient is having trouble swallowing. Edrophonium is administered intravenously and has a very short duration of action (10 to 20 minutes).

62. The drugs used to treat Alzheimer’s disease are well absorbed and distributed through the body. They are metabolized in the liver by the cytochrome P450 system, so caution must be used for patients with hepatic impairment and for cases in which many interacting drugs are used. The drugs used to treat Alzheimer’s disease are excreted in the urine. Galantamine is available in tablet and oral solution form. It has a half-life of 7 hours and is taken twice a day. An extended release form, recently available, can be taken just once a day. Rivastigmine is available in capsule and solution forms to help with patients who have swallowing difficulties, as well as a transdermal patch that is applied once a day. The duration of effects for rivastigmine is 12 hours. Donepezil, with a 70-hour half-life, is available in oral form, as tablets and as a rapidly dissolving tablet. It can be given in once- aday dosing, which is advantageous with a disease that affects memory and the patient’s ability to remember to take pills throughout the day. None of these drugs reverse the effects of the disorder. Studies show that they may somewhat delay the losses seen with the disease.

63. Contraindications and Cautions Anticholinesterase inhibitors are contraindicated in the presence of allergy to any of these drugs to avoid hypersensitivity reactions ; with bradycardia or intestinal or urinary tract obstruction, which could be exacerbated by the stimulation of cholinergic receptors ; in pregnancy because the uterus could be stimulated and labor induced ; and during lactation because of the potential effects on the baby. Caution should be used with any condition that could be exacerbated by cholinergic stimulation. Although the effects of these drugs are generally more localized to the cortex and the neuromuscular junction the possibility of parasympathetic effects must be considered carefully in patients with asthma, coronary disease, peptic ulcer, arrhythmias, epilepsy, or parkinsonism, which could be exacerbated by the effects of parasympathetic stimulation. Drugs used to treat Alzheimer’s disease are metabolized in the liver and excreted in the urine, so caution should be used in the presence of hepatic or renal dysfunction, which could interfere with the metabolism and excretion of the drugs.

64. Adverse Effects The adverse effects associated with agents for treating myasthenia gravis or Alzheimer’s disease are related to stimulation of the parasympathetic nervous system. GI effects can include nausea, vomiting, cramps, diarrhea, increased salivation, and involuntary defecation related to the increase in GI secretions and activity due to parasympathetic nervous system stimulation. Cardiovascular effects can include bradycardia, heart block, hypotension, and even cardiac arrest, related to the cardiac-suppressing effects of the parasympathetic nervous system. Urinary tract effects can include a sense of urgency related to stimulation of the bladder muscles and sphincter relaxation. Miosis and blurred vision, headaches, dizziness, and drowsiness can occur related to CNS cholinergic effects. Other effects may include flushing and increased sweating secondary to stimulation of the cholinergic receptors in the sympathetic nervous system.

65. Clinically Important Drug–Drug Interactions There may be an increased risk of GI bleeding if these drugs are used with nonsteroidal anti-inflammatory drugs (NSAIDs) because of the combination of increased GI secretions and the GI mucosal erosion associated with the use of NSAIDs. If this combination is used the patient should be monitored closely for any sign of GI bleeding. The effect of anticholinesterase drugs is decreased if they are taken in combination with any cholinergic drugs because these work in opposition to each other.

66. Anticholinergic Agents

67. Drugs that are used to block the effects of acetylcholine are called anticholinergic drugs . Because this action lyses, or blocks, the effects of the parasympathetic nervous system, they are also called parasympatholytic agents. This class of drugs was once very widely used to decrease gastrointestinal (GI) activity and secretions in the treatment of ulcers and to decrease other parasympathetic activities to allow the sympathetic system to become more dominant. Today, more specific and less systemically toxic drugs are available for many of the conditions that would benefit from these effects. Therefore, this class of drugs is less commonly used. Atropine is the only widely used anticholinergic drug.

68. Drugs in Focus: Anticholinergic Agents/ Parasympatholytics

69. Pharmacokinetics The anticholinergics are well absorbed after oral and parenteral administration. Atropine and scopolamine are administered through PO, IM, IV, subcutaneous, and ophthalmic routes. Scopolamine is also available as a transdermal system Administration: Applying Dermal Patch Delivery Systems). Meclizine, dicyclomine, and propantheline are oral drugs, although dicyclomine is also available in IM form. Glycopyrrolate is available through PO, IM, IV, and subcutaneous routes. These drugs are widely distributed throughout the body and cross the blood–brain barrier. Their half-lives vary with route and drug. They are excreted in the urine. Aclidinium, ipratropium, tiotropium, and umeclidinium are inhaled drugs with a very rapid onset of action. Darifenacin, fesoterodine , solifenacin , and toliterodine are oral agents. Onset, peak, and half-lives vary by drug. They are metabolized in the liver and excreted in the urine.

70. Variety of adverse effects and toxicities associated with anticholinergic agents.

71. Clinically Important Drug–Drug Interactions The incidence of anticholinergic effects increases if these drugs are combined with anyother drugs with anticholinergic activity, including antihistamines, antiparkinsonism drugs, monoamine oxidase inhibitors, and tricyclic antidepressants. If such combinations must be used the patient should be monitored closely and dose adjustments made. Patients should be advised to avoid over-the-counter products that contain these drugs. The effectiveness of phenothiazines decreases if they are combined with anticholinergic drugs, and the risk of paralytic ileus increases. This combination should be avoided. Anticholinergics also may interact with certain herbal therapies

72. SUMMARY

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