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QUESTION How do "reversible, non-substrate" cholinesterase inhibitor drugs work?

ANSWER The drug binds to the cholinesterase at the site at which ACh binds. After binding, the drug molecule bound to the cholinesterase molecule dissociates and releases the drug molecule and (a fully functional) cholinesterase molecule; the released drug molecule is immediately available to bind a to a molecule of cholinesterase. Because the enzyme does not change the drug molecule, the drug molecule can not be considered a substrate for the enzyme. However, when a molecule of this type of cholinesterase inhibitor is bound to an enzyme molecule, the enzyme can not metabolize a molecule of ACh. The presence of the cholinesterase inhibitor therefore decreases the rate of metabolism of ACh (i.e., the number of ACh molecules which a single molecule of cholinesterase can metabolize per unit time). The duration of action of the drug is dependent simply on the rate at which it is eliminated by excretion and the dose administered. QUESTION What "reversible, non-substrate" cholinesterase inhibitors are available? ANSWER Edrophonium (TENSILON) is the only non-substrate cholinesterase inhibitor. The comparative interactions of ACh and edrophonium with cholinesterase are shown in the figure below. Note, that edrophonium can not be a substrate for cholinesterase because it does not have an ester bond in its structure. Edrophonium is effective to reduce AChEase or ChEase activity simply by competing with ACh to bind the enzyme.

QUESTION What are the clinical uses of edrophonium? ANSWER Edrophonium is used to diagnose myasthenia gravis - edrophonium administration increases muscle strength. It is not used for treatment of this disease because of its short duration of action (less than 60minutes). It is safer to use for diagnosis of myasthenia gravis than other cholinesterase inhibitors because other cholinesterase inhibitors have a significantly greater duration of action problematic if the muscle weakness was not the result of decreased nicotinic receptor density but of excessive activation of cholinergic receptors at NMJs. (Remember muscle weakness can be produced by excessive activation of nicotinic receptors at NMJs due to uncoupling of receptors from the effector mechanism or receptor desensitization). QUESTION How do "reversible, substrate" cholinesterase inhibitors work? ANSWER The drug, like ACh, has an ester moiety also has a carbamate moiety (where ACh has an acetyl moiety). The drug molecule binds to the cholinesterase at the site to which ACh binds: in fact, two bonds are formed between each molecule of ACh and each molecule of the enzyme and between each molecule of enzyme inhibitor and each molecule of enzyme. After binding, the drug molecule bound to the cholinesterase is broken into two pieces (at the ester link): the drug is a substrate for the enzyme. One piece is released into and then diffuses out of the

synaptic gap and is excreted in the urine. The second piece, a carbamate group, remains bound to the cholinesterase molecule and thus the cholinesterase is carbamylated. (Recall that in normal metabolism of ACh, the cholinesterase molecule becomes acetylated when ACh is metabolized.) The carbamylated enzyme is spontaneously hydrolyzed to release a fully functional cholinesterase enzyme ("regenerated" enzyme) molecule (and a carbamate moiety which diffuses out of the synapse and is excreted in the urine). However, hydrolysis of the carbamylated enzyme takes a longer time than the hydrolysis of the acetylated enzyme and carbamylated cholinesterase molecule can not bind to and metabolize a molecule of ACh. The effect of these carbamate drugs, which are alternate substrates to ACh for the cholinesterase enzyme and are more slowly metabolized than is ACh, will be to reduce the rate at which cholinesterase molecules can metabolize ACh molecules. The figure below illustrates the time line of the interaction of a carbamate cholinesterase inhibitor, neostigmine, with cholinesterase compared to the interaction of ACh with the enzyme. Note that the effect of a carbamate cholinesterase inhibitor is effective to reduce the availability of enzyme to metabolize ACh in part because the carbamylated enzyme is stable and longer lived (than the acetylated enzyme produced by breakdown of ACh).

QUESTION What "reversible, substrate" cholinesterase inhibitors are available? ANSWER There are numerous carbamate cholinesterase inhibitors; they are divided into two groups chemically . Those that are charged at physiological pH, and which do not enter the central nervous system from the plasma; those that are uncharged and thus cross the blood brain barrier

and enter the CNS. Thus choice of drug may be based on whether or not the CNS is a desired target of the enzyme inhibitor. Neostigmine (PROSTIGMIN), a charged molecule, and physostigmine (ANTILIRIUM), an uncharged molecule, are older (but still much used) carbamate cholinesterase inhibitors. Newer carbamate ChEase inhibitors include tacrine (COGNEX), and donepezil (ARICEPT). Note that each compound has a ester bond in its structure thus making the molecule a suitable substrate for cholinesterase. QUESTION What are the clinical uses of "reversible, substrate" cholinesterase inhibitors? ANSWER Treatment of muscle weakness diseases especially myasthenia gravis, treatment of glaucoma, treatment of gastrointestinal or bladder atony, treatment of overdose with atropine (and other muscarinic receptor antagonists), reversal of effects of competitive antagonists (e.g., curare) at the neuromuscular junction, treatment of Alzheimers disease. QUESTION How do "irreversible, substrate" cholinesterase inhibitors work? ANSWER The drug, which like ACh has an ester moiety and also has a phosphorous containing moiety and is thus called an organophosphate cholinesterase inhibitor, binds to the cholinesterase at the site to which ACh binds; in fact, two bonds are formed between each molecule of ACh and each molecule of the enzyme and between each molecule of enzyme inhibitor and each molecule of enzyme. After binding, the drug molecule bound to the cholinesterase is broken into two pieces (at the ester link): the drug is therefore a substrate for the enzyme. One piece diffuses out of the synaptic gap and is excreted in urine. The second piece, the phosphorous containing moiety, remains bound to the cholinesterase molecule and thus the cholinesterase is phosphorylated. (Recall that in normal metabolism of ACh, the cholinesterase molecule becomes acetylated.) The phosphorylated enzyme is stable and is not hydrolyzed (to produce "regenerated" enzyme). A phosphorylated cholinesterase molecule can not bind to and metabolize ACH and is essentially "lost". It can only be replaced by production of a new molecule of cholinesterase - thus the idea that the effect of the drug (on a single cholinesterase molecule) is irreversible. The effect of phosphorous-containing cholinesterase inhibitors is long lasting - weeks or months. The figure below illustrates the timeline of interaction of an organophosphate cholinesterase inhibitor, parathion, with cholinesterase compared to the interaction of ACh with the enzyme. Note that the effect of a organophosphate cholinesterase inhibitor is effective to "permanently" reduce the availability of enzyme to metabolize ACh because the phosphorylated enzyme is stable and can not be hydrolyzed.

QUESTION What are the uses of organophosphate cholinesterase inhibitors? ANSWER There are numerous organophosphate cholinesterase inhibitors. As a group they can usually be recognized because most have a generic name ending in "- phate", "-thion", "-fos", "vos", and "phos". Echothiophate (PHOSPHOLINE) is used clinically in treatment of glaucoma (applied to the corneal surface of the eye). Others such as a parathion (NIRAN) and isoflurophate (DFP) are used in insecticides. Others, such as sarin and soman are use in nerve gases. QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the heart? ANSWER Blockade of muscarinic receptors in the heart causes an increased heart rate (a positive chronotropic effect), mediated by receptors in the sino-atrial node, and an increased the rate of conduction of electrical signals through the atrio-ventricular node (a positive dromotropic effect), mediated by receptors in the atrio-ventricular node . The most important clinical situation where this effect is required is the reversal of bradycardia (for any reason) and of reduced conduction in the atrio-ventricular node caused by many general anesthetics.

The most frequently used drugs for this effect are atropine (ISO-ATROPINE) and glycopyrrolate (ROBINUL). QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the gastro-intestinal tract? ANSWER Blockade of muscarinic receptors in the GI Tract causes decreased secretion of acid and various enzymes in the GI tract - the original treatment of gastric ulcers was use of the muscarinic receptor antagonist atropine - and to reduce motility of the GI tract. Movement of materials through the GI tract is slowed: an effect are not desirable in most individuals although useful in individuals in whom the GI tract exhibits spontaneous spasm(s). Glycopyrrolate is used clinically to as a GI tract antispasmodic but muscarinic receptor antagonists are only rarely used to treat excessive acid secretion in GI ulcers (as a result of development of better drugs with other modes of action to reduce acid secretion). QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the bronchioles? ANSWER Blockade of muscarinic receptors on bronchiole smooth muscle causes muscle relaxation and bronchodilation; blockade of receptors on secretory cells within the lungs reduces the volume of mucus secreted into the airways of the lungs. Drugs can be administered by inhalant aerosol so that desired effects in the lungs can be achieved without sufficient drug entering the plasma to affect other organs. These effects are important to ameliorate symptoms of asthma and to maintain efficient respiration in general anesthesia. Ipratropium (ATROVENT) is used, in inhalant aerosols, to treat symptoms of asthma by causing bronchodilation, and atropine and glycopyrrolate (administered by injection) are useful and used for their effects in the lungs (to induce bronchodilation and reduce bronchiole secretions, and thus to permit easier respiration) during general anesthesia. QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the salivary glands and in the nasal passages? ANSWER Blockade of muscarinic receptors in the salivary glands will reduce salivary secretion; the primary usefulness of this effect is during general anesthesia. Blockade of muscarinic receptors on secretory cells of the nasal passages will reduce mucus secretion into these passages - essentially a

decongestant effect. These sites of action are clinically targeted by muscarinic antagonists used as adjuncts to general anesthesia: atropine, glycopyrrolate. QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the bladder? ANSWER Blockade of muscarinic receptors in the bladder - on muscle fibers of the bladder wall and the bladder sphincter - causes relaxation of bladder muscle and constriction of the sphincter permitting urine retention. This effect is utilized in alleviating the symptoms of "constant need to urinate" resulting from "spontaneous" spasms of the bladder wall. Tolterodine (DETROL) and flavoxate (URISPAS) are two muscarinic receptors being used extensively for this purpose. QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the central nervous system? ANSWER Blockade of muscarinic receptors in the CNS is useful in alleviating the onset and symptoms of motion sickness. Scopolamine, administered in a patch placed on the skin behind the ear, has been useful for this purpose. Blockade of muscarinic receptors in the CNS is also useful to alleviate the movement problems exhibited in patients with Parkinsons Disease and in individuals treated with certain drugs to treat psychosis (the movement disorders produced by these drugs are a side effect of the drugs). Trihexyphenidyl (ARCANE), benztropine (COGENTIN), and biperiden (AKINETON) have been most useful for this purpose. QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the treatment of overdose with ChEase inhibitors? ANSWER Blockade of muscarinic receptors is a critical strategy for treatment of overdose of ChEase inhibitors - following medicinal administration, accidental exposure to insecticides, or exposure to nerve gases. Similarly blockade of these receptors is an appropriate strategy in situations where a muscarinic receptor agonist has been administered in excess. Atropine is the drug of choice for these situations.

QUESTION What are the effects of and clinical uses of muscarinic receptor blockade in the eye? ANSWER Blockade of muscarinic receptors in the eye causes pupillary dilation (mydriasis) mediated by receptors on the sphincter muscle of the iris and fixed distant vision (cycloplegia) mediated by receptors on the ciliary muscle controlling lens shape. A potential side effect of this drug-induced mydriasis is decreased drainage of the anterior chamber of the eye - effectively drug-induced glaucoma. Drugs used to induce mydriasis are administered directly to the corneal surface of the eye so that desired effects in the eye can be achieved without sufficient drug entering the plasma to affect other organs. Cyclopentolate (CYCLOGEL) and tropicamide (MYDRIACYL) are the most frequently used muscarinic receptor antagonists to produce mydriasis. QUESTION What are the effects of nicotinic receptor antagonists and agonists which functionally block synaptic transmission in autonomic ganglia? ANSWER A N receptor antagonist such as trimethaphan (ARFONAD) prevents binding of ACh to these receptors on postganglionic neurons reduces the effects of ACh released from preganglionic neurons: this drug is a competitive antagonist at those receptors and thus a competitive blocker of cholinergic transmission in the ganglia. The effect is to decrease frequency of action potentials generation in the cell body of each postganglionic neuron and propagated to each axon terminals. Use of a N receptor agonist such as nicotine to cause receptor desensitization (uncoupling of receptors from the action potential generating mechanisms of the postganglionic neuron) also decreases the frequency of action potentials (generated in the cell body of each postganglionic neuron and propagated to its axon terminals); this drug is a non-competitive, desensitizing blocker of cholinergic transmission in the ganglia. Both the nicotinic receptor antagonist and the nicotinic receptor agonist are effective in producing functional blockade of synapses between preganglionic neurons and postganglionic neurons.The effect of functional blockade of synapses in autonomic ganglia is difficult to predict because these drugs can not selectively target the ganglia of either the sympathetic nervous system or the parasympathetic nervous system - both systems are affected. Thus the effect of functional blockade depends on the tone of each system. One might expect that functional blockade of autonomic ganglia in an individual at rest when the parasympathetic nervous system is dominant would be to induce effects similar to those of decreased activity of the PNS or increased activity of the SNS. Conversely one might expect that autonomic blockade in an individual in whom the flight or fright reflex (i.e., the SNS) has been activated would be to induce effects similar to those of increased activity of the PNS or of decreased activity of the SNS. In other words, these compounds can be difficult to use clinically!!
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What are the clinical uses of nicotinic receptor antagonists and agonists which functionally block synaptic transmission in autonomic ganglia? ANSWER Functional autonomic blockade is useful to reduce blood pressure in hypertensive crisis and to reduce hemorrhage during surgery. The effect of autonomic blockade on the heart is essentially a "no effect" mostly because block of SNS induced positive chronotropic effects are countered by block of PNS induced negative chronotropic effects. However, reduced SNS output to arterioles causes dilation of these vessels and thus reduces blood pressure. Additionally, reduced SNS output to veins causes dilation of these vessels so that more blood pools in these vessels and less blood is returned to the heart; consequently, cardiac output is decreased and blood pressure is reduced. Importantly, the reduced blood pressure cause by vessel dilation caused by autonomic ganglion blockade can not be countered by reflex increased heart rate (because of the ganglion blockade!). In the case of hypertensive crisis, blood pressure can be lowered to a safe level by ganglionic blockade although this approach is not satisfactory for treating chronic hypertension. In the case of hemorrhage during surgery, the ganglionic blockade induced reduction of blood pressure reduces perfusion of blood through all vessels and thus will tend to reduce bleeding from injured or cut blood vessels. QUESTION What are the effects of epinephrine (ADRENALIN)? ANSWER Through postsynaptic , , and receptors. Receptors Constriction of arterioles (especially in skin, mesentery, mucosa). This effect causes an increased total peripheral resistance (TPR),that is resistance to blood flow through blood vessels of the systemic circulation. This increased TPR is rapid (within minutes) and causes a rapid increase of blood pressure (with the potential for a subsequent reflex reduction of heart rate and reversal of the blood pressure change) Constriction of small veins (especially in skin, mesentery,mucosa) This effect causes increased return of blood to the heart and consequently increased output of blood from the heart. This effect leads to an immediate increase of blood pressure (with potential for subsequent reflex decreased heart rate or vasodilation and reversal of the blood pressure change) Mydriasis Constriction of sphincters of bladder and gastrointestinal tract: urine and feces retention Secretion of viscous saliva Decreased renin secretion from kidney leading to vasodilation and increased renal excretion of Na and H O and decreased blood pressure Renin enhances conversion of angiotensin I in the plasma to angiotensin II or AII. AII causes rapid constriction of some arterioles (thus causing an increased TPR and blood pressure). AII also induces secretion of aldosterone from the cortex of the adrenal gland. Aldosterone acts in the kidney to enhance Na and H O reabsorption which leads to increased blood volume and increased
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blood pressure; the increase of blood pressure through this mechanism is slow (taking minutes to hours) Receptors Increased heart rate (+vechronotropic effect) with accompanying increased A-V node conduction(+ve dromotropic effect) and increased stroke volume (+ve inotropic effect) producing increased cardiac output. This effect is rapid and causes a rapid increase of blood pressure blood pressure (with potential subsequent reflex vasodilation to reverse the blood pressure change). That the chronotropic , inotropic and dromotropic effects all occur at the same time is logical: if these effects did not occur together, cardiac arrhythmias would develop. Increased renin secretion from kidney with subsequent increased Na and H O reabsorption in the kidney, increased blood volume and increased blood pressure. Receptors Dilation of vessels of heart and skeletal muscle rapidly causing a reduced total peripheral resistance(TPR) and decreased blood pressure (with potential subsequent reflex increased heart rate) Bronchiole dilation Glycogenolysis (especially in liver) Lipolysis Relaxation of uterus (pregnant female) Urine and feces retention (relaxation of bladder wall and GI wall muscle)
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Total cardiovascular effect of epinephrine Rapid increased systolic blood pressure (as a result of increased cardiac output) and decreased diastolic blood pressure as a result of sum of increased TPR due to constriction of many vessels (especially of skin, mesentery and mucosa) and simultaneous decreased TPR due to vasodilation of skeletal muscle and coronary vessels; no change mean blood pressure resulting from sum of effects on heart and blood vessels. Slow increase of blood pressure resulting from effect on renin secretion. QUESTION What are the effects of norepinephrine (LEVARTERENOL)? ANSWER Through postsynaptic and receptors. Receptors Constriction of arterioles (especially in skin, mesentery, mucosa). Causes rapid increase of TPR and blood pressure (with potential subsequent reflex reduction of heart rate) Constriction of small veins (especially in skin, mesentery, mucosa) leading to increased blood return to the heart, with subsequent increased cardiac output and blood pressure(with potential for subsequent reflex decreased heart rate) Mydriasis Constriction of sphincters of bladder and gastrointestinal tract: urine and feces retention Decreased renin secretion with subsequent (slowly) decreased Na and H O reabsorption in kidney, decreased blood volume, and decreased blood pressure decrease Secretion of viscous saliva
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Receptors Increased heart rate (+ve chronotropic effect) with accompanying increased A-V node conduction (+ve dromotropic effect) and increased stroke volume(+ve inotropic effect) producing increased cardiac output. This effect is rapid and causes a rapid increase of blood pressure blood pressure(with potential subsequent reflex vasodilation to reverse the blood pressure change). That the chronotropic , inotropic and dromotropic effects all occur at the same time is logical: if these effects did not occur together, cardiac arrhythmias would develop. Increased renin secretion from kidney with subsequent increased Na and H O reabsorption in the kidney, increased blood volume and increased blood pressure.
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Total cardiovascular effect of norepinephrine Rapid increased systolic blood pressure and increased mean bp (as a result of increased cardiac output and increased TPR) but no effect on diastolic blood pressure. (Potential activation of cardiovascular reflex to decrease heart rate and decrease cardiac output.) Slow increase of blood pressure resulting from effect on renin secretion Its often written that NE has no effects mediated by b adrenoreceptors. This is correct given that NE can be injected to provide concentrations of NE sufficient to activate a and b receptors but insufficient to activate b receptors (for which norepinephrine has lower affinity). However, with larger doses, to produce higher plasma concentrations of NE, NE would also activate b effects (as induced by epinephrine). However, that "NE has no effects mediated by b adrenoreceptors" is incorrect: remember that NE mediates physiological effects through b receptors at synapses. In the synaptic gap, the NE concentration is sufficiently high to "overcome" the "relatively low" affinity of NE for these receptors so that sufficient receptors are bound and activated to induce responses in the effector cells.
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QUESTION What are the effects of isoproterenol (ISUPREL)? ANSWER Through postsynaptic , and receptors. Receptors Increased heart rate (+ve chronotropic effect) with accompanying increased A-V node conduction (+ve dromotropic effect) and increased stroke volume(+ve inotropic effect) producing increased cardiac output. This effect is rapid and causes a rapid increase of blood pressure blood pressure(with potential subsequent reflex vasodilation to reverse the blood pressure change). That the chronotropic , inotropic and dromotropic effects all occur at the same time is logical: if these effects did not occur together, cardiac arrhythmias would develop. Increased renin secretion from kidney with subsequent increased Na and H O reabsorption in the kidney, increased blood volume and increased blood pressure.
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Receptors
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Dilation of vessels of heart and skeletal muscle producing rapidly reduced total peripheral resistance (TPR),and rapidly decreased blood pressure (with potential subsequent reflex increased heart rate) Bronchiole dilation Glycogenolysis Lipolysis Relaxation of uterus (pregnant female) Urine and feces retention (constriction of GI tract and bladder sphincters and relaxation of bladder and GI wall) Total cardiovascular effect of isoproterenol Rapid increased systolic blood pressure (as a result of increased cardiac output) and rapid and substantial decrease of diastolic blood pressure as a result of vasodilation of skeletal muscle and coronary vessels; mean bp is decreased resulting from sum of effects on heart and blood vessels. Slow increased of blood pressure resulting from effect on renin secretion QUESTION What are the effects of dopamine (INOTROPIN)? ANSWER Through postsynaptic and receptors. Receptors Increased heart rate(+ve chronotropic effect) with accompanying increased A-V node conduction (+ve dromotropic effect) and increased stroke volume (+ve inotropic effect) producing increased cardiac output. This effect is rapid and causes a rapid increase of blood pressure blood pressure(with potential subsequent reflex vasodilation to reverse the blood pressure change). That the chronotropic , inotropic and dromotropic effects all occur at the same time is logical: if these effects did not occur together, cardiac arrhythmias would develop. Increased renin secretion from kidney with subsequent increased Na and H O reabsorption in the kidney, increased blood volume and increased blood pressure.
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Receptors Minor effect (low affinity), same as epinephrine and norepinephrine at these receptors Total cardiovascular effect of dopamine Rapid increase of systolic blood pressure (as a result of increased cardiac output and increased TPR resulting from vasoconstriction of skin, mesentery and mucosa); increased mean blood pressure resulting from sum effect on heart and blood vessels. Slow increase of blood pressure resulting from effect on renin secretion
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It should be noted that the effects of dopamine to increase blood pressure is tempered by the effect of dopamine to cause decreased TPR due to vasodilation mediated by dopamine receptors on the smooth muscle fibers of the wall of arterioles (at lower concentrations than required to activate adrenoreceptors). QUESTION What are the effects of dobutamine (DOBUTREX)?

ANSWER Through postsynaptic receptors. Receptors Increased heart rate(+ve chronotropic effect) with accompanying increased A-V node conduction (+ve dromotropic effect) and increased stroke volume (+ve inotropic effect) producing increased cardiac output. This effect is rapid and causes a rapid increase of blood pressure blood pressure(with potential subsequent reflex vasodilation to reverse the blood pressure change). That the chronotropic , inotropic and dromotropic effects all occur at the same time is logical: if these effects did not occur together, cardiac arrhythmias would develop. Increased renin secretion from kidney with subsequent increased Na and H O reabsorption in the kidney, increased blood volume and increased blood pressure.
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Total cardiovascular effect of dobutamine Rapid increase of systolic and mean blood pressure (as a result of increased cardiac output). Slow increase of blood pressure resulting from effect on renin secretion Effects of dobutamine are vigorous but short lived (due to short half life; 2minutes) unless continuously infused QUESTION What are the effects of phenylephrine (NEO-SYNEPHRINE)? ANSWER Through postsynaptic receptors. Receptors Constriction of arterioles (especially in skin, mesentery, mucosa) producing increased TPR and increased blood pressure (with potential subsequent reflex decreased heart rate) Mydriasis Constriction of sphincters of bladder and gastrointestinal tract: urine and feces retention Decreased renin secretion with subsequent decreased Na and H O reabsorption, decreased blood volume, and decreased blood pressure Secretion of viscous saliva Effective administered orally or injected intravenously to produce all the above effects. Clinical use mostly limited to topical application to the corneal surface of the eye (to produce mydriasis) and to mucosal surfaces of nasal passages (to produce decongestion).) QUESTION
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What are the effects of methoxamine (VASOXYL)? ANSWER Through postsynaptic receptors. Receptors Constriction of arterioles (especially in skin, mesentery, mucosa) producing increased TPR and increased blood pressure (with potential subsequent reflex decreased heart rate) Mydriasis Constriction of sphincters of bladder and gastrointestinal tract: urine and feces retention
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Decreased renin secretion with subsequent decreased Na and H O reabsorption, decreased blood volume, and decreased blood pressure Secretion of viscous saliva QUESTION
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What are the effects of terbutaline (BRETHINE), albuterol (VENTOLIN)? ANSWER Through postsynaptic receptors. Receptors Potent bronchodilator effect Potent relaxant of uterine muscle in pregnant female Used to stop premature labor Vasodilator effect (coronary and skeletal muscle arteries) causes significant decrease of blood pressure; produces reflex tachycardia (increased heart rate) as a side effect Orally effective but for effects on uterus, drug is injected and for effects on bronchiole system, drugs are formulated in aerosol inhalant. QUESTION
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What are the effects of clonidine (CATAPRESS)? ANSWER Through presynaptic receptors. Receptors Particularly high affinity for CNS a receptors. Effect in CNS is to reduce sympathetic "drive" or "output" to peripheral components of SNS Orally effective, antihypertensive use What are the Effects of Indirect and Mixed Sympathomimetic Drugs? Lets suppose that you injected yourself with drug which is an adrenoreceptor agonist and which induced NE release. What effects mediated by adrenoreceptors would you see? QUESTION
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What are the effects of Ephedrine and Pseudoephedrine (SUDAFED)? ANSWER Mixed action: induces NE release and mimics NE. Most marked effects when injected intravenously: stimulates heart, dilates bronchioles Orally effective drugs; penetrate CNS: used to elevate mood, prevent sleep QUESTION What are the clinical uses of sympathomimetics targeting cardiac function? ANSWER

Here the heart is the major targeted organ although not always the actual site of drug action. A-V block, in which conduction of electrical signals through the node is slowed, perhaps so much that it is effectively blocked, so that contraction of atria and ventricles are not coordinated. Cardiac arrest, in which the heart stops all contractile activity. The recommended drugs increase A-V conduction and also increase heart rate and contractility to increase cardiac output (without inducing an increase of blood pressure). isoproterenol, epinephrine Sinus bradycardia in which heart rate is lower than normal and this effect is induced due to malfunction of the S-A node (perhaps an excessive PNS input to the S-A node). The recommended drug increases heart rate by direct action in the S-A node. isoproterenol, epinephrine Paroxysmal atrial tachycardia in which there is an increased heart rate driven by altered function in the atria. This altered atrial activity occurs spontaneously, without any obvious trigger. The actions of the recommended drugs are on the vasculature: drug-induced vasoconstriction (TPR) elevates blood pressure which will induce bradycardia - by reflex. methoxamine, phenylephrine Cardiogenic shock, literally excessive low blood pressure (shock) arising from cardiac malfunction; perhaps most frequently occurring consequent to heart failure. The objective here is to target the heart to increase cardiac output to provide sufficient blood delivery throughout the body to maintain oxygen supply to all tissues and organs. dopamine, dobutamine Anaphylactic shock, literally excessive low blood pressure (resulting from excessive vasodilation) and bronchiole constriction (bronchospasm), arising from allergic reaction induced release of histamine. Heart is major target - bronchiole system is co-target - of drug therapy. epinephrine, isoproterenol QUESTION What are the clinical uses of sympathomimetics when acting locally as vasoconstrictors? ANSWER Here, the drug is added close to the site of desired action - to maximize the desired effects at the site of administration and to minimize drug effects at other sites. Decongestant action: the drug is sprayed into the nasal passages to target the blood vessels of the mucosa of the nasal passages. The resultant vasoconstriction and decreased blood flow reduces mucus production and secretion into the nasal passages and thus reduces nasal congestion. phenylephrine Hemostatic action: the drug is applied in solution at the site of a hemorrhage to induce vasoconstriction and to reduce bleeding. epinephrine Hemostatic action: the drug is applied in solution with a local anesthetic; the hemostatic action is local vasoconstriction. The drug reduces blood flow around the injection site to reduce the rate of removal (in the blood) of the local anesthetic and thus prolongs the effect of the local anesthetic. epinephrine QUESTION

What are the clinical uses of sympathomimetics when acting systemically as vasoconstrictors? ANSWER Here the drug is added intravenously - the target sites for the drugs are all those vessels which have a receptors coupled to a contractile mechanism...to induce vasoconstriction and thus TPR to counter excessive hypotension. Cardiac arrest, anaphylactic shock, acute hypotension Here the drug is added intravenously to target blood vessels to induce vasoconstriction and increased blood pressure norepinephrine, phenylephrine QUESTION
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What are the clinical uses of sympathomimetics targeting the bronchiole system? ANSWER The target is the smooth muscle of the bronchiole system: the drugs will cause relaxation of the muscle fibers and bronchodilation. Air movement into and out of the alveoli (through the bronchioles) is increased Asthma and some respiratory allergic reactions: the drug is usually administered as an aerosol to maximize targeting of the drug to the target cells and to minimize systemic effects. epinephrine, ephedrine, isoproterenol, albuterol, terbutaline QUESTION What are the clinical uses of sympathomimetics targeting the eye? ANSWER The target is the muscle fibers of the iris dilator muscle: activation of receptors on these fibers produces pupillary dilation necessary for examination of the retina. The drugs are applied to the corneal surface of the eye to maximize exposure of the target cells to the drug and at the same time reducing drug effects on any other cells, tissues and organs. phenylephrine, epinephrine QUESTION What are the clinical uses of sympathomimetics targeting the central nervous system? ANSWER CNS "Stimulation" Elevation of mood ("antidepressant" effect) Treatment of narcolepsy - in which the affected individual frequently simply "falls asleep" at inappropriate times. Appetite suppression - to decrease food intake and thus induce weight loss Attention Deficit Disorder - in which the individual is unable to "concentrate on the job at hand" phenylpropanolamine (ppa), methylphenidate (RITALIN)

QUESTION What are the clinical uses of sympathomimetics targeting the uterus? ANSWER Drug is administered by injection to reduce uterine contractions in pregnant women when labor initiates prematurely. The problem with this treatment is that the drugs also cause decreased blood pressure, as a result of dilation of arterioles of skeletal muscle and heart, which by reflex is corrected by increased heart rate (tachycardia) with potential for palpitations and arrhythmias. albuterol, terbutaline QUESTION What adrenoreceptor antagonists are available, what are their effects and what are their clinical uses? ANSWER There are two adrenoreceptor antagonists which you should know about: Phentolamine (REGITINE) is a competitive antagonist at both and adrenoreceptors. By actions in arterioles of skin and mesentery, phentolamine causes vasodilation through effects mediated by adrenoreceptors on smooth muscle in the wall of blood vessels and thus reduces blood pressure; however, this reduction of blood pressure leads to increased cardiac output (increased heart rate) by reflex. By actions in the GI tract, phentolamine increases GI motility Phentolamine is used in short term pharmacological control of blood pressure in pheochromocytoma - a condition due to an epinephrine secreting tumor of the medulla of the adrenal gland (which normally requires surgical removal of these glands) and for which the prime symptom is an excessively high blood pressure. Phentolamine has also been used as an antihypertensive to control high blood pressure in essential hypertension (hypertension caused by an unidentified mechanism). Problems: receptor blockade effectively increases sympathetic tone and produces a number of effects especially tachycardia and arrhythmias potentially leading to angina pectoris and/or myocardial infarction.
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Prazosin (MINIPRESS) is also a competitive antagonist at adrenoreceptors but has low affinity for all other adrenoreceptors. It has all the benefits of phentolamine but does not produce the adrenoreceptor mediated, undesired effects of phentolamine. By actions in arterioles of skin and mesentery, prazosin causes vasodilation and thus reduces blood pressure; however, the reduction of blood pressure leads to increased cardiac output (increased heart rate) by reflex (thus reversing the drugs hypotensive effect). By actions in the GI tract, prazosin increases secretions into the GI tract and increases GI motility Use of prazosin is based on its ability to reduce blood pressure. Prazosin is used to treat hypertension resulting from several types of cardiovascular malfunction and to treat essential hypertension.
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Adrenoreceptor Antagonists These drugs have low affinity for adrenoreceptors but have high affinity for one or both types of adrenoreceptor. These drugs reverse the effects of physiologically active (and clinically administered) epinephrine and norepinephrine mediated through receptors. QUESTION What adrenoreceptor antagonists are available, what are their effects and what are their clinical uses? ANSWER There are two types of adrenoreceptor antagonist which you should know about: those that are antagonists at and receptors and those that are only active act receptors. Propranolol (INDERAL) has high affinity for both and adrenoreceptors. By actions in the heart, propranolol is effectively a "cardiac depressant". Propranolol reduces SNS influence on the heart by actions in the S-A node (a negative chronotropic effect; decreased heart rate), at the A-V node (a negative dromotropic effect; decreased rate of conduction through the A-V node) and on cardiac muscle (a negative inotropic effect; decreased contractility of cardiac muscle) to reduce cardiac output and to reduce blood pressure. Reduced cardiac output results in reduced work performed by the heart and thus reduced oxygen use by the heart. By actions in the kidney, propranolol will cause decreased renin secretion; this effect permits increased urine production with a consequent reduction of blood volume and of blood pressure. Clinical use of propranolol targets the adrenoreceptors of the heart. Reduction of cardiac output is important to reduce blood pressure (in all types of hypertension including essential hypertension) and to reduce work done by the heart (and thus to reduce oxygen use by the heart, thus reversing the oxygen deficit which is the prime mechanistic problem of angina pectoris). Reduction of heart rate, conduction in the A-V node and decreased contractility are also clinically useful effects of propranolol in correcting certain arrhythmias including tachycardia. The problems to therapeutic use of propranolol are related to its effects mediated through adrenoreceptors: the drug tends to produce spasm of the bronchioles and of the arterioles of the heart thus producing asthmatic symptoms and symptoms of angina pectoris (as a result of reduced blood flow to the heart muscle), respectively. The effect to induce symptoms of angina pectoris is ironic considering that propranolol was developed for and is still extensively used for treatment of angina pectoris!! Metaprolol (LOPRESSOR), atenolol (TENORMIN), and pindolol (VISKEN) are adrenoreceptor selective: these drugs have low affinity for all other types of adrenoreceptors. The advantage of these drugs is that they have the advantages of propranolol (with respect to potential therapeutic benefit based on effects in the heart) but not the disadvantages of propranolol (with potential to induce spasm of coronary blood vessels or to induce bronchospasm). Clinical use of these drugs permits reduction of blood pressure (of various types including essential hypertension) and correction of arrhythmias (especially tachycardia) and reversal of oxygen deficit in heart muscle (in angina pectoris). Mixed and Receptor Antagonists These drugs have affinity for , and adrenoreceptors. They have combined advantages of propranolol and prazosin (regarding regulation of blood pressure and maintenance of cardiac
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rhythm) but have retained to some extent the disadvantages of propranolol (regarding bronchospasm and spasm of arterioles of the heart and of skeletal muscle) - the affinity of the drugs for adrenoreceptors is not high.
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QUESTION What mixed adrenoreceptor antagonists are available, what are their effects and what are their clinical uses? ANSWER There are two mixed adrenoreceptor antagonists which you should know about: Labetolol (NORMODYNE) and carvedilol (COREDG) are used to treat hypertension (of multiple causes and including essential hypertension) and certain arrhythmias (especially tachycardia).