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PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

Autonomic Pharmacology 01. How does each of the following drugs affect cholingeric transmission: Tetrodotoxin? Botulinum toxin? Black widow spider toxin? Hemicholinium? Tetrodotoxin is a sodium channel blocker in nerve cells. By blocking the sodium channels, no action potential can be formed in the nerve cell and no calcium can be released into the synaptic terminal. Without calcium in the synaptic terminal, the synaptic vessels do not fuse with the synaptic membrane to release neurotransmitters into the synaptic cleft. Therefore, tetrodotoxin effectively blocks cholinergics (as well as adrenergic) release from all nerve synaptic terminals. Botulinum toxin inhibits the fusion of the acetylcholine synaptic vessels with the synaptic terminal membrane at the neuromuscular junction and the ganglionic synaptic junction. Therefore, it causes generalized muscle weakness by not stimulating striated muscle fibers to contract and it causes symptoms such as dry mouth, gastrointestinal immobility, and urine retention associated with a block in parasympathetic nerve action. Black widow spider toxin causes a massive release of acetylcholine from the synaptic terminal at the neuromuscular junction. The increased amount of acetylcholine in the neuromuscular synaptic cleft results in depolarizing neuromuscular blockade which causes eventually results in muscle flaccidity. Hemicholinium is a drug which blocks the sodium choline cotransport system used to bring choline into the preganglionic nerve cell. This blockage results is less acetylcholine being produced and released into the ganglionic synaptic cleft. Therefore, hemicholinium blocks both sympathetic and parasympathetic transmission to the periphery. As a result, a mixed response is noticed where parasympathetic effects show up at sites normally dominated by the sympathetic nervous system and sympathetic effects show up at sites normally dominated by the parasympathetic system. 02. What is the primary mechanism for terminating the action of acetylcholine at the synapse? What three classes of drugs prevent this? Which class is reversible? Which class is irreversible? Which class carbamylates the esteric site? Which class phosphorylates the esteratic site? Name three reversible inhibitors. Name two irreversible inhibitors. What drug can regenerate cholinesterase if used soon after irreversible inhibition? What is an "aged" cholinesterase enzyme? Acetylcholine is broken down into acetate and choline in the synaptic cleft by the enzyme, acetylcholinesterase. The enzyme has two clefts. One cleft is the anionic site which contains a positively charged amino acid to form an ionic bond with the positively charged quaternary nitrogen of acetylcholine. The other cleft is the esteratic site which has a hydroxyl group which forms a covalent bond with the ester group of the acetylcholine molecule. Once the covalent bond is formed, a water molecule interacts with the complex, causes hydrolysis, and results is the formation of choline and acetate. These degradative compounds are then released from the enzyme and acetylcholinesterase becomes available to breakdown more acetylcholine molecules. Three classes of drugs exist that reduce the effect of acetylcholinesterase One class is the direct

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

acting cholingeric agonists. This catagory includes variations of acetylcholine (i.e. carbechol, methacholine, and bethanechol) and pilocarpine which are not metabolized by acetylcholinesterase as quickly as acetycholine is. The second class of drugs are the reversible anticholingerics which include edrophonium, physostigmine, and neostigmine. These agents compete with acetylcholine to bind to acetylcholinesterase. Edrophonium is a short acting reversible anticholinergic because it binds to the anion site of acetylcholinesterase. On the other hand, physostigmine and neostigmine are long acting reversible anticholingerics because they carbamylate the esteratic site. The third class of drugs are the irreversible anticholingerics which include organophosphates such as isofluorophate. Isofluorophate interacts with the esteratic site and causes the formation of a strong covalent bond between the hydroxyl group of acetylcholinesterase and the phosphate group of the drug. With time, one of the propanol groups of isofluorophate is released by a hydrolysis reaction. This "aged" cholesterase enzyme then cannot be regenerated. However, before aging occurs, pralidoxime (PAM) can be given in order to regenerate the acetylcholinesterase. PAM binds to the anionic site of the acetylcholinesterase molecule and breaks the covalent bond between the phosphate group and the esteratic hydroxyl group. 03. What is the effect of stimulating muscarinic receptors at each of the following sites: pupil size of the eye? Ciliary muscle of the eye? Sweat glands? Heart (rate and contractility)? Lung (bronchial smooth muscle; secretions)? GI tract (tone and secretions)? Genitourinary tract (detrussor muscle; trigone muscle; sphincter)?; does this lead to micturation or urinary retention? In the eye, muscarinic receptor stimulation causes miosis (ie a smaller pupil size). Miosis is caused by the contraction of the parasympathetically innervated sphincter muscles of the iris. Muscarinic receptor stimulation also causes the contraction of the ciliary muscle. Contraction of the ciliary muscle results in the ciliary body being pushed forward in the eye, the fibers that connect the ciliary body to the lens relax, the lens expands and accomodation for near-vision results. In the sweat glands, muscarinic receptor stimulation causes an increase in the production and release of sweat. Similarly, in the salivary gland, muscarinic receptor stimulation results in the production of a watery saliva. (NOTE: The sweat glands actually are innervated by sympathetic cholingeric neurons instead of parasympathetic neurons. Irregardless of this fact, acetylcholine acts on a muscarinic receptor.) In the heart, muscarinic receptor stimulation causes the heart rate to decrease. It also causes the contractility of the heart to decrease. In the atria, muscarinic receptor stimulation causes an decrease in the length of the action potential and effective refractory period. These effects can result in atrial flutter or fibrillation. However, in the AV node, conduction velocity is decreased while the effective refractory period is increased. As a result, adverse changes in the electrophysiology of the atria are not passed on the the ventricle. In the lung, muscarinic receptor stimulation results in bronchial smooth muscle constriction and increased bronchial secretion. In the GI tract, both the tone and the secretions are increased with stimulation of the muscarinic receptor.

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

In the genitourinary tract, muscarinic stimulation causes detrussor muscle contraction and trigone and sphincter muscle relaxation. This results in micturation. 04. Stimulation of muscarinic receptors in the vasculature results in (vasoconstriction or vasodilation)? Vasculature muscarinic receptor stimulation leads to vasodilation. (NOTE: The vasculature is not innervated by parasympathetic neurons; however, it does have muscarinic receptors which can interact with blood-borne acetylcholine or muscarinic agonists.) 05. What is the synthetic scheme of norepinephrine? What is the rate limiting step? What two enzymes are responsible for breaking down catecholamines? What is the primary mechanism for terminating the action of catecholamines? What two distinct drus block this mechanism? The building block for the synthesis of norepinephrine in the synaptic terminal of a postganglionic sympathetic neuron is the amino acid, tyrosine. In the first and rate-limiting step, the phenol group of tyrosine is hydroxylated in the ortho position to form the catechol group of dopa. Tyrosine hydrolyase (in the presence of tetrahydrobiopteryin) is the enzyme that catalyzes this step. Dopa decarboxylase removes the carboxyl group of dopa to form dopamine. Dopamine then is transferred into the synaptic vesicle where dopamine -hydroxylase causes the addition of a hydroxyl group to the -carbon to form norepinephrine. Catecholamines can be broken down in the synaptic cleft or in the presynaptic terminal. In the synaptic cleft, COMT (catacholamine-O-methyl transferase) adds a methyl group to one of the hydroxyl groups on the catechol group. In the presynaptic terminal, MAO (monoamine oxidase) located on the external surface of the inner mitochondrial membrane oxidizes an unsubstituted acarbon to an aldehyde. The primary mechanism for terminating the action of catecholamines is removal of the catecholamines from the synaptic cleft by the Uptake 1 receptor located on the presynaptic terminal. The Uptake 1 receptor can be blocked by cocaine, imipramine and amitriptyline which results in a higher concentration of catecholamines in the synaptic cleft. 06. What is the mechanism of action of guanethidine? reserpine? bretylium? How does each drug get into the nerve terminal? Which cross the blood-brain barrier (BBB)? Reserpine enters the nerve terminal via the Uptake 1 receptor. It binds to the membrane of the synaptic vesicle, weakens the membrane and causes the release of the stored catecholamine neurotransmitters. In the cytoplasm of the presynaptic terminal, the "free" catecholamines are quickly degraded by MAO. As a result of less catecholamine in the presynaptic terminal, less catecholamine is released into the synaptic cleft and the postsynaptic response is weakened. Reserpine can cross the blood-brain barrier. Guanethidine has four properties which characterize its mode of action on the presynaptic sympathetic terminal. First of all, it enters the presynaptic nerve terminal via the Uptake 1 receptor. However, it also causes competitive blockade of the Uptake I receptor like cocaine. Secondly, it causes an increased release of norepinephrine into the synaptic cleft. Thirdly, it

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

binds to the synaptic vesicles to cause the release of stored catecholamine neurotransmitters which are subsequently degraded by the MAO enzymes. Finally, it causes adrenergic neuronal blockade by uncoupling the action potenital from the neurotransmitter release. Guanethidine only acts on the peripheral nervous system because it cannot cross the blood-brain barrier. Bretylium is a potassium-channel blocker. In the presynaptic membrane, it inhibits the conduction of the action potential. Therefore, it prevents the release of neurotransmitters from the presynaptic terminal. Bretylium does not cross the blood-brain barrier. 07. What is an autoreceptor? What subtype of adrenergic receptor is the autoreceptor? When this receptor is stimulated, what is the effect on neurotransmitter release? Which two antihypertensive drugs act by stimulating the autoreceptor centrally? An autoreceptor is a receptor that binds to a compound that is produced in the same cell. The alpha-2 adrenergic receptor is an autoreceptor found on presynaptic adrenergic neurons. The binding of norepinephrine to the alpha-2 receptor results in a decreased production of norepinephrine in the presynaptic terminal (probably by inhibiting the action of tyrosine hydroxylase). Clonidine is one of the drugs that directly stimuate the alpha-2 autoreceptor centrally. Propanol, which is a 1 antagonist, acts in an indirect manner to stimulate the alpha-2 autoreceptor. By binding to the 1 receptor also located on the presynaptic adrenergic neuron, more norepinephrine in the synaptic cleft can bind to the alpha-2 autoreceptor and cause a decrease in the presynaptic production of norepinephrine. 08. What subtypes of adrenergic receptors is/are found in each of the following tissues? and what response do they mediate? Heart? Bronchial smooth muscle? Vascular smooth muscle? Uterus? The heart contains 1 adrenergic receptors. When stimulated, these receptors cause an increase in the heart rate and the contractility. However, in the atria, the velocity of conduction is increased and latent pacemaker cells may also be activated. In the AV node, rate of conduction is increased while the effective refractory period is decreased. These effects may lead to arrhythmias that can be transferred to the ventricles. The bronchial smooth muscles contain 2 receptors. When stimulated, these receptors cause bronchodilation. Vascular smooth muscle contains both alpha-1 and 2 receptors. Alpha-1 receptors are found on all blood vessels and cause vasoconstriction when stimulated. 2 receptors are found in the skeletal, pulmonary, and coronary vasculature and cause vasodilation when stimulated. In the uterus, 2 adrenergic receptors are found. When stimulated, these receptors cause the relaxation of the uterine smooth muscle. 09. The inability to accommodate for near vision is the easiest way to distinguish mydriasis due to a (cholinergic antagonist or sympathomimetic) from mydriasis due to a (cholinergic antagonist or sympathomimetic). Mydriasis (ie an increase in pupil size) can be due to either sympathetic stimulation which causes

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

constriction of the radial muscles of the iris or blockade of parasympathetic stimulation which inhibits constriction of the sphincter muscles of the iris. Since the parasympathetic system is the only one that innervates the ciliary muscle, an inability to accommodate for near vision is a sign of parasympathetic inhibition. Therefore, mydriasis with inability to accommodate is due to a cholingeric antagonist while mydriasis with the ability to accommodate is due to a sympathomimetic. 10. Of the following cholingeric agonists (acetylcholine, methacholine, bethanachol, carbachol), which is/are susceptible to hydrolysis by plasma cholinesterase? By true cholinesterase? Which is most selective for muscarinic receptors? Nicotinic receptors? Prior administration of physostigmine would prolong the duration of action of which drugs? Which drug is best for treating post-operative urinary retention? Acetylcholine is the normal neurotransmitter produced by the body to activate cholingeric receptors. Methacholine, bethanachol and carbachol are artificially synthesized cholinergic agonists that are based on the structure of acetylcholine. Methacholine is acetylcholine methylated on the carbon, carbachol is acetylcholine with a carbamate group, and bethanachol is acetylcholine with both types of modifications. While all of these compounds show susceptibility to plasma cholinesterases and acetylcholinesterases in the synaptic cleft, the rate at which each one is degraded by these enzymes is different. For instance, acetylcholine and methacholine tend to be very susceptible to plasma cholinesterase and true cholinesterase breakdown. Carbachol is broken down at a slower rate and bethanachol is the most resistant of the group to cholinesterase breakdown. In general, the administration of physostigmine would prolong the action of all of these drugs in the synaptic cleft by competitively and reversibly inhibiting the acetylcholinestase enzyme. The drugs in this class also differ by their selectivity for muscarinic receptors. Acetylcholine and methacholine act on both muscarinic and nicotinic receptors. Carbachol interacts more with nicotinic receptors than muscarinic receptors. Only bethanachol seems to be relatively selective for muscarinic receptors. Because of its resistance to degradation by cholinesterases and because of its relative selectivity for muscarinic receptors, bethanachol would be the best drug in this class for use in treating postoperative urinary retention. 11. Name two plant alkaloids that are also muscarinic agonists.

One plant alkaloid that is a muscarinic agonist is pilocarpine. Due to its long duration of action, it mainly is used in the eye as a treatment for glaucoma. Muscarine (as its name indicates) is the other plant alkaloid which acts as a muscarinic receptors. 12. Following IV infusion, nicotine produces a triphasic response in blood pressure. What is the sequence of this response and what is the anatomical basis for this response? Following IV infusion, nicotine produces a triphasic response in blood pressure. During the Phase I response, the blood pressure drops slightly. During the Phase II response, the blood pressure increases slightly. Finally, during the Phase III response, blood pressure increases

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

greatly before finally coming back to baseline after the intermediates are degraded by the body. Nicotine is known to act on the nicotinic neuronal receptors found on the membrane of all postganglionic neurons. The triphasic response can be explained by nicotine's initial stimulatory effect on nicotinic neuronal receptors. When nicotine is initially given intravenously, it causes a decrease in blood pressure by stimulating the nicotinic neuronal receptors located in parasympathetic ganglia of the heart. Eventually, nicotine reaches the more "proximal" sympathetic ganglia and causes an increase in sympathetic neuron stimulation. The resulting release of norepinephrine causes an increase in blood pressure. Finally, nicotine stimulation of the muscarinic receptors located on the cells of the adrenal medulla causing a release of epinephrine which causes an increase in heart rate, vasocontriction and blood pressure. 13. What does the biphasic response of nicotine refer to? The biphasic response of nicotine refers to its property of initially stimulating the nicotinic neuronal receptors followed by its inhibition of the nicotinic neuronal receptors. 14. How does nicotine stimulate respiration? Nicotine (stimulates or inhibits) the release of ADH. Stimulation of respiration is a sign of increased sympathetic activity. Nicotine probably increases respiration by a mechanism similar to the triphasic response it causes in blood pressure. By initially activating the nicotinic neuronal receptors, nicotine increases the release of norepinephrine and epinephrine after a short period of parasympathetic activity. ADH is a hormone which increases water retention from the collecting ducts of the kidney. Nicotine's initial effect is very similar to the fight or flight response of sympathetic activation. Since sympathetic activation tends to result in the cessation of urination, nicotine is likely to increase the release of ADH. 15. How many different nicotine receptors are there? Where are they located? The body basically contains two types of nicotinic receptors. Nicotinic muscle (Nm) receptors are located on the muscle cells at the neuromuscular junction. Nicotinic neuron (Nn) receptors are located on the membranes of all post-synaptic, ganglionic neurons. 16. Of the drugs -- physostigmine, neostigmine, and edrophonium -- which is the shortest acting? Which crosses the BBB? Which is used to diagnose myasthenia gravis? Which is used to treat myasthenia gravis? Which is used to treat atropine poisoning? Which has direct stimulating effect on skeletal muscle? Which (2) are permanently ionized (quaternary amines)? Which would be preferred for topical application to the eye for treatment of glaucoma? Physostigmine, neostigmine and edrophonium belong to a class of drugs known as the reversible anticholinergics. All the drugs competitively bind to acetylcholinesterase in the synaptic cleft and therefore increase the duration of action of acetylcholine on its post-synaptic receptors. Edrophonium is a compound with a quaternary amine group that binds to and carbamylates the esteratic site of acetylcholinesterase. Because the quaternary amine group is always positively charged, edrophonium does not cross the blood brain barrier. Since edrophonium is the short

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

acting reversible anticholingeric, it is commonly used to diagnose myasthenia gravis, an autoimmune disease in which antibodies are produced against the nicotinic muscular receptors. Administration of edrophonium results in an increase in acetylcholine in the neuromuscular junction. Since acetylcholine competes with the autoimmune antibodies for nicotinic muscular receptor sites, the excess of acetylcholine cause a temporary increase in muscle function. This effect of edrophonium is diagnostic for myasthenia gravis. Neostigmine is a quaternary amine compound that is a longer acting, reversible inhibitor of acetylcholinesterase found in the periphery. Due to its permanent positive charge, neostigmine cannot cross the blood-brain barrier. Since neostigmine is limited to action in the peripheral nervous system and since it has some direct stimulating effect on skeletal muscle, it is commonly used for the long term treatment of myasthenia gravis.

Physostigmine is the only uncharged drug of the reversible acetylcholinesterases. Therefore, it can have effects on the central nervous system. Since atropine causes muscarinic receptor blockade which results in both peripheral and central effects, physostigmine probably would be the best antidote for atropine poisoning. By not being permanently charged, physiostigmine can cross membranes easier. Therefore, it is also the drug of choice for topical application to the eye for treatment of glaucoma. 17.Which two organophosphates must be metabolized by cytochrome P450 to an active compound which inhibits cholinesterase? What are the predominant signs and symptoms of organophosphate poisoning? The thio-organophosphates commonly used as insecticides (such as malathion and parathion) need to be metabolized by cytochrome P450 before they can irreversibly inactivate acetylcholinesterase. Cytochrome P450 is needed to convert the phosphorus-sulfur double bond into the phosphorus-oxygen double bond needed for forming a covalent bond between the phosphate group of the pesticide and the hydoxyl oxygen of the acetylcholinesterase esteratic group. By irreversibly blocking acetylcholinesterase, organophosphates cause an increase in the amount of acetylcholine present in the ganglionic and post-ganglionic, adrenergic synaptic clefts and in the neuromuscular junction. The resulting cholinergic crisis is characterized by the effects of increased activity of the parasympathetic nervous system. Acronyms such as SLUD (salivation, lacrimation, urination, diarrhea) and DUMBELS (diarrhea, urinations, miosis, bradycardia, emesis, lacrimation, salivation) are used to describe the body's response to organophosphate poisoning. 18.What is the effect of a ganglion blocker on: pupil size? accommodation? arterial and venous vascular tone? heart rate? gastrointestinal tract (tone and motility)? sweat glands? urinary bladder? Name three ganglion blockers. Ganglionic blockers cause mixed responses since they block both sympathetic and parasympathetic stimulation. In general, though, the ganglionic blocker will block the effect of the system which mainly controls the organ. As a result, the secondary autonomic neuronal

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

system is active and its effects on the organ predominates. Under normal conditions, the eye is under the control of the parasympathetic nervous system. Therefore, a ganglionic blocker would cause mydriasis and would inhibit accomodation. The arterial and venous vascular tone is mainly influenced by the sympathetic nervous system. Therefore, a ganglionic blocker would cause a vasodilation and a decrease in total peripheral resistance. The heart rate is normally under the control of the vagal (parasympathetic) system. So, a ganglionic blocker would result is an increase in heart rate due to the effects of the sympathetic nervous system. Since the parasympathetic system has the dominant effect on the gastrointestinal system, a ganglionic blocker would result in a decrease in tone and motility. Sweat glands are dominantly controlled by the cholingeric sympathetic system. Therefore, a ganglionic blocker would cause a decrease in sweat production. Finally, the urinary bladder is mainly controlled by the parasympathetic system. Therefore, urinary retention would occur with a ganglionic blocker. Three ganglionic blocking agents are trimethaphan, mecamylamine and nicotine. They work by blocking the nicotinic neuronal post-synaptic receptors. (NOTE: Nicotine actually stimulates the post-ganglionic neurons first and then blocks them.)

19.How do snake alpha-toxins cause paralysis? How does succinylcholine work? How do dtubocurarine (curare), gallamine and pancuronium work? Which neuromuscular blockers are competitive? Which are noncompetitive? Which class releases histamine from mast cells? Which class produces muscle fasciculations initially? Alpha-toxins, succinylcholine, decamethonium, d-tubocurarine, gallamine and pancuronium are all selective blockers of the nicotinic muscular receptors. As a result, they block the effect of neurons on muscle contraction. Alpha-toxins, d-tubocurarine, gallamine and pancuronium are all nondepolarizing, reversible blockers of the nicotinic muscular receptors. By binding to these receptors, they prevent acetylcholine binding; therefore, they prevent muscle cell depolarizaton and contraction. At high concentrations, these compounds tend to directly block ion channels on the muscle membrane and their effects cannot be reversed by increasing the amount of acetylcholine in the neuromuscular junction. Of these compounds, alpha-toxins and d-tubocurarine cause the release of histamine from mast cells. This side effect is not observed when gallamine or pancuronium are used. However, gallamine causes sinus tachycardia by blocking the cardiac vagus at the muscarinic sites. Succinylcholine is a reversible, depolarizing blocker of nicotinic muscular receptors. Succinyl choline has a complicated mechanism of action. First of all, it complexes with a receptor which is in the "closed" state. Then, in Phase I, the complex causes the receptor to become "open" and to conduct. Then, in Phase II, the receptor is converted from an "open" state to a "desensitized" state that no longer conducts impulses for muscle contraction. Finally, the succinylcholine is degraded and the receptor is converted from the "desensitized" state back to the "closed" state. Since succinylcholine causes the receptors to depolarize the muscle cells in Phase I, it produces muscle fasiculations initially.

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

20.Neostigmine will reverse the paralysis due to d-tubocurarine (T/F). Neostigmine will augment the paralysis produced by succinylcholine during phase I (T/F). Neostigmine (a reversible anticholinergic) will reverse the paralysis due to d-tubocurarine by increasing the amount of acetylcholine in the synaptic cleft. This excess acetylcholine will compete with the d-tubocurarine for binding to the nicotinic muscular receptors. However, in Phase I of paralysis produced by succinylcholine, neostigmine will augment paralysis by inhibiting plasma cholinterases which degrade succinylcholine. Also, the excess acetylcholine causes further muscle fasiculations during the Phase I effect of succinylcholine. 21.D-tubocurarine paralyzes (small rapidly-moving or large slow-moving) muscles first. Curare paralyzes small rapidly-moving muscles (such as the eye muscles) first. 22.Succinyl choline apnea occurs in individuals (who have two alleles for an atypical isoenzyme of plasma cholinesterase or who have a deficiency of plasma cholinesterase). Succinyl choline apnea occurs in individuals who have two alleles for an atypical isoenzyme of plasma cholinesterase. These isoenzymes take longer to breakdown succinyl choline. Therefore, the anaesthetic effects of succinyl choline on voluntary muscles is increased.

23.A patient taking an organophosphate for glaucoma (would or would not) exhibit prolonged apnea if given succinyl choline. Organophosphate treatment for glaucoma is usually administered topically to the eye in very weak solutions. Therefore, the organophosphate is not likely to enter the peripheral circulation and is not likely to block a significant number of plasma cholinesterase enzymes. As a result, prolonged sleep apnea induced by succinyl choline should not occur in a patient taking organophosphate for glaucoma. 24.What are the receptor specificities for each of the following drugs: norepinephrine, epinephrine, isoproterenol, dopamine, dobutamine? Norepinephrine is selective for alpha-1 adrenergic receptors and slightly for 1 adrenergic receptors. At low doses, epinephrine is 1 and 2 selective; however, at higher doses it can activate alpha-1 receptors. Isoproternol is selective for 1 and 2 receptors. Dopamine is primarily selective for dopamine receptors. However, at medium doses, it can act on 1 and 2 receptors and at high doses it can act of alpha-1 receptors. Finally, dobutamine shows selectivity for beta-1 receptors. 25.What are the effects on heart rate, blood pressure, and peripheral resistance after IV infusion of: norepinephrine? epinephrine? isoproterenol? dopamine?

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

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Norephinephrine is primarily an alpha-1 adrenergic receptor agonist but is also partially a 1 agonist. Therefore, when given in an IV infusion, norephinephrine will act on the heart to increase heart rate and contractility. By increasing cardiac output, the initial 1 effect also increases blood pressure. When norepinephrine enters the vasculature, it causes vasoconstriction. This increases peripheral resistance which also increases blood pressure. It causes constriction of the peripheral vasculature and therefore increases total peripheral resistance. The increase in total peripheral resistance is quite large and leads to the activation of the baroreceptor reflex which causes reflex bradycardia. This reflex bradycardia masks the effects of the tachycardia due to norephinephrine's 1 action. As a result, norepinephrine increases blood pressure and peripheral resistance but decreases heart rate. Isoproterenol is a 1 and 2 adrenergic receptor agonist. When an IV infusion of isoproterenol is given, it will initially activate the 1 receptor of the heart. Therefore, heart rate, contractility and cardiac output will be increased. The increase in cardiac output leads to an increase in blood pressure. As the isoproternenol enters the vasculature, it causes vasodilation of coronary, skeletal and cerebral arteries via the 2 receptors. This vasodilation causes a decrease in total peripheral resistance which causes the blood pressure to decrease. As a result, heart rate will increase, total peripheral resistance will decrease and blood pressure will most likely stay the same although the pulse pressure will increase. Epinephrine is an agonist for 1 and 2 receptors at low concentrations and alpha-2 receptors at higher concentrations. Therefore, if given as an IV in lower concentrations, it leads to the same effects on heart rate, blood pressure and peripheral resistance as isopreterenol. At higher IV doses, it will have similar effects on heart rate, blood pressure and peripheral resistance as norepinephrine.

Dopamine effects on heart rate, blood pressure and peripheral resistance is also dose dependent. If given in low concentrations, dopamine acts selectively on the dopamine receptors. These receptors tend to be located in the vasculature of the kidney. Administration of dopamine leads to renal vessel dilation which decreases total peripheral resistance. Dopamine itself does not seem to have much direct effect on heart rate. Blood pressure would decline due to a decrease in total peripheral resistance. If given in medium doses, dopamine can activate the 1 and 2 receptors and lead to an effect on heart rate, blood pressure and peripheral resistance which is similar to isopreterenol. Finally, if given in high doses, dopamine activates alpha-1 receptors which leads to the effects seen with the administration norepinephrine. 26.What two classes of drug block a reflex tachycardia resulting from the infusion of acetylcholine? Which of these classes would have no effect on the ability of isoproterenol to cause vasodilation? Acetylcholine given by infusion acts on the muscarinic receptors found in the vasculature to cause vasodilation. Vasodilation leads to a drop in total peripheral resistance which leads to a

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

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drop in blood pressure. The drop in blood pressure leads to activation of the baroreceptor reflex. The lower blood pressure causes the carotid baroreceptors to fire less, which causes the inhibitory neuron from the nucleus tractus solitarius to the vasomotor center and the excitatory neuron to the vagal motor center to fire less. As a result, vagal firing to the heart is reduced while firing of the sympathetic pre-synaptic neurons are increased. The increased sympathetic pre-synaptic firing leads to an increased postsynaptic sympathetic neuron firing which results in increased heart rate (reflex tachycardia) and increased vasoconstriction. In order to block the reflex tachycardia effects from the infusion of acetylcholine, either the presynaptic firing of the sympathetic pre-ganglionic neurons must be inhibited or the effects of increased post-synaptic sympathetic firing on the heart must be decreased. The former situation can be accomplished by using a ganglionic blocker such as trimethaprin which the latter situation can be accomplished by using a 1 blocker such as propranolol. Of the two classes of drugs mentioned as possible ways to block reflex tachycardia due to acetycholine administration, only the ganglionic blocker would not effect isoproterenol's ability to cause vasodilation. The beta-blockers such as propranolol also cause 2 receptor inhibition along with 1 receptor inhibition. Since isoproterenol causes its vasodilation effects by stimulating the 2 receptor, propanol would decrease its effectiveness. 27.What is the receptor specificity of phenylephrine? What effect does IV infusion of phenylephrine have on blood pressure? peripheral resistance? heart rate? Is the effect on heart rate direct or indirect? How could you block the effect on heart rate? Phenylephrine is basically a longer lasting analog of norepinephrine. Therefore, like norepinephrine, it works as an alpha-1 (1) adrenergic receptor agonist. Also, like norepinephrine, it causes a decrease in heart rate (via reflex bradycardia), and an increase in total peripheral resistance and blood pressure (via vasoconstriction). As stated in the previous sentence, phenylephrine's effect on the heart rate is indirect via the baroreceptor reflex. To block the reflex bradycardia response, one would have to block the efferent pathway of the baroreceptor reflex. This can be accomplished by giving a ganglionic blocker such as trimethaprin or by giving atropine to block the effect of acetylcholine on muscarinic receptors located in the heart.

28.Describe each of the following: directly acting adrenergic agonist, indirectly acting adrenergic agonist, mixed acting adrenergic agonist. Give examples of each. Adrenergic agonists can be classified by whether they increase the sympathetic response by acting on increasing norepinephrine release from the pre-synaptic, post-ganglionic sympathetic neuron or on the post-synaptic alpha and beta adrenergic receptors. A direct acting adrenergic agonist produces an effect on post-synaptic adrenergic receptors. Examples of a directly acting adrenergic agonists are epinephrine, norepinephrine, isoproterenol, dopamine, dobutamine, phenylephrine, methoxamine, metaproterenol, terbutaline, ritodrine and albuterol. An indirectly acting adrenergic agonist is one that increase sympathetic stimulation by increasing the amount of norepinephrine released from the pre-synaptic terminal into the synaptic cleft. Examples of

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

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indirectly acting adreneric agonists are tyramine and amphetamines. Finally, a compound can increase the sympathetic response by acting on both the pre-synaptic and post-synaptic sides of an adrenergic synaptic cleft. Mixed acting adrenergic agonist include ephedrine and metaraminol. 29.Name three -agonists which are selective for the 2 receptor. Which -agonist is most selective for 2 receptors? What is the greatest limitation of a nonselective -agonist in the treatment of asthma? Threee -agonists which are selective for the 2 receptor are albuterol, terbutaline, and metaproterenol. These drugs are useful asthma treatments since there action of 2 receptors in the lung leads to bronchodilation. Of the three drugs, albuterol is the most 2 selective and metaproterenol is the least selective. The greatest limitation of a nonselective agonist is its effects on 1 receptors which lead to an increase in heart rate and contractility. 30.Name two long acting -blockers? Which is the longest acting? What is ISA? Name 2 "blockers" which demonstrate ISA. Two long acting -blockers are nadolol and atenolol. Nadolol is the longest acting with a halflife of about 20 hours. ISA stands for intrinsic sympathomimetic activity. "-blockers" are partial agonists that weakly stimulate the beta receptors but competitively prevent more potent stimulators from stimulating the beta-receptors. Two "-blockers" which demostrate ISA are pindolol and acebutolol. 31.Labetalol has antagonist activity against alpha and receptors (T/F). Labetatol is a unique -blocker because it also is an alpha-antagonist. 32.Name two selective a2 agonists. Name a selective a2 antagonist. Clondine and methyl-dopa are centrally acting alpha-2 agonists. They bind to presynaptic alpha2 receptors which causes a decrease in the production of norephinephrine by blocking the conversion of tyrosine to dopa. Although phentolamine and phenoxybenzamine block alpha-2 receptors, they are not selective for alpha-2 blockade. An selective alpha-2 antagonist was never discussed.

33.Phenoxybenzamine and dibenamine are (competitive or noncompetitive) a-adrenergic antagonists and they are (reversible or irreversible). Phenoxybenzamine and dibenamine are noncompetitive alpha-adrenergic antagonists and they are irreversible.

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

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34.What is the receptor specificity of prazosin? phentolamine? phenoxybenzamine? Prazosin, phentolamine, and phenoxybenzamine are all alpha antagonists. Phenoxybenzamine is a drug that is an irreversible, noncompetitive antagonist of alpha-1 and alpha-2 receptors. The time required for it to cause an effect is prolonged. Phentolamine is a reversible competitive alpha-1 and alpha-2 antagonist. Finally, prazosin is a competitive, reversible alpha-1 selective antagonist. 35.What class of drug would be used to manage hypertension from pheochromocytoma? Pheochromocytoma is a tumor of the adrenal medulla that results in the excess production of catacholamines (mainly epinephrine). At high concentrations, epinephrine acts like norepinephrine by stimulating vasocontriction via alpha-1 receptors. Since this interaction leads to increased blood pressure, an alpha1-antagonist would block epinephrine's alpha-1 effects and would help manage hypertension secondary to pheochromocytoma. The alpha-1 antagonists, phenoxybenzamine and phentolamine, are the ones most commonly used. 36.Cocaine will shift a dose-response curve of norepinephrine to the (left or right). Physostigmine will shift the dose response curve for acetylcholine to the (left or right). Cocaine is a blocker of the uptake I receptor located on the presynaptic neuron terminal. Therefore, it prevents the removal of norepinephrine from the synaptic cleft. As a result, a smaller dose of exogenous norepinephrine initially can produce a given response since more endogenous norepinephrine is present. In other words, the dose-response curve is initially shifted to the left. However, with the continual use of cocaine, the post-synaptic receptors are endocytosed and the post-synaptic neuron becomes less responsive to a given dose of norepinephrine. Therefore, under chronic cocaine use, the dose-response curve shifts right and should approach the normal dose-response curve. Physostigmine reversibly blocks acetylcholinesterase increasing the concentration of acetylcholine in the synaptic cleft. Therefore, like cocaine's effect on norepinephrine, physostigmine initially cause a shift to the left in the dose-response curve for acetylcholine. However, with chronic administration, the dose-response curve will shift back to the right due to the desensitization of the post-synaptic receptors for acetylcholine. 37.Name two monoamine oxidase inhibitors. Why can't a patient eat unpasteurized cheese, when they are taking a MAO inhibitor? What blood pressure response will foods containing high amounts of tyramine produce in a patient taking a MAO inhibitor? Two monoamine oxidase inhibitors are pargyline and nialamide. By inhibiting monoamine oxidase, both drugs block the pre-synaptic breakdown of taken up by the action of the uptake I receptor. Therefore, the concentration of norepinephrine in the synaptic terminal vesicles and cytoplasm increases. Unpasteurized cheese contains a large amount of tyramine. Tyramine enters the pre-synaptic terminal via the uptake I receptor and causes the release of norepinephrine from the terminal. If tyramine is introduced in a patient on a monoamine oxidase inhibitor, a large amount of norepinephrine is released into the synaptic cleft. This excess norepinephrine causes vasoconstriction and a dramatic increase in blood pressure.

PHARMACOLOGY -- Fall Study Guide (1994)

Autonomic Pharmacology

Isaac

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38.Prior administration of prazosin will convert the (pressor or depressor) response of epinephrine into a (pressor or depressor) response. What is this phenomenon called? Prazosin is an selective alpha-1 antagonist. Epinephrine reacts with 1 and 2 receptors in low doses and alpha-1 receptors in high doses. If a high dose of epinephrine is given, it will act on alpha-1 receptors to produce vasoconstriction and an increase in blood pressure. In prasozin is given prior to the epinephrine, epinephrine will only be able to act of the 1 and 2 receptors. Its actions on the 2 receptors cause vasodilation which results in a drop in blood pressure. Therefore prior administration of prasozin will convert the pressor response of epinephrine into a depressor response. This phenomenon is called epinephrine reversal. 39.After pretreating with atropine, phenylephrine would (increase, decrease, produce no change in) heart rate. After pretreatment with atropine, norepinephrine would (increase, decrease, produce no change in) heart rate. After pretreatment with atropine, acetylcholine would produce (an increase, a decrease, no change) in heart rate. Phenylephrine is a long acting form of norepinephrine. Therefore, it tends to cause vasoconstriction (via its effects on alpha-1 receptors) and the resulting increase in blood pressure leads to an decrease in heart rate (via reflex bradycardia). Therefore, if atropine is given before phenylephrine, the effect of increased acetylcholine release by the baroreceptor reflex will be decreased by the fact that atropine blocks the muscarinic receptors in the heart. As a result, heart rate will increase since the minor 1 effects of phenylephrine will be not be masked by reflex bradycardia. The effect of atropine pretreatment on the heart rate response to norepinephrine is exactly the same as the effect described for phenylephrine. Therefore, atropine pretreatment before norepinephrine administration would lead to an increase in heart rate. With a pretreatment of atropine, the muscarinic receptors in the heart would be blocked. Since acetylcholine causes its decrease in heart rate by acting on the muscarinic receptors of the heart, pretreatment with atropine would block its normal effect. As a result, the heart rate would cause no change in heart rate. This result would occur because there is sympathomimetic agent activated to increase the 1 response of the heart.

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