Pharmacology Chapter 6 PDF

no denegat · nodel we Adrenergic Agonists I. OVERVIEW sympathomimetic sympatholytics , The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sy...

no denegat · nodel we Adrenergic Agonists I. OVERVIEW sympathomimetic sympatholytics , The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. Others, which will be dealt with in Chapter 7, block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons. This chapter describes agents that either directly or indirectly stimulate adrenoceptors (Figure 6.1). II. THE ADRENERGIC NEURON in ? postganglionic Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs (Figure 6.2). A. Neurotransmission at adrenergic neurons ? lioic Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons (see p. 47), except that norepinephrine is the neurotransmitter instead of acetylcholine. in Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure 6.3). aminoacid 1. Synthesis of norepinephrine: Tyrosine is transported by a Na+linked carrier into the axoplasm of the adrenergic neuron, where axoplasi is it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine the cytoplasne hydroxylase.1 This is the rate-limiting step in the formation of norof a neuron epinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. postgang( INFO LINK is the intro DIRECT-ACTING AGENTS Albuterol ACCUNEB, PROAIR HFA, VENTOLIN HFA Clonidine CATAPRES, DURACLON Dobutamine* DOBUTREX Dopamine* INTROPIN Epinephrine* ADRENALIN, EPIPEN, PRIMATENE MIST Fenoldopam CORLOPAM Formoterol FORADIL AEROLIZER, PERFOROMIST Isoproterenol* ISUPREL Metaproterenol ALUPENT Norepinephrine* LEVOPHED Phenylephrine NEO-SYNEPHRINE, SUDAFED PE Salmeterol SEREVENT DISKUS Terbutaline BRETHINE INDIRECT-ACTING AGENTS Amphetamine ADDERALL Cocaine DIRECT AND INDIRECT ACTING (mixed action) AGENTS Ephedrine VARIOUS Pseudoephedrine SUDAFED Figure 6.1 Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines. carboxylic acid of hydroge of hydroxyl into anion or radical usually by the replacement decarboxylation is where carbie dioxide hydroxylation e 6 is lost from 1See Chapter 21 in Lippincott’s Illustrated Reviews: Biochemistry for a discussion of the synthesis of DOPA. 70 6. Adrenergic Agonists Nicotinic receptor Nicotinic receptor Adrenal medulla Epinephrine released into the blood Norepinephrine Adrenergic receptor Adrenergic receptor Effector organs Figure 6.2 Sites of actions of adrenergic agonists. 2. Storage of norepinephrine in vesicles: Dopamine is then transported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine (see p. 96). Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP) and β-hydroxylase as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells along with norepinephrine. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation. 3. Release of norepinephrine: An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. Drugs such as guanethidine block this release (see p. 96). 4. Binding to receptors: Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) secondmessenger system2 and the phosphatidylinositol cycle3 to transduce the signal into an effect. Norepinephrine also binds to presynaptic receptors that modulate the release of the neurotransmitter. 5. Removal of norepinephrine: Norepinephrine may 1) diffuse out of the synaptic space and enter the general circulation, 2) be metabolized to O-methylated derivatives by postsynaptic cell membrane– associated catechol O-methyltransferase (COMT) in the synaptic space, or 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium- or potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure 6.3). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects. 6. Potential fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool in the cytoplasm. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in urine as vanillylmandelic acid, metanephrine, and normetanephrine. 2See Chapter 8 in Lippincott’s Illustrated Reviews: Biochemistry for a INFO LINK discussion of the cyclic AMP second messenger system. 3See Chapter 17 in Lippincott’s Illustrated Reviews: Biochemistry for a discussion of the phosphatidylinositol cycle. II. The Adrenergic Neuron 71 1 SYNTHESIS OF NOREPINEPHRINE 2 Hydroxylation of tyrosine is the rate-limiting step. Inactive metabolites Urine MAO Tyrosine Na+ Dopamine enters a vesicle and is converted to norepinephrine. Norepinephrine Norepinephrine is protected from degradation in the vesicle. Tyrosine Na+ Transport into the vesicle is inhibited by reserpine. DOPA Inactive metabolites Urine MAO 3 Dopamine Dopamine + Released norepinephrine is rapidly taken into the neuron. Presynaptic receptor Reuptake is inhibited by cocaine and imipramine. Urine Influx of calcium causes fusion of the vesicle with the cell membrane in a process known as exocytosis. Synaptic vesicle Ca2+ REMOVAL OF NOREPINEPHRINE RELEASE OF NEUROTRANSMITTER Release is blocked by guanethidine and bretylium. Ca2+ 5 UPTAKE INTO STORAGE VESICLES 4 Norepinephrine Inactive metabolites BINDING TO RECEPTOR Postsynaptic receptor is activated by the binding of neurotransmitter. Catechol-Omethyltransferase (COMT) 6 METABOLISM SYNAPTIC SPACE Norepinephrine is methylated by COMT and oxidized by MAO. INTRACELLULAR RESPONSE Figure 6.3 Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.) B. Adrenergic receptors (adrenoceptors) In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes has revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents. 72 6. Adrenergic Agonists A α Adrenoceptors Epinephrine Norepinephrine Isoproterenol α Receptor High affinity Low affinity B β Adrenoceptors Isoproterenol Epinephrine Norepinephrine β Receptor High affinity Figure 6.4 Types of adrenergic receptors. Low affinity 1. α1 and α2 Receptors: The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 6.4). For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors. a. α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects, originally designated as α-adrenergic, involving constriction of smooth muscle. Activation of α1 receptors initiates a series of reactions through the G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell (Figure 6.5). b. α2 Receptors: These receptors, which are located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors. A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane (see Figure 6.5). The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance, these receptors are acting as inhibitory autoreceptors.] α2 receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances, these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP. c. Further subdivisions: The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, and α2C. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland. 2. β Receptors: β receptors exhibit a set of responses different from those of the α receptors. These are characterized by a strong response II. The Adrenergic Neuron 73 to isoproterenol, with less sensitivity to epinephrine and norepinephrine (see Figure 6.4). For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists, although several others have been identified by gene cloning. [Note: It is known that β3 receptors are involved in lipolysis, but their role in other specific reactions is not known]. β1 receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell. Synaptic vesicle ATP cAMP Adenylyl cyclase α2 Receptor Norepinephrine 3. Distribution of receptors: Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. For example, tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors. For example, the heart contains predominantly β1 receptors. α1 Receptor Membrane phosphoinositides + 4. Characteristic responses mediated by adrenoceptors: It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one type of receptor. Figure 6.6 summarizes the most prominent effects mediated by the adrenoceptors. As a generalization, stimulation of α1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of β1 receptors characteristically causes cardiac stimulation, whereas stimulation of β2 receptors produces vasodilation (in skeletal vascular beds) and smooth muscle relaxation. α2 Receptors Activation of the receptor decreases production of cAMP, leading to an inhibition of further release of norepinephrine from the neuron. DAG IP3 Ca 2+ α1 Receptors Activation of the receptor increases production of DAG and IP3, leading to an increase in intracellular calcium ions. Figure 6.5 Second messengers mediate the effects of α receptors. DAG = diacylglycerol; IP3 = inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate. ADRENOCEPTORS α1 Vasoconstriction Increased peripheral resistance Increased blood pressure Mydriasis α2 β1 β2 Inhibition of norepinephrine release Tachycardia Vasodilation Increased lipolysis Inhibition of acetylcholine release Decreased peripheral resistance Increased myocardial contractility Inhibition of insulin release Increased release of renin Increased closure of internal sphincter of the bladder Figure 6.6 Major effects mediated by α and β adrenoceptors. Bronchodilation Increased muscle and liver glycogenolysis Increased release of glucagon Relaxed uterine smooth muscle 74 6. Adrenergic Agonists OH HO CH 5. Desensitization of receptors: Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon: 1) sequestration of the receptors so that they are unavailable for interaction with the ligand; 2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis, and 3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase α or β-adrenergic receptor kinase. H CH2 N wi CH3 Phenylephrine OH CH H CH N CH3 CH3 III. CHARACTERISTICS OF ADRENERGIC AGONISTS Ephedrine OH HO H CH CH2 N , writ e H HO Norepinephrine Most of the adrenergic drugs are derivatives of β-phenylethylamine (Figure 6.7). Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS. Two important structural features of these drugs are 1) the number and location of OH substitutions on the benzene ring and 2) the nature of the substituent on the amino nitrogen. A. Catecholamines they minic w OH HO Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. These compounds share the following properties: H CH CH2 N CH3 HO write all Epinephrine OH HO S H CH CH2 N CH3 CH HO CH3 Isoproterenol Affinity for β receptors increases as group on the amine nitrogen gets larger. CH2 CH2 N H HO Dopamine ↳ catechol-o-methultransferase , e sotes Figure 6.7 Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in yellow. monoamine oxidase 2. Rapid inactivation: Not only are the catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, but they are also metabolized in other tissues. For example, COMT is in the gut wall, and MAO is in the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and they are ineffective when administered orally because of inactivation. mortila va 3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. similar to : B. Noncatecholamines H HO 1. High potency: Drugs that are catechol derivatives (with – OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors. drugs chemically analog illicit narcotic drugs other or illegal or substances Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. Phenylephrine, which is an analog of epinephrine, has only a single – OH at position 3 on the benzene ring, whereas ephedrine lacks hydroxyls on the ring but has a methyl substitution at the α-carbon. These are poor substrates for MAO and, thus, show a prolonged duration of action, because MAO is an important route of detoxification. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. [Note: Ephedrine and amphetamine may act indirectly by causing the release of stored catecholamines.] IV. Direct-Acting Adrenergic Agonists 75 property C. Substitutions on the amine nitrogen The nature and bulk of the substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist. For example, epinephrine, with a – CH3 substituent on the amine nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol, which has an isopropyl substituent – CH (CH3)2 on the amine nitrogen (see Figure 6.7), is a strong β agonist with little α activity (see Figure 6.4). D. Mechanism of action of the adrenergic agonists por Aqui halitat INDIRECT ACTION Drug enhances release of norepinephrine from vesicles. NEURON aptic 1. Direct-acting agonists: These drugs act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla (Figure 6.8). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine. MIXED ACTION Drug acts both directly and indirectly. se SYNAPSE 2. Indirect-acting agonists: These agents, which include amphetamine, cocaine, and tyramine, may block the uptake of norepinephrine (uptake blockers) or are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (see Figure 6.8). As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the α or β receptors. Examples of uptake blockers and agents that cause norepinephrine release include cocaine and amphetamines, respectively. DIRECT ACTION POSTSYNAPTIC TARGET CELL MEMBRANE Drug directly activates receptor. Figure 6.8 Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists. 3. Mixed-action agonists: Some agonists, such as ephedrine and its stereoisomer, pseudoephedrine, have the capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron (see Figure 6.8). IV. DIRECT-ACTING ADRENERGIC AGONISTS Direct-acting agonists bind to adrenergic receptors without interacting with the presynaptic neuron. The activated receptor initiates synthesis of second messengers and subsequent intracellular signals. As a group, these agents are widely used clinically. A. Epinephrine Epinephrine [ep-i-NEF-rin] is one of four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy. The first three occur naturally in the body as neurotransmitters, and the latter is a synthetic compound. Epinephrine is synthesized from tyrosine in the adrenal medulla and released, along with small quantities of norepinephrine, into the bloodstream. Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are strongest. 1. Actions: a. Cardiovascular: The major actions of epinephrine are on the cardiovascular system. Epinephrine strengthens the contractility of the myocardium (positive inotropic: β1 action) and increases its rate of contraction (positive chronotropic: β1 action). Therefore, Occur naturally : epinephrine norepinephrine 3 doparine Synthatic compand · · · · dobutamine neurotrans 76 6. Adrenergic Agonists cardiac output increases. With these effects comes increased oxygen demands on the myocardium. Epinephrine activates β1 receptors on the kidney to cause renin release. Renin is an enzyme involved in the production of angiotensin II, a potent vasoconstrictor. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects). Renal blood flow is decreased. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure (Figure 6.9). Epinephrine increases the rate and force of cardiac contraction. Pulse rate (per min) 100 Blood pressure (mm Hg) Infusion of epinephrine 180 50 b. Respiratory: Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action). This action relieves all known allergic- or histamine-induced bronchoconstriction. In the case of anaphylactic shock, this can be lifesaving. In individuals suffering from an acute asthmatic attack, epinephrine rapidly relieves dyspnea (labored breathing) and increases tidal volume (volume of gases inspired and expired). Epinephrine also inhibits the release of allergy mediators such as histamines from mast cells. 120 60 Peripheral resistance High Low 0 15 Time (min) Epinephrine decreases the peripheral resistance. Systolic pressure is increased, and diastolic pressure is decreased. Figure 6.9 Cardiovascular effects of intravenous infusion of low doses of epinephrine. c. Hyperglycemia: Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect). These effects are mediated via the cAMP mechanism. d. Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue, which, upon stimulation, activate adenylyl cyclase to increase cAMP levels. cAMP stimulates a hormone-sensitive lipase, which hydrolyzes triacylglycerols to free fatty acids and glycerol.4 2. Biotransformations: Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO and COMT, which has S-adenosylmethionine as a cofactor (see Figure 6.3). The final metabolites found in the urine are metanephrine and vanillylmandelic acid. [Note: Urine also contains normetanephrine, a product of norepinephrine metabolism.] 3. Therapeutic uses a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of any condition of the respiratory tract when bronchoconstriction has resulted in diminished respiratory exchange. Thus, in treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice. Within a few minutes after subcutaneous administration, greatly improved respiratory exchange is observed, and administration may be repeated after a few hours. However, selective β2 agonists, such as albuterol, are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect. INFO LINK 4 See Chapter 16 in Lippincott’s Illustrated Reviews: Biochemistry for a discussion of hormone-sensitive lipase activity. IV. Direct-Acting Adrenergic Agonists b. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. c. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause. d. Anesthetics: Local anesthetic solutions usually contain 1:100,000 parts epinephrine. The effect of the drug is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the injection site before being absorbed into the circulation and metabolized. Very weak solutions of epinephrine (1:100,000) can also be used topically to vasoconstrict mucous membranes to control oozing of capillary blood. 4. Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). The preferred route is intramuscular (anterior thigh) due to rapid absorption. In emergency situations, epinephrine is given intravenously (IV) for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, and by inhalation (Figure 6.10). Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only the metabolites are excreted in urine. 5. Adverse effects: a. CNS disturbances: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor. b. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure. c. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. d. Pulmonary edema: Epinephrine can induce pulmonary edema. 6. Interactions: a. Hyperthyroidism: Epinephrine may have enhanced cardiovascular actions in patients with hyperthyroidism. If epinephrine is required in such an individual, the dose must be reduced. The mechanism appears to involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response. b. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions, because cocaine prevents reuptake of catecholamines into the adrenergic neuron. Thus, like norepinephrine, epinephrine remains at the receptor site for longer periods of time (see Figure 6.3). c. Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. 77 Aerosol Poor penetration into CNS Topical IV SC Metabolites appear in urine the urine Epinephrine Figure 6.10 Pharmacokinetics of epinephrine. CNS = central nervous system; IV = intravenously; SC = subcutaneously. 78 6. Adrenergic Agonists Norepinephrine induces reflex bradycardia. Pulse rate (per min) 100 Blood pressure (mm Hg) Infusion of norepinephrine 180 d. β-Blockers: These prevent epinephrine’s effects on β receptors, leaving α receptor stimulation unopposed. This may lead to an increase in peripheral resistance and an increase in blood pressure. e. Inhalation anesthetics: These agents sensitize the heart to the effects of epinephrine, which may lead to tachycardia. B. Norepinephrine Because norepinephrine [nor-ep-ih-NEF-rin] is the neuromediator of adrenergic nerves, it should, theoretically, stimulate all types of adrenergic receptors. In practice, when the drug is given in therapeutic doses to humans, the α-adrenergic receptor is most affected. 50 1. Cardiovascular actions: a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). Both systolic and diastolic blood pressures increase (Figure 6.11). [Note: Norepinephrine causes greater vasoconstriction than does epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles, etc. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of asthma.] 120 60 Peripheral resistance High Low 0 15 Time (min) Norepinephrine causes increased systolic and diastolic pressure. Norepinephrine constricts all blood vessels, causing increased peripheral resistance. Figure 6.11 Cardiovascular effects of intravenous infusion of norepinephrine. b. Baroreceptor reflex: In isolated cardiac tissue, norepinephrine stimulates cardiac contractility. In vivo, however, little (if any) cardiac stimulation is noted. This is due to the increased blood pressure that induces a reflex rise in vagal activity by stimulating the baroreceptors. This reflex bradycardia is sufficient to counteract the local actions of norepinephrine on the heart, although the reflex compensation does not affect the positive inotropic effects of the drug (see Figure 6.11). c. Effect of atropine pretreatment: When atropine, which blocks the transmission of vagal effects, is given before norepinephrine, stimulation of the heart by norepinephrine is evident as tachycardia. 2. Therapeutic uses: Norepinephrine is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. Other actions of norepinephrine are not considered to be clinically significant. It is never used for asthma or in combination with local anesthetics. Norepinephrine is a potent vasoconstrictor and will cause extravasation (discharge of blood from vessel into tissues) along the injection site. Impaired circulation from norepinephrine may be treated with the α -receptor antagonist phentolamine. [Note: When norepinephrine is used as a drug, it is sometimes called levarterenol [leev-are-TER-a-nole].] 3. Pharmacokinetics: Norepinephrine may be given IV for rapid onset of action. The duration of action is 1 to 2 minutes following the end of the infusion period. It is poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine. IV. Direct-Acting Adrenergic Agonists 79 4. Adverse effects: These are similar to those of epinephrine. In addition, norepinephrine may cause blanching and sloughing of skin along an injected vein (due to extreme vasoconstriction). Isoproterenol causes vasodilation but strongly increases cardiac force and rate. C. Isoproterenol b. Pulmonary: Inhalation products of isoproterenol are no longer available in the United States. c. Other effects: Other actions on β receptors, such as increased blood sugar and increased lipolysis, can be demonstrated, but are not clinically significant. 2. Therapeutic uses: Isoproterenol can be used to stimulate the heart in emergency situations. 3. Pharmacokinetics: Isoproterenol is a marginal substrate for COMT and is stable to MAO action. 4. Adverse effects: The adverse effects of isoproterenol are similar to those of epinephrine. D. Dopamine Dopamine [DOE-pa-meen], the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. Dopamine can activate α- and β-adrenergic receptors. For example, at higher doses, it can cause vasoconstriction by activating α1 receptors, whereas at lower doses, it stimulates β1 cardiac receptors. In addition, D1 and D2 dopaminergic receptors, distinct from the α- and β-adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation. D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release. 1. Actions: a. Cardiovascular: Dopamine exerts a stimulatory effect on the β1 receptors of the heart, having both inotropic and chronotropic effects (Figure 6.13). At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction. Pulse rate (per min) a. Cardiovascular: Isoproterenol produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output (Figure 6.12). It is as active as epinephrine in this action and, therefore, is useful in the treatment of atrioventricular (AV) block or cardiac arrest. Isoproterenol also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressure (see Figure 6.12). 100 50 Blood pressure (mm Hg) 1. Actions: Infusion of isoproterenol 180 120 60 High Peripheral resistance Isoproterenol [eye-soe-proe-TER-e-nole] is a direct-acting synthetic catecholamine that predominantly stimulates both β1- and β2-adrenergic receptors. Its nonselectivity is one of its drawbacks and the reason why it is rarely used therapeutically. Its action on α receptors is insignificant. Low 0 10 Time (min) Isoproterenol causes a significant decrease in peripheral resistance. Isoproterenol causes markedly decreased diastolic pressure, with moderately increased systolic pressure. Figure 6.12 Cardiovascular effects of intravenous infusion of isoproterenol. 80 6. Adrenergic Agonists b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera (see Figure 6.13). These receptors are not affected by α- or β-blocking drugs. Therefore, dopamine is clinically useful in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function. [Note: Similar dopamine receptors are found in the autonomic ganglia and in the CNS.] Isoproterenol β 2. Therapeutic uses: Dopamine is the drug of choice for cardiogenic and septic shock and is given by continuous infusion. It raises the blood pressure by stimulating the β1 receptors on the heart to increase cardiac output and α1 receptors on blood vessels to increase total peripheral resistance. In addition, it enhances perfusion to the kidney and splanchnic areas, as described above. Increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis. In this regard, dopamine is far superior to norepinephrine, which diminishes the blood supply to the kidney and may cause renal shutdown. It is also used to treat hypotension and severe congestive heart failure, primarily in patients with low or normal peripheral vascular resistance and in patients that have oliguria. Bronchodilation β Peripheral vasodilation 3. Adverse effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized to homovanillic acid by MAO or COMT, and its adverse effects (nausea, hypertension, and arrhythmias) are, therefore, short-lived. β Increased cardiac output E. Fenoldopam Fenoldopam [fen-OL-de-pam] is an agonist of peirpheral dopamine D1 receptors, and it also has moderate affinity for α2 receptors. It is used as a rapid-acting vasodilator to treat severe hypertension in hospitalized patients, acting on coronary arteries, kidney arterioles, and mesenteric arteries. Fenoldopam is a racemic mixture, and the R-isomer is the active component. It undergoes extensive first-pass metabolism and has a 10-minute elimination half-life after IV infusion. Headache, flushing, dizziness, nausea, vomiting, and tachycardia (due to vasodilation) may be observed with this agent. Increased blood flow F. Dopaminergic Dopamine Figure 6.13 Clinically important actions of isoproterenol and dopamine. Dobutamine 1. Actions: Dobutamine [doe-BYOO-ta-meen] is a synthetic, direct-acting catecholamine that is a β1 receptor agonist. It is available as a racemic mixture. One of the stereoisomers has a stimulatory activity. It increases cardiac rate and output with few vascular effects. 2. Therapeutic uses: Dobutamine is used to increase cardiac output in acute congestive heart failure (see p. 204) as well as for inotropic support after cardiac surgery. The drug increases cardiac output and does not significantly elevate oxygen demands of the myocardium, a major advantage over other sympathomimetic drugs. 3. Adverse effects: Dobutamine should be used with caution in atrial fibrillation, because the drug increases AV conduction. Other adverse effects are the same as those for epinephrine. Tolerance may develop on prolonged use. IV. Direct-Acting Adrenergic Agonists 81 G. Oxymetazoline Oxymetazoline [OX-ee-mee-TAZ-ih-leen] is a direct-acting synthetic adrenergic agonist that stimulates both α1- and α2-adrenergic receptors. It is primarily used locally in the eye or the nose as a vasoconstrictor. Oxymetazoline is found in many over-the-counter short-term nasal spray decongestant products (applied every 12 hours) as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, and contact lenses. The mechanism of action of oxymetazoline is direct stimulation of α receptors on blood vessels supplying the nasal mucosa and the conjunctiva to reduce blood flow and decrease congestion. Oxymetazoline is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. When administered in the nose, burning of the nasal mucosa and sneezing may occur. Rebound congestion and dependence are observed with long-term use. H. Phenylephrine Phenylephrine [fen-ill-EF-reen] is a direct-acting, synthetic adrenergic drug that binds primarily to α1 receptors. It is not a catechol derivative and, therefore, not a substrate for COMT. Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. It has no effect on the heart itself but, rather, induces reflex bradycardia when given parenterally. It is often used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis. Phenylephrine acts as a nasal decongestant (applied every 4 hours) and produces vasoconstriction. The drug is used to raise blood pressure and to terminate episodes of supraventricular tachycardia (rapid heart action arising both from the AV junction and atria). Large doses can cause hypertensive headache and cardiac irregularities. I. Clonidine Clonidine [KLOE-ni-deen] is an α2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS (see p. 238). It can be used to minimize the symptoms that accompany withdrawal from opiates, tobacco smoking, and benzodiazepines. Clonidine acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. The most common side effects of clonidine are lethargy, sedation, constipation, and xerostomia. These effects generally decrease with therapy progression or dose reduction. Abrupt discontinuance must be avoided to prevent rebound hypertension. J. Metaproterenol Metaproterenol [met-a-proe-TER-a-nole], although chemically similar to isoproterenol, is not a catecholamine, and it is resistant to methylation by COMT. The use of metaproterenol in recent years has decreased due to the availability of longer acting, more selective β2 agonists. K. Albuterol and terbutaline Albuterol [al-BYOO-ter-ole] and terbutaline [ter-BYOO-te-leen] are short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler (Figure 6.14). Terbutaline is used offlabel as a uterine relaxant to suppress premature labor. Side effects of β2 agonists are primarily due to excessive β2-receptor activation. One of the most common side effects of these agents is tremor, but patients Onset of bronchodilation Duration of bronchodilation Epinephrine Isoproterenol Albuterol Salmeterol Terbutaline 0 5 Hours 10 Bronchodilation Figure 6.14 Onset and duration of bronchodilation effects of inhaled adrenergic agonists. 82 6. Adrenergic Agonists tend to develop tolerance to this effect. Other side effects include restlessness, apprehension, and anxiety. The adverse effects may be reduced by starting with low doses and then titrating to higher doses as tolerance to the tremor develops. Systemically administered agents may cause tachycardia or arrhythmia (due to β1-receptor activation), especially in patients with underlying cardiac disease. Adverse cardiovascular effects also increase if patients are using monoamine oxidase inhibitors (MAOIs) concomitantly. It is recommended that there be about a 2-week gap between the use of a MAOI and a β2-receptor agonist. L. Salmeterol and formoterol Salmeterol [sal-ME-ter-ole] and formoterol [for-MOH-ter-ole] are β2-adrenergic selective agonists that are long-acting bronchodilators. A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides sustained bronchodilation over 12 hours, compared with less than 3 hours for albuterol. Unlike formoterol, however, salmeterol has a somewhat delayed onset of action (see Figure 6.14). These agents are not recommended as monotherapy but are highly efficacious when combined with a corticosteroid. Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications. Inhaled β2-receptor agonists should not be used in excess. Death has been reported in overuse of these medications. V. INDIRECT-ACTING ADRENERGIC AGONISTS Indirect-acting adrenergic agonists cause norepinephrine release from presynaptic terminals or inhibit the uptake of nor-epinephrine (see Figure 6.8). They potentiate the effects of norepinephrine produced endogenously, but these agents do not directly affect postsynaptic receptors. A. Amphetamine The marked central stimulatory action of amphetamine [am-FET-ameen] is often mistaken by drug abusers as its only action. However, the drug can also increase blood pressure significantly by α1-agonist action on the vasculature as well as β-stimulatory effects on the heart. Its peripheral actions are mediated primarily through the blockade of norepinephrine uptake and cellular release of stored catecholamines. Thus, amphetamine is an indirect-acting adrenergic drug. The actions and uses of amphetamine are discussed under stimulants of the CNS (see p. 127). The CNS stimulant effects of amphetamine and its derivatives have led to their use for treating hyperactivity in children, narcolepsy, and appetite control. Its use in pregnancy should be avoided because of adverse effects on the development of the fetus. Dextroamphetamine is the dextrorotatory isomer of amphetamine. Methamphetamine, methylphenidate, and dexmethylphenidate are other drugs closely related in structure or that have effects similar to amphetamine. They are used for similar indications as amphetamine. B. Tyramine Tyramine [TIE-ra-meen] is not a clinically useful drug, but it is important because it is found in fermented foods, such as aged cheese and Chianti wine (see p. 158). It is a normal byproduct of tyrosine metabolism. Normally, it is oxidized by MAO in the gastrointestinal tract, but, if the patient is taking MAOIs, it can precipitate serious vasopressor epi- VI. Mixed-Action Adrenergic Agonists 83 sodes. Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors. C. Cocaine Cocaine [koe-KANE] is unique among local anesthetics in having the ability to block the Na+/K+-activated ATPase (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. Therefore, small doses of the catecholamines produce greatly magnified effects in an individual taking cocaine as compared to those in one who is not. In addition, the duration of action of epinephrine and norepinephrine is increased. Like amphetamines, it can increase blood pressure by α1-agonist actions and β-stimulatory effects. [Note: Cocaine as a CNS stimulant and drug of abuse is discussed on pp. 120–121.] Arrhythmias VI. MIXED-ACTION ADRENERGIC AGONISTS Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane (see Figure 6.8). Headache A. Ephedrine and pseudoephedrine Ephedrine [eh-FED-rin] and pseudoephedrine [soo-doe-eh-FED-rin] are plant alkaloids that are now made synthetically. These drugs are mixedaction adrenergic agents. They not only release stored norepinephrine from nerve endings (see Figure 6.8) but also directly stimulate both α and β receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO. Therefore, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS, but pseudoephedrine has fewer CNS effects. Ephedrine is eliminated largely unchanged in urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Ephedrine produces bronchodilation, but it is less potent than epinephrine or isoproterenol in this regard and produces its action more slowly. It has been used in the past for asthma to prevent attacks (rather than to treat the acute attack), although most experts recommend other medications (See Chapter 27). Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. Pseudoephedrine is primarily used orally to treat nasal and sinus congestion and congestion of the eustachian tubes. [Note: The clinical use of ephedrine is declining because of the availability of better, more potent agents that cause fewer adverse effects. Ephedrine-containing herbal supplements (mainly ephedra-containing products) were banned by the U.S. Food and Drug Administration in April 2004 because of life-threatening cardiovascular reactions. Pseudoephedrine has been illegally converted to methamphetamine. Therefore, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter in the United States. Important characteristics of the adrenergic agonists are summarized in Figures 6.15, 6.16, and 6.17. Hyperactivity Insomnia Nausea Tremors Figure 6.15 Some adverse effects observed with adrenergic agonists. 84 6. Adrenergic Agonists TISSUE RECEPTOR TYPE ACTION OPPOSING ACTIONS Heart • Sinus and AV • Conduction pathway • Myofibrils β1 Automaticity Cholinergic receptors β1 Conduction velocity, automaticity Cholinergic receptors β1 Contractility, automaticity Vascular smooth muscle β2 Vasodilation α-Adrenergic receptors Bronchial smooth muscle β2 Bronchodilation Cholinergic receptors Kidneys β1 Renin release α1-Adrenergic receptors Liver β2, α1 Glycogenolysis and gluconeogensis Adipose tissue β3 Lipolysis Skeletal muscle β2 Increased contractility Potassium uptake; glycogenolysis Dilates arteries to skeletal muscle Tremor Eye-ciliary muscle β2 Relaxation Cholinergic receptors GI tract β2 Motility Cholinergic receptors Gall bladder β2 Relaxation Cholinergic receptors Urinary bladder detrusor muscle β2 Relaxation Cholinergic receptors Uterus β2 Relaxation Oxytocin Figure 6.16 Summary of β-adrenergic receptors. AV = atrioventricular; GI = gastrointestinal. — α2-Adrenergic receptors — VI Mixed-Action Adrenergic Agonists 85 DRUG RECEPTOR SPECIFICITY Epinephrine α α β β THERAPEUTIC USES Acute asthma Anaphylactic shock In local anesthetics to increase duration of action CATECHOLAMINES Rapid onset of action Norepinephrine α α β Treatment of shock Isoproterenol β β As a cardiac stimulant Dopamine Dopaminergic α β Brief duration of action Treatment of congestive heart failure Raise blood pressure Not administered orally Do not penetrate the bloodbrain barrier Treatment of shock Dobutamine β Treatment of acute heart failure Oxymetazoline α As a nasal decongestant Phenylephrine α As a nasal decongestant Raise blood pressure Treatment of paroxysmal supraventricular tachycardia Methoxamine α Treatment of supraventricular tachycardia Clonidine α Treatment of hypertension Albuterol Terbutaline β Treatment of bronchospasm (short acting) Longer duration of action Salmeterol Formoterol β Treatment of bronchospasm (long acting) All can be administered orally Amphetamine α β CNS As a CNS stimulant in treatment of children with attention deficit syndrome, narcolepsy, and for appetite control Ephedrine Pseudoephedrine α β CNS As a nasal decongestant NONCATECHOLAMINES Compared to catecholamines: Figure 6.17 Summary of the therapeutic uses of adrenergic agonists. CNS = central nervous system. Raise blood pressure