Adrenergic Agonists .pdf

Pharmacology Autonomic Nervous System Adrenergic Agonists Adrenergic Agonists Content: The Adrenergic Neuron ………………………………………….… 5 Characteristics of Adrenergic Agonists ……………………………………………. 38 Direct-Acting Adrenergic Agonists ……………………………………………. 50 Indirect-Acting Adrenergic Agonists …………………………………………....

Pharmacology Autonomic Nervous System Adrenergic Agonists Adrenergic Agonists Content: The Adrenergic Neuron ………………………………………….… 5 Characteristics of Adrenergic Agonists ……………………………………………. 38 Direct-Acting Adrenergic Agonists ……………………………………………. 50 Indirect-Acting Adrenergic Agonists ………………………………………….... 101 Mixed-Action Adrenergic Agonists ……………………………………………. 107 Adrenergic Agonists Overview: The adrenergic drugs affect receptors that are stimulated by norepinephrine (noradrenaline) or epinephrine (adrenaline). These receptors are known as adrenergic receptors or adrenoceptors. Drugs that activate adrenergic receptors are termed sympathomimetics, and drugs that block activation of adrenergic receptors are termed sympatholytics. Some sympathomimetics directly activate adrenergic receptors (direct-acting agonists), while others act indirectly by enhancing release or blocking reuptake of norepinephrine (indirect-acting agonists). Adrenergic Agonists Overview: Pharmacologically, the most important ones are: Noradrenaline (norepinephrine), a transmitter released by sympathetic nerve terminals. Adrenaline (epinephrine), a hormone secreted by the adrenal medulla. Dopamine, the metabolic precursor of noradrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system. Isoprenaline (isoproterenol), a synthetic derivative of noradrenaline, not present in the body. Adrenergic Agonists Figure 1 – Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines. The Adrenergic Neuron The Adrenergic Neuron Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. Adrenergic drugs act on adrenergic receptors, located either presynaptically on the neuron or postsynaptically on the effector organ (Figure 2). The Adrenergic Neuron Figure 2 – Sites of actions of adrenergic agonists. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: Neurotransmission in adrenergic neurons closely resembles that described for the cholinergic neurons, except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission involves the following steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure 3). The Adrenergic Neuron Figure 3 – Synthesis and release of norepinephrine from the adrenergic neuron. DOPA = dihydroxyphenylalanine; MAO = monoamine oxidase; NE = norepinephrine; SNRI = serotonin–norepinephrine reuptake inhibitor. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 1. Synthesis of Norepinephrine: Tyrosine is transported by a carrier into the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme aromatic L-amino acid decarboxylase to form dopamine in the presynaptic neuron. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 2. Storage of Norepinephrine in Vesicles: Dopamine is then transported into synaptic vesicles by an amine transporter system. This carrier system is blocked by reserpine. Next, dopamine is hydroxylated to form norepinephrine by the enzyme dopamine βhydroxylase. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 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 synaptic vesicles to fuse with the cell membrane and to undergo exocytosis and expel their contents into the synapse. Drugs such as guanethidine block this release. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 4. Binding to Receptors: Norepinephrine released from the synaptic vesicles diffuses into the synaptic space and binds to postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. Binding of norepinephrine to 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. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 4. Binding to Receptors: Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second messenger system and the phosphatidylinositol cycle to transduce the signal into an effect. Norepinephrine also binds to presynaptic receptors (mainly α2 subtype) that modulate the release of the neurotransmitter. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 5. Removal of Norepinephrine: Norepinephrine may: 1. Diffuse out of the synaptic space and enter the systemic circulation. 2. Be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space, or undergo reuptake back into the neuron. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 5. Removal of Norepinephrine: The reuptake by the neuronal membrane involves a sodium–chloride (Na + /Cl−)– dependent norepinephrine transporter that can be inhibited by tricyclic antidepressants (TCAs), such as imipramine; by serotonin–norepinephrine reuptake inhibitors such as duloxetine; or by cocaine. Reuptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of its effects. The Adrenergic Neuron A. Neurotransmission at Adrenergic Neurons: 6. Potential Fates of Recaptured Norepinephrine: Once norepinephrine reenters the adrenergic neuron, it may be taken up into synaptic 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 Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two main families of receptors, designated α and β, are classified based on response to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. Both the α and β receptor types have a number of specific receptor subtypes. Alterations in the primary structure of the receptors influence their affinity for various agents. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: 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 4). For α receptors, the rank order of potency and affinity is epinephrine ≥ norepinephrine >> isoproterenol. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: The α-adrenoceptors are divided into two subtypes, α1 and α2 , based on their affinities for α agonists and antagonists. For example, α1 receptors have a higher affinity for phenylephrine than α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: Figure 4 – Types of adrenergic receptors. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: 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, ultimately resulting in the generation of second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 initiates the release of 𝐶𝑎+2 from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: b. α2 Receptors: These receptors are located primarily on sympathetic presynaptic nerve endings and control the release of norepinephrine. When a sympathetic adrenergic nerve is stimulated, a portion of the released norepinephrine “circles back” and reacts with α2 receptors on the presynaptic membrane (Figure 5). Stimulation of α2 receptors causes feedback inhibition and inhibits further release of norepinephrine from the stimulated adrenergic neuron. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: b. α2 Receptors: This inhibitory action serves as a local mechanism for modulating norepinephrine output when there is high sympathetic activity. Note: In this instance, by inhibiting further output of norepinephrine from the adrenergic neuron, these receptors are acting as inhibitory autoreceptors. α2 Receptors are also found on presynaptic parasympathetic neurons. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: b. α2 Receptors: 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 mechanism to modulate 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 by a fall in the levels of intracellular cAMP. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): Figure 5 – Second messengers mediate the effects of α receptors. DAG = diacylglycerol; IP3 = inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: 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. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 1. α-Adrenoceptors: c. Further Subdivisions: For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostatic hyperplasia. The drug has fewer cardiovascular side effects because it targets α1A subtype receptors found primarily in the urinary tract and prostate gland and does not affect the α1B subtype found in the blood vessels. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 2. β-Adrenoceptors: Responses of β receptors differ from those of α receptors and are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine (Figure 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. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 2. β-Adrenoceptors: 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 effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three types of β receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 3. Distribution of Receptors: Adrenergically innervated organs and tissues usually have a predominant type of receptor. For example, tissues such as the vasculature of skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. Other tissues may have one type of receptor almost exclusively. For example, the heart contains predominantly β1 receptors. The Adrenergic Neuron The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 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 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. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 4. Characteristic Responses Mediated by Adrenoceptors: Stimulation of β1 receptors characteristically causes cardiac stimulation (increase in heart rate and contractility), whereas stimulation of β2 receptors produces vasodilation (in skeletal muscle vascular beds) and smooth muscle relaxation. β3 Receptors are involved in lipolysis (along with β1), and also have effects on the detrusor muscle of the bladder. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): Figure 6 – Major effects mediated by α- and β-adrenoceptors. The Adrenergic Neuron B. Adrenergic Receptors (Adrenoceptors): 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 by decreased synthesis. 3. Inability to couple to G-protein, because the receptor has been phosphorylated on the cytoplasmic side. Characteristics of Adrenergic Agonists Characteristics of Adrenergic Agonists Most adrenergic drugs are derivatives of β-phenylethylamine (Figure 7). Substitutions on the benzene ring or on the ethylamine side chains produce a 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. Characteristics of Adrenergic Agonists Figure 7 – Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in yellow. Characteristics of Adrenergic Agonists A. Catecholamines: 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: 1. High Potency: Catecholamines show the highest potency in directly activating α or β receptors. Characteristics of Adrenergic Agonists A. Catecholamines: 2. Rapid Inactivation: Catecholamines are metabolized by COMT postsynaptically and by MAO intraneuronally, by COMT and MAO in the gut wall, and by MAO in the liver. Thus, catecholamines have only a brief period of action when given parenterally, and they are inactivated (ineffective) when administered orally. 3. Poor Penetration Into The CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most catecholamines have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. Characteristics of Adrenergic Agonists B. Noncatecholamines: Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine (Figure 7). These agents are poor substrates for MAO (an important route of metabolism) and, thus, show a prolonged duration of action. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. Characteristics of Adrenergic Agonists C. Substitutions on the Amine Nitrogen: The nature of the substituent on the amine nitrogen is important in determining 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 (Figure 7), is a strong β agonist with little α activity (Figure 4). Characteristics of Adrenergic Agonists D. Mechanism of Action of Adrenergic Agonists: 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 epinephrine from the adrenal medulla (Figure 8). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, dopamine, and phenylephrine. Characteristics of Adrenergic Agonists D. Mechanism of Action of Adrenergic Agonists: Figure 8 – Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists. Characteristics of Adrenergic Agonists D. Mechanism of Action of Adrenergic Agonists: 2. Indirect-Acting Agonists: These agents may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (Figure 8). The norepinephrine then traverses the synapse and binds to α or β receptors. Examples of reuptake inhibitors and agents that cause norepinephrine release include cocaine and amphetamine, respectively. Characteristics of Adrenergic Agonists D. Mechanism of Action of Adrenergic Agonists: 3. Mixed-Action Agonists: Ephedrine and its stereoisomer, pseudoephedrine, both stimulate adrenoceptors directly and enhance release of norepinephrine from the adrenergic neuron (Figure 8). Characteristics of Adrenergic Agonists D. Mechanism of Action of Adrenergic Agonists: Direct-Acting Adrenergic Agonists Direct-Acting Adrenergic Agonists Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron. As a group, these agents are widely used in clinical practice. Direct-Acting Adrenergic Agonists A. Epinephrine: Epinephrine is one of the four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy. The first three are naturally occurring neurotransmitters, and the latter is a synthetic compound. 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% epinephrine and 20% norepinephrine directly into the circulation. Direct-Acting Adrenergic Agonists A. Epinephrine: 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 the strongest. Direct-Acting Adrenergic Agonists A. Epinephrine: 1. Actions: a. Cardiovascular: The major actions of epinephrine are on the cardiovascular system. Epinephrine strengthens the contractility of the myocardium (positive inotrope: β1 action) and increases its rate of contraction (positive chronotrope: β1 action). Therefore, cardiac output increases. These effects increase 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. Direct-Acting Adrenergic Agonists A. Epinephrine: 1. Actions: a. Cardiovascular: 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). These combined effects result in a decrease in renal blood flow. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure due to β2 receptor–mediated vasodilation in the skeletal muscle vascular bed (Figure 9). Direct-Acting Adrenergic Agonists A. Epinephrine: Figure 9 – Cardiovascular effects of intravenous infusion of low doses of epinephrine. Direct-Acting Adrenergic Agonists A. Epinephrine: 1. Actions: b. Respiratory: Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action). It also inhibits the release of allergy mediators such as histamine from mast cells. Direct-Acting Adrenergic Agonists A. Epinephrine: 1. Actions: 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). Direct-Acting Adrenergic Agonists A. Epinephrine: 1. Actions: d. Lipolysis: Epinephrine initiates lipolysis through agonist activity on the β receptors of adipose tissue. Increased levels of cAMP stimulate a hormone-sensitive lipase, which hydrolyzes triglycerides to free fatty acids and glycerol. Direct-Acting Adrenergic Agonists A. Epinephrine: 2. Therapeutic Uses: a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function. Thus, in treatment of anaphylactic shock, epinephrine is the drug of choice and can be lifesaving in this setting. Within a few minutes after subcutaneous administration, respiratory function greatly improves. Direct-Acting Adrenergic Agonists A. Epinephrine: 2. Therapeutic Uses: b. Anaphylactic Shock: Epinephrine is the drug of choice for the treatment of type I hypersensitivity reactions (including anaphylaxis) in response to allergens. c. Cardiac Arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest. Direct-Acting Adrenergic Agonists A. Epinephrine: 2. Therapeutic Uses: d. Local Anesthesia: Local anesthetic solutions may contain low concentrations (for example, 1:100,000 parts) of epinephrine. Epinephrine greatly increases the duration of local anesthesia by producing vasoconstriction at the site of injection. Epinephrine also reduces systemic absorption of the local anesthetic and promotes local hemostasis. Direct-Acting Adrenergic Agonists A. Epinephrine: 2. Therapeutic Uses: e. Intraocular Surgery: Epinephrine is used in the induction and maintenance of mydriasis during intraocular surgery. Direct-Acting Adrenergic Agonists A. Epinephrine: 3. Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). The preferred route for anaphylaxis in the outpatient setting is intramuscular (anterior thigh) due to rapid absorption. In emergencies, epinephrine is given intravenously (IV) for the most rapid onset of action. Direct-Acting Adrenergic Agonists A. Epinephrine: 3. Pharmacokinetics: Direct-Acting Adrenergic Agonists A. Epinephrine: 3. Pharmacokinetics: It may also be given subcutaneously, by endotracheal tube, or by inhalation (Figure 10). It is rapidly metabolized by MAO and COMT, and the metabolites metanephrine and vanillylmandelic acid are excreted in urine. Direct-Acting Adrenergic Agonists A. Epinephrine: Figure 10 – Pharmacokinetics of epinephrine. CNS = central nervous system. Direct-Acting Adrenergic Agonists A. Epinephrine: 4. Adverse Effects: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor. It can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. Epinephrine can also induce pulmonary edema due to increased afterload caused by vasoconstrictive properties of the drug. Patients with hyperthyroidism may have an increased production of adrenergic receptors in the vasculature, leading to an enhanced response to epinephrine, and the dose must be reduced in these individuals. Direct-Acting Adrenergic Agonists A. Epinephrine: 4. Adverse Effects: Inhalation anesthetics also sensitize the heart to the effects of epinephrine, which may lead to tachycardia. Epinephrine increases the release of endogenous stores of glucose. In diabetic patients, dosages of insulin may have to be increased. Nonselective β-blockers prevent vasodilatory effects of epinephrine on β2 receptors, leaving α receptor stimulation unopposed. This may lead to increased peripheral resistance and increased blood pressure. Direct-Acting Adrenergic Agonists B. Norepinephrine: Because norepinephrine is the neurotransmitter in the adrenergic neurons, it should, theoretically, stimulate all types of adrenergic receptors. However, when administered in therapeutic doses, the α-adrenergic receptor is most affected. 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 11). Direct-Acting Adrenergic Agonists B. Norepinephrine: 1. Cardiovascular Actions: a. Vasoconstriction: Note: Norepinephrine causes greater vasoconstriction than epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of bronchospasm or anaphylaxis. Direct-Acting Adrenergic Agonists B. Norepinephrine: Figure 11 – Cardiovascular effects of intravenous infusion of norepinephrine. Direct-Acting Adrenergic Agonists B. Norepinephrine: 1. Cardiovascular Actions: b. Baroreceptor Reflex: Norepinephrine increases blood pressure, and this stimulates the baroreceptors, inducing a rise in vagal activity. The increased vagal activity produces a reflex bradycardia, which 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 (Figure 11). When atropine, which blocks the transmission of vagal effects, is given before norepinephrine, stimulation of the heart by norepinephrine is evident as tachycardia. Direct-Acting Adrenergic Agonists B. Norepinephrine: 1. Cardiovascular Actions: b. Baroreceptor Reflex: Direct-Acting Adrenergic Agonists B. Norepinephrine: 2. Therapeutic Uses: Norepinephrine is used to treat shock (for example, septic shock), because it increases vascular resistance and, therefore, increases blood pressure. It has no other clinically significant uses. 3. Pharmacokinetics: Norepinephrine is given IV for rapid onset of action. The duration of action is 1 to 2 minutes, following the end of the infusion. It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine. Direct-Acting Adrenergic Agonists B. Norepinephrine: 4. Adverse Effects : These are similar to epinephrine. In addition, norepinephrine is a potent vasoconstrictor and may cause blanching and sloughing of skin along an injected vein. If extravasation (leakage of drug from the vessel into tissues surrounding the injection site) occurs, it can cause tissue necrosis. It should not be administered in peripheral veins, if possible. Impaired circulation from norepinephrine may be treated with the α receptor antagonist phentolamine. Alternatives to phentolamine include intradermal terbutaline and topical nitroglycerin. Direct-Acting Adrenergic Agonists C. Isoproterenol: Isoproterenol is a direct-acting synthetic catecholamine that stimulates both β1 - and β2 - adrenergic receptors. Its nonselectivity is a disadvantage and the reason why it is rarely used therapeutically. Its action on α receptors is insignificant. Isoproterenol produces intense stimulation of the heart (β1 effect), increasing heart rate, contractility, and cardiac output (Figure 12). It is as active as epinephrine in this action. Isoproterenol also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. Direct-Acting Adrenergic Agonists C. Isoproterenol: Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures (Figure 12). Isoproterenol is also a potent bronchodilator (β2 effect). The adverse effects of isoproterenol are similar to the β receptor– related side effects of epinephrine. Direct-Acting Adrenergic Agonists C. Isoproterenol: Figure 12 – Cardiovascular effects of intravenous infusion of isoproterenol. Direct-Acting Adrenergic Agonists D. Dopamine: Dopamine, 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 causes 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. Direct-Acting Adrenergic Agonists D. Dopamine: 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 positive inotropic and chronotropic effects (Figure 13). At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction. Direct-Acting Adrenergic Agonists D. Dopamine: Figure 13 – Clinically important actions of isoproterenol and dopamine. Direct-Acting Adrenergic Agonists D. Dopamine: 1. Actions: b. Renal and Visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera (Figure 13). These receptors are not affected by α- or β-blocking drugs, and in the past, low-dose (“renal-dose”) dopamine was often used in the prevention or treatment of acute renal failure. However, more recent data suggest there is limited clinical utility in the renal protective effects of dopamine. Direct-Acting Adrenergic Agonists D. Dopamine: 2. Therapeutic Uses: Dopamine can be used for cardiogenic and septic shock and is given by continuous infusion. It raises 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. 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 diuresis. Direct-Acting Adrenergic Agonists D. Dopamine: 2. Therapeutic Uses: By contrast, norepinephrine can diminish blood supply to the kidney and may reduce renal function. Dopamine is also used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments. Direct-Acting Adrenergic Agonists D. Dopamine: 3. Adverse Effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized by MAO or COMT, and its adverse effects (nausea, hypertension, and arrhythmias) are, therefore, short lived. Direct-Acting Adrenergic Agonists E. Fenoldopam: Fenoldopam is an agonist of peripheral dopamine D1 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 occur with this agent. Direct-Acting Adrenergic Agonists F. Dobutamine: Dobutamine is a synthetic, direct-acting catecholamine that is primarily a β1 receptor agonist with minor β2 and α1 effects. It increases heart rate and cardiac output with few vascular effects. Dobutamine is used to increase cardiac output in acute heart failure, as well as for inotropic support after cardiac surgery. The drug increases cardiac output and does not elevate oxygen demands of the myocardium as much as other sympathomimetic drugs. Direct-Acting Adrenergic Agonists F. Dobutamine: Dobutamine should be used with caution in atrial fibrillation, because it increases atrioventricular (AV) conduction. Other adverse effects are similar to epinephrine. Tolerance may develop with prolonged use. Direct-Acting Adrenergic Agonists G. Oxymetazoline: Oxymetazoline is a direct-acting synthetic adrenergic agonist that stimulates both a1and a2-adrenergic receptors. Oxymetazoline is found in many over-the-counter nasal spray decongestants, as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, and contact lenses. Oxymetazoline directly stimulates a receptors on blood vessels supplying the nasal mucosa and conjunctiva, thereby producing vasoconstriction and decreasing congestion. It is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. Direct-Acting Adrenergic Agonists G. Oxymetazoline: Local irritation and sneezing may occur with intranasal administration. Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur. Direct-Acting Adrenergic Agonists H. Phenylephrine: Phenylephrine is a direct-acting, synthetic adrenergic drug that binds primarily to α1 receptors. 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, making it useful in the treatment of paroxysmal supraventricular tachycardia. The drug is used to treat hypotension in hospitalized or surgical patients (especially those with a rapid heart rate). Direct-Acting Adrenergic Agonists H. Phenylephrine: Large doses can cause hypertensive headache and cardiac irregularities. Phenylephrine acts as a nasal decongestant when applied topically or taken orally. Although data suggest it may not be as effective, phenylephrine has replaced pseudoephedrine in many oral decongestants, since pseudoephedrine has been misused to make methamphetamine. Phenylephrine is also used in ophthalmic solutions for mydriasis. Direct-Acting Adrenergic Agonists I. Midodrine: Midodrine, a prodrug, is metabolized to the pharmacologically active desglymidodrine. It is a selective α1 agonist, which acts in the periphery to increase arterial and venous tone. Midodrine is indicated for the treatment of orthostatic hypotension. The drug should be given three times daily, with doses at 3- or 4-hour intervals. To avoid supine hypertension, doses within 4 hours of bedtime are not recommended. Direct-Acting Adrenergic Agonists J. Clonidine: Clonidine is an α2 agonist used for the treatment of hypertension. It can also be used to minimize symptoms of withdrawal from opiates, tobacco smoking, and benzodiazepines. Both clonidine and the α2 agonist guanfacine may be used in the management of attention deficit hyperactivity disorder. Clonidine acts centrally on presynaptic α2 receptors to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. Direct-Acting Adrenergic Agonists J. Clonidine: The most common side effects of clonidine are lethargy, sedation, constipation, and xerostomia. Abrupt discontinuation must be avoided to prevent rebound hypertension. Direct-Acting Adrenergic Agonists K. Albuterol, Metaproterenol, and Terbutaline: Albuterol, metaproterenol, and terbutaline are short-acting β2 agonists (SABAs) used primarily as bronchodilators and administered by a metered-dose inhaler (Figure 14). Albuterol is the SABA of choice for the management of acute asthma symptoms, because it is more selective for β2 receptors than metaproterenol. Inhaled terbutaline is no longer available in the United States, but is still used in other countries. Injectable terbutaline is used off-label as a uterine relaxant to suppress premature labor, and use for this indication should not exceed 72 hours. One of the most common side effects of these agents is tremor, but patients tend to develop tolerance to this effect. Direct-Acting Adrenergic Agonists K. Albuterol, Metaproterenol, and Terbutaline: Other side effects include restlessness, apprehension, and anxiety. When these drugs are administered orally, they may cause tachycardia or arrhythmia (due to β1 receptor activation), especially in patients with underlying cardiac disease. Monoamine oxidase inhibitors (MAOIs) also increase the risk of adverse cardiovascular effects, and concomitant use should be avoided. Direct-Acting Adrenergic Agonists K. Albuterol, Metaproterenol, and Terbutaline: Figure 14 – Onset and duration of bronchodilation effects of inhaled adrenergic agonists. Direct-Acting Adrenergic Agonists L. Salmeterol, Formoterol, and Indacaterol: Salmeterol, formoterol, arformoterol (the [R,R]-enantiomer of formoterol), and indacaterol are long-acting β2 selective agonists (LABAs) used for the management of respiratory disorders such as asthma and chronic obstructive pulmonary disease. 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 (Figure 14). Direct-Acting Adrenergic Agonists L. Salmeterol, Formoterol, and Indacaterol: LABAs are not recommended as monotherapy for the treatment of asthma, because they have been shown to increase the risk of asthma-related deaths; however, these agents are highly efficacious when combined with an asthma controller medication such as an inhaled corticosteroid. Direct-Acting Adrenergic Agonists M. Mirabegron: Mirabegron is a β3 agonist that relaxes the detrusor smooth muscle and increases bladder capacity. It is used for patients with overactive bladder. Mirabegron may increase blood pressure and should not be used in patients with uncontrolled hypertension. It increases levels of digoxin and inhibits the CYP2D6 isozyme, which may enhance the effects of other medications metabolized by this pathway (for example, metoprolol). Indirect-Acting Adrenergic Agonists Indirect-Acting Adrenergic Agonists Indirect-acting adrenergic agonists cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine (Figure 8). They potentiate the effects of epinephrine or norepinephrine produced endogenously, but do not directly affect postsynaptic receptors. Indirect-Acting Adrenergic Agonists A. Amphetamine: The marked central stimulatory action of amphetamine 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 β1 stimulatory effects on the heart. Its actions are mediated primarily through an increase in nonvesicular release of catecholamines such as dopamine and norepinephrine from nerve terminals. Thus, amphetamine is an indirect-acting adrenergic drug. Indirect-Acting Adrenergic Agonists B. Tyramine: Tyramine is not a clinically useful drug, but it is important because it is found in fermented foods, such as aged cheese and Chianti wine. It is a normal by-product 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 episodes. Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors. Indirect-Acting Adrenergic Agonists C. Cocaine: Cocaine is unique among local anesthetics in having the ability to block the sodium– chloride (Na + /Cl − )–dependent norepinephrine transporter required for cellular uptake of norepinephrine into the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhanced 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. Indirect-Acting Adrenergic Agonists C. Cocaine: 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. Mixed-Action Adrenergic Agonists Mixed-Action Adrenergic Agonists Ephedrine and pseudoephedrine are mixed-action adrenergic agents. They not only enhance release of stored norepinephrine from nerve endings (Figure 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 catecholamines and are poor substrates for COMT and MAO. Therefore, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption after oral administration and penetrate 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. Mixed-Action Adrenergic Agonists Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation and it is indicated in anesthesia-induced hypotension. Ephedrine produces bronchodilation, but it is less potent and slower acting than epinephrine or isoproterenol. It was previously used to prevent asthma attacks but has been replaced by more effective medications. Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. Mixed-Action Adrenergic Agonists 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 ephedracontaining products) have been banned by the U.S. Food and Drug Administration because of life-threatening cardiovascular reactions. Oral pseudoephedrine is primarily used to treat nasal and sinus congestion. Pseudoephedrine has been illegally used to produce methamphetamine. Therefore, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter in the United States. Mixed-Action Adrenergic Agonists Figure 15 – Some adverse effects observed with adrenergic agonists.