Pharmacology_Katzung

Pharmacology_Katzung. B. Ophthalmologic Disorders Accurate measurement of refractive error in uncooperative patients, eg, young children, requires ciliary paralysis. Also, mydriasis greatly facilitates ophthalmoscopic examination of the retina. Therefore, antimuscarinic agents, administered topically as eye drops or ointment, are very helpful in doing a complete examination. For adults and older children, the shorter-acting drugs are preferred (Table 8–2). For younger children, the greater efficacy of atropine is sometimes necessary, but the possibility of antimuscarinic poisoning is correspondingly increased. Drug loss from the conjunctival sac via the nasolacrimal duct into the nasopharynx can be diminished by the use of the ointment form rather than drops. Formerly, ophthalmic antimuscarinic drugs were selected from the tertiary amine subgroup to ensure good penetration after TABLE 8–2 Antimuscarinic drugs used in ophthalmology.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 8–2 Antimuscarinic drugs used in ophthalmology. conjunctival application. However, glycopyrrolate, a quaternary agent, is as rapid in onset and as long-lasting as atropine. Antimuscarinic drugs should never be used for mydriasis unless cycloplegia or prolonged action is required. Alpha-adrenoceptor stimulant drugs, eg, phenylephrine, produce a short-lasting mydriasis that is usually sufficient for funduscopic examination (see Chapter 9). A second ophthalmologic use is to prevent synechia (adhesion) formation in uveitis and iritis. The longer-lasting preparations, especially homatropine, are valuable for this indication. C. Respiratory Disorders


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Disorders The use of atropine became part of routine preoperative medication when anesthetics such as ether were used, because these irritant anesthetics markedly increased airway secretions and were associated with frequent episodes of laryngospasm. Preanesthetic injection of atropine or scopolamine could prevent these hazardous effects. Scopolamine also produces significant amnesia for the events associated with surgery and obstetric delivery, an adverse effect that was considered desirable. On the other hand, urinary retention and intestinal hypomotility following surgery were often exacerbated by antimuscarinic drugs. Newer inhalational anesthetics are far less irritating to the airways.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with COPD, a condition that occurs more frequently in older patients, particularly chronic smokers, benefit from bronchodilators, especially antimuscarinic agents. Ipratropium, tiotropium (see Figure 8–3), aclidinium, and umeclidinium, synthetic analogs of atropine, are used as inhalational drugs in COPD either alone or in combination with a long-acting β-adrenoceptor agonist. The aerosol route of administration has the advantage of maximal concentration at the bronchial target tissue with reduced systemic effects. This application is discussed in greater detail in Chapter 20. Tiotropium (t1/2 25 hours) and umeclidinium (t1/2 11 hours) have a longer bronchodilator action than ipratropium (t1/2 2 hours) and can be given once daily because they dissociate slowly from M3 receptors. Aclidinium (t1/2 6 hours) is administered twice daily. Glycopyrrolate is now available in inhalational form for twice daily treatment of COPD. Tiotropium reduces the incidence of COPD exacerbations


Pharmacology_Katzung

Pharmacology_Katzung. Aclidinium (t1/2 6 hours) is administered twice daily. Glycopyrrolate is now available in inhalational form for twice daily treatment of COPD. Tiotropium reduces the incidence of COPD exacerbations and is a useful adjunct in pulmonary rehabilitation to increase exercise tolerance. The hyperactive neural bronchoconstrictor reflex present in most individuals with asthma is mediated by the vagus, acting on muscarinic receptors on bronchial smooth muscle cells. Ipratropium and tiotropium are also used as inhalational drugs in asthma.


Pharmacology_Katzung

Pharmacology_Katzung. D. Cardiovascular Disorders Marked reflex vagal discharge sometimes accompanies the pain of myocardial infarction (eg, vasovagal attack) and may depress sinoatrial or atrioventricular node function sufficiently to impair cardiac output. Parenteral atropine or a similar antimuscarinic drug is appropriate therapy in this situation. Rare individuals without other detectable cardiac disease have hyperactive carotid sinus reflexes and may experience faintness or even syncope as a result of vagal discharge in response to pressure on the neck, eg, from a tight collar. Such individuals may benefit from the judicious use of atropine or a related antimuscarinic agent.


Pharmacology_Katzung

Pharmacology_Katzung. Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas’ disease caused by the protozoan Trypanosoma cruzi. Patients with Graves’ disease (hyperthyroidism) also have such autoantibodies that may facilitate the development of atrial fibrillation. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart diseases is unknown, these antibodies have provided clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2) and they favor the formation


Pharmacology_Katzung

Pharmacology_Katzung. have provided clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2) and they favor the formation of receptor dimers.


Pharmacology_Katzung

Pharmacology_Katzung. E. Gastrointestinal Disorders Antimuscarinic agents were used for peptic ulcer disease in the USA but are now obsolete for this indication (see Chapter 62). Antimuscarinic agents can provide some relief in the treatment of common traveler’s diarrhea and other mild or self-limited conditions of hypermotility. They are often combined with an opioid antidiarrheal drug, an extremely effective therapy. In this combination, however, the very low dosage of the antimuscarinic drug functions primarily to discourage abuse of the opioid agent. The classic combination of atropine with diphenoxylate, a nonanalgesic congener of meperidine, is available under many names (eg, Lomotil) in both tablet and liquid form (see Chapter 62). F. Urinary Disorders


Pharmacology_Katzung

Pharmacology_Katzung. F. Urinary Disorders Atropine and other antimuscarinic drugs have been used to provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders (Table 8–3). However, specific antimicrobial therapy is essential in bacterial cystitis. In the human urinary bladder, M2 and M3 receptors are expressed predominantly with the M3 subtype mediating direct activation of contraction. As in intestinal smooth muscle, the M2 subtype appears to act indirectly by inhibiting relaxation by norepinephrine and epinephrine.


Pharmacology_Katzung

Pharmacology_Katzung. Receptors for acetylcholine on the urothelium (the epithelial lining of the urinary tract) and on afferent nerves as well as the detrusor muscle provide a broad basis for the action of antimuscarinic drugs in the treatment of overactive bladder. Oxybutynin, which is somewhat selective for M3 receptors, is used to relieve bladder spasm after urologic surgery, eg, prostatectomy. It is also valuable in reducing involuntary voiding in patients with neurologic disease, eg, children with meningomyelocele. Oral oxybutynin or instillation of the drug by catheter into the bladder in such patients appears to improve bladder capacity and continence and to reduce infection and renal damage. Transdermally applied oxybutynin or its oral extended-release formulation reduces the need for multiple daily doses. Trospium, a nonselective TABLE 8–3 Antimuscarinic drugs used in gastrointestinal and genitourinary conditions. Clidinium 2.5 mg tid–qid Methscopolamine 2.5 mg qid Atropine 0.4 mg tid–qid


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 8–3 Antimuscarinic drugs used in gastrointestinal and genitourinary conditions. Clidinium 2.5 mg tid–qid Methscopolamine 2.5 mg qid Atropine 0.4 mg tid–qid Darifenacin 7.5 mg daily


Pharmacology_Katzung

Pharmacology_Katzung. Scopolamine 0.4 mg tid antagonist, has been approved and is comparable in efficacy and adverse effects to oxybutynin. Darifenacin and solifenacin are antagonists that have greater selectivity for M3 receptors than oxybutynin or trospium. Darifenacin and solifenacin have the advantage of once-daily dosing because of their long half-lives. Tolterodine and fesoterodine, M3-selective antimuscarinics, are available for use in adults with urinary incontinence. They have many of the qualities of darifenacin and solifenacin and are available in extended-release tablets. Propiverine, a newer antimuscarinic agent with efficacy comparable to other muscarinic antagonists, has been approved for urinary incontinence in Europe but not in the USA. The convenience of the newer and longer-acting drugs has not been accompanied by improvements in overall efficacy or by reductions in adverse effects such as dry mouth. Muscarinic antagonists have an adjunct role in therapy of benign prostatic hypertrophy


Pharmacology_Katzung

Pharmacology_Katzung. not been accompanied by improvements in overall efficacy or by reductions in adverse effects such as dry mouth. Muscarinic antagonists have an adjunct role in therapy of benign prostatic hypertrophy when bladder symptoms (increased urinary frequency) occur. Treatment with an α-adrenoceptor antagonist combined with a muscarinic antagonist resulted in a greater reduction in bladder storage problems and urinary frequency than treatment with an α-adrenoceptor antagonist alone.


Pharmacology_Katzung

Pharmacology_Katzung. An alternative treatment for urinary incontinence refractory to antimuscarinic drugs is intrabladder injection of botulinum toxin A. Botulinum toxin A is reported to reduce urinary incontinence for several months after a single treatment by interfering with the co-release of ATP with neuronal acetylcholine (see Figure 6–3). Blockade of the activation by ATP of purinergic receptors on sensory nerves in the urothelium may account for a large part of this effect. Botulinum toxin has been approved for use in patients who do not tolerate or are refractory to antimuscarinic drugs. Imipramine, a tricyclic antidepressant drug with strong antimuscarinic actions, has long been used to reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant CNS toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Antimuscarinic agents have also been used in urolithiasis to relieve the painful ureteral smooth muscle spasm caused by passage of the stone. However, their usefulness in this condition is debatable. G. Cholinergic Poisoning Severe cholinergic excess is a medical emergency, especially in rural communities where cholinesterase inhibitor insecticides are commonly used and in cultures where wild mushrooms are frequently eaten. The potential use of cholinesterase inhibitors as chemical warfare “nerve gases” also requires an awareness of the methods for treating acute poisoning (see Chapter 58). 1.


Pharmacology_Katzung

Pharmacology_Katzung. Antimuscarinic therapy—Both the nicotinic and the muscarinic effects of the cholinesterase inhibitors can be life-threatening. Unfortunately, there is no effective method for directly blocking the nicotinic effects of cholinesterase inhibition, because nicotinic agonists and antagonists cause blockade of transmission (see Chapter 27). To reverse the muscarinic effects, a tertiary (not quaternary) amine drug must be used (preferably atropine) to treat the CNS effects as well as the peripheral effects of the organophosphate inhibitors. Large doses of atropine may be needed to oppose the muscarinic effects of extremely potent agents like parathion and chemical warfare nerve gases: 1–2 mg of atropine sulfate may be given intravenously every 5–15 minutes until signs of effect (dry mouth, reversal of miosis) appear. The drug may have to be given many times, since the acute effects of the cholinesterase inhibitor may last 24–48 hours or longer. In this life-threatening situation, as much as


Pharmacology_Katzung

Pharmacology_Katzung. of miosis) appear. The drug may have to be given many times, since the acute effects of the cholinesterase inhibitor may last 24–48 hours or longer. In this life-threatening situation, as much as 1 g of atropine per day may be required for as long as 1 month for full control of muscarinic excess.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Cholinesterase regenerator compounds—A second class of compounds, composed of substituted oximes capable of regenerating active enzyme from the organophosphorus-cholinesterase complex, is also available to treat organophosphorus poisoning. These oxime agents include pralidoxime (PAM), diacetylmonoxime (DAM), obidoxime, and others.


Pharmacology_Katzung

Pharmacology_Katzung. Organophosphates cause phosphorylation of the serine OH group at the active site of cholinesterase. The oxime group (=NOH) has a very high affinity for the phosphorus atom, for which it competes with serine OH. These oximes can hydrolyze the phosphorylated enzyme and regenerate active enzyme from the organophosphorus-cholinesterase complex if the complex has not “aged” (see Chapter 7). Pralidoxime is the most extensively studied—in humans—of the agents shown and the only one available for clinical use in the USA. It is most effective in regenerating the cholinesterase associated with skeletal muscle neuromuscular junctions. Pralidoxime and obidoxime are ineffective in reversing the central effects of organophosphate poisoning because each has positively charged quaternary ammonium groups that prevent entry into the CNS. Diacetylmonoxime, on the other hand, crosses the blood-brain barrier and, in experimental animals, can regenerate some of the CNS cholinesterase.


Pharmacology_Katzung

Pharmacology_Katzung. Pralidoxime is administered by intravenous infusion, 1–2 g given over 15–30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58.


Pharmacology_Katzung

Pharmacology_Katzung. A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with intermediate-acting enzyme inhibitors that transiently occupy the active site to prevent binding of the much longer-acting organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess.


Pharmacology_Katzung

Pharmacology_Katzung. The use of biological scavengers has emerged as an adjunct to oximes in the reactivation of acetylcholinesterase inactivated by organophosphates. Human acetylcholinesterase, acting catalytically, increased the effectiveness of PAM in reactivating the enzyme. Butyrylcholinesterase can achieve the same effect, but it acts stoichiometrically, and thus large amounts of this bioscavenger are required. (Another use for butyrylcholinesterase is in the treatment of cocaine toxicity because butyrylcholinesterase displays cocaine hydrolase activity. The catalytic efficiency of human butyrylcholinesterase against cocaine has been increased by mutation of the enzyme such that it can prevent the effect of a lethal dose of cocaine in experimental animals.)


Pharmacology_Katzung

Pharmacology_Katzung. Mushroom poisoning has traditionally been divided into rapid-onset and delayed-onset types. The rapid-onset type is usually apparent within 30 minutes to 2 hours after ingestion of the mushrooms and can be caused by a variety of toxins. Some of these produce simple upset stomach; others can have disulfiram-like effects; some cause hallucinations; and a few mushrooms (eg, Inocybe species) can produce signs of muscarinic excess: nausea, vomiting, diarrhea, urinary urgency, sweating, salivation, and sometimes bronchoconstriction. Parenteral atropine, 1–2 mg, is effective treatment in such intoxications. Despite its name, Amanita muscaria contains not only muscarine (the alkaloid was named after the mushroom), but also numerous other alkaloids, including antimuscarinic agents, and ingestion of A muscaria often causes signs of atropine poisoning, not muscarine excess.


Pharmacology_Katzung

Pharmacology_Katzung. Delayed-onset mushroom poisoning, usually caused by Amanita phalloides, Amanita virosa, Galerina autumnalis, or Galerina marginata, manifests its first symptoms 6–12 hours after ingestion. Although the initial symptoms usually include nausea and vomiting, the major toxicity involves hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase. Atropine is of no value in this form of mushroom poisoning (see Chapter 58). H. Other Applications Hyperhidrosis (excessive sweating) is sometimes reduced by antimuscarinic agents. However, relief is incomplete at best, probably because apocrine rather than eccrine glands are usually involved.


Pharmacology_Katzung

Pharmacology_Katzung. Hyperhidrosis (excessive sweating) is sometimes reduced by antimuscarinic agents. However, relief is incomplete at best, probably because apocrine rather than eccrine glands are usually involved. Treatment with atropine or its congeners directed at one organ system almost always induces undesirable effects in other organ systems. Thus, mydriasis and cycloplegia are adverse effects when an antimuscarinic agent is used to reduce gastrointestinal secretion or motility, even though they are therapeutic effects when the drug is used in ophthalmology.


Pharmacology_Katzung

Pharmacology_Katzung. At higher concentrations, atropine causes block of all parasympathetic functions. However, atropine is a remarkably safe drug in adults. Atropine poisoning has occurred as a result of attempted suicide, but most cases are due to attempts to induce hallucinations. Poisoned individuals manifest dry mouth, mydriasis, tachycardia, hot and flushed skin, agitation, and delirium for as long as 1 week. Body temperature is frequently elevated. These effects are memorialized in the adage, “dry as a bone, blind as a bat, red as a beet, mad as a hatter.” Unfortunately, children, especially infants, are very sensitive to the hyperthermic effects of atropine. Although accidental administration of over 400 mg has been followed by recovery, deaths have followed doses as small as 2 mg. Therefore, atropine should be considered a highly dangerous drug when overdose occurs in infants or children.


Pharmacology_Katzung

Pharmacology_Katzung. Overdoses of atropine or its congeners are generally treated symptomatically (see Chapter 58). Poison control experts discourage the use of physostigmine or another cholinesterase inhibitor to reverse the effects of atropine overdose because symptomatic management is more effective and less dangerous. When physostigmine is deemed necessary, small doses are given slowly intravenously (1–4 mg in adults, 0.5–1 mg in children). Symptomatic treatment may require temperature control with cooling blankets and seizure control with diazepam.


Pharmacology_Katzung

Pharmacology_Katzung. Poisoning caused by high doses of quaternary antimuscarinic drugs is associated with all of the peripheral signs of parasympathetic blockade but few or none of the CNS effects of atropine. These more polar drugs may cause significant ganglionic blockade, however, with marked orthostatic hypotension (see below). Treatment of the antimuscarinic effects, if required, can be carried out with a quaternary cholinesterase inhibitor such as neostigmine. Control of hypotension may require the administration of a sympathomimetic drug such as phenylephrine. Recent evidence indicates that some centrally acting drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, anti-anxiety agents, antihistamines) with antimuscarinic actions impair memory and cognition in older patients. Contraindications to the use of antimuscarinic drugs are relative, not absolute. Obvious muscarinic excess, especially that caused by cholinesterase inhibitors, can always be treated with atropine.


Pharmacology_Katzung

Pharmacology_Katzung. Contraindications to the use of antimuscarinic drugs are relative, not absolute. Obvious muscarinic excess, especially that caused by cholinesterase inhibitors, can always be treated with atropine. Antimuscarinic drugs are contraindicated in patients with glaucoma, especially angle-closure glaucoma. Even systemic use of moderate doses may precipitate angle closure (and acute glaucoma) in patients with shallow anterior chambers. In elderly men, antimuscarinic drugs should always be used with caution and should be avoided in those with a history of prostatic hyperplasia. Because the antimuscarinic drugs slow gastric emptying, they may increase symptoms in patients with gastric ulcer. Nonselective antimuscarinic agents should never be used to treat acid-peptic disease (see Chapter 62).


Pharmacology_Katzung

Pharmacology_Katzung. Ganglion-blocking agents competitively block the action of acetylcholine and similar agonists at neuronal nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some members of the group also block the ion channel that is gated by the nicotinic cholinoceptor. The ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow. However, their lack of selectivity confers such a broad range of undesirable effects that they have limited clinical use.


Pharmacology_Katzung

Pharmacology_Katzung. All ganglion-blocking drugs of interest are synthetic amines. Tetraethylammonium (TEA), the first to be recognized as having this action, has a very short duration of action. Hexamethonium (“C6”) was developed and was introduced clinically as the first drug effective for management of hypertension. As shown in Figure 8–7, there is an obvious relationship between the structures of the agonist acetylcholine and the nicotinic antagonists tetraethylammonium and hexamethonium. Decamethonium, the “C10” analog of hexamethonium, is a depolarizing neuromuscular blocking agent. Mecamylamine, a secondary amine, was developed to improve the degree and extent of absorption from the gastrointestinal tract because the quaternary amine ganglion-blocking compounds were poorly and erratically absorbed after oral administration. Trimethaphan, a short-acting, polar, ganglion-blocking drug, is no longer available for clinical use.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 8–7 Some ganglion-blocking drugs. Acetylcholine is shown for reference. A. Mechanism of Action Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and nondepolarizing blockade (see Chapters 7 and 27). Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglion block. Drugs now used as ganglion-blocking drugs are classified as non-depolarizing competitive antagonists. Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine. However, hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself. B. Organ System Effects 1.


Pharmacology_Katzung

Pharmacology_Katzung. B. Organ System Effects 1. Central nervous system—Mecamylamine, unlike the quaternary amine agents and trimethaphan, crosses the blood-brain barrier and readily enters the CNS. Sedation, tremor, choreiform movements, and mental aberrations have been reported as effects of mecamylamine. 2. Eye—The ganglion-blocking drugs cause a predictable cycloplegia with loss of accommodation because the ciliary muscle receives innervation primarily from the parasympathetic nervous system. The effect on the pupil is not so easily predicted, since the iris receives both sympathetic innervation (mediating pupillary dilation) and parasympathetic innervation (mediating pupillary constriction). Ganglionic blockade often causes moderate dilation of the pupil because parasympathetic tone usually dominates this tissue. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Cardiovascular system—Blood vessels receive chiefly vasoconstrictor fibers from the sympathetic nervous system; therefore, ganglionic blockade causes a marked decrease in arteriolar and venomotor tone. The blood pressure may fall precipitously because both peripheral vascular resistance and venous return are decreased (see Figure 6–7). Hypotension is especially marked in the upright position (orthostatic or postural hypotension), because postural reflexes that normally prevent venous pooling are blocked. Cardiac effects include diminished contractility and, because the sinoatrial node is usually dominated by the parasympathetic nervous system, a moderate tachycardia. 4. Gastrointestinal tract—Secretion is reduced, although not enough to treat peptic disease effectively. Motility is profoundly inhibited, and constipation can be marked. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Gastrointestinal tract—Secretion is reduced, although not enough to treat peptic disease effectively. Motility is profoundly inhibited, and constipation can be marked. 5. Other systems—Genitourinary smooth muscle is partially dependent on autonomic innervation for normal function. Therefore, ganglionic blockade causes hesitancy in urination and may precipitate urinary retention in men with prostatic hyperplasia. Sexual function is impaired in that both erection and ejaculation may be prevented by moderate doses. Thermoregulatory sweating is reduced by the ganglion-blocking drugs. However, hyperthermia is not a problem except in very warm environments, because cutaneous vasodilation is usually sufficient to maintain a normal body temperature. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 6. Response to autonomic drugs—Patients receiving ganglion-blocking drugs are fully responsive to autonomic drugs acting on muscarinic, α-, and β-adrenoceptors because these effector cell receptors are not blocked. In fact, responses may be exaggerated or even reversed (eg, intravenously administered norepinephrine may cause tachycardia rather than bradycardia), because homeostatic reflexes, which normally moderate autonomic responses, are absent. Ganglion blocking drugs are used rarely because more selective autonomic blocking agents are available. Mecamylamine blocks central nicotinic receptors and has been advocated as a possible adjunct with the transdermal nicotine patch to reduce nicotine craving in patients attempting to quit smoking. The toxicity of the ganglion-blocking drugs is limited to the autonomic effects already described. For most patients, these effects are intolerable except for acute use.


Pharmacology_Katzung

Pharmacology_Katzung. •DicyclomineCompetitive antagonism at M3 receptors Reduces smooth muscle and secretory activity of gut Irritable bowel syndrome, minor diarrhea •Hyoscyamine: Longer duration of action OPHTHALMOLOGY •AtropineCompetitive antagonism at all M receptors URINARY •OxybutyninSlightly M3-selective muscarinic antagonist Reduces detrusor smooth muscle tone, spasms Urge incontinence; postoperative spasms Darifenacin, solifenacin, and tolterodine: Tertiary amines with somewhat greater selectivity for M3 receptors Trospium: Quaternary amine with less CNS effect Homatropine: Shorter duration of action (12–24 h) than atropine Cyclopentolate: Shorter duration of action (3–6 h) Tropicamide: Shortest duration of action (15–60 min) Retinal examination; prevention of synechiae after surgery Available in oral and parenteral forms • short t½ but action lasts up to 6 hours • Toxicity: Tachycardia, confusion, urinary retention, increased intraocular pressure • Interactions:


Pharmacology_Katzung

Pharmacology_Katzung. Available in oral and parenteral forms • short t½ but action lasts up to 6 hours • Toxicity: Tachycardia, confusion, urinary retention, increased intraocular pressure • Interactions: Used as drops • long (5–6 days) action • Toxicity: Increased intraocular pressure in closed-angle glaucoma • Interactions: With other antimuscarinics • Tiotropium, aclidinium, and umeclidinium: Longer duration of action; used once daily Oral, IV, patch formulations • Toxicity: Tachycardia, constipation, increased intraocular pressure, xerostomia • Patch: Pruritus • Interactions: With other antimuscarinics AChE, acetylcholinesterase; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; IM, intramuscular. Belladonna alkaloids, extract, Generic or tincture Clidinium Generic, Quarzan, others Cyclopentolate Generic, Cyclogyl, others Darifenacin Generic, Enablex Dicyclomine Generic, Bentyl, others Flavoxate Generic, Urispas


Pharmacology_Katzung

Pharmacology_Katzung. Clidinium Generic, Quarzan, others Cyclopentolate Generic, Cyclogyl, others Darifenacin Generic, Enablex Dicyclomine Generic, Bentyl, others Flavoxate Generic, Urispas Glycopyrrolate Generic, Robinul (systemic) Seebri Neohaler (oral inhalation) Homatropine Generic, Isopto Homatropine, others l-Hyoscyamine Anaspaz, Cystospaz-M, Levsin, others Ipratropium Generic, Atrovent Methscopolamine Generic, Pamine Oxybutynin Generic, Ditropan, Gelnique, others Propantheline Generic, Pro-Banthine, others Tolterodine Generic, Detrol Tropicamide Generic, Mydriacyl Ophthalmic, others Trospium Generic, Sanctura CHOLINESTERASE REGENERATOR Pralidoxime Generic, Protopam *Antimuscarinic drugs used in parkinsonism are listed in Chapter 28. Brodde OE et al: Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart. Basic Res Cardiol 2001;96:528.


Pharmacology_Katzung

Pharmacology_Katzung. Brodde OE et al: Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart. Basic Res Cardiol 2001;96:528. Cahill K et al: Pharmacological interventions for smoking cessation: An overview and network meta-analysis. Cochrane Database Syst Rev 2013;5:CD009329. Carrière I et al: Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population. Arch Intern Med 2009;169:1317. Casaburi R et al: Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127:809. Chapple CR et al: A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: Results of the STAR trial. Eur Urol 2005;48:464. Cohen JS et al: Dual therapy strategies for COPD: The scientific rationale for LAMA+LABA. Int J Chron Obstruct Pulmon Dis 2016;11:785.


Pharmacology_Katzung

Pharmacology_Katzung. Cohen JS et al: Dual therapy strategies for COPD: The scientific rationale for LAMA+LABA. Int J Chron Obstruct Pulmon Dis 2016;11:785. Ehlert FJ, Pak KJ, Griffin MT: Muscarinic agonists and antagonists: Effects on gastrointestinal function. In: Fryer AD et al (editors): Muscarinic Receptors. Handb Exp Pharmacol 2012;208:343. Filson CP et al: The efficacy and safety of combined therapy with α-blockers and anticholinergics for men with benign prostatic hyperplasia: A meta-analysis. J Urol 2013;190:2013. Fowler CJ, Griffiths D, de Groat WC: The neural control of micturition. Nat Rev Neurosci 2008;9:453. Kranke P et al: The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: A quantitative systematic review. Anesth Analg 2002;95:133. Kruse AC et al: Muscarinic acetylcholine receptors: Novel opportunities for drug development. Nat Rev Drug Discov 2014;13:549.


Pharmacology_Katzung

Pharmacology_Katzung. Kruse AC et al: Muscarinic acetylcholine receptors: Novel opportunities for drug development. Nat Rev Drug Discov 2014;13:549. Lawrence GW, Aoki KR, Dolly JO: Excitatory cholinergic and purinergic signaling in bladder are equally susceptible to botulinum neurotoxin A consistent with co-release of transmitters from efferent fibers. J Pharmacol Exp Ther 2010;334:1080. Marquardt K: Mushrooms, amatoxin type. In: Olson K (editor): Poisoning & Drug Overdose, 6th ed. New York: McGraw-Hill, 2012. Profita M et al: Smoke, choline acetyltransferase, muscarinic receptors, and fibroblast proliferation in chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2009;329:753. Rai BP et al: Anticholinergic drugs versus non-drug active therapies for nonneurogenic overactive bladder syndrome in adults. Cochrane Database Syst Rev 2012;12:CD003193.


Pharmacology_Katzung

Pharmacology_Katzung. Rai BP et al: Anticholinergic drugs versus non-drug active therapies for nonneurogenic overactive bladder syndrome in adults. Cochrane Database Syst Rev 2012;12:CD003193. Tauterman CS et al: Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. J Med Chem 2013;56:8746. Thai DM et al: Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 2016;335:2016. Wallukat G, Schimke I: Agonistic autoantibodies directed against G-proteincoupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 2014;36:351. Young JM et al: Mecamylamine: New therapeutic uses and toxicity/risk profile. Clin Ther 2001;23:532. Zhang L et al: A missense mutation in the CHRM2 gene is associated with familial dilated cardiomyopathy. Circ Res 2008;102:1426. Treatment of Anticholinesterase Poisoning


Pharmacology_Katzung

Pharmacology_Katzung. Zhang L et al: A missense mutation in the CHRM2 gene is associated with familial dilated cardiomyopathy. Circ Res 2008;102:1426. Treatment of Anticholinesterase Poisoning Nachon F et al: Progress in the development of enzyme-based nerve agent bioscavengers. Chem Biol Interact 2013;206:536. Thiermann H et al: Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds. Toxicol Lett 2010;197:236. Weinbroum AA: Pathophysiological and clinical aspects of combat anticholinesterase poisoning. Br Med Bull 2005;72:119.


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Pharmacology_Katzung. Weinbroum AA: Pathophysiological and clinical aspects of combat anticholinesterase poisoning. Br Med Bull 2005;72:119. JH’s symptoms are often displayed by patients following prostatectomy to relieve significant obstruction of bladder outflow. Urge incontinence can occur in patients whose pros-tatic hypertrophy caused instability of the detrusor muscle. JH should be advised that urinary incontinence and urinary frequency can diminish with time after prostatectomy as detrusor muscle instability subsides. JH can be helped by daily administration of a single tablet of extended-release tolterodine (4 mg/d) or oxybutynin (5–10 mg/d). A transder-mal patch containing oxybutynin (3.9 mg/d) is also available. Italo Biaggioni, MD, & David Robertson, MD*


Pharmacology_Katzung

Pharmacology_Katzung. A 68-year-old man presents with a complaint of light-headedness on standing that is worse after meals and in hot environments. Symptoms started about 4 years ago and have slowly progressed to the point that he is disabled. He has fainted several times but always recovers conscious-ness almost as soon as he falls. Review of symptoms reveals slight worsening of constipation, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson’s disease. Because of urinary retention, he was placed on the α1 antagonist tamsulosin, but the fainting spells got worse. Physical examination revealed a blood pres-sure of 167/84 mm Hg supine and 106/55 mm Hg standing. There was an inadequate compensatory increase in heart rate (from 84 to 88 bpm), considering the degree of ortho-static hypotension. Physical examination is otherwise unre-markable with no evidence of peripheral neuropathy or parkinsonian


Pharmacology_Katzung

Pharmacology_Katzung. in heart rate (from 84 to 88 bpm), considering the degree of ortho-static hypotension. Physical examination is otherwise unre-markable with no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for plasma norepinephrine, which is low at 98 pg/mL (normal for his age 250–400 pg/mL). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypoten-sion and diseases commonly associated with autonomic neuropathy (eg, diabetes, Parkinson’s disease). What precau-tions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?


Pharmacology_Katzung

Pharmacology_Katzung. The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regulation of blood pressure. As illustrated in the case study, the autonomic nervous system is crucial for the maintenance of blood pressure even under relatively minor situations of stress (eg, the gravitational stress of standing). The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites (see Chapter 6). Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues. In other words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter. * The authors thank Drs.Vsevolod Gurevich and Aurelio Galli for helpful comments.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs. The sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (eg, norepinephrine and epinephrine) are direct agonists; they directly interact with and activate adrenoceptors. Others are indirect agonists because their actions are dependent on their ability to enhance the actions of endogenous catecholamines by (1) inducing the release of catecholamines by displacing them from adrenergic nerve endings (eg, the mechanism of action of tyramine), (2) decreasing the clearance of catecholamines by inhibiting their neuronal reuptake (eg, the mechanism of action of cocaine and tricyclic antidepressants), or (3) preventing the enzymatic metabolism of norepinephrine (monoamine oxidase and catechol-O-methyltransferase inhibitors). Some drugs have both direct and indirect actions.


Pharmacology_Katzung

Pharmacology_Katzung. Both types of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to some or all of the characteristic effects of endogenous catecholamines. The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release.


Pharmacology_Katzung

Pharmacology_Katzung. The effects of catecholamines are mediated by cell-surface receptors. Adrenoceptors are typical G protein-coupled receptors (GPCRs; see Chapter 2). The receptor protein has an extracellular N-terminus, traverses the membrane seven times (transmembrane domains) forming three extracellular and three intracellular loops, and has an intracellular C-terminus (Figure 9–1). They are coupled to G proteins that regulate various effector proteins. Each G protein is a heterotrimer consisting of α, β, and γ subunits.


Pharmacology_Katzung

Pharmacology_Katzung. G proteins are classified on the basis of their distinctive α subunits. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase; Gi and Go, the inhibitory G proteins of adenylyl cyclase; and Gq and G11, the G proteins coupling α receptors to phospholipase C. The activation of G protein-coupled receptors by catecholamines promotes the dissociation of guanosine diphosphate (GDP) from the α subunit of the cognate G protein. Guanosine triphosphate (GTP) then binds to this G protein, and the α subunit dissociates from the β-γ unit. The activated GTP-bound α subunit then regulates the activity of its effector. Effectors of adrenoceptor-activated α subunits include adenylyl cyclase, phospholipase C, and ion channels. The α subunit is inactivated by hydrolysis of the bound GTP to GDP and phosphate, and the subsequent reassociation of the α subunit with the β-γ subunit. The β-γ subunits have additional independent effects, acting


Pharmacology_Katzung

Pharmacology_Katzung. inactivated by hydrolysis of the bound GTP to GDP and phosphate, and the subsequent reassociation of the α subunit with the β-γ subunit. The β-γ subunits have additional independent effects, acting on a variety of effectors such as ion channels and enzymes.


Pharmacology_Katzung

Pharmacology_Katzung. Adrenoreceptors were initially characterized pharmacologically by their relative affinities for agonists; α receptors have the comparative potencies epinephrine ≥ norepinephrine >> isoproterenol, and β receptors have the comparative potencies isoproterenol > epinephrine ≥ norepinephrine. The presence of subtypes of these receptors were further characterized by molecular cloning. The genes encoding these receptor subtypes are listed in Table 9–1. Alpha1 Phospholipase CGq GDP ˜°* ˛q ˛q { Activated PKCPKC DAG Ptdlns 4,5P2 +


Pharmacology_Katzung

Pharmacology_Katzung. Alpha1 Phospholipase CGq GDP ˜°* ˛q ˛q { Activated PKCPKC DAG Ptdlns 4,5P2 + FIGURE 9–1 Activation of α1 responses. Stimulation of α1 receptors by catecholamines leads to the activation of a Gq-coupling protein. The activated α subunit (αq*) of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P2). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC). GDP, guanosine diphosphate; GTP, guanosine triphosphate. See text for additional effects of α1-receptor activation. TABLE 9–1 Adrenoceptor types and subtypes.


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Pharmacology_Katzung. TABLE 9–1 Adrenoceptor types and subtypes. Likewise, the endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9–1). These receptors are particularly important in the brain (see Chapters 21, 28, and 29) and in the splanchnic and renal vasculature. Molecular cloning has identified several distinct genes encoding five receptor subtypes, two D1-like receptors (D1 and D5) and three D2-like receptors (D2, D3, and D4). Further complexity occurs because of the presence of introns within the coding region of the D2-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D4 human receptor gene. These subtypes may have importance for understanding the efficacy and adverse effects of novel anti-psychotic drugs (see Chapter 29). A. Alpha Receptors


Pharmacology_Katzung

Pharmacology_Katzung. A. Alpha Receptors Alpha1 receptors are coupled via G proteins in the Gq family to phospholipase C. This enzyme hydrolyzes polyphosphoinositides, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Table 9–1, Figure 9–1). IP3 promotes the release of sequestered Ca2+ from intracellular stores, which increases cytoplasmic free Ca2+ concentrations that activate various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell’s plasma membrane. IP3 is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG cooperates with Ca2+ in activating protein kinase C, which modulates activity of many signaling pathways. In addition, α1 receptors activate signal transduction pathways that stimulate tyrosine kinases. For example, α1 receptors have been found to activate mitogenactivated protein kinases (MAP kinases) and polyphosphoinositol3-kinase (PI-3-kinase).


Pharmacology_Katzung

Pharmacology_Katzung. Alpha2 receptors are coupled to the inhibitory regulatory protein Gi (Figure 9–2) that inhibits adenylyl cyclase activity and causes intracellular cyclic adenosine monophosphate (cAMP) levels to decrease. It is likely that not only α, but also the β-γ subunits of Gi contribute to inhibition of adenylyl cyclase. Alpha2 receptors use other signaling pathways, including regulation of ion channel activities and the activities of important enzymes involved in signal transduction. Indeed, some of the effects of α2 adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example, α2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear whether aggregation is the result of the decrease in cAMP or other mechanisms involving Gi-regulated effectors. B. Beta Receptors Activation of all three receptor subtypes (β1, β2, and β3) results in stimulation of adenylyl cyclase and increased cAMP (Table 9–1,


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 9–2 Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated αi subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMPdependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for


Pharmacology_Katzung

Pharmacology_Katzung. specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of β and α2 adrenoceptors.


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Pharmacology_Katzung. Figure 9–2). Activation of the cyclase enzyme is mediated by the stimulatory coupling protein Gs. Cyclic AMP is the major second messenger of β-receptor activation. For example, in the liver of many species, β-receptor–activated cAMP synthesis leads to a cascade of events culminating in the activation of glycogen phosphorylase. In the heart, β-receptor–activated cAMP synthesis increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. Although the mechanism of the smooth muscle effect is uncertain, it may involve the phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium channels in the heart via coupling to Gs but independent of cAMP. Under certain circumstances, β2 receptors may couple to Gq proteins. These receptors have been demonstrated to activate additional kinases, such as MAP


Pharmacology_Katzung

Pharmacology_Katzung. via coupling to Gs but independent of cAMP. Under certain circumstances, β2 receptors may couple to Gq proteins. These receptors have been demonstrated to activate additional kinases, such as MAP kinases, by forming multi-subunit complexes containing multiple signaling molecules.


Pharmacology_Katzung

Pharmacology_Katzung. The β3 adrenoreceptor is a lower affinity receptor compared with β1 and β2 receptors but is more resistant to desensitization. It is found in several tissues, but its physiologic or pathologic role in humans is not clear. β3 receptors are expressed in the detrusor muscle of the bladder and induce its relaxation. Mirabegron, a selective β3 agonist, is approved for the treatment of symptoms of overactive bladder (urinary urgency and frequency). A small increase in blood pressure was observed in clinical trials; the longterm significance of this finding is not clear. C. Dopamine Receptors The D1 receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D1-receptor–induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 9–2 Relative receptor affinities. 1See text. Examples of clinically useful sympathomimetic agonists that are relatively selective for α1-, α2-, and β-adrenoceptor subgroups are compared with some nonselective agents in Table 9–2. Selectivity means that a drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. However, selectivity is not usually absolute (nearly absolute selectivity has been termed “specificity”), and at higher concentrations, a drug may also interact with related classes of receptors. The effects of a given drug may depend not only on its selectivity to adrenoreceptor types, but also to the relative expression of receptor subtypes in a given tissue.


Pharmacology_Katzung

Pharmacology_Katzung. Responses mediated by adrenoceptors are not fixed and static. The magnitude of the response depends on the number and function of adrenoceptors on the cell surface and on the regulation of these receptors by catecholamines themselves, other hormones and drugs, age, and a number of disease states (see Chapter 2). These changes may modify the magnitude of a tissue’s physiologic response to catecholamines and can be important clinically during the course of treatment. One of the best-studied examples of receptor regulation is the desensitization of adrenoceptors that may occur after exposure to catecholamines and other sympathomimetic drugs. After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent (see Figure 2–12). Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may


Pharmacology_Katzung

Pharmacology_Katzung. (see Figure 2–12). Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents.


Pharmacology_Katzung

Pharmacology_Katzung. Many mechanisms have been found to contribute to desensitization. Some mechanisms occur relatively slowly, over the course of hours or days, and these typically involve transcriptional or translational changes in the receptor protein level, or its migration to the cell surface. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, especially by phosphorylation of specific amino acid residues, association of these receptors with other proteins, or changes in their subcellular location.


Pharmacology_Katzung

Pharmacology_Katzung. There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question. A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are seven members. Specific adrenoceptors become substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization because it specifically involves only agonist-occupied receptors.


Pharmacology_Katzung

Pharmacology_Katzung. Phosphorylation of these receptors enhances their affinity for arrestins, a family of four proteins, of which the two nonvisual arrestin subtypes are widely expressed. Upon binding of arrestin, the capacity of the receptor to activate G proteins is blunted, presumably as a result of steric hindrance (see Figure 2–12). Arrestin then interacts with clathrin and clathrin adaptor AP2, leading to endocytosis of the receptor. In addition to desensitizing agonist responses mediated by G proteins, arrestins can trigger G protein-independent signaling pathways. Recognition that G protein-coupled receptors can signal through both G protein-coupled and G protein-independent pathways has raised the concept of developing biased agonists that selectively activate these arrestin-coupled signaling pathways (see Box: Therapeutic Potential of Biased Agonists at Beta Receptors).


Pharmacology_Katzung

Pharmacology_Katzung. Receptor desensitization may also be mediated by second-messenger feedback. For example, β adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A; protein kinase A can phosphorylate residues on β receptors, resulting in inhibition of receptor function. For the β2 receptor, protein kinase A phosphorylation occurs on serine residues in the third cytoplasmic loop of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. Protein kinase A phosphorylation of the β2 receptor also switches its G protein preference from Gs to Gi, further reducing cAMP response. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes.


Pharmacology_Katzung

Pharmacology_Katzung. Traditional β agonists like epinephrine activate cardiac β1 receptors, increasing heart rate and cardiac workload through coupling with G proteins. This can be deleterious in situations such as myocardial infarction. Beta1 receptors are also coupled through G protein-independent signaling pathways involving β-arrestin, which are thought to be cardioprotective. A “biased” agonist could potentially activate only the cardioprotective, β-arrestin–mediated signaling (and not the G protein-coupled–mediated signals that lead to greater cardiac workload). Such a biased agonist would be of great therapeutic potential in situations such as myocardial infarction or heart failure. Biased agonists potent enough to reach this therapeutic goal have not yet been developed.


Pharmacology_Katzung

Pharmacology_Katzung. Since elucidation of the sequences of the genes encoding the α1, α2, and β subtypes of adrenoceptors, it has become clear that there are relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic importance. Often, distinct polymorphisms occur in specific combinations termed haplotypes. Some polymorphisms are clinically relevant and have been shown to alter susceptibility to diseases such as heart failure, modify the propensity of a receptor to desensitize, or modulate therapeutic responses to drugs in diseases such as asthma. In many other cases, studies have reported inconsistent results as to the pathophysiologic importance of polymorphisms. The Norepinephrine Transporter


Pharmacology_Katzung

Pharmacology_Katzung. When norepinephrine is released into the synaptic cleft, it binds to postsynaptic adrenoceptors to elicit the expected physiologic effect. However, just as the release of neurotransmitters is a tightly regulated process, the mechanisms for removal of neurotransmitter must also be highly effective. The norepinephrine transporter (NET) is the principal route by which this occurs. It is particularly efficient in the synapses of the heart, where up to 90% of released norepinephrine is removed by the NET. Remaining synaptic norepinephrine may escape into the extrasynaptic space and enter the bloodstream or be taken up into extraneuronal cells and metabolized by catechol-O-methyltransferase. In other sites such as the vasculature, where synaptic structures are less well developed, removal may still be 60% or more by NET. The NET, often situated on the presynaptic neuronal membrane, pumps the synaptic norepinephrine back into the neuron cell cytoplasm. In the cell, this norepinephrine may


Pharmacology_Katzung

Pharmacology_Katzung. still be 60% or more by NET. The NET, often situated on the presynaptic neuronal membrane, pumps the synaptic norepinephrine back into the neuron cell cytoplasm. In the cell, this norepinephrine may reenter the vesicles or undergo metabolism through monoamine oxidase to dihydroxyphenylglycol (DHPG). Elsewhere in the body similar transporters remove dopamine (dopamine transporter, DAT), serotonin (serotonin transporter, SERT), and other neurotransmitters. The NET, surprisingly, has equivalent affinity for dopamine as for norepinephrine, and it can sometimes clear dopamine in brain areas where DAT is low, like the cortex.


Pharmacology_Katzung

Pharmacology_Katzung. Blockade of the NET, eg, by the nonselective psychostimulant cocaine or the NET selective agents atomoxetine or reboxetine, impairs this primary site of norepinephrine removal and thus synaptic norepinephrine levels rise, leading to greater stimulation of α and β adrenoceptors. In the periphery this effect may produce a clinical picture of sympathetic activation, but it is often counterbalanced by concomitant stimulation of α2 adrenoceptors in the brain stem that reduces sympathetic activation.


Pharmacology_Katzung

Pharmacology_Katzung. However, the function of the norepinephrine and dopamine transporters is complex, and drugs can interact with the NET to actually reverse the direction of transport and induce the release of intraneuronal neurotransmitter. This is illustrated in Figure 9–3. Under normal circumstances (panel A), presynaptic NET (red) inactivates and recycles norepinephrine (NE, red) released by vesicular fusion. In panel B, amphetamine (black) acts as both an NET substrate and a reuptake blocker, eliciting reverse transport and blocking normal uptake, thereby increasing NE levels in and beyond the synaptic cleft. In panel C, agents such as methylphenidate and cocaine (hexagons) block NET-mediated NE reuptake and enhance NE signaling.


Pharmacology_Katzung

Pharmacology_Katzung. Phenylethylamine may be considered the parent compound from which sympathomimetic drugs are derived (Figure 9–4). This compound consists of a benzene ring with an ethylamine side chain. The presence of –OH groups at the 3 and 4 positions of the benzene ring yields sympathomimetic drugs collectively known as catecholamines. Additional substitutions made on (1) the benzene ring, (2) the terminal amino group, and (3) the α or β carbons produce catechols with different affinity for α and β receptors, from almost pure α agonists (methoxamine) to almost pure β agonists (isoproterenol). In addition to determining relative affinity to receptor subtypes, chemical structure also determines the pharmacokinetic properties and bioavailability of these molecules. A. Substitution on the Benzene Ring


Pharmacology_Katzung

Pharmacology_Katzung. A. Substitution on the Benzene Ring Maximal α and β activity is found with catecholamines, ie, drugs having –OH groups at the 3 and 4 positions on the benzene ring. The absence of one or the other of these groups dramatically reduces the potency of these drugs. For example, phenylephrine (Figure 9–5) is much less potent than epinephrine; its affinity to α receptors is decreased approximately 100-fold, but because its β activity is almost negligible except at very high concentrations, it is a selective α agonist. On the other hand, the presence of –OH groups make catecholamines subject to inactivation by catechol-O-methyltransferase


Pharmacology_Katzung

Pharmacology_Katzung. On the other hand, the presence of –OH groups make catecholamines subject to inactivation by catechol-O-methyltransferase FIGURE 9–3 Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of amphetamine and cocaine on these pathways. See text for details.


Pharmacology_Katzung

Pharmacology_Katzung. (COMT), and because this enzyme is found in the gut and liver, catecholamines are not active orally (see Chapter 6). Absence of one or both –OH groups on the phenyl ring increases the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system (CNS). For example, ephedrine and amphetamine (Figure 9–5) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines. Methamphetamine (“crystal meth,” a common drug of abuse) can be synthesized by simple dehydroxylation of ephedrine, which led to the restriction of over-the-counter distribution of its isomer pseudoephedrine. B. Substitution on the Amino Group


Pharmacology_Katzung

Pharmacology_Katzung. B. Substitution on the Amino Group Increasing the size of alkyl substituents on the amino group tends to increase β-receptor activity. For example, methyl substitution on norepinephrine (yielding epinephrine) enhances activity at β2 receptors, and isopropyl substitution (yielding isoproterenol) increases β activity further. Conversely, the larger the substituent on the amino group, the lower is the activity at α receptors; for example, isoproterenol is very weak at α receptors. Beta2-selective agonists generally require a large amino substituent group. C. Substitution on the Alpha Carbon Substitutions at the α carbon (eg, ephedrine and amphetamine; Figure 9–5) block oxidation by monoamine oxidase (MAO), thus FIGURE 9–4 Phenylethylamine and some important catecholamines. Catechol is shown for reference.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 9–4 Phenylethylamine and some important catecholamines. Catechol is shown for reference. prolonging the duration of action of these drugs. Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body; they are indirectly acting sympathomimetics. FIGURE 9–5 Some examples of noncatecholamine sympathomimetic drugs. The isopropyl group is highlighted in color. Methamphetamine is amphetamine with one of the amine hydrogens replaced by a methyl group. D. Substitution on the Beta Carbon


Pharmacology_Katzung

Pharmacology_Katzung. D. Substitution on the Beta Carbon Direct-acting agonists typically have a β-hydroxyl group, although dopamine does not. In addition to facilitating activation of adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles. General outlines of the cellular actions of sympathomimetics are presented in Tables 6–3 and 9–3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of α and β adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation.


Pharmacology_Katzung

Pharmacology_Katzung. The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, peripheral vascular resistance, and venous return (see Figure 6–7 and Table 9–4). The endogenous catecholamines, norepinephrine and epinephrine, have complex cardiovascular effects because they activate both α and β receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor. A. Effects of Alpha1-Receptor Activation Alpha1 receptors are widely expressed in vascular beds, and their activation leads to arterial and venous vasoconstriction. Their direct TABLE 9–3 Distribution of adrenoceptor subtypes.


Pharmacology_Katzung

Pharmacology_Katzung. effect on cardiac function is of relatively less importance. A relatively pure α agonist such as phenylephrine increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure (Figure 9–6). In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate, which may be quite marked (Figure 9–7). However, cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume. Furthermore, direct α-adrenoceptor stimulation of the heart may have a modest positive inotropic action. It is important to note that any effect these agents have on blood pressure is counteracted by compensatory autonomic baroreflex mechanisms aimed at restoring homeostasis. The magnitude of the restraining effect is quite dramatic. If baroreflex function is


Pharmacology_Katzung

Pharmacology_Katzung. on blood pressure is counteracted by compensatory autonomic baroreflex mechanisms aimed at restoring homeostasis. The magnitude of the restraining effect is quite dramatic. If baroreflex function is removed by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately 10-fold, and bradycardia is no longer observed (Figure 9–7), confirming that the decrease in heart rate associated with the increase in blood pressure induced by phenylephrine was reflex in nature rather than a direct effect of α1-receptor activation.


Pharmacology_Katzung

Pharmacology_Katzung. Patients who have an impairment of autonomic function (due to pure autonomic failure as in the case study or to more common conditions such as diabetic autonomic neuropathy) exhibit this extreme hypersensitivity to most pressor and depressor stimuli, including medications. This is to a large extent due to failure of baroreflex buffering. Such patients may have exaggerated increases in heart rate or blood pressure when taking sympathomimetics with βand α-adrenergic activity, respectively. This, however, can be used as an advantage in their treatment. The α agonist midodrine is commonly used to ameliorate orthostatic hypotension in these patients.


Pharmacology_Katzung

Pharmacology_Katzung. There are major differences in receptor types predominantly expressed in the various vascular beds (Table 9–4). The skin vessels have predominantly α receptors and constrict in response to epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether α or β receptors are activated. The blood vessels of the nasal mucosa express α receptors, and local vasoconstriction induced by sympathomimetics explains their decongestant action (see Therapeutic Uses of Sympathomimetic Drugs). B. Effects of Alpha2-Receptor Activation


Pharmacology_Katzung

Pharmacology_Katzung. B. Effects of Alpha2-Receptor Activation Alpha2 adrenoceptors are present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when α2 agonists are given locally, by rapid intravenous injection or in very high oral doses. When given systemically, these vascular effects are obscured by the central effects of α2 receptors, which lead to inhibition of sympathetic tone and reduced blood pressure. Hence, α2 agonists can be used as sympatholytics in the treatment of hypertension (see Chapter 11). In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact. C. Effects of Beta-Receptor Activation


Pharmacology_Katzung

Pharmacology_Katzung. C. Effects of Beta-Receptor Activation The cardiovascular effects of β-adrenoceptor activation are exemplified by the response to the nonselective β agonist isoproterenol, which activates both β1 and β2 receptors. Stimulation of β receptors in the heart increases cardiac output by increasing contractility and by direct activation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating β2 receptors, leading to vasodilation in certain vascular beds (Table 9–4). The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased (Figure 9–6).


Pharmacology_Katzung

Pharmacology_Katzung. The cardiac effects of β agonists are determined largely by β1 receptors (although β2 and α receptors may also be involved, especially in heart failure). Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Beta-activation in the sinoatrial node increases pacemaker activity and heart rate (positive chronotropic effect). Excessive stimulation of ventricular muscle and Purkinje cells can result in ventricular arrhythmias. Beta TABLE 9–4 Cardiovascular responses to sympathomimetic amines. FIGURE 9–6 Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate. 0 100 0 80 BP mm Hg HR bpm 0 100 0 100 Phe 75 µg Phe 7.5 µg


Pharmacology_Katzung

Pharmacology_Katzung. 0 100 0 80 BP mm Hg HR bpm 0 100 0 100 Phe 75 µg Phe 7.5 µg FIGURE 9–7 Effects of ganglionic blockade on the response to phenylephrine (Phe) in a human subject. Left: The cardiovascular effect of the selective α agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right: The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal (HR scale is different). In the absence of baroreflex buffering, approximately a 10-fold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate.


Pharmacology_Katzung

Pharmacology_Katzung. stimulation in the atrioventricular node increases conduction velocity (positive dromotropic effect) and decreases the refractory period. Beta activation also increases intrinsic myocardial contractility (positive inotropic effect) and accelerates relaxation. In the presence of normal autonomic reflex activity, the direct effects on heart rate may be masked by a reflex response to blood pressure changes (with sympathetic withdrawal and parasympathetic activation, which lower heart rate). These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. Expression of β3 adrenoreceptors has been detected in the human heart and may be upregulated in disease states; its relevance is under investigation. D. Effects of Dopamine-Receptor Activation


Pharmacology_Katzung

Pharmacology_Katzung. D. Effects of Dopamine-Receptor Activation Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of D1 receptors. Activation of the D1 receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates β1 receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular α receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. Noncardiac Effects of Sympathomimetics


Pharmacology_Katzung

Pharmacology_Katzung. Noncardiac Effects of Sympathomimetics Adrenoceptors are distributed in virtually all organ systems. This section focuses on the activation of adrenoceptors that are responsible for the therapeutic effects of sympathomimetics or that explain their adverse effects. A more detailed description of the therapeutic use of sympathomimetics is given later in this chapter. Activation of β2 receptors in bronchial smooth muscle leads to bronchodilation, and β2 agonists are important in the treatment of asthma (see Chapter 20 and Table 9–3). In the eye, the radial pupillary dilator muscle of the iris contains α receptors; activation by drugs such as phenylephrine causes mydriasis (see Figure 6–9). Alpha2 agonists increase the outflow of aqueous humor from the eye and can be used clinically to reduce intraocular pressure. In contrast, β agonists have little effect, but β antagonists decrease the production of aqueous humor and are used in the treatment of glaucoma (see Chapter 10).


Pharmacology_Katzung

Pharmacology_Katzung. In genitourinary organs, the bladder base, urethral sphincter, and prostate contain α1A receptors that mediate contraction and therefore promote urinary continence. This effect explains why urinary retention is a potential adverse effect of administration of the α1 agonist midodrine, and why α1A antagonists are used in the management of symptoms of urinary flow obstruction. Alpha-receptor activation in the ductus deferens, seminal vesicles, and prostate plays a role in normal ejaculation and in the detumescence of erectile tissue that normally follows ejaculation. The salivary glands contain adrenoceptors that regulate the secretion of amylase and water. However, centrally acting sympathomimetic drugs, eg, clonidine, produce symptoms of dry mouth. It is likely that CNS effects are responsible for this side effect, although peripheral effects may contribute.


Pharmacology_Katzung

Pharmacology_Katzung. The apocrine sweat glands, located on the palms of the hands and a few other areas, are nonthermoregulatory glands that respond to psychological stress and adrenoceptor stimulation with increased sweat production. (The diffusely distributed thermo-regulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinergic receptors; see Chapter 6.)


Pharmacology_Katzung

Pharmacology_Katzung. Sympathomimetic drugs have important effects on intermediary metabolism. Activation of β adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Beta3 adrenoceptors play a role in mediating this response in animals, but their role in humans is not clear. Experimentally, the β3 agonist mirabegron stimulates brown adipose tissue in humans. The potential importance of this finding is that brown fat cells (“good fat”) are thermogenic and thus have a positive metabolic function. Brown adipose tissue is present in neonates, but only remnant amounts are normally found in adult humans. Therefore, it is not clear whether β3 agonists can be used therapeutically for the treatment of obesity. Human fat cells also contain α2 receptors that inhibit lipolysis by decreasing intracellular cAMP. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation. In the human


Pharmacology_Katzung

Pharmacology_Katzung. that inhibit lipolysis by decreasing intracellular cAMP. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation. In the human liver, the effects of catecholamines are probably mediated mainly by β receptors, although α1 receptors may also play a role. Catecholamines in high concentration may also cause metabolic acidosis. Activation of β2 adrenoceptors by endogenous epinephrine or by sympathomimetic drugs promotes the uptake of potassium into cells, leading to a fall in extracellular potassium. This may result in a fall in the plasma potassium concentration during stress or protect against a rise in plasma potassium during exercise. Blockade of these receptors may accentuate the rise in plasma potassium that occurs during exercise. On the other hand, epinephrine has been used to treat hyperkalemia in certain conditions, but alternatives are more commonly used. Beta receptors and α2 receptors that are expressed in


Pharmacology_Katzung

Pharmacology_Katzung. exercise. On the other hand, epinephrine has been used to treat hyperkalemia in certain conditions, but alternatives are more commonly used. Beta receptors and α2 receptors that are expressed in pancreatic islets tend to increase and decrease insulin secretion, respectively, although the major regulator of insulin release is the plasma concentration of glucose.


Pharmacology_Katzung

Pharmacology_Katzung. Catecholamines are important endogenous regulators of hormone secretion from a number of glands. As mentioned above, insulin secretion is stimulated by β receptors and inhibited by α2 receptors. Similarly, renin secretion is stimulated by β1 and inhibited by α2 receptors; indeed, β-receptor antagonist drugs may lower blood pressure in patients with hypertension at least in part by lowering plasma renin. Adrenoceptors also modulate the secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin; however, the physiologic significance of these control mechanisms is probably limited. In high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of sequestered white blood cells back into the general circulation.


Pharmacology_Katzung

Pharmacology_Katzung. The action of sympathomimetics on the CNS varies dramatically, depending on their ability to cross the blood-brain barrier. The catecholamines are almost completely excluded by this barrier, and subjective CNS effects are noted only at the highest rates of infusion. These effects have been described as ranging from “nervousness” to “an adrenaline rush” or “a feeling of impending disaster.” Furthermore, peripheral effects of β-adrenoceptor agonists such as tachycardia and tremor are similar to the somatic manifestations of anxiety. In contrast, noncatecholamines with indirect actions, such as amphetamines, which readily enter the CNS from the circulation, produce qualitatively very different effects on the nervous system. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not readily assigned to either αor β-mediated actions and may represent


Pharmacology_Katzung

Pharmacology_Katzung. boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not readily assigned to either αor β-mediated actions and may represent enhancement of dopamine-mediated processes or other effects of these drugs in the CNS.


Pharmacology_Katzung

Pharmacology_Katzung. Epinephrine (adrenaline) is an agonist at both α and β receptors. It is therefore a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly β1 receptors) and the vasoconstriction induced in many vascular beds (α receptors). Epinephrine also activates β2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation. Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection (Figure 9–6; Table 9–4). Activation of β2 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine functions largely as a hormone; it is released from the adrenal medulla and carried in the blood to distant sites of action.


Pharmacology_Katzung

Pharmacology_Katzung. Norepinephrine (levarterenol, noradrenaline) is an agonist at both α1 and α2 receptors. Norepinephrine also activates β1 receptors with similar potency as epinephrine, but has relatively little effect on β2 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained.


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6–5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the CNS and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson’s disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs. Phenylephrine was discussed previously when describing the actions of a relatively pure α1 agonist (Table 9–2). Because it is not a catechol derivative (Figure 9–5), it is not inactivated by COMT and has a longer duration of action than the catecholamines. It is an effective mydriatic and decongestant and can be used to raise the blood pressure (Figure 9–6).


Pharmacology_Katzung

Pharmacology_Katzung. Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α1-receptor agonist. The peak concentration of desglymidodrine is achieved about 1 hour after midodrine is administered orally. The primary indication for midodrine is the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function. Midodrine increases upright blood pressure and improves orthostatic tolerance, but it may cause hypertension when the subject is supine.


Pharmacology_Katzung

Pharmacology_Katzung. Alpha2-selective agonists decrease blood pressure through actions in the CNS that reduce sympathetic tone (“sympatholytics”) even though direct application to a blood vessel may cause vasoconstriction. Such drugs (eg, clonidine, methyl-dopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11. Sedation is a recognized side effect of these drugs, and newer α2 agonists (with activity also at imidazoline receptors) with fewer CNS side effects are available outside the USA for the treatment of hypertension (moxonidine, rilmenidine). On the other hand, the primary indication of dexmedetomidine is for sedation in an intensive care setting or before anesthesia. It also reduces the requirements for opioids in pain control. Finally, tizanidine is used as a centrally acting muscle relaxant.


Pharmacology_Katzung

Pharmacology_Katzung. Oxymetazoline is a direct-acting α agonist used as a topical decongestant because of its ability to promote constriction of the vessels in the nasal mucosa and conjunctiva. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (see Chapter 11). Oxymetazoline has significant affinity for α2A receptors. Isoproterenol (isoprenaline) is a very potent β-receptor agonist and has little effect on α receptors. The drug has positive chronotropic and inotropic actions; because isoproterenol activates β receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9–4; Figure 9–6).


Pharmacology_Katzung

Pharmacology_Katzung. Beta subtype-selective agonists are very important because the separation of β1 and β2 effects (Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications.


Pharmacology_Katzung

Pharmacology_Katzung. Beta1-selective agents (Figure 9–8) increase cardiac output with less reflex tachycardia than nonselective β agonists such as isoproterenol, because they are less effective in activating vasodilator β2 receptors. Dobutamine was initially considered a relatively β1-selective agonist, but its actions are more complex. Its chemical structure resembles dopamine, but its actions are mediated mostly by activation of α and β receptors. Clinical formulations of dobutamine are a racemic mixture of (–) and (+) isomers, each with contrasting activity at α1 and α2 receptors. The (+) isomer is a potent β1 agonist and an α1-receptor antagonist. The (–) isomer is a potent α1 agonist, which is capable of causing significant vasoconstriction when given alone. The resultant cardiovascular effects of dobutamine reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly β-receptor activity. It has relatively greater inotropic than chronotropic


Pharmacology_Katzung

Pharmacology_Katzung. reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly β-receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol. Activation of α1 receptors probably explains why peripheral resistance does not decrease significantly.


Pharmacology_Katzung

Pharmacology_Katzung. Beta2-selective agents (eg, Figure 9–8) have achieved an important place in the treatment of asthma and are discussed in Chapter 20). FIGURE 9–8 Examples of β1and β2-selective agonists. Ephedrine occurs in various plants and has been used in China for over 2000 years; it was introduced into Western medicine in 1924 as the first orally active sympathomimetic drug. It is found in ma huang, a popular herbal medication (see Chapter 64). Ma huang contains multiple ephedrine-like alkaloids in addition to ephedrine. Because ephedrine is a noncatechol phenylisopropylamine (Figure 9–5), it has high bioavailability and a relatively long duration of action—hours rather than minutes. As with many other phenylisopropylamines, a significant fraction of the drug is excreted unchanged in the urine. Since it is a weak base, its excretion can be accelerated by acidification of the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Ephedrine has not been extensively studied in humans despite its long history of use. Its ability to activate β receptors probably accounted for its earlier use in asthma. Because it gains access to the CNS, it is a mild stimulant. The US Food and Drug Administration (FDA) has banned the sale of ephedra-containing dietary supplements because of safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale.


Pharmacology_Katzung

Pharmacology_Katzung. As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (Figure 9–3). First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or “displacers.” Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET. A. Amphetamine-Like Amphetamine is a racemic mixture of phenylisopropylamine (Figure 9–5) that is important chiefly because of its use and misuse as a CNS stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine; however, amphetamine enters the CNS even more readily, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its d-isomer is more potent than the l-isomer. Amphetamine’s actions are mediated through the release of norepinephrine and, to some extent, dopamine.


Pharmacology_Katzung

Pharmacology_Katzung. Methamphetamine (N-methylamphetamine) is very similar to amphetamine, with an even higher ratio of central to peripheral actions. Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in children with attention deficit hyperactivity disorder (see Therapeutic Uses of Sympathomimetic Drugs). Modafinil is a psychostimulant that differs from amphetamine in structure, neurochemical profile, and behavioral effects. Its mechanism of action is not fully known. It inhibits both norepinephrine and dopamine transporters, and it increases synaptic concentrations not only of norepinephrine and dopamine, but also of serotonin and glutamate, while decreasing γ-aminobutyric acid (GABA) levels. It is used primarily to improve wakefulness in narcolepsy and some other conditions. It is often associated with increases in blood pressure and heart rate, although these are usually mild (see


Pharmacology_Katzung

Pharmacology_Katzung. It is used primarily to improve wakefulness in narcolepsy and some other conditions. It is often associated with increases in blood pressure and heart rate, although these are usually mild (see Therapeutic Uses of Sympathomimetic Drugs).


Pharmacology_Katzung

Pharmacology_Katzung. Tyramine (see Figure 6–5) is a normal byproduct of tyrosine metabolism in the body. It is an indirect sympathomimetic, inducing the release of catecholamines from noradrenergic neurons. Tyramine can be produced in high concentrations in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9–5) but is normally inactive when taken orally because it is readily metabolized by MAO in the liver (ie, low bioavailability because of a very high first-pass effect). In patients treated with MAO inhibitors—particularly inhibitors of the MAO-A isoform—the sympathomimetic effect of tyramine may be greatly intensified, leading to marked increases in blood pressure. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibitors should avoid tyramine-containing foods (aged cheese, cured meats, and pickled food). There are differences in the effects of various MAO inhibitors on tyramine


Pharmacology_Katzung

Pharmacology_Katzung. Patients taking MAO inhibitors should avoid tyramine-containing foods (aged cheese, cured meats, and pickled food). There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer (see Chapters 28 and 30).


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 9–5 Foods reputed to have a high content of tyramine or other sympathomimetic agents. Note: In a patient taking an irreversible monoamine oxidase (MAO) inhibitor drug, 20–50 mg of tyramine in a meal may increase the blood pressure significantly (see also Chapter 30: Antidepressant Agents). Note that only cheese, sausage, pickled fish, and yeast supplements contain sufficient tyramine to be consistently dangerous. This does not rule out the possibility that some preparations of other foods might contain significantly greater than average amounts of tyramine. Amounts in mg as per regular food portion. B. Catecholamine Reuptake Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. B. Catecholamine Reuptake Inhibitors Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants, can inhibit norepinephrine and serotonin reuptake to different degrees. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking α1 receptors, but the mechanism remains unclear.


Pharmacology_Katzung

Pharmacology_Katzung. Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Reboxetine (investigational in the USA) has similar characteristics to atomoxetine but is used mainly for major depression disorder. Because reuptake inhibitors potentiate norepinephrine actions, there is concern about their cardiovascular safety. Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the CNS to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, especially during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors can cause orthostatic


Pharmacology_Katzung

Pharmacology_Katzung. reuptake is particularly important in the heart, especially during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors can cause orthostatic tachycardia. Pharmacoepidemiologic studies have not found significant adverse cardiovascular events associated with the use of norepinephrine reuptake inhibitors. However, sibutramine, a serotonin and norepinephrine reuptake inhibitor used as an appetite suppressant, was taken off the market because it was associated with a small increase in cardiovascular events, including strokes, in patients with a history of cardiovascular disease. Duloxetine is a widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects (see Chapter 30). Increased cardiovascular risk has not been reported with duloxetine. Duloxetine and milnacipran, another serotonin and norepinephrine transporter blocker, are approved for the treatment of pain in fibromyalgia (see Chapter 30).


Pharmacology_Katzung

Pharmacology_Katzung. Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (Figure 9–3). It readily enters the CNS and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the CNS is to inhibit dopamine reuptake into neurons in the “pleasure centers” of the brain. These properties and the fact that a rapid onset of action can be obtained when smoked, snorted, or injected have made cocaine a heavily abused drug (see Chapter 32). It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets. Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson’s disease and prolactinemia. These agents are discussed in Chapters 28 and 37.


Pharmacology_Katzung

Pharmacology_Katzung. Fenoldopam is a D1-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is in the intravenous treatment of severe hypertension (see Chapter 11). In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions. A. Treatment of Acute Hypotension