Cholinergic Antagonists 5
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Cholinergic Antagonists 5 I. OVERVIEW ANTIMUSCARINIC AGENTS The cholinergic antagonists (also called cholinergic blockers, para- Atropine ISOPTO ATROPINE, sympatholytics, or anticholinergic drugs) bind to cholinoceptors, but they Benztropine COGENTIN do not trigger the usual receptor-mediated intracellular effects. The most Cyclopentolate AK-PENTOLATE, CYCLOGYL useful of these agents selectively block muscarinic receptors of the para- Darifenacin ENABLEX sympathetic nerves. The effects of parasympathetic innervation are, thus, Fesoterodine TOVIAZ interrupted, and the actions of sympathetic stimulation are left unop- Ipratropium ATROVENT posed. A second group of drugs, the ganglionic blockers, show a prefer- Oxybutynin DITROPAN, GELNIQUE, OXYTROL ence for the nicotinic receptors of the sympathetic and parasympathet- Scopolamine ISOPTO HYOSCINE, SCOPACE, ic ganglia. Clinically, they are the least important of the anti cholinergic TRANSDERM SCŌP drugs. A third family of compounds, the neuromuscular-blocking agents, Solifenacin VESICARE interfere with transmission of efferent impulses to skeletal muscles. These Tiotropium SPIRIVA HANDIHALER agents are used as skeletal muscle relaxant adjuvants in anesthesia dur- Tolterodine DETROL ing surgery, intubation, and various orthopedic procedures. Figure 5.1 Trihexyphenidyl ARTANE summarizes the cholinergic antagonists discussed in this chapter. Tropicamide MYDRIACYL, TROPICACYL Trospium chloride SANCTURA II. ANTIMUSCARINIC AGENTS GANGLIONIC BLOCKERS Mecamylamine NOT AVAILABLE Commonly known as antimuscarinics, these agents (for example, atropine Nicotine COMMIT, NICODERM, NICORETTE, and scopolamine) block muscarinic receptors (Figure 5.2), causing inhibi- NICOTROL INHALER tion of all muscarinic functions. In addition, these drugs block the few NEUROMUSCULAR BLOCKERS exceptional sympathetic neurons that are cholinergic, such as those Atracurium ONLY GENERIC innervating salivary and sweat glands. In contrast to the cholinergic Cisatracurium NIMBEX agonists, which have limited usefulness therapeutically, the cholinergic Pancuronium PAVULON blockers are beneficial in a variety of clinical situations. Because they do Rocuronium ZEMURON not block nicotinic receptors, the antimuscarinic drugs have little or no Succinylcholine ANECTINE, QUELICIN action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia. Vecuronium ONLY GENERIC [Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity.] Figure 5.1 A. Atropine Summary of cholinergic antagonists. Atropine [A-troe-peen] is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds competitively and prevents acetylcholine (ACh) from binding to those sites (Figure 5.3). Atropine acts both centrally and peripherally. Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. Neuroeffector organs have varying sensitivity to atropine. The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva (Figure 5.4). Pharm 5th 3-21-11.indb 59 3/21/11 2:20:53 PM 60 5. Cholinergic Antagonists AUTONOMIC SOMATIC Sympathetic innervation Sympathetic Parasympathetic of adrenal medulla Preganglionic neuron Ganglionic transmitter Acetylcholine Acetylcholine Acetylcholine No ganglia Sites of action of ganglionic blockers Nicotinic Nicotinic Nicotinic receptor receptor receptor Postganglionic Adrenal medulla neurons Site of action Neuroeector Epinephrine and Norepinephrine Acetylcholine Acetylcholine transmitter of neuro- norepinephrine muscular released into the blood blockers Adrenergic Adrenergic Nicotinic Site of action receptor receptor Muscarinic receptor receptor of antimuscarinic Skeletal muscle drugs Eector organs Figure 5.2 Sites of actions of cholinergic antagonists. 1. Actions: a. Eye: Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis (dilation of the pupil, see Figure 4.6, p. 52), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with narrow-angle glaucoma, intraocular pressure may rise dangerously. Shorter-acting agents, such as the antimuscarinic tropicamide, or an α -adrenergic drug, such as phenylephrine, are generally favored for producing mydriasis in Atropine Acetylcholine ophthalmic examinations. Scopolamine b. Gastrointestinal (GI): Atropine (as the active isomer, l-hyoscyamine) can be used as an antispasmodic to reduce activity of the GI tract. Atropine and scopolamine (which is discussed below) are probably the most potent drugs available that produce this effect. Although gastric motility is reduced, hydrochloric acid production is not significantly affected. Thus, the drug is not Muscarinic receptor effective in promoting healing of peptic ulcer. [Note: Pirenzepine (see p. 51), an M1-muscarinic antagonist, does reduce gastric Figure 5.3 acid secretion at doses that do not antagonize other systems.] In Competition of atropine and addition, doses of atropine that reduce spasms also reduce saliva scopolamine with acetylcholine secretion, ocular accommodation, and micturition (urination). for the muscarinic receptor. These effects decrease patient compliance with the use of these medications. Pharm 5th 3-21-11.indb 60 3/21/11 2:20:54 PM II. Antimuscarinic Agents 61 c. Urinary system: Atropine-like drugs are also used to reduce hyper motility states of the urinary bladder. It is still occasionally used in enuresis (involuntary voiding of urine) among children, but α-adrenergic agonists with fewer side effects may be more effective. Hallucinations and d. Cardiovascular: Atropine produces divergent effects on the >10.0 mg delirium; coma cardiovascular system, depending on the dose (Figure 5.4). At low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to central activation atropine of vagal efferent outflow, the effect is now known to result from Rapid heart rate; blockade of the M receptors on the inhibitory prejunctional (or palpitation; marked 1 5.0 mg dryness of the mouth; presynaptic) neurons, thus permitting increased ACh release. Dose of dilation of pupil; some blurring of near vision With higher doses of atropine, the M2 receptors on the sinoatrial node are blocked, and the cardiac rate increases modestly. This 2.0 mg generally requires at least 1 mg of atropine, which is a higher dose Slight cardiac slowing; 0.5 mg some dryness of the than ordinarily given. Arterial blood pressure is unaffected, but, mouth; inhibition of at toxic levels, atropine will dilate the cutaneous vasculature. sweating e. Secretions: Atropine blocks the salivary glands, producing a Figure 5.4 drying effect on the oral mucous membranes (xerostomia). Dose-dependent eects of atropine. The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature, which can be dangerous in children and the elderly.] 2. Therapeutic uses: a. Ophthalmic: In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits the measurement of refractive errors without interference by the accommodative capacity of the eye. [Note: Phenylephrine or similar α-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not required]. Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to the prolonged mydriasis observed with atropine (7–14 days versus 6–24 hours with other agents). Atropine may induce an acute attack of eye pain due to sudden increases in eye pressure in individuals with narrow-angle glaucoma. b. Antispasmodic: Atropine (as the active isomer, l-hyoscyamine) is used as an antispasmodic agent to relax the GI tract and bladder. c. Antidote for cholinergic agonists: Atropine is used for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic substances that block cholinesterases). Massive doses of the antagonist may be required over a long period of time to counteract the poisons. The ability of atropine to enter the central nervous system (CNS) is of particular importance. The drug also blocks the effects of excess ACh resulting from acetylcholinesterase (AChE) inhibitors such as physostigmine. d. Antisecretory: The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery. Pharm 5th 3-21-11.indb 61 3/21/11 2:20:54 PM 62 5. Cholinergic Antagonists 3. Pharmacokinetics: Atropine is readily absorbed, partially metabo- Scopolamine lized by the liver, and eliminated primarily in urine. It has a half-life of about 4 hours. 4. Adverse eff ects: Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, Motion and constipation. Eff ects on the CNS include restlessness, confu- sickness sion, hallucinations, and delirium, which may progress to depres- For nausea due to . sion, collapse of the circulatory and respiratory systems, and death. Low doses of cholinesterase inhibitors, such as physostigmine, may be used to overcome atropine toxicity. In older individuals, the use Figure 5.5 of atropine to induce mydriasis and cycloplegia is considered to be Scopolamine is an eective anti– too risky, because it may exacerbate an attack of glaucoma due to an motion sickness agent.