Figure 7-1 Dose-dependent effects of atropine. Low doses of atropine inhibit salivation and sweating, and the magnitude of these effects increases as the dosage increases. Higher doses produce tachycardia, urinary retention, and central nervous system effects.
(1) OCULAR EFFECTS. Atropine and other muscarinic receptor blockers relax the iris sphincter muscle, and this leads to pupillary dilatation (mydriasis). Muscarinic blockers also relax the ciliary muscle, thereby increasing the tension on the suspensory ligaments attached to the lens and causing the lens to flatten so that it is focused on distant objects. This prevents the lens from increasing its refractive power to focus on near objects (accommodation), a condition that is called cycloplegia (paralysis of accommodation). Atropine also inhibits lacrimal gland secretion and can cause dry eyes.
(2) CARDIAC EFFECTS. Standard doses of atropine and related drugs increase the heart rate and atrioventricular conduction velocity by blocking the effects of the vagus nerve on the sinoatrial and atrioventricular nodes. When intravenous administration of atropine is begun, however, the low dose of the drug causes a paradoxical slowing of the heart rate. This effect probably results from stimulation of the vagal motor nucleus in the brain stem. After the full therapeutic dose has been administered, the increase in heart rate is observed.
(3) RESPIRATORY TRACT EFFECTS. In addition to producing bronchial smooth muscle relaxation and bronchodilation, atropine and other muscarinic receptor antagonists act as potent inhibitors of secretions in the upper and lower respiratory tract.
(4) GASTROINTESTINAL AND URINARY TRACT EFFECTS. Atropine reduces lower esophageal muscle tone and can cause gastroesophageal reflux. Muscarinic receptor blockers relax gastrointestinal muscle, except sphincters, and reduce intestinal motility, thereby increasing gastric emptying time and intestinal transit time. They also inhibit gastric acid secretion. Sufficient doses of these drugs can cause constipation. Atropine relaxes the detrusor muscle of the urinary bladder and can cause urinary retention.
(5) CENTRAL NERVOUS SYSTEM EFFECTS. Atropine, scopolamine, and other tertiary amines are distributed to the central nervous system, where they can block muscarinic receptors and produce either sedation or excitement. Scopolamine, which is more sedating than is atropine, has been used as an adjunct to anesthesia. Standard doses of atropine typically cause mild stimulation, followed by a slower and longer-lasting sedative effect. With higher doses of atropine, patients can experience an acute confusional state known as delirium. Higher doses of muscarinic antagonists can also cause hallucinations.
(6) OTHER EFFECTS. The muscarinic receptor antagonists inhibit sweating, which can reduce heat loss and lead to hyperthermia, especially in children. The increased body temperature can cause cutaneous vasodilatation, and the skin can become hot, dry, and flushed.
INDICATIONS
(1) OCULAR INDICATIONS. To obtain a relatively localized effect on ocular tissues, muscarinic receptor blockers are administered via topical instillation of a solution or ointment. These drugs are typically used to produce mydriasis and facilitate ophthalmoscopic examination of the peripheral retina. They can also be used to produce cycloplegia and permit the accurate determination of refractive errors, especially in younger patients with a strong accommodation. Because muscarinic receptor blockers can reduce muscle spasm and pain caused by inflammation, they are useful in the treatment of iritis and cyclitis (inflammation of the iris and ciliary muscles) associated with infection, trauma, or surgery.
(2) CARDIAC INDICATIONS. Atropine can be used to treat sinus bradycardia in cases in which the slow sinus rhythm reduces the cardiac output and blood pressure and produces symptoms of hypotension or ischemia. This type of symptomatic bradycardia sometimes occurs after a myocardial infarction. Atropine is usually administered intravenously for this purpose, but it can be injected endotracheally if a vein is not accessible. In patients with symptomatic atrioventricular block, atropine or glycopyrrolate can be used to increase the atrioventricular conduction velocity.
(3) RESPIRATORY TRACT INDICATIONS. Because of its bronchodilating effects, atropine was once used to treat asthma and other obstructive lung diseases. It is no longer used for this purpose, however, because of its many adverse effects. For example, it impairs ciliary activity, thereby reducing the clearance of mucus from the lungs and causing accumulation of viscid material in the airways. As discussed later in this chapter (see “Ipratropium and Tiotropium”), ipratropium is now used instead of atropine to treat obstructive lung diseases. Atropine and other muscarinic receptor blockers are used to reduce salivary and respiratory secretions and thereby prevent airway obstruction in patients who are receiving general anesthetics. Glycopyrrolate is often used for this purpose today (see “Other Indications”).
(4) GASTROINTESTINAL AND URINARY TRACT INDICATIONS. Atropine and related drugs are used to relieve intestinal spasms and pain associated with several gastrointestinal disorders, and they are also used to relieve urinary bladder spasms in persons with overactive bladder.
In the past, atropine was frequently used to reduce gastric acid secretion in patients with peptic ulcers. Large doses were required, however, and these doses often produced intolerable side effects, such as dry mouth, blurred vision, and urinary retention. For this reason, atropine and other nonselective muscarinic receptor blockers are seldom used to treat peptic ulcers today. As discussed later, a selective muscarinic M1 receptor blocker, pirenzepine, is available in some countries to treat peptic ulcer disease.
(5) CENTRAL NERVOUS SYSTEM INDICATIONS. A transdermal formulation of scopolamine can be used to prevent motion sickness. The skin patch slowly releases scopolamine over a period of 3 days and is thought to work by blocking acetylcholine neurotransmission from the vestibular apparatus to the vomiting center in the brain stem. As discussed in Chapter 21, muscarinic receptor blockers are also used in the treatment of Parkinson’s disease.
(6) OTHER INDICATIONS. Atropine and glycopyrrolate are used in two other clinical contexts. First, they are used to prevent muscarinic side effects when cholinesterase inhibitors are given to patients with myasthenia gravis. Second, as discussed in Chapter 6, they are used to reverse the muscarinic effects of cholinesterase inhibitor overdose. In this setting, supranormal doses may be required to counteract the large concentrations of acetylcholine that have accumulated at acetylcholine synapses, and the atropine dosage must be titrated to the patient’s response. Atropine and glycopyrrolate will not counteract the effects of nicotinic receptor activation caused by cholinesterase inhibition. The muscle weakness resulting from nicotinic receptor stimulation can be attenuated by adding pralidoxime to the treatment regimen.
Hyoscyamine
Hyoscyamine, the levorotatory isomer of racemic atropine, is the natural form of the alkaloid that occurs in plants. It is primarily responsible for the pharmacologic effects of atropine. Formulations of hyoscyamine for oral or sublingual administration are used to treat intestinal spasms and other gastrointestinal symptoms.
Semisynthetic and Synthetic Muscarinic Receptor Antagonists
In the search for a more selective muscarinic receptor antagonist, investigators have developed a large number of semisynthetic and synthetic blocking agents. Although the pharmacologic effects of these agents are similar to those of atropine, their unique pharmacokinetic properties are advantageous in specific situations.
Ipratropium and Tiotropium
Ipratropium (Atrovent) and tiotropium (Spiriva), quaternary amine derivatives of atropine, are administered by inhalation to patients with obstructive lung diseases. Because these drugs are not well absorbed from the lungs into the systemic circulation, they produce few adverse effects. For example, unlike atropine, they do not impair the ciliary clearance of secretions from the airways. This makes them particularly useful in treating patients with asthma, emphysema and chronic bronchitis. The respiratory effects and uses of these compounds are discussed more thoroughly in Chapter 27.
Dicyclomine, Oxybutynin, Solifenacin, Tolterodine, and Trospium
Dicyclomine is a synthetic tertiary amine used to relax intestinal smooth muscle and thereby relieve irritable bowel symptoms, such as intestinal cramping. Oxybutynin, tolterodine, darifenacin, solifenacin, and trospium are used to reduce the four major symptoms of overactive bladder: daytime urinary frequency, nocturia (frequent urination at night), urgency, and incontinence. Compared to other muscarinic receptor antagonists, darifenacin, solifenacin, tolterodine, and trospium appear to have a more selective action on the urinary bladder and cause fewer adverse effects such as dry mouth and blurred vision. These “uroselective” blockers are administered once or twice daily.
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