Page 132 - Basic _ Clinical Pharmacology ( PDFDrive )

118 SECTION II Autonomic Drugs

nervous system, are qualitatively quite similar to the effects of the ■ CLINICAL PHARMACOLOGY
direct-acting cholinomimetics (Table 7–3).
OF THE CHOLINOMIMETICS
3. Cardiovascular system—The cholinesterase inhibitors can
increase activity in both sympathetic and parasympathetic ganglia The major therapeutic uses of the cholinomimetics are to treat
supplying the heart and at the acetylcholine receptors on neuroef- diseases of the eye (glaucoma, accommodative esotropia), the gas-
fector cells (cardiac and vascular smooth muscles) that receive trointestinal and urinary tracts (postoperative atony, neurogenic
cholinergic innervation. bladder), and the neuromuscular junction (myasthenia gravis,
In the heart, the effects on the parasympathetic limb pre- curare-induced neuromuscular paralysis), and to treat patients
dominate. Thus, cholinesterase inhibitors such as edrophonium, with Alzheimer’s disease. Cholinesterase inhibitors are occasionally
physostigmine, or neostigmine mimic the effects of vagal nerve used in the treatment of atropine overdosage and, very rarely, in
activation on the heart. Negative chronotropic, dromotropic, and the therapy of certain atrial arrhythmias.
inotropic effects are produced, and cardiac output falls. The fall
in cardiac output is attributable to bradycardia, decreased atrial Clinical Uses
contractility, and some reduction in ventricular contractility. The A. The Eye
latter effect occurs as a result of prejunctional inhibition of nor-
epinephrine release as well as inhibition of postjunctional cellular Glaucoma is a disease characterized by increased intraocular pres-
sympathetic effects. sure. Muscarinic stimulants and cholinesterase inhibitors reduce
Cholinesterase inhibitors have minimal effects by direct action intraocular pressure by causing contraction of the ciliary body
on vascular smooth muscle because most vascular beds lack so as to facilitate outflow of aqueous humor and perhaps also by
cholinergic innervation (coronary vasculature is an exception). diminishing the rate of its secretion (see Figure 6–9). In the past,
At moderate doses, cholinesterase inhibitors cause an increase in glaucoma was treated with either direct agonists (pilocarpine,
systemic vascular resistance and blood pressure that is initiated at methacholine, carbachol) or cholinesterase inhibitors (physostig-
sympathetic ganglia in the case of quaternary nitrogen compounds mine, demecarium, echothiophate, isoflurophate). For chronic
and also at central sympathetic centers in the case of lipid-soluble glaucoma, these drugs have been largely replaced by prostaglandin
agents. Atropine, acting in the central and peripheral nervous sys- derivatives and topical β-adrenoceptor antagonists.
tems, can prevent the increase of blood pressure and the increased Acute angle-closure glaucoma is a medical emergency that is
plasma norepinephrine. frequently treated initially with drugs but usually requires sur-
The net cardiovascular effects of moderate doses of cholines- gery for permanent correction. Initial therapy often consists of a
terase inhibitors therefore consist of modest bradycardia, a fall in combination of a direct muscarinic agonist (eg, pilocarpine) and
cardiac output, and an increased vascular resistance that results in other drugs. Once the intraocular pressure is controlled and the
a rise in blood pressure. (Thus, in patients with Alzheimer’s disease danger of vision loss is diminished, the patient can be prepared
who have hypertension, treatment with cholinesterase inhibitors for corrective surgery (laser iridotomy). Open-angle glaucoma and
requires that blood pressure be monitored to adjust antihyperten- some cases of secondary glaucoma are chronic diseases that are not
sive therapy.) At high (toxic) doses of cholinesterase inhibitors, amenable to traditional surgical correction, although newer laser
marked bradycardia occurs, cardiac output decreases significantly, techniques appear to be useful. Other treatments for glaucoma are
and hypotension supervenes. described in the Box: The Treatment of Glaucoma in Chapter 10.
Accommodative esotropia (strabismus caused by hypermetro-
4. Neuromuscular junction—The cholinesterase inhibitors pic accommodative error) in young children is sometimes diag-
have important therapeutic and toxic effects at the skeletal nosed and treated with cholinomimetic agonists. Dosage is similar
muscle neuromuscular junction. Low (therapeutic) concentrations to or higher than that used for glaucoma.
moderately prolong and intensify the actions of physiologically
released acetylcholine. This increases the strength of contraction, B. Gastrointestinal and Urinary Tracts
especially in muscles weakened by curare-like neuromuscular In clinical disorders that involve depression of smooth muscle
blocking agents or by myasthenia gravis. At higher concentra- activity without obstruction, cholinomimetic drugs with direct or
tions, the accumulation of acetylcholine may result in fibrillation indirect muscarinic effects may be helpful. These disorders include
of muscle fibers. Antidromic firing of the motor neuron may also postoperative ileus (atony or paralysis of the stomach or bowel fol-
occur, resulting in fasciculations that involve an entire motor lowing surgical manipulation) and congenital megacolon. Urinary
unit. With marked inhibition of acetylcholinesterase, depolarizing retention may occur postoperatively or postpartum or may be sec-
neuromuscular blockade occurs and that may be followed by a ondary to spinal cord injury or disease (neurogenic bladder). Cho-
phase of nondepolarizing blockade as seen with succinylcholine linomimetics were also sometimes used to increase the tone of the
(see Table 27–2 and Figure 27–7). lower esophageal sphincter in patients with reflux esophagitis but
Some quaternary carbamate cholinesterase inhibitors, eg, neo- proton pump inhibitors are usually indicated (see Chapter 62). Of
stigmine and pyridostigmine, have an additional direct nicotinic the choline esters, bethanechol is the most widely used for these
agonist effect at the neuromuscular junction. This may contribute disorders. For gastrointestinal problems, it is usually administered
to the effectiveness of these agents as therapy for myasthenia. orally in a dose of 10–25 mg three or four times daily. In patients