Page 367 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 353

The larger doses necessary for more effective bronchodilation and reverse fatigue of the diaphragm in patients with COPD.
cause nervousness and tremor. Very high doses, from accidental or This effect—rather than an effect on the respiratory center—may
suicidal overdose, can cause medullary stimulation, convulsions, account for theophylline’s ability to improve the ventilatory
and even death. response to hypoxia and to diminish dyspnea even in patients with
irreversible airflow obstruction.
B. Cardiovascular Effects
Methylxanthines have positive chronotropic and inotropic effects Clinical Uses
on the heart. At low concentrations, these effects result from Of the xanthines, theophylline is the most effective bronchodila-
inhibition of presynaptic adenosine receptors in sympathetic tor. It relieves airflow obstruction in acute asthma and reduces the
nerves, increasing catecholamine release at nerve endings. The severity of symptoms in patients with chronic asthma. However,
higher concentrations (>10 μmol/L, 2 mg/L) associated with the efficacy and safety of other drugs, especially inhaled β -
2
inhibition of phosphodiesterase and increases in cAMP may result agonists and inhaled corticosteroids, and the toxicities and need
in increased influx of calcium. At much higher concentrations for monitoring of blood concentration of theophylline have made
(>100 μmol/L), sequestration of calcium by the sarcoplasmic it almost obsolete in asthma treatment.
reticulum is impaired.
The clinical expression of these effects on cardiovascular
function varies among individuals. Ordinary consumption of ANTIMUSCARINIC AGENTS
methylxanthine-containing beverages usually produces slight
tachycardia, an increase in cardiac output, and an increase in Observation of the use of leaves from Datura stramonium for
peripheral resistance, potentially raising blood pressure slightly. asthma treatment in India led to the discovery of atropine, a
In sensitive individuals, consumption of a few cups of coffee may potent competitive inhibitor of acetylcholine at postganglionic
result in arrhythmias. High doses of these agents relax vascular muscarinic receptors, as a bronchodilator. Interest in the potential
smooth muscle except in cerebral blood vessels, where they cause value of antimuscarinic agents increased with demonstration of
contraction. the importance of the vagus nerves in bronchospastic responses
Methylxanthines decrease blood viscosity and may improve of laboratory animals and with the development of ipratropium,
blood flow under certain conditions. The mechanism of this a potent atropine analog that is poorly absorbed after aerosol
action is not well defined, but the effect is exploited in the treat- administration and is therefore relatively free of systemic atropine-
ment of intermittent claudication with pentoxifylline, a dimeth- like effects.
ylxanthine agent.
Mechanism of Action
C. Effects on Gastrointestinal Tract
The methylxanthines stimulate secretion of both gastric acid Muscarinic antagonists competitively inhibit the action of ace-
and digestive enzymes. However, even decaffeinated coffee has a tylcholine at muscarinic receptors and are therefore sometimes
potent stimulant effect on secretion, which means that the pri- referred to as “anticholinergic agents” (see Chapter 8). In the air-
mary secretagogue in coffee is not caffeine. ways, acetylcholine is released from efferent endings of the vagus
nerve, and muscarinic antagonists block the contraction of airway
D. Effects on Kidney smooth muscle and the increase in secretion of mucus that occurs
The methylxanthines—especially theophylline—are weak diuret- in response to vagal activity (Figure 20–6). This selectivity of
ics. This effect may involve both increased glomerular filtration muscarinic antagonists accounts for their usefulness as investiga-
and reduced tubular sodium reabsorption. The diuresis is not of tive tools to examine the role of parasympathetic reflex pathways
sufficient magnitude to be therapeutically useful, although it does in bronchomotor responses but limits their usefulness in prevent-
counteract some of the cardiovascular effects and limits the degree ing bronchospasm. In the doses given, antimuscarinic agents
of hypertension produced. inhibit only that portion of the response mediated by muscarinic
receptors, which varies by stimulus and which further appears to
E. Effects on Smooth Muscle vary among individual responses to the same stimulus.
The bronchodilation produced by the methylxanthines is the
major therapeutic action in asthma. Tolerance does not develop, Clinical Uses
but adverse effects, especially in the central nervous system, limit Antimuscarinic agents are effective bronchodilators. Even when
the dose (see below). In addition to their effect on airway smooth administered by aerosol, the bronchodilation achievable with
muscle, these agents—in sufficient concentration—inhibit anti- atropine, the prototypic muscarinic antagonist, is limited by
gen-induced release of histamine from lung tissue. absorption into the circulation and across the blood-brain barrier.
Greater bronchodilation, with less toxicity from systemic absorp-
F. Effects on Skeletal Muscle tion, is achieved with a selective quaternary ammonium derivative
The respiratory actions of methylxanthines are not confined to of atropine, ipratropium bromide, which can be inhaled in high
the airways; they also improve contractility of skeletal muscle doses because of its poor absorption into the circulation and poor