Page 145 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 8 Cholinoceptor-Blocking Drugs 131

tight collar. Such individuals may benefit from the judicious use TABLE 8–3 Antimuscarinic drugs used in
of atropine or a related antimuscarinic agent. gastrointestinal and genitourinary
Pathophysiology can influence muscarinic activity in other conditions.
ways as well. Circulating autoantibodies against the second
extracellular loop of cardiac M muscarinic receptors have been Drug Usual Dosage
2
detected in some patients with idiopathic dilated cardiomyopathy Quaternary amines
and those afflicted with Chagas’ disease caused by the protozoan Anisotropine 50 mg tid
Trypanosoma cruzi. Patients with Graves’ disease (hyperthyroidism) Clidinium 2.5 mg tid–qid
also have such autoantibodies that may facilitate the development
of atrial fibrillation. These antibodies exert parasympathomimetic Mepenzolate 25–50 mg qid
actions on the heart that are prevented by atropine. In animals Methscopolamine 2.5 mg qid
immunized with a peptide from the second extracellular loop of Oxyphenonium 5–10 mg qid
the M receptor, the antibody is an allosteric modulator of the Propantheline 15 mg qid
2
receptor. Although their role in the pathology of heart diseases is Trospium 20 mg bid
unknown, these antibodies have provided clues to the molecular Tertiary amines
basis of receptor activation because their site of action differs from
the orthosteric site where acetylcholine binds (see Chapter 2) and Atropine 0.4 mg tid–qid
they favor the formation of receptor dimers. Darifenacin 7.5 mg daily
Dicyclomine 10–20 mg qid
E. Gastrointestinal Disorders Oxybutynin 5 mg tid
Antimuscarinic agents were used for peptic ulcer disease in the Scopolamine 0.4 mg tid
USA but are now obsolete for this indication (see Chapter 62). Solifenacin 5 mg daily
Antimuscarinic agents can provide some relief in the treatment of Tolterodine 2 mg bid
common traveler’s diarrhea and other mild or self-limited condi-
tions of hypermotility. They are often combined with an opioid
antidiarrheal drug, an extremely effective therapy. In this combi- antagonist, has been approved and is comparable in efficacy and
nation, however, the very low dosage of the antimuscarinic drug adverse effects to oxybutynin. Darifenacin and solifenacin are
functions primarily to discourage abuse of the opioid agent. The antagonists that have greater selectivity for M receptors than
3
classic combination of atropine with diphenoxylate, a nonanalge- oxybutynin or trospium. Darifenacin and solifenacin have the
sic congener of meperidine, is available under many names (eg, advantage of once-daily dosing because of their long half-lives.
Lomotil) in both tablet and liquid form (see Chapter 62).
Tolterodine and fesoterodine, M -selective antimuscarinics,
3
are available for use in adults with urinary incontinence. They
F. Urinary Disorders have many of the qualities of darifenacin and solifenacin and are
Atropine and other antimuscarinic drugs have been used to pro- available in extended-release tablets. Propiverine, a newer anti-
vide symptomatic relief in the treatment of urinary urgency caused muscarinic agent with efficacy comparable to other muscarinic
by minor inflammatory bladder disorders (Table 8–3). However, antagonists, has been approved for urinary incontinence in Europe
specific antimicrobial therapy is essential in bacterial cystitis. In but not in the USA. The convenience of the newer and longer-
the human urinary bladder, M and M receptors are expressed acting drugs has not been accompanied by improvements in over-
2
3
predominantly with the M subtype mediating direct activation all efficacy or by reductions in adverse effects such as dry mouth.
3
of contraction. As in intestinal smooth muscle, the M subtype Muscarinic antagonists have an adjunct role in therapy of benign
2
appears to act indirectly by inhibiting relaxation by norepineph- prostatic hypertrophy when bladder symptoms (increased urinary
rine and epinephrine. frequency) occur. Treatment with an α-adrenoceptor antagonist
Receptors for acetylcholine on the urothelium (the epithelial combined with a muscarinic antagonist resulted in a greater
lining of the urinary tract) and on afferent nerves as well as the reduction in bladder storage problems and urinary frequency than
detrusor muscle provide a broad basis for the action of antimus- treatment with an α-adrenoceptor antagonist alone.
carinic drugs in the treatment of overactive bladder. Oxybutynin, An alternative treatment for urinary incontinence refractory
receptors, is used to relieve to antimuscarinic drugs is intrabladder injection of botulinum
which is somewhat selective for M 3
bladder spasm after urologic surgery, eg, prostatectomy. It is also toxin A. Botulinum toxin A is reported to reduce urinary incon-
valuable in reducing involuntary voiding in patients with neuro- tinence for several months after a single treatment by interfer-
logic disease, eg, children with meningomyelocele. Oral oxybu- ing with the co-release of ATP with neuronal acetylcholine (see
tynin or instillation of the drug by catheter into the bladder in Figure 6–3). Blockade of the activation by ATP of purinergic
such patients appears to improve bladder capacity and continence receptors on sensory nerves in the urothelium may account for a
and to reduce infection and renal damage. Transdermally applied large part of this effect. Botulinum toxin has been approved for
oxybutynin or its oral extended-release formulation reduces use in patients who do not tolerate or are refractory to antimus-
the need for multiple daily doses. Trospium, a nonselective carinic drugs.