-BLOCKING ACTIVITY Labetalol
3. D. What is shown is an increase in pressure caused by norepinephrine and the reduction of the effect
by drug X. Therefore, drug X is an antagonist of norepinephrine. Two of the choices are adrenocep-tor antagonists, prazosin and propranolol, which are
- and -receptor antagonists, respectively. The adrenoceptors that mediate vasoconstriction are -receptors. Therefore, prazosin, the -blocker, is the correct choice. Cocaine, because it blocks neuronal uptake of norepinephrine, would actually enhance the response to this catecholamine, as would guanethidine, because it also blocks neuronal up-take of norepinephrine. Atropine is a muscarinic re-ceptor antagonist and would not affect responses to norepinephrine.
4. C. The vasodilation produced by drug Y is antago-nized by timolol, a -receptor antagonist. Although bradykinin, histamine, acetylcholine, and terenol will all cause vasodilation, only isopro-terenol does so by activating -receptors.
Phenylephrine is a sympathomimetic that is
selec-tive for -receptors and would be expected to in-crease, rather than dein-crease, perfusion pressure.
5. A. Both sets of responses to isoproterenol are me-diated by -adrenoceptors, and all the choices are
-antagonists. However, drug X is more effective in antagonizing cardiac responses to isoproterenol than it is the bronchiolar responses. Drug X is therefore a cardioselective -blocker, that is, selec-tive for 1over 2receptors. Metoprolol is the only
1-selective antagonist among the choices.
S U P P L E M E N TA L R E A D I N G
Brodde O-E.1- and 2-adrenoceptors in the human heart: Properties, function, and alterations in chronic heart failure. Pharmacol Rev 1991;43:203–242.
Brooks AM and Gillies WE. Ocular beta blockers in glaucoma management: Clinical pharmacology as-pects. Drugs Aging 1992;2:208–221.
Bylund DB et al. Nomenclature of adrenoceptors.
Pharmacol Rev 1994;46:1211–1236.
Cruickshank JM and Prichard BNC. Beta-Blockers in Clinical Practice (2nd ed). London: Churchill Livingstone, 1994.
Harrison JK et al. Molecular characterization of
1- and 2- adrenoceptors. Trends Pharmacol Sci 1991;12:62–67.
Lonnqvist F et al. Evidence for a functional 3 -adreno-ceptor in man. Br J Pharmacol 1993;110:929–936.
Piascik MT and Perez DM. Alpha 1-adrenergic recep-tors: New insights and directions. J Pharmacol Exp Ther 2001;298:403–410.
Ruffolo RR Jr. et al. Structure and function of -adrenoceptors. Pharmacol Rev 1991;43:475–505.
120 II DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM
C a s e
S t u d y
Cardiopulmonary Complications of EyedropsA
61-year-old man with congenital heart disease and a history of chronic congestive heart fail-ure was seen by an ophthalmologist for a routine eye examination. In general, the patient’s health was reasonable and cardiac output was well com-pensated. During the examination, the physician found that the patient had open-angle glaucoma that required treatment to reduce the pressure in the eye. The ophthalmologist prescribed one eye-drop twice daily in each eye. Several months later the patient began to gain weight, became dyspneic and complained of “asthmatic attacks.” An exami-nation showed bronchospasm and severe congestive heart failure with a slow ventricular rate.Gastrointestinal function was normal. The eyedrops were stopped and the patient’s condition stabilized.
Is it possible that the eyedrops were responsible for the development of cardiopulmonary complications, and if so, what is a likely offending drug?
ANSWER:The finding that the patient’s symptoms sub-sided after terminating the treatment certainly im-plicates the eyedrops in precipitating the congestive heart failure. Although it is unusual to absorb enough drug through the eye to produce systemic effects, it does happen and physicians should be aware of it. The usual classes of drugs used to treat open-angle glaucoma include the carbonic anhy-drase inhibitors (e.g., acetazolamide), cholinergic
miotic agents (e.g., pilocarpine),-adrenoceptor an-tagonists (e.g., timolol), and epinephrinelike drugs.
Acetazolamide is unlikely to be the offending agent because it is usually administered orally. The clinical symptoms in this patient, including the bronchocon-striction and slow heart rate, are not consistent with the actions of epinephrine, which would be ex-pected to cause bronchodilation and an increase in heart rate.
Pilocarpine, a naturally occurring cholino-mimetic, and timolol, a -blocking agent, both should be considered. Pilocarpine, because of its ag-onistic effect at muscarinic receptors, can cause bronchoconstriction and precipitate an asthmatic attack;-blockers, such as timolol, should always be used with caution in an asthmatic patient and are known to worsen symptoms in some individuals with congestive heart failure. The weight gain in this patient, due to edema, and the dyspnea, due to pul-monary congestion, are classic signs of congestive heart failure and can be caused in a susceptible in-dividual by a -blocker. The slow heart rate is also consistent with either a -blocker or use of pilo-carpine. One might have expected gastrointestinal disturbances if the reaction to the glaucoma med-ication was due to the systemic accumulation of pi-locarpine. All in all, the most likely choice is a -blocker, and a different class of drug should be used to treat the glaucoma in this patient.
121
Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces. This class of drugs includes agents that act directly as agonists at cholinoreceptors and agents that act indirectly by in-hibiting the enzymatic destruction of endogenous ACh (i.e., cholinesterase inhibitors). The directly acting choli-nomimetics can be subdivided into agents that exert their effects primarily through stimulation of mus-carinic receptors at parasympathetic neuroeffector junctions (parasympathomimetic drugs) and agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction (see Chapter 9). This chapter focuses on the parasympathomimetic drugs and cholinesterase inhibitors. Drugs acting at nicotinic re-ceptors are presented in Chapters 14 and 28.
Muscarinic Receptors and Signal Transduction
Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid iso-lated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings, from which the general notion that muscarinic agonists have parasympatho-mimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic re-ceptors have a broader distribution and many func-tional roles. To understand the actions of choli-nomimetic drugs it is essential to recognize that muscarinic receptors: (1) mediate the activation of ef-fectors by ACh released from parasympathetic nerve D R U G L I S T
Directly and Indirectly Acting Cholinomimetics
William F. Wonderlin
12 12
GENERIC NAME PAGE
Acetylcholine 122
Ambenonium 126
Bethanechol 123
Carbachol 123
Demecarium 130
Donepezil 128
Echothiophate 130
Edrophonium 126
Galanthamine 128
GENERIC NAME PAGE
Isofluorophate 127
Methacholine 123
Neostigmine 130
Physostigmine 130
Pilocarpine 123
Pralidoxime 131
Pyridostigmine 127
Rivastigmine 127
Tacrine 128
endings; (2) mediate the activation of sweat glands by ACh released from sympathetic fibers; (3) are found on vascular endothelial cells that receive no cholinergic in-nervation; (4) are widely distributed in the central ner-vous system (CNS), from basal ganglia to neocortex; and (5) are present on presynaptic nerve terminals, including terminals that release ACh and terminals associated with other neurotransmitter systems, such as the cate-cholamines. Therefore, the activation of muscarinic re-ceptors may influence most of the organ systems along with CNS pathways involved in regulating voluntary motor activity, memory, and cognition. Activation of presynaptic muscarinic receptors can inhibit the release of endogenous neurotransmitters, and may account for some paradoxical effects of cholinomimetic stimulation.
Binding studies with high-affinity receptor antago-nists revealed four subtypes of muscarinic receptors that can be distinguished on the basis of (1) the rank or-der of potency of specific antagonists in functional ex-periments and (2) the affinity of these antagonists for muscarinic receptors in the same tissues. More recently, molecular studies have revealed five genetically distinct receptor subtypes, named M1 through M5, the first four of which correspond to functionally defined receptors.
The different subtypes of muscarinic receptors are het-erogeneously distributed: (1) M1 receptors are present in brain, exocrine glands, and autonomic ganglia. (2) M2 receptors are found in the heart, brain, autonomic gan-glia, and smooth muscle. (3) M3 receptors are present in smooth muscle, exocrine glands, brain, and endothelial cells. (4) M4 receptors are present in brain and auto-nomic ganglia. (5) M5 receptors are found in the CNS.
All muscarinic receptors are members of the seven transmembrane domain, G protein–coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic re-ceptors by an agonist triggers the release of an intracel-lular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently dis-tinguished. Activation of M1, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated re-lease of intracellular calcium, the rere-lease of diacylglyc-erol (which can activate protein kinase C), and stimula-tion of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle.
Activation of M2 and M4 receptors inhibits adeny-lyl cyclase, and activation of M2 receptors opens potas-sium channels. The opening of potaspotas-sium channels hy-perpolarizes the membrane potential and decreases the excitability of cells in the sinoatrial (SA) and atrioven-tricular (A-V) nodes in the heart. The inhibition of adenylyl cyclase decreases cellular cyclic adenosine
monophosphate (cAMP) levels, which can override the opposing stimulation of adenylyl cyclase by -adreno-ceptor agonists.
Although muscarinic receptors as a class can be se-lectively activated and they demonstrate strong stereo-selectivity among both agonists and antagonists (see Chapter 13), the therapeutic use of cholinomimetics is limited by the paucity of drugs selective for specific sub-types of muscarinic receptors. This lack of specificity combined with the broad-ranging effects of muscarinic stimulation on different organ systems makes the ther-apeutic use of cholinomimetic drugs a challenge, and the careful consideration of the pharmacokinetic prop-erties of the drugs plays an especially important role in making therapeutic decisions.