Page 129 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 115

resembles simultaneous discharge of both the parasympathetic ■ BASIC PHARMACOLOGY
and sympathetic nervous systems. In the case of the cardiovascu-
lar system, the effects of nicotine are chiefly sympathomimetic. OF THE INDIRECT-ACTING
Dramatic hypertension is produced by parenteral injection of CHOLINOMIMETICS
nicotine; sympathetic tachycardia may alternate with a brady-
cardia mediated by vagal discharge. In the gastrointestinal and The actions of acetylcholine released from autonomic and somatic
urinary tracts, the effects are largely parasympathomimetic: motor nerves are terminated by enzymatic hydrolysis of the mol-
nausea, vomiting, diarrhea, and voiding of urine are commonly ecule. Hydrolysis is accomplished by the action of acetylcholin-
observed. Prolonged exposure may result in depolarizing block- esterase, which is present in high concentrations in cholinergic
ade of the ganglia. synapses. The indirect-acting cholinomimetics have their primary
Primary autoimmune autonomic failure provides a patho- effect at the active site of this enzyme, although some also have
physiologic example of the effects of suppression of nicotinic direct actions at nicotinic receptors. The chief differences between
receptor function at autonomic ganglia. In some patients, members of the group are chemical and pharmacokinetic—their
neither diabetic neuropathy nor amyloidosis can account for pharmacodynamic properties are almost identical.
the autonomic failure. In those individuals, circulating auto-
antibodies selective for the α3β4 nicotinic receptor subtype Chemistry & Pharmacokinetics
are present and cause orthostatic hypotension, reduced sweat-
ing, dry mouth and eyes, reduced baroreflex function, urinary A. Structure
retention, constipation, and erectile dysfunction. These signs There are three chemical groups of cholinesterase inhibitors:
of autonomic failure can be ameliorated by plasmapheresis, (1) simple alcohols bearing a quaternary ammonium group, eg,
which also reduces the concentration of autoantibodies to the edrophonium; (2) carbamic acid esters of alcohols having quater-
α3β4 nicotinic receptor. nary or tertiary ammonium groups (carbamates, eg, neostigmine);
Deletion of either the α3 or the β2 and β4 subunits causes and (3) organic derivatives of phosphoric acid (organophosphates,
widespread autonomic dysfunction and blocks the action of eg, echothiophate). Examples of the first two groups are shown in
nicotine in experimental animals. Humans deficient in α3 Figure 7–6. Edrophonium, neostigmine, and pyridostigmine are
subunits are afflicted with microcystis (inadequate develop- synthetic quaternary ammonium agents used in medicine. Physo-
ment of the urinary bladder), microcolon, intestinal hypo- stigmine (eserine) is a naturally occurring tertiary amine of greater
peristalsis syndrome; urinary incontinence, urinary bladder lipid solubility that is also used in therapeutics. Carbaryl (carbaril)
distention and mydriasis also occur. is typical of a large group of carbamate insecticides designed for
Neuronal nicotinic receptors are present on sensory nerve end- very high lipid solubility, so that absorption into the insect and
ings, especially afferent nerves in coronary arteries and the carotid distribution to its central nervous system are very rapid.
and aortic bodies as well as on the glomus cells of the latter. Acti- A few of the estimated 50,000 organophosphates are shown
vation of these receptors by nicotinic stimulants and of muscarinic in Figure 7–7. Many of the organophosphates (echothiophate is
receptors on glomus cells by muscarinic stimulants elicits complex an exception) are highly lipid-soluble liquids. Echothiophate, a
medullary responses, including respiratory alterations and vagal thiocholine derivative, is of clinical value because it retains the
discharge. very long duration of action of other organophosphates but is
more stable in aqueous solution. Sarin is an extremely potent
9. Neuromuscular junction—The nicotinic receptors on the “nerve gas.” Parathion and malathion are thiophosphate (sulfur-
neuromuscular end plate apparatus are similar but not identi- containing phosphate) prodrugs that are inactive as such; they are
cal to the receptors in the autonomic ganglia (Table 7–1). Both converted to the phosphate derivatives in animals and plants and
types respond to acetylcholine and nicotine. (However, as noted are used as insecticides.
in Chapter 8, the receptors differ in their structural requirements
for nicotinic blocking drugs.) When a nicotinic agonist is applied B. Absorption, Distribution, and Metabolism
directly (by iontophoresis or by intra-arterial injection), an imme- Absorption of the quaternary carbamates from the conjunctiva,
diate depolarization of the end plate results, caused by an increase skin, gut, and lungs is predictably poor, since their permanent
in permeability to sodium and potassium ions (Figure 7–4B). charge renders them relatively insoluble in lipids. Thus, much
The contractile response varies from disorganized fasciculations larger doses are required for oral administration than for paren-
of independent motor units to a strong contraction of the entire teral injection. Distribution into the central nervous system is
muscle depending on the synchronization of depolarization of end negligible. Physostigmine, in contrast, is well absorbed from all
plates throughout the muscle. Depolarizing nicotinic agents that sites and can be used topically in the eye (Table 7–4). It is distrib-
are not rapidly hydrolyzed (like nicotine itself) cause rapid devel- uted into the central nervous system and is more toxic than the
opment of depolarization blockade; transmission blockade persists more polar quaternary carbamates. The carbamates are relatively
even when the membrane has repolarized (discussed further in stable in aqueous solution but can be metabolized by nonspecific
Chapters 8 and 27). This latter phase of block is manifested as esterases in the body as well as by cholinesterase. However, the
flaccid paralysis in the case of skeletal muscle. duration of their effect is determined chiefly by the stability of