The subtypes of cholinoreceptors are set forth in Table 5–1.
At present, subtype-selective agonists for the muscarinic receptors
are not clinically available. Direct-acting nicotinic agonists may
be classified on the basis of whether ganglionic (NN) or
neuromuscular (NM) stimulation predominates, but agonist
selectivity is very limited. Several molecular mechanisms for receptor
signaling have been identified for muscarinic receptors (Table 5–1).
In general, these receptors modulate the formation of second messengers
or the activity of ion channels. In contrast, all nicotinic receptors
cause the opening of a channel selective for sodium and potassium that
results in cellular depolarization. This signaling mechanism occurs
in the autonomic ganglia and at the neuromuscular junction.
Direct-acting cholinoceptor agonists are classified pharmacologically
by the type of receptor—muscarinic or nicotinic—that
is activated (Figure 5–1). Direct-acting agonists’ physiologic
effects are the result of their interaction with either the muscarinic
or nicotinic receptors. Indirect-acting agonists are classified
as such because they inhibit the hydrolysis and inactivation of
endogenous acetylcholine (Figure 5–1). This increases the
concentration of acetylcholine in the synapse and augments acetylcholine
binding to receptors. Indirect-acting agonists are less specific
in their stimulation of muscarinic compared to nicotinic receptors.
The spectrum of action of direct- and indirect-acting cholinomimetic drugs and a summary of their pharmacokinetics are outlined in Table
Direct-acting agonists are divided into two groups based on chemical
structure. The first group consists of choline esters, typified
by acetylcholine,carbachol, and bethanechol. The second group includes
naturally occurring alkaloids such as nicotine,
muscarine, and pilocarpine. Further
classification is based on whether muscarinic or nicotinic receptor
In general, direct-acting muscarinic agonists are parasympathomimetics
in that they mimic stimulation of the parasympathetic system (Table
5–3). One exception is that these agents will also stimulate
muscarinic receptors located on eccrine sweat glands which are responsible
for thermoregulation and are under sympathetic, not parasympathetic,
nerve control. Additionally, vasodilation is observed with clinical
use of these drugs; however, this is not a parasympathetic response.
The vasodilation is the result of the release of endothelium-derived
relaxing factor (EDRF) from uninnervated muscarinic receptors on
endothelial cells lining the vascular walls. This vasodilation may
result in a decrease in blood pressure.
Table 5–3. Effects
of Cholinoceptor Stimulation1 ||Download (.pdf)
Table 5–3. Effects
of Cholinoceptor Stimulation1
|Central nervous system||Complex stimulatory effects: mild alerting reaction (nicotinic), tremor, emesis, excitation
of respiratory centers, convulsions|
|Autonomic nervous system||Complex stimulatory effects: stimulation of autonomic ganglia
results in either parasympathetic or sympathetic response depending on
each organ system (nicotinic), stimulation of target organ see below
|Sphincter muscle of iris||Contraction (miosis)|
|Ciliary muscle||Contraction for near vision (accommodation, cyclospasm)|
|Sinoatrial node||Decrease in rate (negative chronotropy)|
|Atria||Decrease in contractile strength (negative inotropy); decrease
in refractory period|
|Atrioventricular node||Decrease in conduction velocity (negative dromotropy); decrease
in refractory period|
|Ventricles||Small decrease in contractile strength|
|Blood vessels||Dilation (via EDRF2)|
|Sphincters||Relaxation (via enteric nervous system)|
|Trigone and sphincter||Relaxation|
|Glands||Increased secretion: thermoregulatory sweat, lacrimal, salivary, bronchial, gastric, intestinal glands|
|Skeletal muscle||Activation of neuromuscular end plates; contraction of muscle|
The physiologic response for nicotinic receptor stimulation is
dependent upon whether NM or NN receptors are
activated. The tissue and organ level effects of NN receptor
stimulation in the ganglia depends on the organ system involved.
The blood vessels are dominated by sympathetic innervation; therefore,
nicotinic receptor activation of postganglionic neurons results
in vasoconstriction. In contrast, the gastrointestinal (GI) system
is dominated by parasympathetic control. Here stimulation of postganglionic
neurons results in an increased motility and secretion. Stimulation
of NM receptors at the neuromuscular junction when activated
by direct-acting nicotinic agonists results in fasciculations and
muscle spasms. Prolonged stimulation of NM receptors results
in desensitization of the receptors and muscle paralysis. The latter
event is a hazard of pesticides containing nicotine.
A summary of the clinical applications of direct-acting muscarinic
and nicotinic agonists is presented in Table 5–4.
Table 5–4. Clinical
Applications of Some Cholinomimetics ||Download (.pdf)
Table 5–4. Clinical
Applications of Some Cholinomimetics
|Postoperative and neurogenic ileus and urinary retention||Bethanechol||Activates bowel and bladder smooth muscle|
|Glaucoma||Carbachol||Activates pupillary sphincter and ciliary muscles of eye|
|Glaucoma, Sjögren’s syndrome||Pilocarpine||Activates pupillary sphincter andciliary muscle of eye; stimulates
|Smoking deterrence (patch, chewing gum)||Nicotine||Replaces rapid-onset actions (cigarette) with slower action|
|Postoperative and neurogenic ileus and urinary retention||Neostigmine||Amplifies endogenous ACh|
|Myasthenia gravis, reversal of neuromuscular blockade||Neostigmine, pyridostigmine, edrophonium||Amplifies endogenous ACh|
|Glaucoma||Physostigmine, echothiophate||Amplifies effects of ACh|
|Alzheimer dementia||Tacrine, donepezil, galantamine, rivastigmine||Amplifies effects of ACh in the CNS|
Muscarinic agonists find a wide clinical application. In glaucoma,
these drugs decrease intraocular pressure. They also assist in micturition
in the hypotonic bladder after surgery or neurologic damage. In
contrast, nicotinic agonists find limited clinical application except
in tobacco abstention. The use of succinylcholine to provide skeletal
muscle paralysis as an adjuvant to general anesthesia is related
to inhibition at the neuromuscular junction. This drug will be discussed
with the nicotinic antagonists in the last section of this chapter.
The adverse effects associated with stimulation of muscarinic
or nicotinic receptors vary depending upon the organ system. For
muscarinic agonists, these include both central nervous system (CNS)
and peripheral tissue responses. The CNS effect may include generalized
stimulation resulting in hallucinations or seizures. In the
eye, miosis and spasm of ocular accommodation may occur. At
higher doses, the peripheral responses may be generalized to excessive
parasympathomimetic stimulation with bronchoconstriction and excessive
mucus production, gastrointestinal distress, hyperactivity of the
detrusor muscle of the bladder with increased frequency of voiding,
and hypotension. Bradycardia may occur, but the hypotension
usually evokes a reflex tachycardia. Finally, stimulation of muscarinic receptors
on the eccrine sweat glands, which are under sympathetic control,
may result in sweating.
Nicotinic agonists acting within the CNS may initiate seizures,
coma, and respiratory depression. In the peripheral tissues, stimulation
of the autonomic NN receptors results in either parasympathetic
or sympathetic manifestations, depending upon the organ system,
as previously discussed. Significant clinical manifestations may
include hypertension and cardiac arrhythmias. Prolonged stimulation
of the NM receptors at the neuromuscular junction and subsequent
muscle paralysis leads to decreased respiratory muscle function
and hypoventilation. The chronic exposure to nicotine associated
with tobacco use may result in additional pathophysiologic manifestations.
Nicotine has a strong addictive potential. Chronic use of nicotine
has an association with cancer, increased gastrointestinal ulcers,
and increased risk of vascular disease and sudden coronary death.
Indirect-acting cholinergic agonists fall into three major classes
based on chemical structure and duration of effect (Figure 5–1).
These classes are alcohols (e.g., edrophonium),
carbamates (e.g., neostigmine) and
organophosphates (e.g., echothiophate).
Both the carbamate and organophosphate classes bind to acetylcholinesterase
and undergo hydrolysis. Following this enzymatic activity, the metabolite
is released slowly, preventing the binding and inactivation of acetylcholine.
The carbamates are released over a period of hours, whereas the
organophosphates require days to weeks to be released by the acetylcholinesterase. The
alcohol class (edrophonium) binds to the active site electrostatically
and by hydrogen bonds. The binding is short lived—on the
order of minutes. Based on the binding, all three classes may be
considered pseudoirreversible antagonists of acetylcholinesterase.
Finally, some drugs in this class also have some direct-acting agonist
activity. For example, neostigmine both inhibits acetylcholinesterase
and directly activates the postsynaptic NM receptor at
the neuromuscular junction.
By inhibiting acetylcholinesterase, indirect-acting cholinergic
agonists amplify the actions of endogenous acetylcholine at both
muscarinic and nicotinic synapses. Thus, these drugs may augment
sympathetic or parasympathetic functions in the peripheral tissues.
The response varies based on the organ system. In the GI tract,
bladder, and lungs, parasympathetic activity predominates. At the
neuromuscular junction, these drugs increase the force of muscle
contractions, followed by fasciculations at higher concentrations,
and ending ultimately with paralysis. Finally, cholinergic activity
in the CNS parallels what was previously described for the direct-acting
cholinergic agonists (Table 5–3). The one exception to
this parallelism is that the indirectly acting drugs do not normally
cause vasodilation because endothelial cells are not innervated,
and do not release EDRF when these drugs are administered.
The clinical use of indirect-acting agonists differs somewhat
from the direct-acting muscarinic and nicotinic agonists. The carbamates
receive wider clinical use compared to the organophosphates. The
clinical use of the alcohol edrophonium is limited because of the
short action of the drug (5–15 minutes). Unique to these
indirect-acting agonists is their use in the treatment of myasthenia gravis
and dementia (Table 5–4). Direct-acting muscarinic or nicotinic
agonists are not currently in clinical use for either of these conditions.
The clinical hazards of indirect-acting agonists parallel those
of the direct-acting agonists with the following exceptions. First,
vasodilation is late and uncommon, and bradycardia is more common than
reflex tachycardia. The CNS manifestations are common following
organophosphate overdose, with convulsions followed by respiratory
and cardiovascular depression. A mnemonic for remembering the spectrum
of adverse effects is DUMBBELSS (diarrhea, urination, miosis, bronchoconstriction,
bradycardia, excitation of skeletal muscle and the CNS, lacrimation,
salivation, and sweating). As with nicotinic agonists, prolonged
stimulation of the NM receptors at the neuromuscular junction
results in muscle paralysis, and is a hazard of pesticides containing
these indirect-acting agonists.