Drugs Acting on the Parasympathetic Nervous System

Parasympathetic Nervous System
Responses to activation of the parasympathetic
system. Parasympathetic
nerves regulate processes connected
with energy assimilation (food intake,
digestion, absorption) and storage.
These processes operate when the body
is at rest, allowing a decreased tidal volume
(increased bronchomotor tone)
and decreased cardiac activity. Secretion
of saliva and intestinal fluids promotes
the digestion of foodstuffs; transport
of intestinal contents is speeded up
because of enhanced peristaltic activity
and lowered tone of sphincteric muscles.
To empty the urinary bladder (micturition),
wall tension is increased by
detrusor activation with a concurrent
relaxation of sphincter tonus.
Activation of ocular parasympathetic
fibers (see below) results in narrowing
of the pupil and increased curvature
of the lens, enabling near objects to
be brought into focus (accommodation).
Anatomy of the parasympathetic
system. The cell bodies of parasympathetic
preganglionic neurons are located
in the brainstem and the sacral spinal
cord. Parasympathetic outflow is channelled
from the brainstem (1) through
the third cranial nerve (oculomotor n.)
via the ciliary ganglion to the eye; (2)
through the seventh cranial nerve (facial
n.) via the pterygopalatine and submaxillary
ganglia to lacrimal glands and
salivary glands (sublingual, submandibular),
respectively; (3) through the
ninth cranial nerve (glossopharyngeal
n.) via the otic ganglion to the parotid
gland; and (4) via the tenth cranial
nerve (vagus n.) to thoracic and abdominal
viscera. Approximately 75 % of all
parasympathetic fibers are contained
within the vagus nerve. The neurons of
the sacral division innervate the distal
colon, rectum, bladder, the distal ureters,
and the external genitalia.
Acetylcholine (ACh) as a transmitter.
ACh serves as mediator at terminals
of all postganglionic parasympathetic
fibers, in addition to fulfilling its transmitter
role at ganglionic synapses within
both the sympathetic and parasympathetic
divisions and the motor endplates
on striated muscle. However, different
types of receptors are present at
these synaptic junctions:


Cholinergic Synapse
Acetylcholine (ACh) is the transmitter
at postganglionic synapses of parasympathetic
nerve endings. It is highly concentrated
in synaptic storage vesicles
densely present in the axoplasm of the
terminal. ACh is formed from choline
and activated acetate (acetylcoenzyme
A), a reaction catalyzed by the enzyme
choline acetyltransferase. The highly
polar choline is actively transported into
the axoplasm. The specific choline transporter
is localized exclusively to membranes
of cholinergic axons and terminals.
The mechanism of transmitter release
is not known in full detail. The vesicles
are anchored via the protein synapsin
to the cytoskeletal network. This arrangement
permits clustering of vesicles
near the presynaptic membrane, while
preventing fusion with it. During activation
of the nerve membrane, Ca2+ is
thought to enter the axoplasm through
voltage-gated channels and to activate
protein kinases that phosphorylate synapsin.
As a result, vesicles close to the
membrane are detached from their anchoring
and allowed to fuse with the
presynaptic membrane. During fusion,
vesicles discharge their contents into the
synaptic gap. ACh quickly diffuses
through the synaptic gap (the acetylcholine
molecule is a little longer than
0.5 nm; the synaptic gap is as narrow as
30–40 nm). At the postsynaptic effector
cell membrane, ACh reacts with its receptors.
Because these receptors can also
be activated by the alkaloid muscarine,
they are referred to as muscarinic
(M-)cholinoceptors. In contrast, at ganglionic
and motor endplate
cholinoceptors, the action of ACh is
mimicked by nicotine and they are,
therefore, said to be nicotinic cholinoceptors.
Released ACh is rapidly hydrolyzed
and inactivated by a specific acetylcholinesterase,
present on pre- and postjunctional
membranes, or by a less specific
serum cholinesterase (butyryl cholinesterase),
a soluble enzyme present in
serum and interstitial fluid.
M-cholinoceptors can be classified
into subtypes according to their molecular
structure, signal transduction, and
ligand affinity. Here, the M1, M2, and M3
subtypes are considered. M1 receptors
are present on nerve cells, e.g., in ganglia,
where they mediate a facilitation of
impulse transmission from preganglionic
axon terminals to ganglion cells.
M2 receptors mediate acetylcholine effects
on the heart: opening of K+ channels
leads to slowing of diastolic depolarization
in sinoatrial pacemaker cells
and a decrease in heart rate. M3 receptors
play a role in the regulation of
smooth muscle tone, e.g., in the gut and
bronchi, where their activation causes
stimulation of phospholipase C, membrane
depolarization, and increase in
muscle tone. M3 receptors are also
found in glandular epithelia, which similarly
respond with activation of phospholipase
C and increased secretory activity.
In the CNS, where all subtypes are
present, cholinoceptors serve diverse
functions, including regulation of cortical
excitability, memory, learning, pain
processing, and brain stem motor control.
The assignment of specific receptor
subtypes to these functions has yet to be
achieved.
In blood vessels, the relaxant action
of ACh on muscle tone is indirect, because
it involves stimulation of M3-cholinoceptors
on endothelial cells that respond
by liberating NO (= endotheliumderived
relaxing factor). The latter diffuses
into the subjacent smooth musculature,
where it causes a relaxation of
active tonus.



Parasympathomimetics
Acetylcholine (ACh) is too rapidly hydrolyzed
and inactivated by acetylcholinesterase
(AChE) to be of any therapeutic
use; however, its action can be mimicked
by other substances, namely direct
or indirect parasympathomimetics.
Direct Parasympathomimetics.
The choline ester, carbachol, activates
M-cholinoceptors, but is not hydrolyzed
by AChE. Carbachol can thus be effectively
employed for local application to
the eye (glaucoma) and systemic administration
(bowel atonia, bladder atonia).
The alkaloids, pilocarpine (from Pilocarpus
jaborandi) and arecoline (from
Areca catechu; betel nut) also act as direct
parasympathomimetics. As tertiary
amines, they moreover exert central effects.
The central effect of muscarinelike
substances consists of an enlivening,
mild stimulation that is probably
the effect desired in betel chewing, a
widespread habit in South Asia. Of this
group, only pilocarpine enjoys therapeutic
use, which is limited to local application
to the eye in glaucoma.
Indirect Parasympathomimetics.
AChE can be inhibited selectively, with
the result that ACh released by nerve
impulses will accumulate at cholinergic
synapses and cause prolonged stimulation
of cholinoceptors. Inhibitors of
AChE are, therefore, indirect parasympathomimetics.
Their action is evident
at all cholinergic synapses. Chemically,
these agents include esters of carbamic
acid (carbamates such as physostigmine,
neostigmine) and of phosphoric
acid (organophosphates such as paraoxon
= E600 and nitrostigmine = parathion
= E605, its prodrug).
Members of both groups react like
ACh with AChE and can be considered
false substrates. The esters are hydrolyzed
upon formation of a complex with
the enzyme. The rate-limiting step in
ACh hydrolysis is deacetylation of the
enzyme, which takes only milliseconds,
thus permitting a high turnover rate
and activity of AChE. Decarbaminoylation
following hydrolysis of a carbamate
takes hours to days, the enzyme
remaining inhibited as long as it is carbaminoylated.
Cleavage of the phosphate
residue, i.e. dephosphorylation,
is practically impossible; enzyme inhibition
is irreversible.
Uses. The quaternary carbamate
neostigmine is employed as an indirect
parasympathomimetic in postoperative
atonia of the bowel or bladder. Furthermore,
it is needed to overcome the relative
ACh-deficiency at the motor endplate
in myasthenia gravis or to reverse
the neuromuscular blockade (p. 184)
caused by nondepolarizing muscle relaxants
(decurarization before discontinuation
of anesthesia). The tertiary
carbamate physostigmine can be used
as an antidote in poisoning with parasympatholytic
drugs, because it has access
to AChE in the brain. Carbamates
(neostigmine, pyridostigmine, physostigmine)
and organophosphates (paraoxon,
ecothiopate) can also be applied
locally to the eye in the treatment of
glaucoma; however, their long-term use
leads to cataract formation. Agents from
both classes also serve as insecticides.
Although they possess high acute toxicity
in humans, they are more rapidly degraded
than is DDT following their
emission into the environment.
Tacrine is not an ester and interferes
only with the choline-binding site of
AChE. It is effective in alleviating symptoms
of dementia in some subtypes of
Alzheimer’s disease.



Parasympatholytics
Excitation of the parasympathetic division
of the autonomic nervous system
causes release of acetylcholine at neuroeffector
junctions in different target organs.
The major effects are summarized
in A (blue arrows). Some of these effects
have therapeutic applications, as indicated
by the clinical uses of parasympathomimetics
(p. 102).
Substances acting antagonistically
at the M-cholinoceptor are designated
parasympatholytics (prototype: the alkaloid
atropine; actions shown in red in
the panels). Therapeutic use of these
agents is complicated by their low organ
selectivity. Possibilities for a targeted
action include:
• local application
• selection of drugs with either good or
poor membrane penetrability as the
situation demands
• administration of drugs possessing
receptor subtype selectivity.
Parasympatholytics are employed
for the following purposes:
1. Inhibition of exocrine glands
Bronchial secretion. Premedication
with atropine before inhalation anesthesia
prevents a possible hypersecretion
of bronchial mucus, which cannot
be expectorated by coughing during intubation
(anesthesia).
Gastric secretion. Stimulation of
gastric acid production by vagal impulses
involves an M-cholinoceptor subtype
(M1-receptor), probably associated with
enterochromaffin cells. Pirenzepine (p.
106) displays a preferential affinity for
this receptor subtype. Remarkably, the
HCl-secreting parietal cells possess only
M3-receptors. M1-receptors have also
been demonstrated in the brain; however,
these cannot be reached by pirenzepine
because its lipophilicity is too
low to permit penetration of the bloodbrain
barrier. Pirenzepine was formerly
used in the treatment of gastric and duodenal
ulcers (p. 166).
2. Relaxation of smooth musculature
Bronchodilation can be achieved by the
use of ipratropium in conditions of increased
airway resistance (chronic obstructive
bronchitis, bronchial asthma).
When administered by inhalation,
this quaternary compound has little effect
on other organs because of its low
rate of systemic absorption.
Spasmolysis by N-butylscopolamine
in biliary or renal colic (p. 126). Because
of its quaternary nitrogen, this
drug does not enter the brain and requires
parenteral administration. Its
spasmolytic action is especially marked
because of additional ganglionic blocking
and direct muscle-relaxant actions.
Lowering of pupillary sphincter tonus
and pupillary dilation by local administration
of homatropine or tropicamide
(mydriatics) allows observation
of the ocular fundus. For diagnostic uses,
only short-term pupillary dilation is
needed. The effect of both agents subsides
quickly in comparison with that of
atropine (duration of several days).
3. Cardioacceleration
Ipratropium is used in bradycardia and
AV-block, respectively, to raise heart
rate and to facilitate cardiac impulse
conduction. As a quaternary substance,
it does not penetrate into the brain,
which greatly reduces the risk of CNS
disturbances (see below). Relatively
high oral doses are required because of
an inefficient intestinal absorption.
Atropine may be given to prevent
cardiac arrest resulting from vagal reflex
activation, incident to anesthetic induction,
gastric lavage, or endoscopic
procedures.



4. CNS-dampening effects
Scopolamine is effective in the prophylaxis
of kinetosis (motion sickness, sea
sickness, see p. 330); it is well absorbed
transcutaneously. Scopolamine (pKa =
7.2) penetrates the blood-brain barrier
faster than does atropine (pKa = 9), because
at physiologic pH a larger proportion
is present in the neutral, membrane-
permeant form.
In psychotic excitement (agitation),
sedation can be achieved with
scopolamine. Unlike atropine, scopolamine
exerts a calming and amnesiogenic
action that can be used to advantage
in anesthetic premedication.
Symptomatic treatment in parkinsonism
for the purpose of restoring a
dopaminergic-cholinergic balance in
the corpus striatum. Antiparkinsonian
agents, such as benzatropine (p. 188),
readily penetrate the blood-brain barrier.
At centrally equi-effective dosage,
their peripheral effects are less marked
than are those of atropine.
Contraindications for
parasympatholytics
Glaucoma: Since drainage of aqueous
humor is impeded during relaxation of
the pupillary sphincter, intraocular
pressure rises.
Prostatic hypertrophy with impaired
micturition: loss of parasympathetic
control of the detrusor muscle exacerbates
difficulties in voiding urine.
Atropine poisoning
Parasympatholytics have a wide therapeutic
margin. Rarely life-threatening,
poisoning with atropine is characterized
by the following peripheral and
central effects:
Peripheral: tachycardia; dry
mouth; hyperthermia secondary to the
inhibition of sweating. Although sweat
glands are innervated by sympathetic
fibers, these are cholinergic in nature.
When sweat secretion is inhibited, the
body loses the ability to dissipate metabolic
heat by evaporation of sweat (p.
202). There is a compensatory vasodilation
in the skin allowing increased heat
exchange through increased cutaneous
blood flow. Decreased peristaltic activity
of the intestines leads to constipation.
Central: Motor restlessness, progressing
to maniacal agitation, psychic
disturbances, disorientation, and hallucinations.
Elderly subjects are more
sensitive to such central effects. In this
context, the diversity of drugs producing
atropine-like side effects should be
borne in mind: e.g., tricyclic antidepressants,
neuroleptics, antihistamines,
antiarrhythmics, antiparkinsonian
agents.
Apart from symptomatic, general
measures (gastric lavage, cooling with
ice water), therapy of severe atropine
intoxication includes the administration
of the indirect parasympathomimetic
physostigmine (p. 102). The most
common instances of “atropine” intoxication
are observed after ingestion of
the berry-like fruits of belladonna (children)
or intentional overdosage with
tricyclic antidepressants in attempted
suicide.