Pharmacology

Lec. 3+4
Dr .Noor ali
Autonomic nervous system
The autonomic nervous system (ANS) as part of nervous system consider the major
regulatory systems for controlling homeostatic functions. ANS regulate and coordinate the
cardiovascular, respiratory, gastrointestinal, renal, reproductive, metabolic, and immunologic
systems.
Nervous system

Brain
Central nervous
system
Spinal cord

↑Afferent division
Peripheral nervous
Somatic system Sympathetic NS
system
↓Efferent division
Autonomic system Parasympathetic
NS

Enteric NS

Figure 1: autonomic nervous system part of nervous system

The ANS carries nerve impulses from the CNS to the effector organs by way of two types of
efferent neurons: the preganglionic neurons and the postganglionic neurons. In this pre and
post ganglionic complex the ganglia function is embodied in acting as relay stations between
the preganglionic neuron and the second nerve cell, the postganglionic neuron (figure 2)

Figure 2: preganglionic and post ganglionic neurons

The function of the ANS can be explained by exploring the function of each part as the
following:
A) Functions of the sympathetic nervous system

10
 1. Effects of stimulation of the sympathetic division: The effect of sympathetic output
is to:
1. Increasing heart rate and contractility, and thus, increasing blood pressure.
2. Constriction of the blood vessels of skin, mucous membranes, and splanchnic area,
and dilation of skeletal muscles vessels.
3. Dilation of the pupils (mydriasis).
4. Bronchodilation.
5. Inhibit salivation.
6. Decrease GI motility.
7. Stimulation of ejaculation.
8. Inhibit bladder contraction.
9. Stimulate glucose production and release.

2. Fight-and-flight response: The changes experienced by the body during emergencies

are referred to as the “fight and flight” response. These reactions are triggered both by
direct sympathetic activation of the effector organs and by stimulation of the adrenal
medulla to release epinephrine and lesser amounts of norepinephrine. Hormones
released by the adrenal medulla directly enter the bloodstream and promote responses
in effector organs that contain adrenergic receptors. The sympathetic nervous system
tends to function as a unit and often discharges as a complete system, for example,
during severe exercise or in reactions to fear.

Accordingly, the sympathetic division has the property of adjusting in response to stressful
situations, such as trauma, fear, hypoglycaemia, cold, and exercise.

B) Functions of the parasympathetic nervous system

The parasympathetic division is involved with maintaining homeostasis within the
body. It is required for life, since it maintains essential bodily functions, such as
digestion and elimination of wastes. The parasympathetic division usually acts to
oppose or balance the actions of the sympathetic division and generally predominates
the sympathetic system in “rest-and-digest” situations. Unlike the sympathetic system,
the parasympathetic system never discharges as a complete system. If it did, it would
produce massive, undesirable, and unpleasant symptoms, such as involuntary
urination and defecation. Instead, parasympathetic fibres innervating specific organs
such as the gut, heart, or eye are activated separately, and the system functions to
affect these organs individually.

So, the effect of parasympathetic output can be summarised in:

1. Pupil contraction (miosis).
2. Bronchoconstriction.
3. Stimulation of erection.

10
 4. Stimulation tears and saliva secretion.
5. Decreasing heart rate and contractility.
6. Increasing the muscle motility and tone of the gastrointestinal system.

C) Functions of the enteric nervous system (ENS)

The enteric nervous system is a collection of neurons in the gastrointestinal tract that
constitutes the “brain of the gut” and can function independently of the central
nervous system. This system controls the motility, exocrine and endocrine secretions,
and microcirculation of the gastrointestinal tract.
D) Functions of the somatic nervous system
The somatic system is the part of the peripheral nervous system that is responsible for
carrying motor and sensory information both to and from the central nervous system
without the mediation of ganglia. This system is made up of nerves that connect to the
skin, sensory organs, and all skeletal muscles. The system is responsible for nearly all
voluntary muscle movements as well as for processing sensory information that
arrives via external stimuli including hearing, touch, and sight.

The ANS requires sensory input from peripheral structures to provide information on the
current state of the body. This feedback is provided by streams of afferent impulses,
originating in the viscera and other autonomically innervated structures that travel to
integrating centres in the CNS, such as the hypothalamus and spinal cord. These centres
respond to the stimuli by sending out efferent reflex impulses via the ANS. This process of
initiating an afferent impulse that travel to the CNS and replying by efferent impulse to
get a response is called reflex arc (figure 3).

Figure 3: reflex arc

Usually, most of the afferent impulses are involuntary translated into reflex responses. For
example, a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the

10
heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular
centres in the brain. This prompts a reflex response of increased sympathetic output to the
heart and vasculature and decreased parasympathetic output to the heart, which results in a
compensatory rise in blood pressure and tachycardia.
According to the above explanation, the reflex arcs of the ANS comprise a sensory (or
afferent) arm and a motor (or efferent or effector) arm.

Neurotransmitters
Neurotransmission in the ANS is an example of the more general process of chemical
signalling between cells using neurotransmitters. Neurotransmitters are specific chemical
signals that are released from nerve terminals to establish the communication between nerve
cells, and between nerve cells and effector organs.
In spite of recognising more than 50 signals molecules (neurotransmitters) in the nervous
system, just norepinephrine (and the closely related epinephrine), acetylcholine, dopamine,
serotonin, histamine, glutamate, and γ-aminobutyric acid are the most commonly involved
neurotransmitters in the actions of therapeutically useful drugs. Each type of
neurotransmitters can bind with a specific receptor in order to give the biological desirable
response.
The primary chemical signals in the ANS are the acetylcholine and norepinephrine as they
are involved in conducting wide variety functions in the CNS.
The autonomic nerve fibres can be classified to cholinergic and adrenergic neurons based on
the type of the released neurotransmitters whether they are acetylcholine or epinephrine and
norepinephrine.
Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both
the sympathetic and parasympathetic nervous systems. Transmission from the autonomic
postganglionic nerves to the effector organs in the parasympathetic system, and a few
sympathetic system organs also involve the release of acetylcholine (figure 4). In the somatic
nervous system, transmission at the neuromuscular junction (the junction of nerve fibres and
voluntary muscles) is also cholinergic.
In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from
autonomic postganglionic nerves to effector organs except few sympathetic fibres, such as
those involved in sweating, are cholinergic.

10
 Figure 4: Neurotransmitters

Cholinergic agonist
The cholinergic drugs act on receptors that are activated by acetylcholine (ACh). These
receptors include nicotinic and muscarinic receptors and can be mainly recognised in
sympathetic and parasympathetic nervous system and somatic nervous system as well.

Neurotransmission at cholinergic neurons

Neurotransmission in cholinergic neurons involves six sequential steps: 1) synthesis, 2)
storage, 3) release, 4) binding of ACh to a receptor, 5) degradation of the neurotransmitter in
the synaptic cleft (that is, the space between the nerve endings and adjacent receptors located
on nerves or effector organs), and 6) recycling of choline and acetate (figure 5)

10
 Figure 5: Ach synthesis

1. Synthesis of acetylcholine: Choline is transported from the extracellular fluid into the
cytoplasm of the cholinergic neuron by an energy-dependent carrier system. Choline
acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form
ACh (an ester) in the cytosol.

2. Storage of acetylcholine in vesicles: ACh is packaged and stored into presynaptic vesicles.

3. Release of acetylcholine: When an action potential propagated at a nerve ending, voltage-

sensitive calcium channels on the presynaptic membrane open, causing an increase in the
‫تعزز‬ ‫اتحاد‬
concentration of intracellular calcium. Elevated calcium levels promote the fusion of
synaptic vesicles with the cell membrane and the release of their contents into the synaptic
space.

4. Binding to the receptor: ACh released from the synaptic vesicles diffuses across the
synaptic space and binds its receptors. The postsynaptic cholinergic receptors on the surface
of the effector organs are divided into two classes: muscarinic and nicotinic. Binding to a
receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse
in a postganglionic fiber or activation of specific enzymes in effector cells.

5. Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly

terminated, because AChE (acetylcholine esterase) cleaves ACh to choline and acetate in the
synaptic cleft.
‫استعادة‬
6. Recycling of choline: Choline may be recaptured by a sodium-coupled uptake system that
transports the molecule back into the neuron. There, it is acetylated into ACh that is stored
until released by a subsequent action potential.

10
CHOLINERGIC RECEPTORS (CHOLINOCEPTORS)

Cholinoceptors can be classified into two types: muscarinic and nicotinic receptors. They are
different mainly in their affinities for agents that mimic the action of ACh (cholinomimetic
agents).

1. Muscarinic receptors: It is one of the G protein–coupled receptors that have high

affinity to bind with muscarine (an alkaloid that is present in certain poisonous
mushrooms) and ACh but low affinity to bind with nicotine. Five sub-classes are
recognised for this receptor family; however, only M1, M2, and M3 receptors have
been functionally characterised.
a. Locations of muscarinic receptors: These receptors are found:
- On ganglia of the peripheral nervous system.
- On the autonomic effector organs (such as the heart, smooth muscle, brain,
and exocrine glands).
- In addition, M1 receptors are also found on gastric parietal cells, M2 receptors
on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine
glands, and smooth muscle.

b. Muscarinic agonists: Pilocarpine is an example of a nonselective muscarinic

agonist used in clinical practice to treat xerostomia and glaucoma. Attempts are
currently underway to develop muscarinic agonists and antagonists that are
directed against specific receptor subtypes. M1 receptor agonists are being
investigated for the treatment of Alzheimer’s disease.

2. Nicotinic receptors
These receptors, in addition to binding ACh, also recognise nicotine but show only a
weak affinity for muscarine. Nicotine at low concentration stimulates the receptor,
whereas nicotine at high concentration blocks the receptor. The nicotinic receptor
functions as a ligand-gated ion channel.
Location: Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic
ganglia, and the neuromuscular junction (NMJ) in skeletal muscles. Those at the NMJ are
sometimes designated NM, and the others, NN. The nicotinic receptors of autonomic
ganglia differ from those of the NMJ. For example, ganglionic receptors are selectively
blocked by mecamylamine, whereas NMJ receptors are specifically blocked by
atracurium.

10
DIRECT-ACTING CHOLINERGIC AGONISTS
Definition: Materials that mimic the effects of ACh by binding directly to cholinoceptors
(muscarinic or nicotinic).
Types:
1) Endogenous choline esters, which include ACh and synthetic esters of choline, such as
carbachol and bethanechol.
2) Naturally occurring alkaloids, such as nicotine and pilocarpine. The main advantage of
this group of drugs that have a longer duration of action than ACh.
The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to
muscarinic receptors and are sometimes referred to as muscarinic agents. As a group, the
direct-acting agonists demonstrate little specificity in their actions, which limits their clinical
usefulness.

Acetylcholine
Acetylcholine is a quaternary ammonium compound; hence it cannot penetrate membranes.
In spite of considering the ACh as a neurotransmitter of parasympathetic and somatic nerves
as well as autonomic ganglia, it lacks therapeutic importance because of its pluralism of
actions and its rapid inactivation by the cholinesterases. ACh has both muscarinic and
nicotinic activity. Its actions include the following:
1. Decrease in heart rate and cardiac output: The actions of ACh on the heart imitate
the effects of vagal stimulation. For example, if injected intravenously, ACh produces
a brief decrease in cardiac rate (negative chronotropy) and stroke volume as a result
of a reduction in the rate of firing at the sinoatrial (SA) node.
2. Decrease in blood pressure: As a result of ACh injection, vasodilation and lowering
of blood pressure can be observed. This is due to an indirect mechanism of action
because the ACh activates M3 receptors that found on endothelial cells lining the
smooth muscles of blood vessels. This leads to produce a nitric oxide that act as a
vasodilator from arginine. In the absence of administered cholinergic agents, the
vascular cholinergic receptors have no known function, because ACh is never released
into the blood in significant quantities. Atropine blocks these muscarinic receptors and
prevents ACh from producing vasodilation.
3. Other actions
ACh administration can stimulate:
a. Salivary secretion stimulates intestinal secretions and motility.
b. Bronchiolar secretions.

10
 c. Urination.
Moreover, ACh causes miosis (marked constriction of the pupil). Accordingly, ACh
(1% solution) is instilled into the anterior chamber of the eye to produce miosis
during ophthalmic surgery.
Therapeutic uses of direct-acting cholinergic agonists:
✓ bethanechol is used to stimulate the atonic bladder, particularly in postpartum or
postoperative, nonobstructive urinary retention.
✓ Carbachol eye as a miotic agent to treat glaucoma by causing pupillary contraction
and a decrease in intraocular pressure.
✓ Pilocarpine is used to treat glaucoma and is the drug of choice in the emergency
lowering of intraocular pressure in glaucoma. It is also beneficial in promoting
salivation in patients with xerostomia (dry mouth) resulting from irradiation therapy
of the head and neck cancer or due to Sjogren’s syndrome (an autoimmune disease in
which the moisture-producing glands of the body are affected causing mainly
symptoms of dry eyes and dry mouth).

Adverse effects of Ach and other cholinergic agonists: causes the effects of
generalized cholinergic stimulation.
• Bronchospasm and increase secretions.
• GI: nausea, vomiting, and diarrhea.
• Miosis.
• Urinary urgency.
• Sweating (diaphoresis) and salivation.
• Pilocarpine can enter the brain (because it’s a tertiary amine (unionized)) and cause
CNS disturbances. Poisoning with this agent is characterized by exaggeration of
various parasympathetic effects.
To counteract the poisoning effect of the pilocarpine and Bethanechol, Parenteral atropine, at
doses that can cross the blood–brain barrier, is administered to counteract the toxicity of the
cholinergic material.

INDIRECT-ACTING CHOLINERGIC AGONISTS (ANTICHOLINESTERASE

AGENTS (REVERSIBLE))

ACh is uaually deactivated by the AChE (Acetylcholine esterase), which is an enzyme that
specifically cleaves ACh to acetate and choline. It can be found at both pre- and
postsynaptically in the nerve terminal where it is membrane bound.
Accordingly, inhibition of AchE can indirectly provide a cholinergic action by preventing the
degradation of ACh. This results in an accumulation of ACh in the synaptic space. This
process can be carried out by using the anticholinesterase agents or cholinesterase inhibitors.

10
These drugs can provoke a response at all cholinoceptors in the body, including both
muscarinic and nicotinic receptors of the ANS, as well as at the NMJ and in the brain.

Therapeutic uses of acetylcholinesterase inhibitors (reversible)

‫أدرو فونيام‬ ‫بيريدو ستگمني‬ ‫أمبنو نيوم‬

Edrophonium, pyridostigmine, and ambenonium: They are used in the diagnosis and
management of myasthenia gravis, which is an autoimmune disease caused by antibodies to
the nicotinic receptor at NMJs. This causes their degradation, making fewer receptors
available for interaction with the neurotransmitter.

Physostigmine
It increases intestinal and bladder motility, which serve as its therapeutic action in
atony of either organ.
used to treat glaucoma, but pilocarpine is more effective.
as an antidote for drugs with anticholinergic actions.

Neostigmine
• used to stimulate the bladder and GI tract.
‫تبو كِرارين‬
• as an antidote for tubocurarine and other competitive neuromuscularblocking agents.
• also used to treat myasthenia gravis.

‫تاكرين‬ ‫دونة بزَل‬ ‫رڤستگمني‬

Tacrine, donepezil, rivastigmine, and galantamine
Patients with Alzheimer disease have a deficiency of cholinergic neurons in the CNS. This
observation led to the development of anticholinesterases as possible remedies for the loss of
cognitive function. Tacrine was the first to become available, but it has been replaced by
others because of its hepatotoxicity. Despite the ability of donepezil, rivastigmine, and
galantamine to delay the progression of Alzheimer disease, none can stop its progression.

Adverse effects of acetylcholinesterase inhibitors (reversible):

Adverse effects include those of generalized cholinergic stimulation, such as
salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and
bronchospasm.
Inhibition of AChE at the skeletal NMJ causes the accumulation of ACh and,
ultimately, results in paralysis of skeletal muscle.
Physostigmine can enter and stimulate the cholinergic sites in the CNS. The effects on
the CNS may lead to convulsions when high doses are used. Bradycardia and a fall in
cardiac output may also occur.

10
INDIRECT-ACTING CHOLINERGIC AGONISTS (ANTICHOLINESTRASE
AGENTS (IRREVERSIBLE))

A number of synthetic organophosphate compounds have the capacity to bind

covalently to AChE. The result is a long-lasting increase in ACh at all sites where it is
released. Many of these drugs are extremely toxic and were developed by the military
as nerve agents. Related compounds, such as parathion and malathion, are used as
insecticides.
Table: Summary of echothiophate actions, therapeutic uses and its adverse
effect.
Anticholinesterase Actions Therapeutic uses Adverse effect
agent
(Irreversible)
Echothiophate *Covalently binds *A topical solution *Represented by
to the AChE. of the drug is for the generalised
the treatment of cholinergic
open-angle stimulation.
glaucoma. *Paralysis of motor
function (causing
breathing
difficulties).
*Convulsions.

Cholinergic Antagonists

10
Cholinergic antagonist is a general term for agents that bind to cholinoceptors (muscarinic or
nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.

There are three types of cholinergic antagonist drugs, which are:

1. Antimuscarinic agents (anticholinergic drugs) block muscarinic receptors, causing

inhibition of muscarinic functions. Because they do not block nicotinic receptors, the
anticholinergic drugs (more precisely, antimuscarinic drugs) have little or no action at
skeletal neuromuscular junctions (NMJs).

2. Ganglionic blockers (specifically act on the nicotinic receptors of both

parasympathetic and sympathetic autonomic ganglia)

3. The neuromuscular-blocking agents (mostly nicotinic antagonists), which block

cholinergic transmission between motor nerve endings and the nicotinic receptors
on the skeletal muscle

1. Atropine (antimuscarinic agents): It is an alkaloid with a high affinity for

muscarinic receptors. It binds competitively and prevents ACh from binding to
those sites. Atropine acts both centrally and peripherally. Its general actions
last about 4 hours, except when placed topically in the eye, where the action
may last for days. Neuroeffector organs have varying sensitivity to atropine.

Effects:
• CNS: confusion, delirium.
• Decrease GI motility and acid secretions without interfering with hydrochloric
secretion.
• Increase heart rate at high doses, i.e. higher than (0.5 mg). At low doses slight
decrease in heart rate.
• Decrease body secretions like saliva (xerostomia), bronchial secretions, and sweat
(elevate body temperature).
• Mydriasis (cycloplegic to permits the measurement of refractive errors without
interference by the accommodative capacity of the eye).
Therapeutic uses:

Treatment of bradycardia.

In ophthalmology to cause cycloplegia and mydriasis.

Antimotility agent to treat diarrhea.

Antisecretory agent to block the secretions in the upper and lower respiratory tracts
before surgery.

10
Side effects: Blurred vision, decrease secretions, hyperthermia, constipation, urinary
retention, delirium, and hallucinations.
✓ Scopolamine is another antagonist used for motion sickness.

✓ Ipratropium used as inhaler to decrease bronchoconstriction and bronchial secretions

in COPD (chronic obstructive pulmonary disease) and asthma.

2. Nicotine (Ganglionic blockers): although nicotine considers as an agonist at

nicotinic receptors, but at higher does it blocks the autonomic ganglia (figure
6). Nicotine produces initial stimulation and varying degrees of subsequent
block through a mechanism analogous to that of succinylcholine (see later).

Nicotine is a component of cigarette smoke, is a poison with many undesirable

actions. However, it can be used in a controlled way to help in giving up
smoking. It is found in more than one pharmaceutical dosage forms like
sublingual tablets, lozenges and as chewing gum. Its action can be summarised
in these points: Increasing the blood pressure and cardiac rate and at higher
doses, the blood pressure falls because of ganglionic blockade, and activity in
both the GI tract and bladder musculature ceases.

10
 Figure 6: position of nicotinic receptor in autonomic ganglia

3. The neuromuscular-blocking agents: These drugs block cholinergic transmission

between motor nerve endings and the nicotinic receptors on the skeletal muscle. They
possess some chemical similarities to ACh, and they act either as antagonists
(nondepolarising type) or as agonists (depolarising type) at the receptors on the
endplate of the NMJ. Neuromuscular blockers are clinically useful during surgery to
facilitate tracheal intubation and provide complete muscle relaxation at lower
anaesthetic doses, allowing for more rapid recovery from anesthesia and reducing
postoperative respiratory depression.

1. Nondepolarising (competitive) blockers: At low doses: Nondepolarising agents

competitively block ACh at the nicotinic receptors. That is, they compete with ACh at
the receptor without stimulating it. Thus, these drugs prevent depolarisation of the
muscle cell membrane and inhibit muscular contraction. On the other hand, on high
doses, these drugs can lead to complete blockade and the muscle does not respond to
direct electrical stimulation. All neuromuscular-blocking agents are injected
intravenously or occasionally intramuscularly since they are not effective orally. In

10
 general, these agents are safe with minimal side effects; however, they can rarely
cause bronchospasm.

2. Depolarising agents: Depolarising blocking agents work by depolarising the plasma

membrane of the muscle fibre, similar to the action of ACh. However, these agents
are more resistant to degradation by acetylcholinesterase (AChE) and can thus more
persistently depolarise the muscle fibres. Succinylcholine is the only depolarising
muscle relaxant in use today. Succinylcholine attaches to the nicotinic receptor and
acts like ACh to depolarise the junction. This leads to a transient twitching of the
muscle. Continued binding of the depolarising agent renders the receptor incapable of
transmitting further impulses leading to flaccid paralysis. Therapeutically,
succinylcholine (which is administered IV) is useful when rapid endotracheal
intubation is required during the induction of anaesthesia. The main side effects of
this drug are the hyperthermia, apnea and hyperkalaemia.

10