SPP 331 - PARASYMPATHETIC PHARMACOLOGY

The nervous system is divided into central nervous system (CNS: brain and spinal cord) and peripheral
nervous system (PNS). PNS can be further divided into somatic nervous system and autonomic nervous
system (ANS) (See chart in TARA). The ANS has two divisions – sympathetic and parasympathetic. The
sympathetic division arises from thoracolumbar region (T1–L3, thoracolumbar outflow) and the
parasympathetic division arises from two separate regions in the CNS - cranial nerves (III, VII, IX and X)
and sacral nerves from S2, S3 and S4 spinal roots (craniosacral outflow).

In sympathetic system, the preganglionic fibres are short and postganglionic fibres are long. On the
contrary, the parasympathetic preganglionic fibres are long and postganglionic fibres are short (Fig. 2.1).

The nervous system controls the body’s organs and plays a role in nearly all bodily functions. Nerve cells,
also known as neurons, and their neurotransmitters play important roles in this system. Nerve cells fire
nerve impulses. They do this by releasing neurotransmitters, also known as the body’s chemical
messengers that transmit signals from nerve cells to target cells. These signals help regulate bodily
functions ranging from heart rate to appetite.

Structure of a Neuron (Nerve cells)

There are three basic parts of a neuron: the cell body, the dendrites, and the axon.

1. The cell body (or soma) contains the nucleus and is responsible for producing all of the proteins
needed to keep the neuron healthy and functioning. The dendrites and axons extend from the cell body.

2. Dendrites are the extensions that branch off of the cell body and receive signals from other neurons.
Some neurons have few dendritic branches, while others are highly branched in order to receive a great
deal of information. For example, a single neuron in the brain can create thousands of connections with
other neurons with its dendrites.

3. The axon extends from the cell body and is what we commonly refer to as a nerve fiber. The axon
transmits information away from the cell body to the nerve ending. Most neurons have only one axon,
and it is often covered in a fatty substance called myelin that insulates the nerve fiber and assists with
transmitting the signal. Depending on the area of the body, some neurons have very short axons, while
others can be quite long.

Function of a Neuron

The nervous system is comprised of sensory neurons, motor neurons, and interneurons, each having a
unique function. They also work together to perform complex functions in the human body.

1. Sensory neurons (or afferent neurons) carry information from the sensory receptor cells located
throughout the body such as the eyes, ears, and skin, to the brain for processing. Sensory neurons help
you taste, see, hear, and smell. We can also feel touch, pressure, and temperature.
2. Motor neurons (or efferent neurons) transmit information from the brain to the muscles and glands
of the body to take action. There are two types: upper motor neurons and lower motor neurons. Upper
motor neurons originate in the primary motor cortex of the brain and travel down the spinal cord. The
lower motor neurons continue the signal by extending from the spinal cord out to the target muscles
and glands. For example, by activating the motor neurons of your muscle fibers, you can swat a fly, kick
a ball, and chew your food.

3. Interneurons are responsible for communicating information between sensory and motor neurons via
the spinal cord and brain. Complex movements such as walking and talking require the coordination of
many muscles. This involves a sensory-motor feedback loop that allows for fine-tuning of gestures in
real time. Interneurons also assist with reflexive actions, like pulling your hand off of the hot stove.

Neurotransmitters

neurotransmitters are chemical agents released by neurons (nerve cells) to stimulate neighbouring
neurons or muscle or gland cells, thus allowing impulses to be passed from one cell to the next
throughout the nervous system. Neurotransmitters relay their messages by traveling between cells and
attaching to specific receptors on target cells. After neurotransmitters deliver their messages, the body
breaks them down or recycles them.

Neurotransmitters are synthesized by neurons and are stored in vesicles located in the axon’s terminal
end, also known as the presynaptic terminal. The presynaptic terminal is separated from the neuron or
muscle or gland cell onto which it impinges by a gap called the synaptic cleft. The synaptic cleft,
presynaptic terminal, and receiving dendrite of the next cell together form a junction known as the
synapse.

Characteristics of neurotransmitters (criteria)

Classical neurotransmitter criteria are

1. The neurotransmitter has to be synthesized within the neurone in question.

2. Stimulation of the neurone results in liberation of this substance (neurotransmitter).

3. Liberation of the substance as a result of axonal stimulation has an effect similar to exogenous
administration of the same substance.

4. The neurotransmitter should be able to bind to its specific receptors on the postsynaptic cell
membrane.

5. There must be a mechanism of removing or metabolizing this substance within the tissue
(inactivation).

Theory of chemical neurotransmitter

When a nerve impulse arrives at the presynaptic terminal of one neuron, neurotransmitter-filled vesicles
migrate through the cytoplasm and fuse with the presynaptic terminal membrane. The neurotransmitter
molecules are then released through the presynaptic membrane and into the synaptic cleft. In
milliseconds, they travel across the synaptic cleft to the postsynaptic membrane of the adjoining
neuron, where they then bind to receptors. Receptor activation results in either the opening or the
closing of ion channels in the membrane of the second cell, which alters the cell’s permeability. In many
instances, the change in permeability results in depolarization, causing the cell to produce its own action
potential, thereby initiating an electrical impulse. In other cases, the change leads to hyperpolarization,
which prevents the generation of an action potential by the second cell.

Inactivation of neurotransmitter

The activities of neurotransmitters can be terminated by three mechanisms:

• Diffusion: The NT may diffuse out of the synaptic cleft, away from the receptive cell.

• Reuptake: They also can be taken back up into the presynaptic terminal via transporter molecules, or

• Degradation: they may be metabolized by enzymes in the synaptic cleft so that it is not recognize by
the receptor.

Neurotransmitters have different types of actions:

• Excitatory: These types of neurotransmitters have excitatory effects on the neuron, meaning they
increase the likelihood that the neuron will fire an action potential. Some of the major excitatory
neurotransmitters include epinephrine and norepinephrine.

• Inhibitory: These types of neurotransmitters have inhibitory effects on the neuron; they decrease the
likelihood that the neuron will fire an action potential. Some major inhibitory neurotransmitters include
serotonin and gamma-aminobutyric acid (GABA). In some cases, these neurotransmitters have a
relaxation-like effect.

• Modulatory: These neurotransmitters, often referred to as neuromodulators, are capable of affecting

a larger number of neurons at the same time. These neuromodulators also influence the effects of other
chemical messengers. Where synaptic neurotransmitters are released by axon terminals to have a fast-
acting impact on other receptor neurons, neuromodulators diffuse across a larger area and are more
slow-acting. Examples of neuromodulators include acetylcholine, dopamine, serotonin, histamine, and
cannabinoids.

Abnormalities in neurotransmitter release and activity have been linked to various diseases and
disorders, particularly neuropsychiatric and neurodegenerative disorders. For example, dysfunction of
the neurotransmitters dopamine, glutamate, and GABA has been reported in schizophrenia, while
reductions in levels and activity of norepinephrine and serotonin have been reported in persons with
depression. Decreased levels of dopamine, attributed to the loss of so-called dopaminergic neurons, is a
central feature of Parkinson disease.
Types of neurotransmitters

Different types of neurotransmitters have been identified. Based on chemical and molecular properties,
the major classes of neurotransmitters include amino acids, such as glutamate and glycine;
monoamines, such as dopamine and norepinephrine; peptides, such as somatostatin and opioids; and
purines, such as adenosine triphosphate (ATP). Some gaseous substances, such as nitric oxide, can also
act as neurotransmitters, as can endogenous substances known as trace amines, which are related
chemically to the monoamines; examples include tryptamine and the phenethylamines. Acetylcholine is
the primary neurotransmitter of the parasympathetic nervous system. The major inhibitory
neurotransmitter of the nervous system is GABA (gamma-aminobutyric acid), which acts to dampen
neuronal activity.

Cholinergic neurons: are neurons or nerve cells which mainly uses the neurotransmitter acetylcholine
(ACh) to send its messages.

Acetylcholine

Synthesis: Acetylcholine is synthesized from acetyl coenzyme A and choline by the enzyme choline
acetyltransferase (CAT). In the nervous system, this enzyme is thought to exist primarily in the nerve
terminal cytoplasm. Coenzyme A is synthesized in mitochondria, liver, and from dietary sources. Both
CAT and ACh may be found throughout the neuron, but their highest concentration is in axon terminals.
The presence of CAT is the "marker" that a neuron is cholinergic, as only cholinergic neurons contain
CAT.

Acetyl CoA + Choline ----------> Choline acetyltransferase ----------> Acetylcholine

The rate-limiting step in the synthesis of acetylcholine is transport of choline into the nerve terminal via
the high-affinity choline transporter i.e acetylcholine synthesis in cholinergic neurons is dependent on
the availability of its precursor, choline, most of which is derived from the circulation and enters
cholinergic neurons via a process catalyzed by a high-affinity Na+/choline transporter. Some of the
choline used for ACh synthesis is stored in membrane phosphatidylcholine (PC).

Storage: At the presynaptic terminal, acetylcholine storage occurs within the presynaptic vesicle in the
axon terminals. With the stimulation of the presynaptic terminal, acetylcholine is released from the
vesicles and into the synaptic cleft, where the neurotransmitter is free to bind with receptors.

Release: The release of acetylcholine occurs when an action potential is relayed and reaches the axon
terminus (synaptic knob/bulb) in which depolarization causes voltage-gated calcium channels to open
and conduct an influx of calcium, which will allow the vesicles containing acetylcholine for release into
the synaptic cleft.

Reuptake: Most of the synthesized acetylcholine is actively transported from the synaptic cleft into
synaptic vesicles by a specific transporter.
Metabolism/degradation: Termination of acetylcholine action in the synaptic junction occurs when
acetylcholine rapidly binds, then unbinds from its receptor in the target cell’s surface and gets
subsequently cleaved by acetylcholinesterase into choline and acetate. Acetylcholinesterase is present
in the synaptic cleft as a free molecule or protein on the surface of the postsynaptic cell. Choline is
recycled back to the presynaptic neuron via choline transporters (CT1).

Cholinesterases
ACh is rapidly hydrolysed to choline and acetic acid by enzyme cholinesterases. There are two types of
cholinesterase:

1. True cholinesterase or acetylcholinesterase (AChE): It is found in cholinergic neurons, ganglia, RBCs

and neuromuscular junction (NMJ). It rapidly hydrolyses ACh and methacholine.
2. Pseudocholinesterase or butyrylcholinesterase: It is found in plasma, liver and glial cells.
Pseudocholinesterase can act on a wide variety of esters including ACh (hydrolysis is slow) but does not
hydrolyse methacholine.

Clinical Significance of Acetylcholine

Alteration or interference with acetylcholine in the nervous system can result in several different
pathologies. Acetylcholine (ACh) is clinically significant in many disease processes, the most commonly
seen of which include Alzheimer disease (AD), Lambert-Eaton myasthenic syndrome (LEMS), and
myasthenia gravis (MG).

1. Patients with AD have reduced cerebral content of choline acetyltransferase, which leads to a
decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors
(donepezil, rivastigmine, and galantamine) increase cholinergic transmission by inhibiting cholinesterase
at the synaptic cleft and provide modest symptomatic benefit in some patients with dementia.

2. LEMS is a disorder of reduced Ach release from the presynaptic nerve terminals, despite normal ACh
vesicle number, normal ACh presynaptic concentration, and normal postsynaptic acetylcholine
receptors. This condition occurs when there is autoimmunity (production of autoantibodies) to the
voltage-gated calcium channels found on presynaptic neurons' axon terminus.

3. MG is an autoimmune disorder recognized by the rapid weakening of the skeletal muscles because of
a decrease in the number of acetylcholine receptors. The weakness is due to an antibody-mediated
process in which some antibodies have a tropism for acetylcholine receptors or their proteins located in
the postsynaptic membrane of neuromuscular junctions.

Cholinergic receptors

These refers to those receptors that respond to the acetylcholine in the parasympathetic nervous
system. There are two types of cholinergic receptors: nicotinic and muscarinic receptors. Muscarinic
receptors are further divided into five different subtypes: M 1–M5. All muscarinic receptors are G-
protein–coupled receptors and regulate the production of intracellular second messengers.
M1 - Locations: Gastric glands, Autonomic ganglia, CNS

M2: Heart

M3: Smooth muscles, Exocrine glands, Endothelial cells

M4 and M5: CNS

Nicotinic receptors are divided into two subtypes – N N and NM. Activation of these receptors directly
opens ion channels and causes depolarization of the membrane.

NN receptors are located on - Autonomic ganglia, Adrenal medulla, CNS

NM receptors are located in the Neuromuscular junction (NMJ)

Differences between nicotinic and muscarinic receptors

NICOTINIC RECEPTORS MUSCARINIC RECEPTORS

Nicotinic receptors are a group of cholinergic receptors Muscarinic receptors are a group of G-protein coupled
linked to ion channels in the cell membrane cholinergic receptors that phosphorylate second
messengers

Has two types: N1 and N2 Has five types: M1, M2, M3, M4, and M5

Excitatory receptors M1, M2, and M5 are excitatory receptors while M3 and
M4 are inhibitory receptors

N1 receptors are located in neuromuscular junctions; Found in the brain, heart, and smooth muscles
N2 receptors are located in the brain, autonomic and
parasympathetic nervous system

Become ion channels upon activation Phosphorylate various second messengers

Mediate fast synaptic transmission of nerve impulses Mediate a slow metabolic response via second
messenger cascades

Respond to nicotine Respond to muscarine

Characteristics of muscarinic and nicotinic receptor subtypes

● Intracellularly, M1 and M3 increases Inositol triphosphate (IP3) and diacylglycerol (DAG). This increases
learning and memory, promotes glandular secretion and smooth muscle contraction.

● M2 decreases Cyclic adenosine monophosphate (cAMP), opening of K + channels leading to

hyperpolarization. This depresses the sino atrial (SA) node, depresses atrioventricular (AV) node,
decreases atrial and ventricular contraction.
● NN causes the opening of ion channels (Na+ , K+), leading to depolarization and release of adrenaline
and noradrenaline from adrenal medulla.

● NM causes the opening of ion channels (Na+ , K+), leading to depolarization and skeletal muscle
contraction.

● Agonist: M1 - Oxotremorine

M2 - Methacholine

M3 - Bethanechol

NN - Nicotine

NM - Nicotine

● Antagonist: M1 - Pirenzepine, Telenzepine

M2
- Methoctramine, Tripitramine
M3 - Solifenacin, Darifenacin
NN - Tubocurarine, alpha-Bungarotoxin
NM - Hexamethonium, Trimethaphan

Drugs acting on the parasympathetic nervous system

a) Parasympathomimetics or cholinergic drugs: are drugs which mimic acetylcholine or the effects of
parasympathetic nerve stimulation.
b) Parasympatholytics: are drugs that inhibit parasympathetic nervous system activity or that of
cholinergic drugs

Cholinergic drugs or Parasympathomimetics

These are drugs which produce actions similar to that of ACh, either by directly interacting with
cholinergic receptors (cholinergic agonists) or by increasing availability of ACh at these sites
(anticholinesterases). They are classified as

1. Directly acting: (a) Choline esters e.g Acetylcholine, Bethanechol, Carbachol

(b) Alkaloids e.g Pilocarpine, Muscarine, Arecoline

2. Indirectly acting (anticholinesterases): they are subclassified into

(a) Reversible: - Carbamates e.g Physostigmine, Neostigmine, Pyridostigmine, Rivastigmine

- Others e.g Donepezil, Galantamine, Tacrine

(b) Irreversible: - Organophosphorus (OP) compounds e.g Parathion, Malathion (insecticide), Sarin,
soman, tabun (nerve gases for chemical warfare), Dyflos, Echothiophate

- Carbamates e.g Propoxur (Baygon), Carbaryl (insecticide)

1. Directly acting cholinergic drugs

Choline Esters - e.g Acetylcholine

Pharmacodynamics of choline esters

Depending on the type of receptor through which it is mediated, the peripheral actions of ACh are
classified as muscarinic or nicotinic.

Muscarinic Actions
1. Cardiovascular system
+
(a) Heart: ACh, by stimulating M2 receptors of the heart, opens K channels resulting in
hyperpolarization. Therefore, SA and AV nodal activity is reduced. rate of impulse generation is reduced
—bradycardia or even cardiac arrest may occur (decrease heart rate).

(b) Blood vessels: ACh stimulates M3 receptors of vascular endothelial cells, which release endothelium-
dependent relaxing factor (EDRF; NO) leading to vasodilatation and a fall in blood pressure (BP).
2. Smooth muscles
(a) Gastrointestinal tract: Smooth muscle in most organs is contracted (mainly through M 3 receptors).
Tone and peristalsis in the gastrointestinal tract is increased and sphincters relaxed leading to abdominal
cramps and evacuation of bowel (increase tone of the gut, increase peristaltic movement, increase
secretion)
(b) Urinary bladder: Peristalsis in ureter is increased. The detrusor muscle contracts while the bladder
trigone and sphincter relaxes leading to voiding of bladder.
(c) Bronchi: By binding to M3 receptors, ACh contracts the bronchial smooth muscle (bronchospasm),
increases tracheobronchial secretion — therefore, cholinergic drugs are contraindicated in asthmatics
N/B: asthmatics are highly sensitive to ACh, leading to bronchospasm, dyspnoea, precipitation of an
attack of bronchial asthma.
3. Exocrine glands: Secretion from all parasympathetically innervated glands is increased via M3 and
some M2 receptors: sweating, salivation, lacrimation, increased tracheobronchial and gastric secretion.
4. Eye: ACh does not produce any effect on topical administration because of its poor penetration
through tissues. It affects two important muscles in the eyes
(a) Circular muscle: ACh causes excessive contraction of circular muscle of iris leading to miosis
(shrinking).

(b) Ciliary muscle: ACh causes contraction of ciliary muscle leading to spasm of accommodation. This
facilitate drainage of aqueous humour and reduce intraocular pressure (IOP) in glaucoma.
Ciliary muscle contraction → Relaxation of suspensory ligaments of lens → Bulging of lens → Vision
fixed for near distance
Nicotinic Actions:. To elicit nicotinic actions, larger doses of ACh are required.
1. Autonomic ganglia: Higher doses of ACh produce dangerous muscarinic effects especially on the
heart. Hence, prior administration of atropine is necessary to elicit nicotinic actions. Higher doses of ACh
stimulate both sympathetic and parasympathetic ganglia, causing tachycardia and rise in BP.
2. Skeletal muscles: At high concentration, ACh initially produces twitching, fasciculations followed by
prolonged depolarization of NMJ and paralysis.
3. Actions on CNS: Intravenously administered ACh does not cause any central effects because of its
poor penetration through the blood–brain barrier (BBB).

Pharmacokinetics of Choline esters

Acetylcholine is poorly absorbed from the gastric mucosa; therefore it is ineffective if given orally. The
recommended way of administration is parenteral. In the blood it is rapidly hydrolyzed by the enzyme
cholinesterase into acetic acid and choline; this makes its duration of action very short and unreliable for
therapeutic purposes.

Uses: Choline esters are rarely, if ever, clinically used. ACh is not used because of evanescent (quickly
fading or vanishing) and nonselective action. Methacholine was occasionally used to terminate
paroxysmal supraventricular tachycardia but is obsolete now.

Cholinomimetic Alkaloids
They mimic the actions of ACh; examples are pilocarpine, muscarine and arecoline.

Pilocarpine: Pilocarpine is a cholinomimetic alkaloid obtained from Pilocarpus microphyllus. It is a

tertiary amine. It produces muscarinic and nicotinic effects by directly interacting with the receptors. It
has predominant muscarinic actions especially on secretory activity.
Uses
1. Pilocarpine 0.5%–4% solution is used topically in the treatment of open-angle glaucoma and acute
congestive glaucoma. It increases the tone of the ciliary muscle and causes miosis by contracting
sphincter pupillae, opens the trabecular meshwork around the canal of Schlemm, facilitates drainage of
aqueous humour and reduces intraocular pressure (IOP). It acts rapidly but has short duration of action.
2. It is used alternatively with mydriatics to break adhesions between the iris and lens.
3. It is used to reverse the pupillary dilatation after refraction testing.
4. Pilocarpine is used as a sialagogue (drug used to augment salivary secretion).
Adverse Effects: They are salivation, sweating, bradycardia, diarrhoea and bronchospasm; pulmonary
oedema can occur following systemic therapy.

Muscarine: It occurs in poisonous mushrooms Amanita muscaria and Inocybe species and has only
muscarinic actions. It is not used therapeutically but is of toxicological importance.

Mushroom poisoning: Depending on the toxic principle present in the particular species, there are 3
types of mushroom poisoning.

1. Muscarine type (Early mushroom poisoning): Caused by Inocybe species. It is characterized by early
onset of action, excessive muscarinic effects, vomiting, diarrhoea, bradycardia, salivation, sweating,
bronchospasm, hypotension, etc. (due to toxin muscarine). These effects are promptly reverse by i.v.
atropine.

2. Hallucinogenic type: Caused by Amanita muscaria and Psilocybe species. Toxin is muscimol. They
activate amino acid receptors, and block muscarinic receptors in the brain, producing hallucinogenic
property. It produces mainly central effects. There is no specific antidote; atropine is contraindicated.
Supportive care should be given.

3. Phalloidin type (Late mushroom poisoning): Also known as delayed onset type. Caused by Amanita
phalloides, Galerina and related species. These inhibit RNA and protein synthesis. The symptoms start
after many hours and are due to damage to the gastrointestinal mucosa, liver and kidney. Toxin is
amatoxin. It does not respond to atropine and is treated with thioctic acid. Supportive care is required.

2. Indirectly acting cholinergic drugs (Anticholinesterases)

Irreversible indirectly acting anticholinesterase

Anti-ChEs are either esters of carbamic acid (Carbamates) or,derivatives of phosphoric acid
(Organophosphorus compounds).
They inhibit the enzyme cholinesterase that is responsible for hydrolysis of ACh. Thus, ACh is not
metabolized, gets accumulated at muscarinic and nicotinic sites and produces cholinergic effects. Hence,
anticholinesterases are called indirectly acting cholinergic drugs.

Mechanism of action: ACh is rapidly hydrolysed by both true and pseudocholinesterases. ACh binds to
anionic and esteratic sites of cholinesterase and acetylate the enzyme. The acetylated enzyme
undergoes rapid hydrolysis to produce acetate and free enzyme (Choline).

Carbamates bind to both the sites (i.e. anionic and esteratic) of cholinesterase (so ACh cannot bind the
enzyme), the carbamylated enzyme then undergoes slow hydrolysis to release the enzyme.

Organophosphates bind covalently to esteratic site of cholinesterases and inhibit them irreversibly as
hydrolysis of phosphorylated enzyme is extremely slow.

Organophosphorus Insecticides. OP compounds have only toxicological importance. OP poisoning is one

of the most common poisoning all over the world. Common OP compounds are parathion, malathion,
dyflos, etc. They irreversibly inhibit cholinesterases and cause accumulation of ACh at muscarinic and
nicotinic sites.

Pharmacokinetics: They are absorbed from all sites including intact skin and lungs. They are hydrolyzed
as well as oxidized in the body and little is excreted unchanged.
Signs and Symptoms of OP Poisoning
1. Muscarinic effects: Profuse sweating, salivation, lacrimation, increased tracheobronchial secretions,
bronchospasm, vomiting, abdominal cramps, miosis, bradycardia or tachycardia, cardiac arrhythmias,
hypotension, involuntary urination and defecation.

2. Nicotinic effects: Twitchings, fasciculations, muscle weakness and paralysis are due to prolonged
depolarization.

3. Central effects: Headache, restlessness, ataxia, disorientation, irritability, confusion, convulsions,

coma and death are usually due to respiratory failure.
Diagnosis. OP poisoning can be diagnosed by: History of exposure, Characteristic signs and symptoms,
Estimating the cholinesterase activity in blood, which is decreased
Treatment. General measures

1. Termination of further exposure to the poison—fresh air, remove the contaminated clothes, wash the
skin and mucous membranes with soap and water, gastric lavage according to need or the returning
fluid is clear.
2. Maintain patent airway - artificial respiration should be given if necessary, positive pressure
respiration if it is failing.
3. Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam.

Specific Measures/Antidotes
1. Atropine: Atropine is the first drug to be given in OP poisoning. Inject atropine 2 mg i.v. stat and it
should be repeated every 5–10 minutes doubling the dose, if required, till the patient is fully atropinized
(fully dilated, nonreactive pupils, tachycardia, etc.). Atropine should be continued for 7–10 days.
Atropine competitively blocks the muscarinic effects of OP compounds (competitive antagonism).
Atropine is not effective for reversal of neuromuscular paralysis. It is highly effective in counteracting
the muscarinic symptoms, but higher doses are required to antagonize the central effects. It does not
reverse peripheral muscular paralysis which is a nicotinic action.

2. Cholinesterase reactivators like Oximes: Neuromuscular transmission can be improved by giving

cholinesterase reactivators such as pralidoxime and obidoxime. Pralidoxime is administered
intravenously slowly in a dose of 1–2 g. Oximes bind with high affinity to anionic site, react with
phosphorus atom of the OP compound, dephosphorylate the enzyme, and reactivate it. Early
administration of oximes is necessary before the phosphorylated enzyme undergoes ‘aging’ (loses alkyl
groups) and becomes resistant to reactivation.

Reversible Anticholinesterases: Physostigmine, Neostigmine, Pyridostigmine, Edrophonium,

Galantamine, Rivastigmine, Donepezil
Reversible anticholinesterases inhibit both true and pseudocholinesterases reversibly
Physostigmine (Eserine): It is an alkaloid obtained from Physostigma venenosum. It is a tertiary amine
and has good penetration through tissues. Its actions are similar to those of other cholinergic agents.

Pharmacokinetics: it is rapidly absorbed from g.i.t. and parenteral sites. Applied to the eye, it penetrates
cornea freely. It crosses blood-brain barrier and is disposed after hydrolysis by ChE.

Uses
1. Glaucoma: Physostigmine reduces IOP by producing miosis, thus facilitates the drainage of aqueous
humour. On chronic use, it accelerates cataract formation; hence, it is rarely used in glaucoma.
2. Atropine poisoning: Intravenous physostigmine is used for severe atropine and other antimuscarinic
drug poisoning because it has both central and peripheral actions. It competitively reverses the effects
of atropine poisoning, but it should be used cautiously by slow i.v. injection as it may cause bradycardia.
Neostigmine: Neostigmine is a synthetic anticholinesterase agent. Its actions are pronounced on NMJ,
gastrointestinal tract (GIT) and urinary bladder than on cardiovascular system (CVS) or eye. On skeletal
muscle, it has both direct and indirect actions.
- Indirect Actions: By inhibiting cholinesterases, neostigmine increases ACh concentration at NMJ.
- Direct Actions: Because of structural similarity with ACh (i.e. quaternary ammonium compound),
neostigmine also directly stimulates NM receptors at NMJ. Thus, it improves muscle power in patients
with myasthenia gravis.

Pharmacokinetics: neostigmine and its congeners are poorly absorbed orally; oral dose is 20–30 times
higher than parenteral dose. They do not effectively penetrate cornea or cross blood-brain barrier. They
are partially hydrolysed and partially excreted unchanged in urine.
Neostigmine does not cross BBB and has no central side effects. Therefore, neostigmine is preferred to
physostigmine in myasthenia gravis. It is available for oral, s.c., i.v. and i.m. administration.

Adverse Effects of Anticholinesterases: They are due to overstimulation of both muscarinic and
nicotinic receptors – increased sweating, salivation, nausea, vomiting, abdominal cramps, bradycardia,
diarrhoea, tremors and hypotension.

Therapeutic Uses of Reversible Anticholinesterases

1. Eye
(a) Glaucoma
(b) To reverse pupillary dilatation after refraction testing
(c) Miotics are used alternatively with mydriatics to break adhesions between iris and lens

Glaucoma is optic nerve damage with loss of visual function that is frequently associated with raised
IOP. Normal IOP varies between 10 and 20 mm Hg. Management of this disorder is almost always
directed at lowering the existing IOP either by improving drainage or decreasing the formation of
aqueous humour. Two types: Acute congestive glaucoma which is a medical emergency and chronic
simple glaucoma.

Drugs for glaucoma

(i) Osmotic agents: Mannitol (20%) i.v. infusion (1.5 g/kg body weight) and 50% glycerol oral (1.5 g/kg)
are used. They draw fluid from the eye into the circulation by osmotic effect and reduce IOP in acute
congestive glaucoma.
(ii) Carbonic anhydrase inhibitors: Acetazolamide (oral, i.v.), dorzolamide (topical) and brinzolamide
(topical) are carbonic anhydrase inhibitors. They inhibit carbonic anhydrase enzyme, decrease
bicarbonate formation in ciliary epithelium and decrease the formation of aqueous humour. Topical
carbonic anhydrase inhibitors, which have a much lower risk of systemic side effects, are preferred to
systemic carbonic anhydrase inhibitors in chronic simple glaucoma. In acute congestive glaucoma,
acetazolamide is administered intravenously and orally.
(iii) Alpha-Adrenergic blockers: Topical nonselective beta-blockers are timolol, betaxolol, levobunolol
and carteolol. They decrease aqueous humour formation by blocking beta 2-receptors on ciliary
epithelium. Beta-Blockers also decrease ocular blood flow.
Timolol is widely used in glaucoma because (i) it lacks local anaesthetic or partial agonistic properties; (ii)
it does not affect pupil size or accommodation; (iii) it has longer duration of action; (iv) it is well
tolerated; (v) it is less expensive. Topical timolol is safer and highly effective.

(iv) Prostaglandins (PGs): They reduce IOP probably by facilitating uveoscleral outflow. Topical PGs such
as latanoprost, travoprost and bimatoprost (PGF 2 alpha-analogues) are the drug of choice in open-angle
glaucoma because of their longer duration of action (once a day dosing), high efficacy and low incidence
of systemic toxicity. They are also useful in acute congestive glaucoma. Latanoprost is also available in
combination with timolol. They usually do not cause systemic side effects but may cause ocular irritation
and iris pigmentation.
(v) Miotics: Pilocarpine is a tertiary amine and is well absorbed through cornea. It is used topically in the
treatment of open-angle and acute congestive glaucoma. It facilitates drainage of aqueous humour and
reduces IOP.

2. Myasthenia gravis: Myasthenia gravis is an autoimmune disorder where antibodies are produced
against NM receptors of NMJ resulting in a decrease in the number of N M receptors. There is marked
muscular weakness varying in degree at different times and fatigue.

Treatment. Anticholinesterases (neostigmine, pyridostigmine and ambenonium) are effective in

providing symptomatic relief. They inhibit metabolism of ACh, thus prolonging its action at the
receptors. Neostigmine also directly activates the N M receptors. Pyridostigmine is commonly used. Long-
term use or overdose of anticholinesterases leads to cholinergic crisis (severe muscular weakness and
neuromuscular paralysis due to prolonged depolarization).

ASSIGNMENT: DISCUSS THE DIFFERENCES BETWEEN CHOLINERGIC CRISIS AND MYASTHENIC CRISIS

Myasthenic crisis is characterized by acute weakness of respiratory muscles. It is managed by tracheal

intubation and mechanical ventilation. Generally, i.v. methylprednisolone pulse therapy is given while
anti-ChEs are withheld for 2–3 days followed by their gradual reintroduction. Most patients can be
weaned off the ventilator in 1–3 weeks. Plasmapheresis hastens recovery.

Cholinergic crisis: occurs due to overtreatment with anti-ChEs. If the dose of the antiChE is not adjusted
according to the fluctuating requirement, relative overdose may occur from time-to-time. Overdose also
produces weakness by causing persistent depolarization of muscle endplate, and is called cholinergic
weakness. Late cases with high anti-ChE dose requirements often alternately experience myasthenic and
cholinergic weakness and these may assume crisis proportions.
The two types of weakness require opposite treatments. They can be differentiated by edrophonium
test—

- Inject edrophonium (2 mg. i.v.) ---improvement --------> myasthenic crisis

- Inject edrophonium (2 mg. i.v.) --- no improvement or worsening -----> cholinergic crisis
Other treatments for myasthenia gravis involves
- Corticosteroids afford considerable improvement in such cases by their immunosuppressant action.
They inhibit production of nicotinic receptor NR-antibodies and may increase synthesis of NRs.

- Removal of antibodies by plasmapheresis (plasma exchange) is another therapeutic approach.

- Thymectomy is effective in a majority of the cases. Thymus may contain modified muscle cells with NRs
on their surface, which may be the source of the antigen for production of anti-NR antibodies in
myasthenic patients.

- Immunosuppressants like azathioprine or cyclophosphamide are useful in the induction and

maintenance of remission.
3. Postoperative urinary retention and paralytic ileus: Neostigmine is used because it increases the
tone of the smooth muscle and relaxes the sphincters.
4. Curare poisoning and reversal of nondepolarizing neuromuscular blockade: Edrophonium or
neostigmine is used. They antagonize neuromuscular blockade by increasing the concentration of ACh at
the NMJ. Prior administration of atropine is a must to block the muscarinic side effects.
5. Belladonna poisoning: Physostigmine is preferred because it reverses both central and peripheral
effects of atropine poisoning.
6. Alzheimer’s disease: It is a neurodegenerative disease of the cerebral cortex characterized by
progressive dementia. Donepezil, galantamine and rivastigmine are cerebroselective
anticholinesterases. They increase cerebral levels of ACh and have shown to produce some benefit in
these patients.

7. Cobra bite: Cobra venom has a curare like neurotoxin. Though specific antivenom serum is the
primary treatment, neostigmine + atropine prevent respiratory paralysis.
ANTICHOLINERGIC AGENTS

These are drugs that blocks the actions of ACh on all the muscarinic and nicotinic receptors. They are
classified as

1. Antimuscarinic agents

2. Antinicotinic agents - subdivided into: (i) Ganglion blockers (N N blockers) (ii) Neuromuscular blockers
(NM blockers).

Antimuscarinic agents (Muscarinic Receptor Antagonists)

These drugs block muscarinic receptor mediated actions of ACh on heart, CNS, smooth muscles and
exocrine glands. Atropine and scopolamine are belladonna alkaloids. Atropine is obtained from Atropa
belladonna and scopolamine (Hyoscine) from Hyoscyamus niger.
Mechanism of Action: Both natural and synthetic drugs competitively block the muscarinic effects of
ACh (competitive antagonism).

Classification of Antimuscarinic Agents

1. Natural alkaloids (Belladonna alkaloids): Atropine, Hyoscine (Scopolamine).
2. Semisynthetic derivatives: Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium
bromide, Tiotropium bromide.

3. Synthetic antimuscarinic agents:

(a) Used as mydriatic – cyclopentolate, tropicamide
(b) Used in peptic ulcer – pirenzepine, telenzepine, clidinium, propantheline
(c) Used as antispasmodic – dicyclomine, valethamate, flavoxate, oxybutynin, tolterodine (Roliten),
darifenacin
(d) Used as preanaesthetic agent – glycopyrrolate
(e) Used in parkinsonism – benzhexol (trihexyphenidyl), benztropine, biperiden, procyclidine

Atropine: Atropine is the prototype drug and the chief alkaloid of belladonna. It is a tertiary amine. It
blocks actions of ACh on all the muscarinic receptors. Atropine is administered by topical (eye), oral and
parenteral routes.

Pharmacological Actions of Atropine

1. CNS: In therapeutic doses, atropine has mild CNS stimulant effect. It produces antiparkinsonian effect
by reducing cholinergic overactivity in basal ganglia. It suppresses vestibular disturbances and produces
antimotion sickness effect. Large doses can produce excitement, restlessness, agitation, hallucinations,
medullary paralysis, coma and death.
2. CVS: At low doses, atropine causes initial bradycardia due to blockade of presynaptic muscarinic
autoreceptors (M1) on vagal nerve endings. In therapeutic doses, tachycardia is seen due to blockade of
M2 receptors of the heart; it also improves A–V conduction. In high doses, flushing of the face and
hypotension may occur due to cutaneous vasodilatation.
3. Glands: All secretions under cholinergic influence are reduced due to blockade of M3 receptors, i.e.
sweat, salivary, nasal, throat, bronchial, gastric, lacrimal, etc. Milk and bile secretions are not affected.
The skin and mucous membranes become dry.

4. Eye: Effects of atropine on eye are depicted as follows

(i) Atropine causes paralysis of constrictor pupillae due to blockade of M3 receptors. This results in
passive mydriasis.
(ii) Atropine causes paralysis of ciliary muscle leading to loss of accommodation due to blockade of M3
receptors. This leads to Cycloplegia.

5. Smooth muscles:
(a) GIT: Atropine decreases tone and motility of the gut, but increases sphincter tone and may cause
constipation. It also relaxes smooth muscle of the gall bladder.
(b) Urinary bladder: Atropine relaxes detrusor muscle of the bladder, but increases the tone of trigone
and sphincter – may cause urinary retention, especially in elderly men with enlarged prostate.
(c) Bronchi: Atropine relaxes the bronchial smooth muscle. It also reduces secretion and mucociliary
clearance resulting in mucus plug that may block the airway.
Pharmacokinetics: Atropine, scopolamine and most of the synthetic tertiary amines are well absorbed
from the conjunctiva and GI tract; are widely distributed all over the body; cross BBB; partly metabolized
in liver and partly excreted unchanged in urine.

Therapeutic Uses of Atropine and Its Substitutes

1. Ophthalmic uses:
As mydriatic and cycloplegic – for refraction testing. Atropine, homatropine, cyclopentolate or
tropicamide are used topically. The action of atropine lasts for 7–10 days. Tropicamide is the preferred
mydriatic as it has a short duration of action. In children, atropine is preferred because of its greater
efficacy.
2. As preanaesthetic medication: Atropine or glycopyrrolate is used. They are used prior to the
administration of general anaesthetics to prevent vagal bradycardia during anaesthesia and to prevent
laryngospasm by decreasing respiratory secretions.

3. Sialorrhoea: Synthetic derivatives (glycopyrrolate) are used to decrease excessive salivary secretion,
e.g. in heavy metal poisoning and parkinsonism.

4. Chronic obstructive pulmonary disease (COPD) and bronchial asthma: Ipratropium bromide and
tiotropium bromide are used in COPD and bronchial asthma. They are administered by metered dose
inhaler or nebulizer. They produce bronchodilatation without affecting mucociliary clearance, hence are
preferred to atropine.

5. Anticholinergics: are useful as antispasmodic in dysmenorrhoea, intestinal and renal colic. They are
less effective in biliary colic.
6. Urinary disorders: Oxybutynin and flavoxate have more prominent effect on bladder smooth muscle,
hence are used to relieve spasm after urologic surgery. Tolterodine has selective action on bladder
smooth muscle (M3), hence is used to relieve urinary incontinence.

7. Poisoning:
■ In OP poisoning, atropine is the life-saving drug.

■ In some types of mushroom poisoning (Inocybe species), atropine is the drug of choice.
■ Atropine is used in curare poisoning with neostigmine to counteract the muscarinic effects of
neostigmine.

8. As vagolytic: Atropine is used to treat sinus bradycardia and partial heart block due to increased vagal
activity. It improves A–V conduction by vagolytic effect.
9. Parkinsonism: Centrally acting anticholinergic drugs such as benzhexol (trihexyphenidyl), benztropine,
biperiden, procyclidine, etc. are the preferred agents for prevention and treatment of drug-induced
parkinsonism. They are also useful in idiopathic parkinsonism, but less effective than levodopa. They
control tremor and rigidity of parkinsonism.
Adverse Effects and Contraindications
The adverse effects of atropine are due to the extension of its pharmacological actions.
1. GIT: Dryness of mouth and throat, difficulty in swallowing, constipation, etc.
2. Eye: Photophobia, headache, blurring of vision; in elderly persons with shallow anterior chamber,
they may precipitate acute congestive glaucoma. Hence, anticholinergics are contraindicated in
glaucoma.
3. Urinary tract: Difficulty in micturition and urinary retention especially in elderly men with enlarged
prostate. So, they are contraindicated in these patients.
4. CNS: Large doses produce restlessness, excitement, delirium and hallucinations.
5. CVS: Tachycardia, palpitation and hypotension.
6. Acute belladonna poisoning: It is more common in children. The presenting features include fever,
dry and flushed skin, photophobia, blurring of vision, difficulty in micturition, restlessness, excitement,
confusion, disorientation and hallucinations.

Severe poisoning may cause respiratory depression, cardiovascular collapse, convulsions, coma and
death.
Treatment of belladonna poisoning (Atropine poisoning): It is mainly symptomatic.
1. Hospitalization.
2. Gastric lavage with tannic acid in case poison was ingested.
3. Tepid sponging to control hyperpyrexia.
4. Diazepam to control convulsions.
5. The antidote for severe atropine poisoning is physostigmine (1–4 mg). It is injected intravenously
slowly. It is a tertiary amine – counteracts both peripheral and central effects of atropine poisoning.
Hence, physostigmine is preferred to neostigmine.

Scopolamine

Scopolamine (hyoscine), another belladonna alkaloid, produces all the actions of atropine. In
therapeutic doses, it produces prominent CNS depression with sedation and amnesia. Scopolamine has
shorter duration of action than atropine. It has more prominent actions on eye and secretory glands.

By blocking cholinergic activity, scopolamine suppresses vestibular disturbances and prevents motion
sickness. It is the drug of choice for motion sickness – can be administered orally or as a transdermal
patch. It is more effective for prevention of motion sickness, hence should be given (0.2 mg oral) at
least half an hour before journey. The patch is placed behind the ear over the mastoid process. The
patch should be applied at least 4–5 hours before the journey, and its effect lasts 72 hours.
Scopolamine causes sedation and dryness of mouth. It can be administered parenterally as a
preanaesthetic agent.

Drug Interactions of Anticholinergics: H1-blockers, tricyclic antidepressants (TCAs), phenothiazines, etc.

have atropine-like action, hence may potentiate anticholinergic side effects.
Atropine alters absorption of some drugs by delaying gastric emptying – the bioavailability of levodopa
is reduced, whereas the absorption of tetracyclines and digoxin is enhanced due to increased GI transit
time.
Ganglion Blockers
They act at NN receptors of the autonomic ganglia (block both parasympathetic and sympathetic ganglia)
and produce widespread complex effects. The ganglion blockers have ‘atropine-like’ action on heart
(palpitation and tachycardia), eyes (mydriasis and cycloplegia), GIT (dryness of mouth and constipation),
bladder (urinary retention). They decrease sweat secretion and cause impotence in males. Blockade of
sympathetic ganglia results in marked postural hypotension.
No selective ganglion blockers are available till now. Hence, they are rarely used in therapy

Trimethaphan: is a short-acting ganglion blocker that must be given by i.v. infusion. At present, the only
use of trimethaphan is to produce controlled hypotension during neurosurgery.
Nicotine: is obtained from tobacco leaves. It has initial stimulating, later a prolonged blocking effect on
the autonomic ganglia. Tobacco smoking and chewing is a serious risk factor for oral, lung, heart and
other diseases.
Treatment of nicotine addiction
Nicotine chewing gum and transdermal patch: They are useful as nicotine replacement therapy.
Bupropion: It inhibits NA and DA reuptake and is used for smoking cessation.
Varenicline: It is a partial agonist at nicotinic receptors. It decreases craving and withdrawal symptoms
during smoking cessation.