Cholinergic drugs

Dr Maham Israr
MBBS, Mphil.
 Cholinomimetics

Acetylcholine-receptor stimulants and cholinesterase

inhibitors make up a large group of drugs that mimic
acetylcholine and are known as cholinomimetic or
parasympathomimetic agents.
 Cholinergic nerve endings
• All the pre-ganglionic nerve fibres (Both sympathetic
and parasympathetic fibres).
• All the post-ganglionic parasympathetic nerve fibres.
• Post-ganglionic sympathetic nerve fibres supplying
the sweat gland.
• Vascular smooth muscle in skeletal muscle has
sympathetic cholinergic dilator fibers
 Cholinoceptors
• Muscarinic receptors :
• Nicotinic receptors : and
Receptor Main location Postreceptor Functional response
Mechanism
CNS : Cortex , IP3, DAG cascade • Gastric secretion
Hippocompus • CNS excitation
Gastric parietal cell
Heart, nerves, Inhibition of cAMP • Cardiac inhibition
smooth muscle production,activation • Neural inhibition
of K+ channels • CNS : Tremor
hypothermia
Glands, smooth IP3, DAG cascade • Increased gastric,
muscle,endothelium salivary secretion
• GIT muscle contraction
• Ocular accomodation
• Vasodilatation
CNS Inhibition of cAMP
production

CNS IP3, DAG cascade

Muscle type, end Na+, K+ depolarizing ion Skeletal muscle
plate receptor channel contraction

Neuronal type, Na+, K+ depolarizing ion Excitation

ganglion receptor channel
 Heteroreceptor
These are pre-synaptic receptors, which respond to
neurotransmitters or neurohormones released from
adjacent neurons or cells.
Autoreceptors
These are pre-synaptic receptors, which respond to
neurotransmitters or neurohormones released from
same nerve ending and can modify transmitter
synthesis and release.
 Classification of Cholinomimetic drugs
Cholinergic grugs

Indirectly acting
Directly acting

Esters of choline Alkaloids Reversible Irreversible

Ach Nicotine Lipid soluble Water soluble OPC Carbamates

Bethaenochol Pilocarpine Physostigmine Neostigmine
Carbachol Muscarin e Tacrine Pyridostigmin
Methacholine Lobeline
Esters of Choline Alkaloids
 Mode of action of Cholinomimetic drugs

Direct-acting cholinomimetic agents

Direct-acting cholinomimetic agents bind to and activae
muscarinic or nicotinic receptors.

Indirect-acting cholinomimetic agents

Indirect-acting cholinomimetic agents produce their
primary effects by inhibiting acetylcholinesterase, which
hydrolyzes acetylcholine to choline and acetic acid .
 Direct-acting cholinomimetic agents

Pharmakokinetics
• Choline esters are poorly absorbed orally.
• They have a permanently charged quaternary ammonium group,
which renders them relatively insoluble in lipids. They are poorly
distributed into the central nervous system because they are
hydrophilic.
• Acetylcholine is very rapidly hydrolyzed by cholinesterase.
Thus, can’t be given by oral route. Large amounts must be
infused intravenously to achieve concentrations sufficient to
produce detectable effects.
• The tertiary natural cholinomimetic alkaloids (pilocarpine,
nicotine, lobeline are well absorbed from most sites of
administration.
• Nicotine, a liquid, is sufficiently lipid-soluble to be
absorbed across the skin.
• Muscarine, a quaternary amine, is less completely
absorbed from the gastrointestinal tract than the tertiary
amines but is nevertheless toxic when ingested eg, in
certain mushrooms—and it even enters the brain.
• Lobeline is a plant derivative similar to nicotine.
• These amines are excreted chiefly by the kidneys.
• Acidification of the urine accelerates clearance of the
tertiary amines.
 Pharmacodynamics
Mechanism of Action
• Parasympathetic nerves activates muscarinic
receptors on effector cells to alter organ function
directly.
• Second, acetylcholine released from
parasympathetic nerves interacts with muscarinic
receptors on nerve terminals to inhibit the release
of their neurotransmitter.
Properties of choline esters
Organ system effects
 Organ system effects
CVS effects

• On heart : ↓ HR,↓ force of contraction, ↓ conduction velocity

and AV block→↓ CO→ ↓ BP.

• On blood vessels : Release of EDRF from the endothelial

cells → activation of NO/cGMP pathway. ↓ peripheral
resistance → ↓ BP.
Effects in Eye
• ↑ lacrimal gland secretion →↑ lacrimation

• Contraction of sphincter pupillae muscle →Miosis

• Contraction of ciliary muscle → cyclospasm → The iris is

pulled away from the angle of the anterior chamber → The
trabecular meshwork is opened →↑ outflow of aqueous humor
into the canal of schelmm →↑ drainage of aqueous humor →↓
IOP → releif of glaucoma.
Effects on respiratory system
• Bronchial muscle Contraction (bronchoconstriction)
• Bronchial glands Stimulation

Aggravation of bronchial asthma

Effects on GIT
• Motility Increases
• Sphincters Relaxation
• Secretion Stimulation

Aggravation of PUD and diarrhoea

Effects on Genitourinary System

• Detrusor Contraction
• Trigone and sphincter Relaxation Promotes voiding

Effects on exocrine glands

Sweat (Eccrine M) , salivary, ↑ secretion

lacrimal, nasopharyngeal

Effects on CNS
Tremor, hypothermia, anti-nociception
Effects due to nicotinic receptor activation
1.Effects due to receptor activation at post synaptic
autonomic ganglia
Ach has nicotinic action in autonomic ganglia. So initial response
is stimulation of both sympathetic and parasympathetic nervous
system.
• In CVS →sympathomimetic→↑ BP,↑ HR
• In GIT → parasympathomimetic → diarrhoea, vomiting
• In GU → parasympathomimetic
2. Effects due to receptors activation at NMJ
Immediate depolarization causes contraction of skeletal muscle
followed by flaccid paralysis.
INDIRECT ACTING CHOLINOMIMETICS

There are three chemical groups of cholinesterase inhibitors:

(1) simple alcohols bearing a quaternary ammonium group,
eg, Edrophonium
(2) carbamic acid esters of alcohols having quaternary or
tertiary ammonium groups (carbamates, eg, neostigmine)
(3)organic derivatives of phosphoric acid
(organophosphates, eg, echothiophate)
Reversible
Lipid soluble Water soluble
Physostigmine Neostigmine
Tacrine Pyridostigmine
Donepezil Edrophonium
Rivastigmine
Gallantamine

Irreversible
Organophosphates Carbamates
Malathion Carbaryl
Parathion propoxur
Diazinon Aldicarb
Ecothiophate
Nerve gases (Tabun, serin, soman)
 Pharmacokinetics

• Physostigmine, is well absorbed from all sites and it is

distributed into the central nervous system and is more toxic.

• Absorption of the quaternary carbamates is predictably poor and

it is metabolized by non-specific esterases in the body.

• The organophosphate cholinesterase inhibitors (except for

echothiophate) are well absorbed from the skin, lung, gut,
conjunctiva and are distributed to CNS.

• Echothiophate is highly polar and more stable than most other

organophosphates.
 Pharmacodynamics
Mechanism of Action
• Indirectly acting cholinomimetics inhibit acetylcholinesterase ,
butyrylcholinesterase is also inhibited.
• Acetylcholinesterase is an extremely active enzyme.

1. In the initial catalytic step, acetylcholine binds to the enzyme’s

active site and is hydrolyzed, yielding free choline and the
acetylated enzyme.

2. In the second step, the covalent acetyl-enzyme bond is split,

with the addition of water(hydration).
The entire process occurs in approximately 150microseconds.
The molecular details of their interaction with the enzyme vary
according to the three chemical subgroups mentioned above.

• The first group consists of quaternary alcohols e.g. edrophonium.

These agents reversibly bind electrostatically and by hydrogen
bonds to the active site, thus preventing access of acetylcholine.
This bond is short-lived (2–10 minutes).

• The second group consists of carbamate esters, eg,neostigmine

and physostigmine. These agents undergo a two-step hydrolysis
sequence analogous to that described for acetylcholine. However,
the covalent bond of the carbamoylated enzyme is considerably
more resistant to the second (hydration) process, and this step is
correspondingly prolonged ( 30 minutes to 6 hours).
• The third group consists of the organophosphates.
These agents also undergo initial binding and hydrolysis
by the enzyme, resulting in a phosphorylated active site.
The covalent phosphorus enzyme bond is extremely
stable and hydrolyzes in water at a very slow rate
(hundreds of hours).
Process of Aging
After the initial binding-hydrolysis step, the phosphorylated enzyme
complex may undergo a process called aging. This process apparently
involves the breaking of one of the oxygen-phosphorus bonds of the
inhibitor and further strengthens the phosphorus-enzyme bond.

The rate of aging varies

Soman 10 min
VX 48 hours

Organophosphates cause phosphorylation of the serine OH group at the

active site of cholinesterase. The oxime group (ÓNOH) has a very high
affinity for the phosphorus atom, for which it competes with serine OH. If
given before aging has occurred, strong nucleophiles like pralidoxime are
able to break the phosphorus-enzyme bond and can be used as
“cholinesterase regenerator” drugs for organophosphate insecticide
poisoning.
 Organ System Effects

Central nervous system

In low concentrations → alerting response.
In higher concentration → generalized convulsions, which may be
followed by coma and respiratory arrest.

Eye, respiratory tract, gastrointestinal tract, urinary tract

Similar effects like direct acting cholinomimetics
Cardiovascular system
Cholinesterase inhibitors have minimal effects by direct
action on vascular smooth muscle because most vascular
beds lack cholinergic innervation (coronary vasculature is
an exception).
At mod dose
• ↓ HR , ↓CO
↑ BP Because of activation of sympathetic ganglia.
• At high (toxic) doses of cholinesterase inhibitors,
marked bradycardia occurs, cardiac output decreases
significantly, and hypotension supervenes.
Neuromuscular junction
• Low (therapeutic) concentrations →increases the strength of
contraction.

• At higher concentrations, the accumulation of acetylcholine may

result in fibrillation of muscle fibers.

• With marked inhibition of acetylcholinesterase, depolarizing

neuromuscular blockade occurs and that may be followed by a
phase of nondepolarizing blockade as seen with succinylcholine.

• Some quaternary carbamate cholinesterase inhibitors, eg,

neostigmine, have an additional direct nicotinic agonist effect at
the neuromuscular junction. This may contribute to the
effectiveness of these agents as therapy for myasthenia .
 Indications/ clinical uses of cholinomimetics
• EYE
Glaucoma (pilocarpine)
Accomodative estropia
• GIT
Dry mouth with sjogren’s syndrome (Cevimeline)
Post-operative ileus (Neostigmine)
Congenital megacolon
Reflux esophagitis Bethanechol
• Urinary tract
Neurogenic bladder (Neostigmine)
Urine retention due to spinal cord injury (Neostigmine)
• Neuromuscular Junction
Treatment and diagnosis of Myasthenia gravis
Curare induced neuromuscular paralysis
• CVS
paroxysmal supraventricular tachycardia
(edrophonium) Now replaced by newer drugs with different
mechanisms.
• In poisoning
Atropine poioning (physostigmine)
D- tubocurarine poisoning (Neostigmine)
• CNS
Alzheimer’s disease
Clinical uses of drugs

• Pilocarpine : Acute angle closure glaucoma,

↑ salivary secretion,
Accomodative estropia

• Edrophonium : MG,
SVT

• Cevimeline : Sjogren’s syndrome

• Pyridostigmine : MG

• Physostigmine : TCA antidepressant,

Atropine intoxication
• Methacholine : Methacholine challenge test (Diagnosis of bronchial
hyperreactivity in patients who do not have clinically
apparent asthma)

• Neostigmine : Paralytic ileus,

Neurogenic bladder,
Alternate drug for MG,
Post-op paralytic ileus,
Post-op urinary retention,
Snake bite poisoning (Nasal spray),
To revert the pharmacologic paralysis produced
during G/A.
Toxicity
A. Direct-Acting Muscarinic Stimulants
Drugs such as pilocarpine and the choline esters cause predictable signs
of muscarinic excess when given in overdosage. The effects are all
blocked competitively by atropine and its congeners.

Mushroom poisoning
Certain mushrooms, especially those of the genus Inocybe, contain
muscarinic alkaloids. Ingestion of these mushrooms causes typical signs
of muscarinic excess within 15–30 minutes. Treatment is with atropine,
1–2 mg parenterally.

Amanita muscaria → low content of muscarine

CNS effects predominates irritability,
restlessness, ataxia, hallucinations, delirium to
drowsiness and sedation.
Atropine is contraindicated
Direct-Acting Nicotinic Stimulants
Nicotine
• Source : Tobacco, insecticides
• Acute toxicity : The fatal dose = 40 mg, or 1 drop of the pure liquid.

Toxic effects
• CNS : convulsions and may progress to coma and respiratory arrest
• NM : skeletal muscle end plate depolarization, which may lead to depolarization blockade
and respiratory paralysis
• CVS : Hypertension and cardiac arrhythmias.

Treatment
• Symptomatic
• ABCD management
• Atropine → Muscarinic excess
• Diazepam →convulsions
• Mechanical ventilation→ NM blockade.

Fortunately, nicotine is metabolized and excreted relatively rapidly.

Patients who survive the first 4 hours usually recover completely if hypoxia and brain
damage have not occurred.
Chronic toxicity
Cause Nicotine
Replacement Therapy
• nicotine in the form of gum, transdermal patch, nasal spray, or inhaler.

• Their action derives from slow absorption of nicotine that occupies

α4β2 receptors in the central nervous system and reduces the desire to
smoke and the pleasurable feelings of smoking.

• Another quite effective agent for smoking cessation is varenicline, a

synthetic drug with partial agonist action at α4β2 nicotinic receptors.
Varenicline also has antagonist properties that persist because of its
long half-life; this prevents the stimulant effect of nicotine at
presynaptic α4β2 receptors that causes release of dopamine.Side
effects : nausea, insomnia, anxiety and depression

• Other drug for smoking cessation : bupropion, an antidepressant

Cholinesterase Inhibitors
OPC poisoning
• Source : Insecticide used in agriculture can cause slowly or rapidly
developing symptoms, which persist for days.
• As chemical warfare agents (soman, sarin, VX) induce effects rapidly
because of the large concentrations present.
Clinical features
EYE Miosis
CVS bradycardia, hypotension
RESP Bronchoconstriction
GIT Diarrhoea, vomiting, hyperacidity (heart burn)
GU Urinary urgency
Exocrine Severe salivation and sweating
CNS Tremor, restlessness, convulsion, hypothermia, resp
centre stimulation
NMJ Flaccid paralysis of skeletal muscles (depolarizing blockade)
 ↑ HR, HTN rarely because of stimulation of nicotinic
receptors
• Cause of death in OPC poisoning Resp muscle paralysis
Management
A) General Management
1. Immediate ABCD resuscitation.
2. A short and complete history→ To confirm about the poisoning and
to make treatment plan
3. Examination of vital signs: BP, HR,RR,Temp, UO, Pupil ,lumg base,
Heart
4. Contaminated clothing’s should be removed and stored for Medico-
legal purpose
5. Contaminated skin should be washed by normal saline
6. Gastric suction : By 2 % KMn
7. Catheterization ( Before giving first dose of atropine)
B) Specific Management
1. Atropine :1–2 mg of atropine sulfate may be given intravenously
every 5–15 minutes until signs of effect (dry mouth, reversal of
miosis) appear. 1 g of atropine per day may be required for as long
as 1 month for full control of muscarinic excess.
2. Pralidoxime is administered by intravenous infusion, 1–2 g given
over 15–30 minutes before the aging process.
3. Diazepam : If convulsions present
4. NaHC : If metabolic acidosis present.

C) Monitoring of patients → vital signs

D) Follow up → Patient is advised to rest after discharge.

• Preventive therapy for cholinesterase inhibitors used as chemical
warfare agents has been developed to protect soldiers and
civilians.
• Personnel are given autoinjection syringes containing a carbamate
pyridostigmine, and atropine.
• The protection is limited to the peripheral nervous system because
pyridostigmine does not readily enter the central nervous system.
• Chronic exposure to certain organophosphate compounds,
including some organophosphate cholinesterase inhibitors, causes
delayed neuropathy associated with demyelination of axons.

• Triorthocresyl phosphate, an additive in lubricating oils, is the

prototype agent of this class. The effects are not caused by
cholinesterase inhibition but rather by neuropathy target esterase
(NTE) inhibition whose symptoms (weakness of upper and lower
extremities, unsteady gait) appear 1–2 weeks after exposure.

• Another nerve toxicity called intermediate syndrome occurs 1–

4 days after exposure to organophosphate insecticides. This
syndrome is also characterized by muscle weakness; its origin is
not known but it appears to be related to cholinesterase
inhibition.
Adverse effects
CVS : Bradycardia, hypotension
Resp: Bronchoconstriction
GIT: Diarrhoea, vomiting, hyperacidity
GU: urinary urgency
Exocrine: severe salivation, sweating
CNS: Tremor, hypothermia, respiratory centre
stimulation
Contraindications
• Bronchial asthma
• PUD
• Mechanical obstruction of GIT
• Obstructive urinary retention
Myasthenia gravis

• Myasthenia gravis is an autoimmune disease affecting

skeletal muscle neuromuscular junctions.
• In this disease, antibodies are produced against the main
immunogenic region found on α1 subunits of the
nicotinic receptor-channel complex.
• Antibodies are detected in 85% of myasthenic patients.
• The autoimmune antibodies reduce nicotinic receptor
function.
• The disease resembles the neuromuscular paralysis
produced by d-tubocurarine and similar nondepolarizing
neuromuscular blocking drugs.
• Lambert-Eaton syndrome- SLE
Clinical features
• Intermittent ptosis
• Diplopia
• Difficulty in speaking and swallowing
• Weakness in the extremeties
• Weakness in the muscle of respiration (Severe disease)
Drug interactions
• Patients with myasthenia are exquisitely sensitive to the
action of curariform drugs.
• Other drugs that interfere with neuromuscular
transmission, eg, aminoglycoside antibiotics .
Treatment plan for myasthenia gravis

• Cholinesterase inhibitors : Neostigmine, Pyridostigmine.

• Patients with ocular myasthenia may be treated with
cholinesterase inhibitors alone.
• Patients having more widespread muscle weakness are also treated
with immunosuppressant drugs (steroids, cyclosporine, and
azathioprine).
• In some patients, the thymus gland is removed
• Very severely affected patients may benefit from administration of
immunoglobulins and from plasmapheresis.
• Long-term therapy for myasthenia gravis is usually accomplished with
pyridostigmine; neostigmine or ambenonium are alternatives.

• These drugs are relatively short-acting and therefore require frequent

dosing (every 6 hours for pyridostigmine and ambenonium and every 4
hours for neostigmine.

• Sustained-release preparations are available but should be used only at

night and if needed.

• The dose requirement in this disease changes too rapidly to permit

smooth control of symptoms so long-acting drugs are avoided.

• If muscarinic effects of such therapy are prominent, they can be

controlled by the administration of anti-muscarinic drugs such as
atropine. Frequently, tolerance to the muscarinic effects of the
cholinesterase inhibitors develops, so atropine treatment is not required.
Tensilon test
• Edrophonium is a short acting synthetic
anticholinesterase and is used as a diagnostic test for
myasthenia.
• A 2 mg dose is injected intravenously after baseline
muscle strength has been measured.
• If no reaction occurs after 45 seconds, an additional 8 mg
may be injected. If the patient has myasthenia gravis, an
improvement in muscle strength that lasts about 5
minutes can usually be observed.
• It will not improve or even worsen the condition if it is
due to cholinergic crisis.
Cholinergic crisis

• If excessive amounts of cholinesterase inhibitor have been used,

patients may become paradoxically weak because of nicotinic
depolarizing blockade of the motor end plate.

• These patients may also exhibit symptoms of excessive

stimulation of muscarinic receptors (abdominal cramps, diarrhea,
increased salivation, excessive bronchial secretions, miosis,
bradycardia).
 Ocular Pharmacology
Structure Receptor Cellular effect Effect of agonist
drug
Sphincter pupillae muscle ↑ IP3 , DAG Contraction (Miosis)

Dilator pupillae muscle ↑ IP3 , DAG, Contraction

↑ Calcium (Mydriasis)

Cilliary muscle ↑ IP3 , DAG Contraction

(Cyclospasm)
↑ cAMP Relaxation
(Cycloplegia)
Cilliary epithelium ↑ cAMP Vasodilatation
 Drug delivery system of eye
• Systemic routes
These are two blood- ocular barriers.
1. Blood- aqueous barrier
2. Blood-retinal barrier
• Local or topical routes
1. Aqueous or viscous solutions as drops
2. Ointments
3. Sub-conjunctival inj
4. Retro-bulbar inj
5. Drug impregnated contact lens
6. Membrane release system (Ocusert)
7. Inj directly into the eye
 Ocular Hypertension and Glaucoma
Ocular hypertension
Raised IOP > 21 mmHg (on two consecutive occasions)
Absence of detectable glaucomatous damage :
• No cupping of the optic disc
• No change of visual field
Normal IOP = 10-20 mm Hg
• Rate of secretion of aqueous humor
• Rate of outflow
Glaucoma
Any two of the followings are diagnosed as glaucoma
• Raised IOP ( measured by tonometer)
• Structural damage : Cupping of optic disc ( Measured by ophthalmoscope)
• Functional damage Changes in the visual field and visual acuity (Measured
by automated perimetry).
Normotensive glaucoma
Two major types of glaucoma are recognized:
Open-angle
The open-angle form of glaucoma is a chronic condition, and
treatment is largely pharmacologic.

Closed-angle (also called narrow-angle)

The closed-angle form is associated with a shallow anterior chamber,
in which a dilated iris can occlude the outflow drainage pathway at
the angle between the cornea and the ciliary body.
Management
Diagnosis
• History
• S/S
• D/D
Treatment
Angle closure glaucoma
• Emergency
Acetazolamide, Topical pilocarpine, Steroid, B blocker, Analgesic,
Anti-emetic.
• After 1 hour
Pilocarpine continued. If IOP still doesn’t fall then glycerin is given
orally or mannitol IV.
• After 48 hours
Gonioscopy done
If peripheral anterior synechia < 50% then peripheral iridectomy is
done.
If > 50% trabeculectomy is done.
Fellow eye Prophylactic iridectomy.
NANC NEURONS
• It has been known for many years that autonomic effector tissues (eg, gut,
airways, bladder) contain nerve fibers that do not show the histochemical
characteristics of either cholinergic or adrenergic fibers.

• Both motor and sensory NANC fibers are present.

• These neurons contain one or more of the following: nitric oxide synthase
(NO), calcitonin gene-related peptide, cholecystokinin, dynorphin,
enkephalins, gastrin-releasing peptide, 5-hydroxytryptamine (serotonin),
neuropeptide Y, somatostatin, substance P, and vasoactive intestinal
peptide (VIP). Some neurons contain as many as five different
transmitters.

• The sensory fibers in the nonadrenergic, noncholinergic systems are

probably better termed “sensory-efferent” or “sensorylocal effector” fibers
because, when activated by a sensory input, they are capable of releasing
transmitter peptides from the sensory ending itself, from local axon
branches, and from collaterals that terminate in the autonomic ganglia.
• The enteric nervous system (ENS) is sometimes
considered a third division of the ANS. It is found in the
wall of the GI tract from the esophagus to the distal
colon and is involved in both motor and secretory
activities of the gut.
• The ENS includes the myenteric plexus (the plexus of
Auerbach) and the submucous plexus (the plexus of
Meissner).
• These neuronal networks receive
preganglionic fibers parasympathetic system
postganglionic sympathetic axons.
• They also receive sensory input from within the wall of
the gut.
• Sensory fibers transmit chemical and mechanical
information from the mucosa and from stretch receptors
to motor neurons in the plexuses and to postganglionic
neurons in the sympathetic ganglia.
• Deprivation of input from both ANS divisions does not
abolish GI activity. In fact, selective denervation may
result in greatly enhanced motor activity.
• The ENS functions in a semiautonomous manner,
utilizing input from the motor outflow of the ANS for
modulation of GI activity and sending sensory
information back to the CNS.