FA C U LT Y O F N U R S I N G

NUR 205-PHARMACOLOGY FOR

NURSES
2 0 2 4 / 2 0 2 5 FA L L T E R M

CHOLINERGIC AND
ANTICHOLINERGIC AGENTS
CHOLINERGIC RECEPTORS
• Acetylcholine receptors include:
a. Nicotinic receptors
b. Muscarinic receptors

Nicotinic receptors:
• Nicotinic Ach receptors are ionotropic receptors-
directly linked to membrane ion channels. Therefore,
binding of the neurotransmitter occurs rapidly.
• Nicotinic receptors include:
a. Muscle type (Nm) occur at neuromuscular junction(NMJ).
b. Neuronal type(Nn) found in the autonomic ganglia, brain.
Muscarinic Ach receptors
• Muscarinic receptors are metabotropic
receptors- coupled to the second messenger
system (G-protein coupled receptors).
• Muscarinic receptors include:
§ M1 , M3, M5, stimulate PLC to
increase IP3 (inositol triphosphate).
§ M2, M4, inhibit Adenylate cyclase to
decease cAMP.
CHOL I NERGI C DRUGS

§ Cholinergic drugs are often called parasympathomimetic or cholinomimetic drugs, because their
action mimics the action of acetylcholine.

§ Stimulate parasympathetic nervous system in same manner as does the endogenous acetylcholine.
§ May stimulate cholinergic receptors directly or slow acetylcholine metabolism at synapses (by
inhibiting acetylcholinesterase)
§ Parasympathomimetic drugs are classified into:
1. Direct acting
2. Indirect acting
DI RECT ACTI NG CHOL I NERGI C AGONI S T

§ They act by binding directly to cholinoceptors.

§ Have affinity for both muscarinic and nicotinic receptors, however, they act mostly on
the M type receptors (not subtype selective).
§ Most do not readily enter the CNS so effects are peripheral.
§ Resistant to metabolism by acetylcholinesterase.
§ Examples:

Choline esters Choline alkaloids

• Acetylcholine • Pilocarpine
• Bethanechol • Cevimeline
• Carbachol • Muscarine**
• Methacholine
DIRECT ACTING CHOLINERGIC AGENTS

ACETYLCHOLINE (Ach)
§ Acetylcholine is a quaternary ammonium compound that cannot penetrate the membrane.
§ Rarely used clinically because of rapid inactivation by acetylcholinesterase, poor
receptor selectivity, and uncontrolled systemic effect.
Actions:
§ Decreases heart rate and cardiac output.
§ Decreases blood pressure:- causes vasodilation and lowering of blood pressure by an
indirect mechanism of action: (through M2 receptor activation, then nitric oxide which
relaxes smooth muscles of blood vessels.
§ It increases salivary secretion and stimulates intestinal secretions and motility.
§ It causes bronchoconstriction and enhances bronchiolar secretions.
§ ACh increases the tone of the detrusor muscle, causing urination
DIRECT ACTING CHOLINERGIC AGENTS

BETHANECHOL
§ Not hydrolyzed by acetylcholinesterase.
§ It lacks nicotinic actions but does have strong muscarinic activity.

Actions:
§ Directly stimulates M receptors causing increased intestinal motility & tone.

§ Stimulates detrusor muscle of the bladder causing expulsion of urine.

Therapeutic Use:
§ Paralytic ileus

§ Urinary retentions
§ Can be used to manage postsurgical atony of the bladder and GI tract
DIRECT ACTING CHOLINERGIC AGENTS
METHACHOLINE
§ Effective orally (though its absorption upon oral administration varies); more muscarinic action
§ 3 times more resistant to hydrolysis by true cholinesterase and totally resistant to hydrolysis by
pseudocholinesterase
§ Longer duration of action than Ach
§ Used in diagnosing bronchial hyper-reactivity in asthma patients
CARBACHOL
§ Not destroyed by cholinesterase (both true & pseudo)
§ More potent than bethanechol & methacholine
• Has both muscarinic and nicotinic actions
§ Stimulates autonomic ganglia & skeletal muscles
• Can be used as a miotic agent to treat glaucoma by causing pupillary contraction and a decrease in
intra- ocular pressure.
DIRECT ACTING CHOLINERGIC AGENTS
PILOCARPINE
§ An alkaloid Obtained from leaves of Pilocarpus microphyllus
§ Lipid soluble, crosses the blood-brain barrier and cause CNS disturbance
§ Stable to hydrolysis by cholinesterase.
§ Exhibits muscarinic activity
Actions:
§ When applied locally to the eye, it produces rapid miosis & contraction of ciliary muscle.
§ Pilocarpine is a potent stimulator of secretions such as sweat, tears, and saliva.
Therapeutic Use:
§ To treat glaucoma and for emergency lowering of intraocular pressure (promotes drainage of aqueous humor and
decreases intraocular pressure).
§ Oral Pilocarpine is used for Sjören’s syndrome (dry mouth and lack of tears)
§ The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine
I NDI RECT ACTI NG CHOL I NERGI C AGONI S TS
§ They act by inhibiting acetylcholinesterase leading to the accumulation of acetylcholine,
that enhances the activation of the nicotinic and muscarinic receptors.
§ Anticholinesterase agents are classified into:
1) Reversible Anticholinesterase agents (e.g: Physostigmine, Neostigmine,
Edrophonium, Pyridostigmine, Donepezil)
• Water soluble and short acting
2) Irreversible Anticholinesterase agents
(a) Organophosphates (e.g: Echothiophate, Malathion, Parathion, Sarin)
• Lipid soluble and very long acting
(b) Carbamates (e.g: Carbaryl)
• Intermediate acting
I NDI RECT ACTI NG CHOL I NERGI C AGONI S TS
PHYSOSTIGMINE
§ Reversibly inactivates AChE thereby potentiating cholinergic activity in the body.

§ Stimulates muscarinic and nicotinic sites of ANS and neuromuscular junction (NMJ).
§ Duration of action is about 30 minutes to 2 hours (intermediate-acting agent).

§ Capable of entering and stimulating the cholinergic sites in the CNS.

Therapeutic use:
§ Used as an antidote for overdose of drugs with anticholinergic actions such e.g Atropine, Phenothiazines and TCA.

§ May also be used in the treatment of glaucoma.

§ Increases intestinal and bladder motility, hence can be used in the case of atony in either organs.

Side effects:
§ Paralysis of skeletal muscle due to over accumulation of ACh at NMJ.

§ The effects on the CNS may lead to convulsions when high doses are used .
I NDI RECT ACTI NG CHOL I NERGI C AGONI S TS

NEOSTIGMINE
§ Prototype (synthetic) anticholinesterase agent.
§ Does not cross the blood-brain barrier.
§ Reversibly inhibits AChE.

§ Duration of action (30 mins-2hrs).

Therapeutic use
§ Used for long-term treatment of myasthenia gravis.

§ Used to stimulate the bladder and GIT.

§ Antidote for neuromuscular blocking agents in surgery.
Side effects (Generalized cholinergic stimulation)
§ Salivation, flushing, decreased blood pressure, nausea, diarrhea and bronchospasm.
I NDI RECT ACTI NG CHOL I NERGI C AGONI S TS

EDROPHONIUM
§ Prototype short acting AChE inhibitor.
§ Binds reversibly to the active site of AChE preventing ACh hydrolysis.
§ It is rapidly absorbed and has a short duration of action of 10 to 20 minutes due to rapid renal
elimination.
§ Edrophonium is a quaternary amine, and its actions are limited to the periphery.
Therapeutic use:
§ Used in diagnosis of myasthenia gravis.
§ IV injection rapidly increases muscle strength in myasthenia gravis.
§ reversing the effects of nondepolarizing neuromuscular blockers after surgery
§ Use is limited due to the risk of cholinergic crisis.
I NDI RECT ACTI NG CHOL I NERGI C AGONI S TS
PYRIDOSTIGMINE
§ The maintenance drug of choice for patients with Myasthenia gravis.
§ Its actions are limited to the periphery.

§ Intermediate duration of action of 3 to 6 hours.

TA C R I N E , D O N E P E Z I L , R I VA S T I G M I N E

§ Acts like edrophonium.

§ Lipid soluble, crosses the blood-brain barrier.
§ Increases brain Ach, helps to increase or maintain memory and learning capabilities.
§ Symptomatic management of mild to moderate in Alzheimer`s disease (AD).
Myasthenia gravis
§ Chronic autoimmune neuromuscular disease characterized by
weakness of the skeletal muscles that often first appears in the
muscles of the face, neck and jaw.
§ The autoimmune attack occurs when autoantibodies form against
the nicotinic acetylcholine postsynaptic receptors at the
neuromuscular junction of skeletal muscles
Symptoms:
§ Drooping of one or both eyelids (ptosis)
§ Double vision (diplopia), which may be horizontal or
vertical, and improves or resolves when one eye is closed.
§ Change facial expressions
§ Impaired speech
§ Difficulty swallowing
I N D I R E C T AC T I N G C H O L I N E RG I C AG O N I S T S

E C H O T H I O P H AT E (Irreversible anticholinesterase agent)

§ A Synthetic organophosphate compound that has the capacity to bind covalently to AChE.
§ The result is a long-lasting (up to 100 hours) increase in ACh at all sites where it is released.

§ Echothiophate action include generalized cholinergic stimulation, paralysis of motor function

(causing breathing difficulties), and convulsions.
§ A topical ophthalmic solution of echothiophate is available for the treatment of open-angle
glaucoma.
§ Echothiophate is rarely used due to its side effect profile, which includes the risk of causing
cataracts.
COMMON SIDE EFFECTS OF CHOLINERGIC AGONIST
§ Cardiovascular effects:
• Decrease heart rate( Bradycardia)
• Vasodilation (nitric oxide- mediated)
§ GIT and bladder:
• Increase gastric secretions
• Increase gastrointestinal motility
• Increase urinary frequency
§ Eye:
• Constriction (miosis), Spasm of accommodation
• Reduce intraocular pressure (increased outflow)
§ Respiratory effects:
• Bronchial constriction, narrowed airways
• Increase salivation and sweating
C H O L IN E RG IC A N TAG O N IS T S /
A N T I C H O L I N E RG I C S
 CHOLINERGIC ANTAGONISTS

§ Cholinergic antagonists are agents that bind to cholinoceptors and block the effects of
acetylcholine and other cholinergic agonists.
§ The effects of parasympathetic innervation are interrupted, and the actions of
sympathetic stimulation are left unopposed.
§ Cholinergic antagonists can also be called:
§ Parasympatholytic drugs
§ Anticholinergic drugs
§ Mechanism of action: The act by blocking either the nicotinic or muscarinic receptors
§ Antimuscarinic agents: Atropine, Scopolamine, Ipratropium, Benztropine,
§ Nicotinic antagonists: Pancuronium, Succinylcholine
ANTI-MUSCARINIC AGENTS
AT R O P I N E
§ A belladonna alkaloid (tertiary amine) with a high affinity for muscarinic receptors.
§ Competitively binds to muscarinic receptors and prevents ACh from binding.
§ 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.
Actions:
§ Eye: Mydriasis, unresponsiveness to light, and cycloplegia (inability to focus for near vision).
§ GI: Antispasmodic, decreases GIT activity, decreases saliva secretion.
§ CVS:- At low doses, the predominant effect is a slight decrease in heart rate.
-Higher doses cause a progressive increase in heart rate.
§ Atropine is used for the treatment of organophosphate poisoning and also as an antidote for overdose
of clinically used anticholinesterase agents.
Side effects (dose dependent):
Dry mouth, Blurred vision, Tachycardia, Constipation, Urinary retention
ANTI-MUSCARINIC AGENTS

SCOPOLAMINE I P R AT R O P I U M a n d T I O T R O P I U M
§ Tertiary amine plant alkaloid, produces
peripheral effects similar to those of atropine § They are quaternary derivatives of atropine.

§ Scopolamine has greater action on the CNS and § Do not enter the systemic circulation or the CNS.
a longer duration of action as compared to § Approved as Inhalation bronchodilators for
atropine.
maintenance treatment of bronchospasm associated
§ Have sedative effects.
with chronic obstructive pulmonary disease
§ Used to prevent motion sickness
(COPD).
§ Adjunct drug in anesthetic procedures to
prevent nausea and vomiting.
§ Side effects: same as Atropine
ANTI-MUSCARINIC AGENTS
OXYBUTYNIN and TOLTERODINE
§ Synthetic atropine-like drugs.
§ Used for overactive urinary bladder disease.
§ Block muscarinic receptors in the bladder, increasing bladder capacity and reduces frequency of
bladder contraction.
§ Side effects: dry mouth, constipation and blurred vision.
§ Oxybutynin transdermal patch shows reduced mouth dryness than with oral preparations.

TROPOCAMIDE and CYCLOPENTOLATE

§ Ophthalmic solutions for mydriasis and cycloplegia.
§ Duration of action(6 and 24 hours respectively) is shorter than that of atropine, hence they have
largely replaced atropine due to the prolonged mydriasis observed with atropine.
A NT I - NI C OT I NI C AG E NT S

§ These agents block/inhibit the nicotinic receptors.

§ By inhibiting nicotinic acetylcholine receptors, these agents can modulate
neurotransmission and muscle contraction, offering diverse therapeutic applications from
anesthesia to potential treatments for neurological disorders.
§ Anti-nicotinic agents are classified into:
a) Ganglion blockers
b) Neuromuscular blockers
§ Depolarizing neuromuscular blockers
§ Non-depolarizing neuromuscular blockers
GANGLION BLOCKERS
§ Ganglionic blockers specifically act on the nicotinic receptors of both para-sympathetic
and sympathetic autonomic ganglia.
§ These drugs block the entire output of the autonomic nervous system at the nicotinic
receptor.
§ Ganglionic blockade is rarely used therapeutically, but mostly used in experimental
models to prevent vagal reflex responses to changes in blood pressure such as to prevent
reflex bradycardia caused by NE.
Side effects:
• Severe orthostatic hypotension, constipation, sexual dysfunction (may prevent erection
and ejaculation), urinary retention in men with prostatic hyperplasia.
Examples: Hexamethonium, Mecamylamine, Trimethaphan
NEUROMUSCULAR BLOCKERS

§ Neuromuscular blockers 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
(nondepolarizing type) or as agonists (depolarizing 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
anesthetic doses.
§ Helps in reducing postoperative respiratory depression.
NEUROMUSCULAR BLOCKERS

Depolarizing Neuromuscular Blockers

§ Depolarizing blocking agents work by depolarizing
the plasma membrane of the muscle fiber.

§ They are more resistant to degradation by

acetylcholinesterase (AChE) and can thus more
persistently depolarize the muscle fibers.

Example: 1: Cholinergic motor neuron

• Succinylcholine (Suxamethonium) 2: motor end-plate
3: vesicles
4: NMR
5: mitochondrion
Depolarizing Neuromuscular Drugs
Succinylcholine
§ Succinylcholine have affinity and sub-maximal intrinsic activity at Nm receptor.
§ Has short duration of action (5-10 mins) and rapid onset of action (1 – 2 mins).
Mechanism of action:
§ Binds to nicotinic acetylcholine receptors located on the motor end plate of the neuromuscular junction and causes
initial muscle contractions (fasciculations).
§ Does not dissociate rapidly from the receptors resulting in prolonged depolarization and inactivation of Na+ channels.
§ This prolonged depolarization prevents further action potentials from being generated, leading to muscle paralysis.
Therapeutic use:
§ Because of its rapid onset of action, succinylcholine is useful when rapid endotracheal intubation is required during the
induction of anesthesia
§ It is also used during electroconvulsive shock treatment.
Side effects:
Arrhythmias, muscle twitch, Increased intraocular pressure, Hyperkalemia (K+ efflux from muscles, life threatening in heart
failure, patient on diuretics)
Non-depolarizing Neuromuscular Blockers

§ Competitive blockers with no intrinsic activity (antagonist).

§ They act by competing with acetylcholine for nicotinic receptor sites at the
muscle end plate.

§ Three types based on their activity:

§ Long Acting : d-Tubocurarine, Pancuronium, Pipecuronium, Gallamine
§ Intermediate : Vecuronium, Rocuronium, Atracuronium
§ Short Acting : Mivacuronium, Ropcacuronium
Mechanism of action of Non-depolarizers
§ Low Doses:
– Competitive antagonists of Ach
– Thus, prevent depolarization at end plate- (inhibition of muscle contraction)
– Action reversed by ACh esterase inhibitors
§ Large Doses:
– Ion Channel is blocked
– More weakness of neuromuscular transmission
– Action may not be reversed by ACh esterase inhibitors
Other actions:
– Can block pre-junctional Na+ channels and interfere with mobilization of
ACh at nerve endings
Non-depolarizing Neuromuscular Drugs
D-Tubocurarine
§ First agent to undergo clinical investigation
§ Duration of action: 1- 2 hours
§ Undergoes minimal metabolism-
• Excreted: 10% in urine, 45% in bile
§ Side effects
§ Hypotension frequently occurs even at doses < ED95
§ Histamine release (skin flushing frequently)
§ Autonomic ganglionic blockade- (which manifests as hypotension)
§ Clinical use is limited due to its long duration of action and CVS side effects.
Non-depolarizing Neuromuscular Drugs

§ Gallamine § Pencuronium
– Less potent than curare – Long duration of action
– Tachycardia – Tachycardia
§ Mivacurium § Vecuronium
– Metabolized by – Intermediate duration of action
pseudocholinesterase – Fewer side effects (no histamine
– Fast onset and short duration release, no ganglion blockade,
no anti-muscarinic action)
§ Atracurium
– Rapid recovery
– Safe in hepatic & renal impairment
– Spontaneous inactivation to
laudanosine (seizures)