CHOLINERGIC PHARMACOLOGY

Neurotransmission at the cholinergic

neurons
• Six sequential steps are involved
 Synthesis of acetylcholine
 Storage of the neurotransmitter
 Release of the neurotransmitter
 Binding of acetylcholine to the receptor
 Degradation of acetylcholine in the synaptic cleft
 Recycling of choline
 Cholinergic receptors
• Muscarinic receptors
• Nicotinic receptors

These are distinguished from each other based on their different

affinities for the agents that mimic the action of
acetylcholine(Ach)- cholinomimetic agents
 Muscarinic receptors
• These have higher affinity for muscarine and low affinity for
nicotine and acetylcholine.
• They are located on the autonomic effector organs such as
heart, smooth muscles, brain and exocrine glands.
 Subtypes of muscarinic receptors
• M1 receptors, found on gastric parietal cells
• M2 receptors found on cardiac cells and smooth muscle
• M3 receptors found on the bladder, exocrine glands, smooth
muscles
• M4 receptors found in the CNS neurons
• M5 found in vascular endothelium
 Nicotinic receptors
• In addition to binding Ach, also recognize nicotine but only
with weak affinity for muscarinic
• Nicotine at low concentration stimulates receptors whereas
nicotine at high concentrations blocks the receptors
 Location of nicotinic receptors
• CNS
• Adrenal medulla
• Autonomic ganglia
• Neuromuscular junction ( NMJ) in skeletal muscles
 Cholinergic drugs
• Cholinergic agonists and antagonists
• These act on the receptors activated by
acetylcholine
• They act by either stimulating or blocking
receptors of the ANS
 Cholinergic agonists
• Direct-acting agonists
 Acetylcholine
 Bethanechol
 Carbachol
 Cevemeline
 Methacholine
 Nicotine
 pilocarpine
 Cont…
• Direct acting drugs mimic the effect of
acetylcholine by binding directly to
cholinoceptors( nicotinic and muscarinic )
• They are classified into two groups
Choline esters and
Naturally occurring alkaloids
 Cont…
• Choline esters
 Endogenous acetylcholine and synthetic esters
of choline eg carbachol and bethanechol.
• Naturally occurring alkaloids
 Nicotine
 Pilocarpine
All direct-acting cholinergic drugs have a longer
duration of action than ACh
 acetylcholine
• It lacks therapeutic importance because of its multiple actions
• Its rapidly inactivated by cholinesterase
• It has both nicotinic and muscarinic activity
• Its actions include
 Decrease heart rate and cardiac output
 Decrease blood pressure
 Increase salivary secretions
 Increase gastric acid secretions
 Stimulates intestinal secretions
 Stimulates intestinal motility
 Enhances bronchiolar secretions
 Cause bronchoconstriction
 Increases the tone of the detrusor muscle causing urination
 Cause miosis( constriction of the pupil)
Bethanechol
• Therapeutic uses
 In urologic treatment to stimulate the atonic bladder in the
postpartum or postoperative
 In non obstructive urinary retention
 In treatment of neurogenic atony and megacolon

Methacholine is used to diagnose bronchial hyperreactivity

in patients without clinically apparent asthma
 Adverse effects of bethanechol
• Causes generalized cholinergic stimulation with sweating,
salivation,flushing,decreased blood pressure, nausea,
abdominal pain, diarrhea, urinary retention, miosis(pupil
constriction), etc.
• NOTE; antidote is atropine sulfate
 Reversible and irreversible
Indirect-acting agonists

Reversible indirect-acting agonists

• Donepezil
• Edrophonium
• Neostigmine
• Physostigmine
• Pyridostigmine
• Rivastigmine
Irreversible indirect-acting agonists
• Echothiophate
• Isoflurophate
 pyridostigmine
• Cholinesterase inhibitor
• Used in management of chronic myasthenia gravis
 pralidoxime
• Reactivates actetylcholinesterase
• Used to combat poisoning by
organophosphates conjunction with atropine
and diazepam
 Summary of actions of cholinergic agonists
Bethanechol Physostigmine Rivastigmine, galantamin
• In treatment of urinary • Increases intestinal and donepezil
retention bladder motility • Used as a first line trea
• Bind preferentially at • Reverse CNS and cardiac for alzheimer disease
muscarinic receptors effects of TCAs (tricyclic • Can be used with mem
antidepressants) NMDA antagonist)
• Uncharged tertiary amine
that can penetrate the CNS.
Carbachol Neostigmine Echothiophate
• Binds to both muscarinic and • Prevents postoperative • Used in treatment of ope
nicotinic receptors abdominal distension and angle glaucoma.
• Produces miosis during ocular urinary retension • Has a longer duration of
surgery • Treatment of myasthenia gravis 100hrs.
• Used topically to reduce • Used as an antidote for • Its irreversible indirect-a
intraocular pressure in open competitive neuromuscular cholinergic agonist
angle or narrow angle blocker
glaucoma tolerant to • Has intermediate duration of
pilocarpine action, 0.5-2hrs
 Cont…
Pilocarpine Edrophonium Acetylcholine
• Reduces intraocular • Used for diagnosis of • Used to produce miosis
pressure in open angle myasthenia gravis in ophthalmic surgery
and narrow angle • Used as an antidote for
glaucoma. competitive
• Binds preferentially to neuromuscular
muscarinic receptors blockers
• Uncharged, tertiary • Has short duration of
amine that can action,10-20mins
penetrate CNS
 Cholinergic antagonists
• This describes any agent that bind to
cholinoceptors( muscarinic and nicotinic) and
prevent the effects of acetylcholine
• The most clinical use of these agents are
selective blockers of muscarinic receptors.
• They are commonly known as anticholinergic
agents
 Summary of selected cholinergic
antagonists
• Antimuscarinic agents
• Ganglionic blockers
• Neuromuscular blockers
 Antimuscarinic agents
• Aclidinium, Atropine
• Benzotropine, Cyclopentolate
• Darifenacin, Fesoterodine
• Gycopyrrolate, Hyoscyamine
• Ipratropium, Oxybutynin
• Scopolamine
• Solifenacine
• Tiotropium
• Tolerodine
• Tropicamide
• trospium
 Conti…
• Commonly used antimuscarinic agents are
 Atropine
 Scopolamine
• These block muscarinic receptors causing inhibition of muscarinic
functions
• They also block sympathetic neurons that are cholinergic such as those
innervating the
 Salivary glands and sweat glands
• Because they do not block nicotine receptors, they have no or little
effect or action at skeletal neuromuscular junction or autonomic
ganglia
• NOTE; antihistamines and tricyclic antidepressants have antimuscarinic
activity.
 A. atropine
• It’s a tertiary amine extracted from belladonna
alkaloids
• It has a high affinity for muscarinic receptors
that bind competitively to prevent Ach from
binding.
• Its action lasts about 4hrs
• Topical administration in the eye may last for
days.
 Actions of atropine
• Block muscarinic activity in the eye resulting in
 Mydriasis( pupil dilation)
 Unresponsiveness to light
 Cycloplegia (inability to focus for near vision)
• Rises intraocular pressure in patients with
angle closure glaucoma
 Therapeutic uses of atropine
• Ophthalmic –prolongs mydriasis
• Antispasmodic-used to relax the GIT
• Cardiovascular-injectable atropine used to treat
bradycardia
• Antisecretory-blocks secretions in the respiratory
tract prior surgery
• Antidote for cholinergic agonists-organophosphate
poisoning (insecticides),overdoses of
anticholinesterases like physostigmine, some
mushroom poisoning
 Pharmacokinetics of atropine
• Atropine is readily absorbed,
• Has half life of about 4hrs,
• partially metabolized by the liver,
• Eliminated in urine
 Adverse effects of atropine
• Dry mouth
• Blurred vision
• Sandy eyes
• Tachycardia
• Urinary retention
• Constipation
CNS effects
o Restlessness
o Confusion
o Hallucinations
o Delirium
o Depression
o Circulatory system collapses
 B. scopolamine
• It’s a tertiary amine plant alkaloid
• Produces peripheral effects similar to those of
atropine
• It has a greater action on the CNS
• Has longer duration of action than atropine
 Actions of scopolamine
• Most effective drug for motion sickness
• Has unusual effect on blocking the short term
memory
• Produces sedation but at high doses produces
excitement
• May produce euphoria and is susceptible to
abuse
 Therapeutic uses of scopolamine
• Prevents motion sickness
• Used in Postoperative nausea and vomiting

NOTE. Pharmacokinetic and adverse effects are

similar to those of atropine except it has a
longer half life
 C. aclidinium, glycopyrrolate,lpratropium and
tiotropium

• Ipratropium and tiotropium quaternary derivatives of

atropine
• Aclidinium and glycopyrrolate are synthetic quaternary
compounds
• Ipratropium is short acting
• aclidinium, glycopyrrolate, and tiotropium are long acting
muscarinic antagonists and they are bronchodilators thus
used in COPD( chronic obstructive pulmonary disease)
• Ipratropium is used in acute asthma
• Tiotropium is used in chronic asthma
D. Tropicamide and cyclopentolate
• This are used as ophthalmic solutions for
mydriasis and cycloplegia.
• Shorter duration of action than atropine
• Tropicamide produces mydriasis for 6hrs, and
cyclopentolate for 24hrs
 E. Benztropium and trihexyphenidyl
• Are useful as adjuncts with other
antiparkinson agents to treat Parkinson
disease
 F. Oxybutynin and other antimuscarinic
agents for overactive bladder.

• Oxybutynin,Darifenacin,Fesoterodine,Solifena
cin, Tolterodine and trospium are synthetic
atropine-like drugs with antimuscarinic actions
• Therapeutic use;
 Management of overactive bladder
 Management of urinary incontinence
 Oxybutynin is used in patients with
neurogenic bladder
 Ganglionic blockers
• Specifically act on the nicotinic receptors of
both parasympathetic and sympathetic
autonomic ganglia
• They are non selective-block the entire output
of the autonomic nervous system at the
nicotinic receptors
• Example ;nicotine
 nicotine
• It’s a component of cigarette smoke
• It’s a poison with many undesirable actions
• Has no therapeutic benefit
• It is deleterious/dangerous to health
• Nicotine depolarizes the autonomic ganglia
resulting in stimulation then in paralysis of all
ganglia
 Cont..
• The stimulatory effects of nicotine are complex and results from increased release of
the neurotransmitters due to effects on both sympathetic and parasympathetic
ganglia as shown below
 Dopamine
Pleasure, appetite suppression.
 Norepinephrine
Arousal, appetite suppression
 Acetylcholine
Arousal and cognitive enhancement
 Glutamate
Learning and memory enhancement
 Serotonin
Mood modulation, appetite suppression
 Beta endorphin
Reduction of anxiety and tension
 GABA
Reduction of anxiety and tension
 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 act either as
antagonists( nondepolarizing) or as agonists ( depolarizing) at the
receptors on the. endplate of the NMJ
NOTE; these agents are clinically useful to facilitate rapid intubation in
respiratory failure during surgery
 They provide complete muscle relaxation at lower anesthetic doses
 This increases the safety of anesthesia by allowing the patient to
recover quickly or completely
 Are used in ICU as adjuvant therapy to facilitate intubation and
mechanical ventilation
 Cont…
• Neuromuscular blockers are classified into two
 Non depolarizing ( competitive) blockers and
 depolarizing
 Non depolarizing blockers
• The first known was curare which amazon
hunters used to paralyze a prey,
• Followed by tubocurare but has been replaced
by agents with fewer side effects e.g
Cisatracurium, mivacurium, pancuronium,
rocuronium,vecuronium
 Mechanism of action of nondepolarizing
blockers
A. At low doses
• NMBs competitively block Ach at the nicotinic
receptors. They compete with Ach at the
receptor without stimulating it thus prevent
depolarization of the muscle cell membrane
and inhibit muscle contraction. Their
competitive action can be overcome by
cholinesterase inhibitors like neostigmine and
edrophium
 Cont…
B. At high doses
• Nondepolarizing agents can block the ion
channels of the motor endplate. This leads to
further weakening of neuromuscular
transmission, reducing the ability of
cholinesterase inhibitors to reverse the action
of nondepolarizing agent.
 pharmacokinetics
• All are NMBs are injected IVs or occasionally
IM.
• They penetrate membranes very poorly and
don’t enter cells or cross the blood-brain
barrier
• Pancuronium is excreted in urine
 Adverse effects
• The side effects of these agents are minimal
• Increased heart rate
• Postoperative muscle pain
• Hyperkalemia
 Drug interractions
a. Cholinesteraze inhibitors
Drugs such neostigmine,
physostigmine,pyridostigmine and edrophium
can overcome the action of nondepolarizing
agents
 Cont…
b. Halogenated hydrocarbon anesthetics
Drugs such as desflurane act to enhance
neuromuscular blockade by exerting a stabilizing
action at the NMJ.
 Cont…
c. Aminoglycoside antibiotics
Drugs such gentamycin and tobramycin inhibit
Ach release from cholinergic nerves by
competing with calcium ions. They synergize
with competitive blockers enhancing
neuromuscular blockade.
 d. Calcium channel blockers
• These may increase the neuromuscular
blockade of competitive blockers.
 Depolarizing agents
• depolarizing neuromuscular blocking agents
work by depolarizing the plasma membrane of
the muscle fiber, similar to the action of acetyl
choline. However these agents are more
resistant to degradation by
acetylcholinesterase and are more persistently
depolarize the muscle fibers.
• Example is only succinylcholine as a
depolarizing muscle relaxant today.
 Mechanism of action
• It attaches to the nicotinic receptor and acts
like Ach to depolarize the junction
 Therapeutic uses
• Succinylcholine is useful when rapid
endotracheal intubation is required.
• It is also used during electroconvulsive shock
treatment
 pharmacokinetics
• Its injected IV, its brief duration of action
results from redistribution and rapid
hydrolysis by plasma cholinesterase. Drug
effects rapidly disappear upon discontinuation
 Adverse effects
• Malignant hyperthermia
• Apnea due to paralysis of the diaphragm
• Hyperkalemia due to increased potassium
release from intracellular stores