These are drugs that acts on cholinoceptors. It includes their mode of action and he classes of cholinoceptor simulants.

1. Cholinomimetic drugs
• Mimic actions of acetylcholine (Ach)
• Classified in various ways based on:
– Based on spectrum of activity
• Based on the type of receptor that is activated,
nicotinic versus muscarinic
– Based on their mode of action
• Bind directly to cholinoceptors: direct-acting
• Act indirectly by inhibiting hydrolysis of endogenous
Ach: cholinesterase inhibitors

2. Classes of cholinoceptor stimulants

3. • They can be selective or non-selective to the
cholinoceptors
– Selective to nicotinic or muscarinic, or nicotinic
receptors in NMJ vs. autonomic ganglia
– Non-selective
• Cause very diffuse & marked alterations in organ
system function because Ach has multiple sites of
action with excitatory or inhibitory effects
– Selective
• Have a degree of selectivity
• Limits to desired effects & avoids or minimizes adverse
effects

4. DIRECT- ACTING CHOLINOCEPTOR
STIMULANTS

5. Direct-acting cholinoceptor stimulants

6. • “ Direct-acting cholinergic agents” or
“cholinergic agonists”
• Mimic effects of ACh by binding directly to &
activating cholinoceptors (muscarinic or
nicotinic)
• Pilocarpine & bethanechol preferentially bind
to muscarinic receptors - muscarinic agonists
• However, as a group, the direct-acting
agonists show little specificity in their actions,
which limits their clinical usefulness

7. • Agonists bind & activate muscarinic & nicotinic
receptors
• Activity on muscarinic receptors:
– Activation of the parasympathetic nervous system
modifies organ function by two major mechanisms:
i. ACh activates muscarinic receptors on effector cells to
alter organ function directly
ii. ACh interacts with muscarinic receptors on nerve
terminals to inhibit the release of their neurotransmitter
– Therefore, ACh release & circulating muscarinic agonists
indirectly alter organ function by modulating the effects
of the parasympathetic & sympathetic nervous systems &
perhaps nonadrenergic, noncholinergic (NANC) systems
Direct-acting cholinergic agonists: mode of
action

8. Direct-acting cholinergic agonists: mode of
action - ii
• Activity on nicotinic receptors
– Nicotinic receptor activation causes depolarization of
the nerve cell or neuromuscular end plate membrane
– In skeletal muscle, the depolarization initiates an
action potential that propagates across the muscle
membrane & causes contraction
– Prolonged agonist occupancy of nicotinic receptor
abolishes the effector response i.e. postganglionic
neuron stops firing (ganglionic effect) & the skeletal
muscle cell relaxes (neuromuscular end plate effect)

9. Direct-acting cholinergic agonists: mode of
action - ii
– Continued presence of nicotinic agonist prevents
electrical recovery of the postjunctional
membrane.
– A state of “depolarizing blockade” occurs initially
during persistent agonist occupancy of the
receptor
– Continued agonist occupancy is associated with
return of membrane voltage to the resting level
– Rreceptor becomes desensitized to agonist & this
state is refractory to reversal by other agonists

10. • Both muscarinic & nicotinic activity
• Has multiplicity of actions (leading to diffuse effects)
•  in heart rate & cardiac output
•  in blood pressure
• GI tract effects –  salivary secretion & stimulates
intestinal secretions & motility
• Enhances bronchiolar secretions
• Genitourinary tract -  tone of detrusor muscle, causing
urination
• Eye:
– Stimulation of ciliary muscle contraction for near vision
– Constriction of pupillae sphincter muscle, causing miosis
(marked constriction of the pupil)
• Clinical use: to produce miosis in ophthalmic surgery
Acetylcholine - effects

11. Benathechol
• No nicotinic actions
• Strong muscarinic activity
– Major actions on smooth muscle of the bladder &
GI tract
– Duration of action - 1 hour
• Effects
–  intestinal motility & tone
– Stimulation of detrusor muscle of bladder,
relaxation of trigone & sphincter muscles to
produce urination

12. Carbachol
• Muscarinic & nicotinic actions
• Actions:
• Profound effects on cardiovascular & GI systems because of
ganglion-stimulating activity
– First stimulate & then depress these systems
• Release of epinephrine from adrenal medulla by its nicotinic
action
• Locally instilled into the eye - causes miosis & a spasm of
accommodation (ciliary muscle of the eye remains in a
constant state of contraction)
• Therapeutic uses:
• Miotic agent in the eye to treat glaucoma
– Causes pupillary contraction &  in intraocular pressure
• Adverse effects:
• At doses used ophthalmologically, little or no side effects
occur due to lack of systemic penetration

13. Pilocarpine
• Stable to hydrolysis by AChE
• Less potent than choline esters
• Active in CNS
• Exhibits muscarinic activity
• Actions:
– Topical application to the eye - rapid miosis &
contraction of ciliary muscle
• During miosis, eye experiences a spasm of accommodation
• Vision becomes fixed at some particular distance, making it
impossible to focus
– Stimulates secretion of sweat, tears & saliva

14. Pilocarpine - ii
• Clinical uses:
• In opthalmology
– Miotic action useful in reversing mydriasis due to
atropine
• Treatment of glaucoma
– Drug of choice for emergency lowering of intraocular
pressure of both open-angle & angle-closure
glaucoma
• Promoting salivation in patients with xerostomia
resulting from irradiation of the head & neck
•
lack of tears) - oral pilocarpine tablets

15. Indirect-acting cholinoceptor stimulants –
mode of action
• Group of drugs that act by inhibiting the AChE enzyme, that
specifically cleaves ACh to acetate & choline terminating action of
Ach
– AChE is an extremely active enzyme
– Initial catalytic step, ACh binds to the enzyme’s active site & is hydrolyzed,
yielding free choline & the acetylated enzyme
– In the 2nd
step, the covalent acetyl-enzyme bond is split, with the addition
of water (hydration) to release enzyme & form acetate
– Entire process occurs in approx. 150 microseconds
– AChE is located both pre - & postsynaptically in the nerve terminal where
it is membrane bound
• Inhibitors of AChE indirectly provide a cholinergic action by
preventing the degradation of ACh
• Results in an accumulation of ACh in the synaptic space
• Provoke a response at all cholinoceptors in the body, including both
muscarinic & nicotinic receptors of the ANS, NMJ & in the brain

17. Indirect-acting cholinoceptor stimulants
• ‘Anticholinesterases, cholinesterase inhibitors’

18. Short - acting reversible
anticholinesterase
Edrophonium
– Prototype short-acting AChE inhibitor
•Mode of action
– Binds reversibly to the active center (anionic site) of
AChE, preventing hydrolysis of Ach
– Reversible ionic bond formed, hence brief action of
drug
•Pharmacokinetics
– Rapidly absorbed
– Short duration of action: 10 - 20 minutes due to rapid
renal elimination
– A quaternary amine & its actions are limited to the
periphery (does not gain access to CNS)

19. Edrophonium: clinical uses
• Diagnosis of myasthenia gravis
– Autoimmune disease caused by antibodies to the
nicotinic receptor at the NMJ
– This causes their degradation, making fewer
receptors available for interaction with ACh
– i.v injection leads to a rapid  in muscle strength
– Caution: excess drug may provoke a cholinergic
crisis (atropine is the antidote)
• Due to the availability of other agents,
edrophonium use has become limited

20. Intermediate - acting reversible
anticholinesterases

21. Intermediate - acting reversible
anticholinesterases – mode of action
• Carbamic acid esters, also called carbamates
– Posses a carbamyl group that binds to the anionic
site of AChE enzyme to form a carbamylated
enzyme
– Carbamylated enzyme takes longer to hydrolyze
from the drug, minutes vs. microseconds
• Slow recovery of carbamylated enzyme results
in a more long lasting effect of drug

22. Pyridostigmine & ambenonium
• Durations of action:
– 3 - 6 hours & 4 - 8 hours respectively
– Longer than that of neostigmine
• Clinical use
– Long term management of myasthenia gravis
• Adverse effects
– Similar to those of neostigmine
Demecarium – Glaucoma treatment

23. Tacrine, donepezil, rivastigmine &
galantamine
• Patients with Alzheimer’s disease have a
deficiency of cholinergic neurons in the CNS
• Anticholinesterases developed to manage the
loss of cognitive function asscoaited with
deficiency of cholinergic neurons
• Tacrine – oldest, causes hepatotoxicity
– Replaced by newer agents – donepezil,
rivastigmine & galantamine, are more selective
• Donepezil – no hepatotoxicity

24. Irreversible anticholinesterases: mode of
action
• Undergo binding & hydrolysis by AChE resulting in a
phosphorylated active site
• Covalent phosporous enzyme bond in phoshorylated
enzyme is extremely stable & hydrolyzes in water at
a very slow rate (hundreds of hours)
• Phosphorylated enzyme complex may undergo a
process called ‘ageing’ after initial binding reaction
• Ageing results in strengthening of phosphorous
enzyme bond
Ageing – loss of alkyl group

25. Irreversible anticholinesterases: mode of
action - ii
• Strong nucleophiles (pralidoxime) if given before ageing
has occurred, may break the phosporous-enzyme bond
to release the enzyme i.e. cholinesterase regeneration
• Once ageing has occurred, enzyme inhibitor-complex is
more stable & more difficult to break even with use of an
oxime regenerator compounds
• Organophosphate insecticide poisoning – cholinesterase
regenerators used
• Organophosphate insecticides may cause poisoning,
results in nicotinic & muscarinic signs & symptoms
(cholinergic crisis)
– Depending on the agent, the effects can be peripheral or
can affect the whole body

26. Major therapeutic uses of cholinomimetics
Opthalmology
•Glaucoma
•Accomodative esotropia
•Miosis during opthalmic surgery
Carbachol
Pilocarpine
Physostigmime
Acetylcholine
Echothiophate
Demecarium
Gastrointestinal & urinary tract diseases
Urologic treatment – postpartum or postoperative, non-
obstructive urinary retention
Treatment of neurogenic atony & megacolon
Benathechol
Neostigmine
Physostigmine
Xerostomia resulting from irradiation of the head & neck Pilocarpine
Cevimeline
Neuromuscular junction blockade
Myasthenia gravis
Edrophonium
Ambenonium
Pyridostigmine
Neostigmine
Alzheimers disease Tacrine, donepezil,
galantamine, rivastigmine
Atropine overdosage anticholinesterases

27. Cholinergic antagonists

29. Muscarinic antagonists
• Also called ‘antimuscarinics’, ‘parasympatholytics’
(least preferred)
• Most clinically useful class
• Block muscarinic receptors, hence effects of
parasympathetic innervation are, interrupted & the
actions of sympathetic stimulation are left unopposed
• Also block the few exceptional sympathetic neurons
that are cholinergic, such as those innervating the
salivary & sweat glands
• Don’t block nicotinic receptors, hence little or no
action at skeletal neuromuscular junctions (NMJs) or
autonomic ganglia

30. Muscarinic antagonists - ii
• Large group of drugs
• Some are alkaloids derived from plants,
others semi-synthetic & others synthetic
molecules
• A number of antihistamines, antidepressants
(mainly tricyclic antidepressants) &
antipsychotics also have antimuscarinic
activity

31. Antimuscarinic agents
• Atropine
• Scopolamine/hyosci
ne
• Benztropine
• Cyclopentolate
• Darifenacin
• Fesoterodine
• Oxybutynin
• Solifenacin
• Tiotropium
• Tolterodine
• Trihexyphenidyl
• Tropicamide
• Trospium
• Tridihexethyl
• Propantheline
• Glycopyrrolate
• Pirenzepine
• Dicyclomine
• Homatropine
• Methantheline
• Methscopolamine

32. Atropine – mode of action
• Belladonna alkaloid with a high affinity for
muscarinic receptors
• It binds competitively & prevents ACh from
binding to those sites
• Atropine acts both centrally & peripherally
• Duration of action ~ 4 hours, except when placed
topically in the eye, where the action may last
for days
• Neuroeffector organs have varying sensitivity to
atropine
• Greatest inhibitory effects are on bronchial
tissue & the secretion of sweat & saliva

33. Atropine - effects
• Eye
– Blocks muscarinic
activity in the eye,
resulting in:
• Mydriasis (dilation of
the pupil)
• Unresponsiveness to
light
• Cycloplegia (inability to
focus for near vision)
– In patients with angle-
closure glaucoma,
intraocular pressure
may rise dangerously
• Gastrointestinal tract
–  activity of GI tract
– Although gastric motility
is , hydrochloric acid
production is not
significantly affected
(not effective in peptic
ulcer)
• Urinary bladder
–  urination

34. Atropine – effects - ii
• Secretions:
– Blockage of muscarinic
receptors in the salivary
glands, producing dryness
of the mouth (xerostomia)
– Salivary glands are
exquisitely sensitive to
atropine
– Inhibition of sweat &
lacrimal glands [Note:
Inhibition of secretions by
sweat glands can cause
elevated body temperature,
which can be dangerous in
children & the elderly.]
• Cardiovascular:
• Divergent effects on the
cardiovascular system,
depending on the dose
• Low doses - predominant
effect is a slight  in heart rate
– Results from blockade of M1
receptors on the inhibitory
prejunctional (or presynaptic)
neurons, thus permitting
increased ACh release
• Higher doses - cause a
progressive  in heart rate by
blocking M2 receptors on
sinoatrial node

35. Atropine: clinical uses
• Ophthalmic:
– Topical atropine exerts both
mydriatic & cycloplegic
effects
– Permits measurement of
refractive errors without
interference by the
accommodative capacity of
the eye
– Shorter-acting
antimuscarinics
(cyclopentolate &
tropicamide) have largely
replaced atropine due to
prolonged mydriasis
observed with atropine (7 -
14 days vs. 6 - 24 hours with
other agents)
– [NB: Phenylephrine or
similar α-adrenergic
drugs are preferred for
pupillary dilation if
cycloplegia is not
required]
• As an antispasmodic
agent to relax the GI tract
• Cardiovascular:
– Treatment of
bradycardia of varying
causes
• Antisecretory agent to
block secretions in the
upper & lower respiratory
tracts prior to surgery

36. Atropine clinical uses - ii
• Antidote for cholinergic agonists:
– Organophosphate (insecticides, nerve gases)
poisoning
– Overdose of clinically used anticholinesterases e.g.
physostigmine, some types of mushroom poisoning
– Massive doses of atropine may be required over a
long period of time to counteract the poisons
– Atropine enters CNS, important in treating central
toxic effects of anticholinesterases

37. Hyoscine
• Actions:
• One of the most effective
anti–motion sickness drugs
available
• Also blocks short-term
memory
• Sedation
• At higher doses, it can
produce excitement
• Euphoria & is susceptible to
abuse
• Pharmacokinetics & adverse
effects similar to atropine
• Therapeutic uses:
• Prevention of
postoperative nausea &
vomiting
• Prevention of motion
sickness
– For motion sickness, it
is available as a topical
patch that provides
effects for up to 3 days
– [NB:much more
effective
prophylactically than
for treating motion
sickness once it occurs]

38. Hyoscine butylbromide
• Similar to atropine
• Poorly absorbed
• Lacks CNS effects
• Has significant ganglion-blocking activity
• Clinical uses
– Mainly for gastrointestinal hypermotility -
antispamodic (relax gastrointestinal smooth
muscles)

39. Ipratropium & tiotropium
• Delivered via inhalation
• Do not enter systemic
circulation or the CNS,
isolating their effects to
the pulmonary system
• Tiotropium is
administered once daily
• Ipratropium – multiple
dosing up to 4 times
daily
• Clinical uses
– Bronchodilators for
maintenance
treatment of
bronchospasm
associated with
chronic obstructive
pulmonary disease
(COPD)
– Ipratropium - acute
management of
bronchospasm in
asthma

40. Tropicamide & cyclopentolate
• Shorter duration of action than that of
atropine
• Tropicamide produces mydriasis for 6 hours
• Cyclopentolate for 24 hours
• Clinical uses
– Ophthalmic solutions for mydriasis & cycloplegia

41. Benztropine & trihexyphenidyl
• Used as adjunct to other antiparkinsonian
agents to treat Parkinson’s disease & other
types of parkinsonian syndromes, including
antipsychotic- induced extrapyramidal
symptoms
– Affect extrapyramidal system,  the involuntary
movement & rigidity of patients with Parkinson’s
disease
– Counteract extrapyramidal side effects of many
antipsychotic drugs

42. Pirenzepine
• M1 receptor selective antagonist
• Actions
– Inhibits gastric secretion by action on ganglion cells
– Little effect on smooth muscle or CNS
• Uses
– Peptic ulcer
• NB: Its use has been superseded by other
antiulcer agents (histamine H2 antagonists &
proton pump inhibitors)

43. Other antimuscarinic agents
Drug Clinical uses Adverse effects
Darifenacin • M3 receptor
selective
• Block muscarinic
receptors in the
bladder to lower
intravesical
pressure, bladder
capacity is  & the
frequency of
bladder
contractions is 
• Treatment of
overactive bladder
• Dry mouth
• Constipation
• Blurred vision
• Limit tolerability of these
agents if used continually
• Oxybutynin - available as a
transdermal system
(topical patch), better
tolerated because it
causes less dry mouth
than oral formulations
• Overall efficacies of these
antimuscarinic drugs are
similar
Fesoterodine
Oxybutynin –
Solifenacin
Tolterodine
Trospium
chloride

44. Ganglion Blockers: introduction
• Competitively block action of Ach & similar agonists at
nicotinic (NN) receptors of both parasympathetic &
sympathetic autonomic ganglia
• Some members of the group also block the ion
channel that is gated by the nicotinic cholinoceptor
• Ganglion-blocking drugs are used in pharmacologic &
physiologic research because they can block all
autonomic outflow
• Lack selectivity, hence a broad range of undesirable
effects leading to limited clinical use
• Cause both depolarizing & non-depolarizing blockade

45. Ganglion Blockers: examples
• Tetraethylammonium
• Hexamethonium
• Mecamylamine
• Trimethaphan

46. NEUROMUSCULAR BLOCKERS
NMJB

47. Site of action: neuromuscular blockers

48. Neuromuscular blockers - ii
• Block cholinergic
transmission between
motor nerve endings &
nicotinic (NM) receptors on
skeletal muscle – skeletal
muscle relaxation
• Possess some chemical
similarities to ACh
• Act either as:
– Antagonists
(nondepolarizing type) at
receptors on NMJ endplate
– Agonists (depolarizing type)
at receptors on NMJ
endplate
Perijunctional
zone
Perijunctional
zone

49. Neuromuscular blockers: uses
• Group of skeletal muscle relaxants
• During surgery to facilitate tracheal
intubation & provide complete muscle
paralysis at lower anaesthetic doses,
allowing for more rapid recovery from
anaesthesia & reducing postoperative
respiratory depression
• In intensive care unit (ICU) to produce
muscle paralysis

50. Neuromuscular transmission
• Arrival of an action
potential at motor
nerve terminal causes
an influx of calcium &
release of ACh
• ACh diffuses across the
synaptic cleft to
activate nicotinic
receptors located on
motor end plate
• Adult NM receptor is
composed of 5
peptides: 2 α peptides,
1 β, 1 γ & 1 δ peptide

51. Full Nicotinic acetylcholine receptor
(nAChR)
• Intrinsic membrane
protein with 5 distinct
subunits (α2βδγ)
• N termini of 2 subunits
cooperate to form 2
distinct binding
pockets for
acetylcholine (Ach)
• Pockets occur at α-β &
δ-α subunit interfaces

52. Neuromuscular transmission - ii
• Binding of 2 Ach molecules to receptors on
the α-β & δ-α subunits causes opening of the
channel
• Subsequent movement of Na+ & K+ through
the channel is associated with a graded
depolarization of the end plate membrane
• Change in voltage - motor end plate potential
• Magnitude of end plate potential directly
related to amount of Ach released

53. Neuromuscular transmission - iii
• Small potential – permeability & end plate
potential return to normal without impulse
propagation from the end plate region to the
rest of the muscle membrane
• Large potential - adjacent muscle membrane is
depolarized & action potential propagation along
the entire muscle fiber
• Muscle contraction initiated by excitation-
contraction coupling
• Released Ach is quickly removed from the end
plate region by both diffusion & enzymatic
destruction by the local AChE enzyme

54. Neuromuscular transmission - iv
• 2 additional types of ACh receptors found
within the neuromuscular apparatus
– Ach receptor on presynaptic motor axon terminal
• Activation results in mobilization of additional Ach for
subsequent release by moving more ACh vesicles
toward the synaptic membrane
– Ach receptor found on perijunctional cells
• Not normally involved in neuromuscular transmission
• But, under certain conditions (e.g. prolonged
immobilization, thermal burns), these receptors may
proliferate sufficiently to affect subsequent
neuromuscular transmission

55. Neuromuscular blockers
• Neuromuscular relaxants
• Classified based on their modes of action
– Nondepolarizing relaxants
– Depolarising relxants
• 2 modes of action:
– Nondepolarizing neuromuscular blockade
• Antagonist action
• Competitive binding with Ach
– Depolarizing muscular blockade
• Agonists action

56. I. Nondepolarizing relaxants

57. Nondepolarizing relaxants
Mode of action
•Nondepolarizing drugs block
physiologic agonist, Ach by
preventing access to its
receptor, thereby preventing
depolarization
•Nondepolarizing drugs do not
stimulate Nicotinic receptors
– Prototype of this subgroup is
d-tubocurarine
•At small doses, act
predominantly at nicotinic
receptor site by competing with
Ach
• Competitively overcome
by administration of
anticholinesterases e.g.
neostigmine &
edrophonium, which 
concentration of ACh in
NMJ
• Skeletal muscle can
respond to direct electrical
stimulation from a
peripheral nerve
stimulator (allows for
monitoring of extent of
neuromuscular blockade)

58. Interaction of Ach & nicotinic
receptor
Interaction of non-
depolarizing blocker with
nicotinic receptor

59. Mode of action: depolarizing relaxants

60. Succinyl choline: actions
• Order of muscle blockade similar to
nondepolarizing relaxants
• Initially produces brief muscle fasciculations
that cause muscle soreness
– Prevented by administering a small dose of
nondepolarizing relaxant prior to succinylcholine
– Succinylcholine that gets to NMJ is not
metabolized by AChE, allowing the agent to bind
to nicotinic receptors & redistribution to plasma
is necessary for metabolism (therapeutic benefits
last only for a few minutes)

61. Neuromuscular blockers: clinical uses
• Surgical relaxation
• Endotracheal intubation
– Relaxes pharyngeal & laryngeal muscles,facilitating
laryngoscopy & placement of the endotracheal tube
• Control of ventilation
– In critically ill patients who have ventilatory failure to
provide adequate gas exchange & to prevent
atelectasis
• Treatment of convulsions i.e. succinylcholine
– Reduce peripheral (motor) manifestations of
convulsions associated with status epilepticus or local
anaesthetic toxicity