Cholinergic drugs and their pharmacology.

1. Autonomic Nervous System
Lecture 2
Cholinergic Drugs

2. Parasympathetic Nervous System
• Works to save energy, aids in digestion,
and supports restorative, resting body
functions.
–Decrease in heart rate
–Increased gastro intestinal tract tone and
peristalsis
–Urinary sphincter relaxation
–Vasodilation – decrease in blood pressure

3. Body Responses – “rest and digest”
• Dilation of blood vessels in skin
• Decrease heart rate (bradycardia)
• Increase secretion of digestive enzymes
• Constriction of smooth muscle of bronchi
• Increase in sweat glands - cooling
• Contraction of smooth muscles of urinary
bladder
• Contraction of smooth muscle of skeletal
system

4. Cholinergic Receptors
M1 Secretory glands salivation, stomach acid,
sweating, lacrimation
M2 Heart Decreases heart rate 
bradycardia
M3 Smooth muscle
(GI/GU/Resp)
Contraction of smooth
muscles (some)  diarrhea,
bronchospasm, urination
M3 Pupil and ciliary muscle Contracts  Miosis
Increased flow of aqueous
humor
Nm Skeletal muscle end
plate
Contraction of skeletal
muscle
Nn Autonomic ganglia,
Adrenal Medulla
Secretion of Epinephrine
Controls ANS

5. Cholinergic Drugs
• Often called parasympathomimetic drugs, because
their action mimics the action of the PSNS.
• Also called as cholinomimetic.
• Stimulate parasympathetic nervous system in same
manner as does acetylcholine
• May stimulate cholinergic receptors directly or slow
acetylcholine metabolism at synapses (affect the
enzyme acetylcholinesterase)
• Cholinergic agonists are two types :
1.Direct acting
2.Indirect acting

7. Direct acting cholinergic agonist
• They act by binding directly to cholinoceptors. Direct acting
cholinergics are lipid insoluble.
• Do not readily enter the CNS so effects are peripheral.
• Resistant to metabolism by acetylcholinesterase.
• Effects are longer acting than with acetylcholine.
• Acetylcholine
• Methacholine Muscarine
• Carbachol Pilocarpine
• Bethanechol Arecoline

8. Drug Effects of Cholinergic Agents
• Cardiovascular effects
– Decreased heart rate( Bradycardia)
– Vasodilation (NO mediated)
• Stimulate intestine and bladder
– Increased gastric secretions
– Increased gastrointestinal motility
– Increased urinary frequency

9. Drug Effects of Cholinergic Agents
• Stimulate pupil
– Constriction (miosis), Spasm of accomodation
– Reduced intraocular pressure (increased outflow)
• Respiratory effects
– Bronchial constriction, narrowed airways
• Increased salivation and sweating

10. Drug Effects of Cholinergic Agents
“MSLUBDD”
Many Smart Ladies Ultimately Bring Disaster for
Dudes!
Miosis
Salivation
Lacrimation
Urination
Bronchoconstriction
Defaecation
Decreased heart rate

11. Acetylcholine
• One of the main neurotransmitters of the ANS is
acetylcholine
• Acetylcholine is released at preganglionic fibers of
both the sympathetic and parasympathetic nervous
system
• Also released from postganglionic sympathetic
neurons that innervate the sweat glands and from
motor neurons that innervate the skeletal muscles
• It is a quaternary ammonium compound so cannot
penetrate the membrane.
• Does not have any therapeutic importance, because
rapid inactivation by acetylcholinesterases.
• It has both Muscarinic & Nicotinic actions .

12. Bethanechol
• Not hydrolyzed by acetylcholinesterases
• Actions
• Directly stimulates M receptors causing increased
intestinal motility & tone
• It stimulates detrusor muscle of the bladder while
trigone & sphincters are relaxed causing expulsion of
urine
• Therapeutic Uses:
• Paralytic ileus
• Urinary retentions
• Helpful for postsurgical atony of the bladder
and GI tract

13. Pilocarpine
An alkaloid, lipid soluble & is stable to hydrolysis
by cholinsterases.
Actions:
When applied locally to cornea Produces rapid
miosis & contraction of ciliary muscle produces
spasm of accommodation & vision is fixed at
particular distance making it impossible to
focus for far situated objects
Therapeutic Use : In Glaucoma it opens trabecular
meshwork around schlemm’s canal
• causes drainage of aqueous humor
• IOP immediately decreases.

14. Indirect acting Cholinergic agonists
• They act through inhibition of Acetyl cholinesterase
enzyme, so increases Acetylcholine level in the
synapse.
• Accumulation of acetylcholine then occurs which
enhances the activation of the nicotinic and
muscarinic receptors.
• Anticholinesterase drugs are either reversible or
irreversible inhibitors of acetylcholinesterase

15. • Reversible: Irreversible:
• Neostigmine Organophosphates
• Physostigmine Dyflos,
Echothiopate
• Pyridostigmine Parathion,
Malathion
• Edrophonium Tabun, Sarin,
Soman
• Tacrine Carbamates
• Donepezil Carbaryl,
Propoxur(baygon)

16. • Physostigmine - only anticholinesterase
capable of crossing the blood brain barrier. Is
more lipid soluble. Used as an antidote for
overdosage of anticholinergics such as:
atropine, antihistamines, TCA, phenothiazines.
May also be used in treatment of glaucoma.
• Pyridostigmine - is the maintenance drug of
choice for patients with Myasthenia gravis.

17. • Neostigmine - prototype anticholinesterase agent.
Used for long-term treatment of myasthenia gravis
and as an antidote for tubocurarine and other non-
depolarizing agents in surgery.
• Donepezil -
• Used in the treatment of mild to moderate
Alzheimer’s disease.
• Helps to increase or maintain memory and
learning capabilities.

18. Uses of Indirect Cholinergic agonists
• Glaucoma – Pilocarpine, Physostigmine
• Edrophonium to test Myasthenia gravis,
Neostigmine and pyridostigmine in treatment
of M.gravis.
• Postoperative paralytic ileus - Neostigmine
• Postoperative decurarization –
Neostigmine(reverses muscle paralysis)

19. • Cobra bite – edrophonium (prevent respiratory
paralysis.
• atropine poisoning – Physostigmine
(antogonizes both central and peripheral
effects).
• Alzheimer’s Disease – Donepezil,
galantamine, tacrine, rivastigmine.
• TCA, Phenothiazines, overdose –
Physostigmine.

20. Cholinergic Agents: Side Effects
Side effects are a result of overstimulation
of the PSNS.
• Cardiovascular:
– Bradycardia, hypotension, conduction
abnormalities (AV block and cardiac arrest)
• CNS:
– Headache, dizziness, convulsions
• Gastrointestinal:
– Abdominal cramps, increased secretions,
nausea, vomiting

21. Cholinergic Agents: Side Effects
• Respiratory:
–Increased bronchial secretions,
bronchospasms
• Other:
–Lacrimation, sweating, salivation, loss
of binocular accommodation, miosis

22. Acute toxic effects of irreversible
cholinesterase inhibitors (OP poisoning )
• These agents are lipid soluble
• Can enter the body by the eye,skin, respiratory
system and GI tract.
• organophosphate insecticides (malathion,
parathion) or nerve gases (sarin, tabun, soman)
• These agents cause excessive cholinergic
stimulation (muscarinic) and neuromuscular
blockade

23. • Cholinergic crisis occurs because the
irreversible anticholinesterase poison binds to
the enzyme acetylcholinesterase and
inactivates it. Thus, acetylcholine remains in
cholinergic synapses causing excessive
stimulation of muscarinic and nicotinic
receptors.

24. Treatment of OP poisoning
Emergency treatment includes:
• Decontamination of clothing
• Flushing poison from skin and eyes
• Activated charcoal and lavage for GI
ingestion
• Atropine to counteract the muscarinic
effects (2mg IV every 10 min till pupil
dilates, max 50-100mg)

25. • To relieve the neuromuscular blockade by
nicotinic effects, give pralidoxime, a
cholinesterase reactivator.
• Pralidoxime causes the anticholinesterase
poison to release the enzyme
acetylcholinesterase.
• Give Pralidoxime as soon as possible as if too
much time passes, the poison bond becomes
too strong (aging) for the pralidoxime to
work.
• Other oximes- obidoxime, diacetylmonoxime

26. Thank you!