1. DIRECT CHOLINERGIC DRUGS Profs. Abdalqader Alhaider & Hanan Hagar
Pharmacology Unit

2. By the end of this lecture the student should know
Classification of nervous system.
Describe the various steps in cholinergic transmission.
Mention the different types, locations and actions of cholinergic receptors.
Describe the effects of acetylcholine on major organs
Classify cholinomimetic drugs.
Describe the kinetics, actions and uses of direct and indirect-acting cholinomimetic drugs.

3. Nervous system Central nervous system Peripheral nervous system
Afferent Division
(Sensory)
Efferent Division
(Motor)
Autonomic nervous
system
Somatic system
(skeletal muscles)
Enteric nervous system
Parasympathetic nervous system
Sympathetic nervous system

4. Somatic N.S Autonomic N.S
What are the differences between the somatic and the autonomic nervous system?
Somatic N.S Autonomic N.S
Control skeletal muscles Control internal viscera
Voluntary Involuntary
Somatic nerve is one fiber autonomic nerve is two fibers (Preganglionic &
Postganglionic)

5. Autonomic nerve Somatic nerve Post-ganglionic fiber ganglia
Pre-ganglionic fiber
Somatic nerve
One fiber

6. Division of Autonomic Nervous System
Sympathetic nervous system.
Parasympathetic nervous system.
Enteric nervous system.

7. Parasympathetic Nervous System
Is a craniosacral outflow

8. Neurotransmitters
Neurotransmitter in parasympathetic nervous system or cholinergic system is acetylcholine and nerves are called cholinergic nerves

9. Cholinergic transmission
The release of neurotransmitter Ach from cholinergic nerves include the following steps:
Synthesis of Ach
Storage of Ach in storage vesicles
Release of Ach
Binding of Ach to postsynaptic receptors to give actions

10. Cholinergic transmission
5) Metabolism by acetyl cholinesterase in synaptic cleft to give choline and acetate.
acetyl cholinesterase
Acetylcholine acetate + choline
6) Recycling of choline

11. Cholinergic transmission

12. Cholinergic transmission

13. Cholinergic or parasympathetic receptors
Nicotinic receptors (N) = central receptors.
Muscarinic receptors (M)= peripheral receptors
Central nicotinic receptor
Peripheral muscarinic receptor

14. Nicotinic receptors Type I receptors : ion channel linked receptors
Located in:
Skeletal muscles (neuromuscular junction, Nm )
Autonomic ganglia (sympathetic and parasympathetic ganglia, Nn).
Adrenal medulla (Nn).
CNS (Nn).
Nicotinic receptors

15. Muscarinic receptors Five subclasses ; M1, M2, M3, M4 and M5
Type II receptors : G-protein linked receptors
Five subclasses ; M1, M2, M3, M4 and M5
M1, M3, M5 are excitatory or stimulatory in function (stimulation)
M2, M4 are inhibitory in function (inhibition).
Located at all target organs that are innervated by parasympathetic fibers (e.g, heart, CVS, eye, bladder, etc).

17. Muscarinic receptors Pharmacological actions Locations Receptor
CNS excitation
Gastric acid secretion
CNS
gastric parietal cells
M1 Excitatory
Cardiac inhibition
(Bradycardia)
Heart
M2 Inhibitory
Secretion of glands
Smooth muscle contraction
Vasodilatation (via nitric oxide)
Exocrine glands
Smooth muscles (GIT, urinary tract, bronchial muscles)
Vascular endothelium M3
Excitatory
memory, arousal, attention and analgesia
M4 & M5

18. Cholinergic or parasympathetic receptors
Muscarinic receptors
Peripheral cholinoceptors
Nicotinic receptors
Central cholinoceptors
Excitatory or inhibitory
Almost excitatory
On all peripheral organs innervated by postganglionic parasympathetic fibers
Autonomic ganglia Nn
sympathetic & parasympathetic stimulation
Heart (bradycardia, M2)
exocrine glands (secretion, M3)
Adrenal medulla Nn
release of catecholamines (adrenaline & noradrenaline)
Smooth muscles (contraction, M3)
(GIT, urinary tract, bronchial muscles, uterus)
Skeletal muscles Nm
contraction

19. Pharmacological actions of parasympathetic N.S.
Actions that are due to effects of Ach on nicotinic receptors and muscarinic receptors thus divided in two actions
1) Nicotinic actions
2) Muscarinic Actions

20. Nicotinic actions of Ach
Skeletal muscles:
Low conc. of Ach  muscle contraction
High conc. of Ach persistent depolarization & relaxation.
Stimulation of Autonomic ganglia
Stimulation of adrenal medulla: release of catecholamines (Adrenaline & Noradrenaline).
Nicotinic actions of Ach

21. Muscarinic actions of Ach
Cholinergic actions
Organs
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
Decrease in intraocular pressure (IOP)
Eye
bradycardia ( decrease in heart rate ) (M2)
Release of NO (EDRF)
Heart
endothelium
Constriction of bronchial smooth muscles
Increase in bronchial secretion M3
Lung
Increase in motility (peristalsis)
Increase in secretion
Relaxation of sphincter -defecation M3
GIT
Contraction of muscles
Relaxation of sphincter M3
Urination
Urinary bladder
Increase of secretions of exocrine glands
sweat, saliva, lacrimal, bronchial, intestinal secretions M3
Exocrine glands

24. Parasympathomimetics
Cholinomimetics
Parasympathomimetics
Drugs that produce actions similar to stimulation of parasympathetic system or similar to Ach.

25. Types of cholinomimetics
Direct cholinomimetics
cause direct stimulation of cholinergic receptors.
Indirect cholinomimetics (anticholinesterases)
acts indirectly by inhibiting acetyl cholinesterase thus prevent the hydrolysis of Ach.

26. Direct Cholinomimetics
Naturally occurring alkaloids e.g. Pilocarpine
Synthetic choline esters
Acetylcholine (M,N)
Carbachol (M,N)
Bethanechol (M)
Cevimeline (M)
Direct Cholinomimetics

27. Acetylcholine (Ach) Muscarinic and nicotinic agonist
Not used clinically because Ach
Is not selective as it acts on both nicotinic and muscarinic receptors
Has short duration of action. Why?
Due to rapid metabolism by acetycholinesterase

28. Synthetic choline esters
include drugs as bethanechol, carbachol
Quaternary ammonium compounds
contain N+ (polar)
Poor distribution
can not cross BBB (No CNS effects)
Not metabolized by cholinesterase.
Have longer duration of action than Ach.
Never given I.V. or I.M BUT S.C.

30. Carbachol
Has muscarinic actions similar to ACh
Has nicotinic actions similar to Ach (side effects)
Longer duration of action
Used for treatment of glaucoma
Bethanechol
Has no nicotinic actions
Used for treatment of paralytic ileus & urinary retention.

31. Carbachol
Muscarinic actions on Eye, GIT, UT. (see the previous table).
Has nicotinic actions (what are these actions?)
Used for
Mainly in glaucoma
Urinary retention & paralytic ileus (rarely used due to its nicotinic actions)

32. Bethanechol
Prominent muscarinic actions on GIT, UT.
No nicotinic action
Used for
Paralytic ileus
Urinary retention in cases of
post-operative atony & neurogenic bladder

33. Pilocarpine (natural alkaloids)
Tertiary amine non polar = lipophilic
well absorbed, good distribution
Cross BBB (has central effects).
Not metabolized by cholinesterase
Long duration of action
Direct muscarinic agonist
(mainly on eye & secretion).

34. Pilocarpine (continue…)
Uses:
Xerostomia (dry mouth).
Drug of choice in emergency glaucoma applied as eye drops.
Adverse effects:
Profuse sweating
Salivation
Bronchoconstriction
Diarrhea
CNS effects

35. (autoimmune disease characterized by decreased salivation).
Cevimeline
Direct acting muscarinic agonist
Used for treatment of dry mouth symptom
associated with Sjogren's syndrome
(autoimmune disease characterized by
decreased salivation).

36. Pilocarpine Bethanechol Carbachol ACh
Tertiary
non polar
Quaternary Polar
Chemistry
Complete
better absorbed than Ach
NOT
Absorption
NOT metabolized by cholinesterase
metabolized by cholinesterase
Metabolism
by cholinesterase
Longer (++)
Very short
Duration
oral,
eye drops
Oral
S.C.
Oral,
I.V.
administration

37. direct Cholinomimetic More on eye, exocrine glands
Cevimeline M
Pilocarpine
Bethanechol
Carbachol
M,N
ACh
M, N
Muscarinic
Nicotinic
Receptors
+++
Exocrine glands
More on eye, exocrine glands
GIT, Urinary
bladder
Eye, GIT
Urinary bladder
NOT
Selectivity NO
Sjogren's syndrome
Glaucoma
Xerostomia
Paralytic ileus
Urinary retention
Uses

38. Contraindications of direct cholinomimetics
Bronchial asthma.
Peptic ulcer.
Angina pectoris
Incontinence
Intestinal obstruction

39. Thank you