cholinergic drugs

1. Cholinergic
Acting Drugs
Associate prof. PhD Yulia Sorokina

2. Prescription writing
1. 0,1% solution of Physostigmine
salicylate as eye drops, bottle 10 ml
2. 10 tablets of Neostigmine
methylsulfate, 0,015; BID
3. 0,01% solution of Atropine sulfate
for SC injection; 5 ampoules 1 ml
each. OD

3. Autonomic Nervous System

4. Sites of Cholinergic Activity
-Preganglionic synapses of both sympathetic and parasympathetic ganglia
- Parasympathetic postganglionic neuroeffector junctions
- All somatic motor end plates on skeletal muscles
M2 M4 M5
M3
M1
Gi Go
Adenylyl cyclase
cAMP
Hyperpolarization (heart)
Cardiac inhibition
Antagonism of smooth
muscle relaxation
RECEPTOR
INTRACELLULAR
TRANSDUCER
ELECTRICAL
MECHANICAL
PHYSIOLOGICAL
RESPONSES
Gq
Phospholipase C
Diacyl-glycerol IP3
Depolarization
Smooth muscle contraction
Glandular secretion

5. Nicotinic Receptors
(Activated by nicotine from tobacco)
M2
(Heart &
SM)
M3
(Heart &
SM)
M4
(SM & Glands)
M5
(CNS)
NM
(Neuromuscular)
NN
Autonomic
ganglia,
Adrenal medulla
&
CNS
(Blocked by Trimethaphan)
(Blocked by
Tubocurarine)
Muscarinic Receptors
(Activated by muscarine from Amanita muscaria)
Cholinergic Receptors: Receptors Activated by Ach
M1
(Nerve Cells)

6. Muscarinic receptor types
experiments that led to their discovery
M1 - CNS excitation, gastric secretion
M2 - bradycardia, tremor, autoinhibition of release in several
brain regions
M3 - Smooth muscle contraction, gland secreation, pupil dilation,
ocular accommodation
food intake
M4 and M5 – Central Nervous System (CNS) roles, Enhanced locomotion

7. Parasympathetic Responses

12. Classes of cholinergic stimulants
Direct-acting
Receptor agonists
Choline esters
ACETYLCHOLINE
BETHANECOL
CARBACOL
Alkaloids
PILOCARPINE
Cholinesterase inhibitors
Carbamates
PHYSOSTIGMINE
NEOSTIGMINE
PYRIDOSTIGMINE
EDROPHONIUM
Phosphates
ISOFLUROPHATE
Indirect-acting

13. Cholinergic Agents
• Direct acting - act on the receptors to
activate a tissue response
• Indirect acting - inhibit the action of the
enzyme Acetylcholinesterase:

14. Chemical Structure of Cholinergic agonists
Tertiary amines
Quaternary ammonium

15. Cholinergic System -
Agonists
Parasympathomimetics
The extremely short half-life of AcCholine
makes it therapeutically useless =>
• CARBACHOL:
– Not hydrolyzed by AcCholinesterase
– Also activates N receptors
• BETHANECHOL:
– Not hydrolyzed by AcCholinesterase
– Does not activate N receptors
– Lacks cardiovascular effects
– Treatment of urinary retention
Bethanechol

16. Cholinergic System - Agonists
Muscarinic Parasympathomimetics
Pilocarpine:
– Topically !
– Used to treat glaucoma
Ciliary muscle
contraction=>increased
outflow of aqueous humor
=> reduction in intraocular
pressure

17. Side effects
- Eyes: contraction of ciliary muscle and smooth muscle of
the iris sphincter (miosis) – aqueous humor outflow,
drainage of the anterior chamber
- Cardiovascular: Bradycardia (possibly preceded by
tachycardia), vasodilation (all vascular beds including
pulmonary and coronary – M3) and hypotension,
reduction of the contraction strength (atrial and
ventricular cells, IK+ , ICa2+ diastolic depolarization , NO-
inhibitable ATP?), negative chronotropic effect (inhibition
of adrenergic activation).

18. - GI - increases in tone, amplitude of contractions, and peristaltic
activity of the stomach and intestines, enhances secretory
activity of the gastrointestinal tract.
- Urinary bladder - increase ureteral peristalsis, contract the
detrusor muscle of the urinary bladder, increase the maximal
voluntary voiding pressure, and decrease the capacity of the
bladder.
- Other effects – Increased secretion from all glands that
receive parasymphatetic enervation (salivary, lacrimal,
tracheobronchial, digestive and exocrine sweat glands)
- IMPORTANT - BROCHOCONSTRICTION
Side effects

20. Contraindications ?
• Peptic ulcer
• Asthma
• Ischemic heart
• Hyperthyroids

21. Toxicity/Mycetism
• Exaggeration of all symptoms of muscarinic agonism
• Significance: Higher consumption of wild mushrooms
(culinary)
30-60 minutes, salivation, lacrimation, excessive sweating, nausea, vomiting
diarrhea, bronchospasm, headache, visual disturbances, abdominal colic,
bradychardia, hypotension, shock
ALL SYMPTOMS REVERTED BY ATROPINE 1 - 2 mg intramuscular
A. muscaria

22. Cholinergic System inderct Agonists
Acetylcholinesterase Inhibitors
=> Extend half-life of AcCholine => trigger activation of both M and N receptors

23. Acetylcholinesterase
Inhibitors
Reversible Inhibitors:
Used to treat Glaucoma (topical)
and Myasthenia Gravis (systemic)
• Carbamates:
– Physostigmine
– Neostigmine
• Quarternary alcohols:
– Edrophonium
Used to diagnose
Myasthenia Gravis (very
short half-life)

24. Acetylcholinesterase
Inhibitors
Irreversible Inhibitors:
• Organophosphates:
– Insecticides
• Malathion
• Parathion
– Nerve gases
• Sarin
• Tabun
• Soman
Quick Time™a nd a
TIFF( Unco mpre ssed ) dec ompr esso r
ar e nee ded to see this pictur e.
Antidote
PRALIDOXIME

25. Cholinergic System - Antagonists
= Cholinolytics = Parasympatholytics
• Muscarinic receptor blockers:
– Widespread medical applications:
• Inhibition of bronchial and gastric secretion
• Relaxation of smooth muscles
• Cardioacceleration
• CNS-altering effects
• Relieving nause
• Nicotinic receptor blockers:
– Ganglion-specific blockers
– Neuromuscular blockers: Muscle relaxants

26. Muscarinic antagonism
Attropa belladona

27. History/sources
• Atropa belladona - used in the renaissance
• Deadly nightshade - used in the middle ages for poisoning
Jimson plant leaves burned in India to treat Asthma (1800) purification
of atropine (1831)

28. Muscarinic Antagonists
ATROPINE
SCOPOLAMINE

29. Muscarinic Antagonists
ATROPINE
SCOPOLAMINE Attropa belladona
- Atropine and Scopolamine are belladona alkaloids
(competitive inhibitors)
-Drugs differ in their CNS effects, scopolamine permeates the
blood-brain barrier
-At therapeutic doses atropine has negligible effect upon the CNS,
scopolamine even at low doses has prominent CNS effects.

30. Muscarinic Parasympatholytics
Clinical applications:
• Atropine:
– before anesthesia: prevent hypersecretion of bronchial mucus
– Bradycardy
– Acetylcholinesterase-inhibitor and mushroom poisoning
– Ophtalmology (eye exams) BETTER Tropicamide and Cyclopentolate
– Antidote
• Scopolamine:
– Motion sickness (as patches)
• Ipratropium and Thiotropium:
– Inhalation for asthma and COPD, rainy nose nasal drops
• Pirenzepine:
– Peptic ulcers: selectively inhibits M1 =>reduced gastric acid production
• Hyoscine butylbromidum:
– Spasmolytic (intestinal or menstrual cramps)

31. Toxidrome
• Anticholinergic examples of industrial
chemicals and potential chemical
warfare/terrorism agents: BZ (3-
quinuclidinyl benzilate), and other
glycolate anticholinergics (tropane
alkaloids) [atropine, hyoscyamine,
scopolamine].
• The clinically relevant routes of exposure
and types of sources: Inhalation, ingestion,
and dermal.

32. Toxidrome
• Blind as a bat
• dry as a bone
• full as a flask
• hot as hell
• red as a beet
• mad as a hatter
• tacky (tachycardic) as a leisure suit (pink
flamingo); phantom behaviors

33. Nicotinic Parasympatholytics
Two classes (both act as neuromuscular blockers => muscle relaxants):
• Competitive antagonists = Nondepolarizing blockers
– Act by competing with AcCh for binding to the N receptors
– Prevent depolarization of the endplate
– Action can be reversed by increasing AcCh concentrations (e.g.
via AcCh-esterase inhibitors)
• Agonists = Depolarizing blockers
– AcCh mimetics that are not hydrolyzed by AcCh-esterase (but
hydrolyzed by plasma esterases)
– Act by triggering a sustained depolarization of the neuromuscular
endplate
– No new action potential can be generated
– Can NOT be reversed increasing AcCh concentrations (would
cause further depolarization)

34. Cholinergic System -
Antagonists
Nicotinic Parasympatholytics
Nondepolarizing blockers
• Curare:
– Plant derived arrow poison in S-America
– Active ingredient is d-Tubocurarine
– Death occurs through respiratory paralysis
– Tubocurarine is not absorbed orally => no risk eating the prey
– Tubocurarine was used clinically as muscle relaxant during surgery
but: Tubocurarine triggers histamine release => blood pressure drops

35. Cholinergic System -
Antagonists
Nicotinic Parasympatholytics
Nondepolarizing blockers
Synthetic quarternary ammonium compounds
– Replaced tubocurarine as muscle relaxants
– No or little histamine release
• Pancuronium long-lasting action (1-2h)
Used in lethal injection (together with barbiturate + KCl)
• Vecuronium intermediate-lasting action (<30min)
• Atracurium intermediate-lasting action
• Mivacurium short action (<15min)
• etc.
Pancuroniu
m

36. Cholinergic System -
Antagonists
Nicotinic Parasympatholytics
Depolarizing blockers
• Succinylcholine = Suxamethonium
– “dimeric” Acetylcholine
– Acts agonistic like AcCh
– NOT hydrolyzed by AcCh-
esterase (only by plasma-
esterases)
– Initial depolarization triggers
muscle twitching
– Followed by persistent
depolarization (~10min)

37. Cholinergic System
Parasympathetic Drugs - Summary

38. At home
• Describe Ganglion-specific blockers
• Recall the sympathetic nervous system
compounds and its effects on the organs
functioning
• Describe the following pharmacological classes
• Alpha – blockers (1 student)
• Drugs affecting the entire sympathetic nervous
system

39. How to describe?
• The name of the pharmacological group
• Available classification
• Mechanism of action
• Pharmacological effects
• Indications
• Side effects
• Contraindications
• Antidotes

40. Questions
1. What anticholinesterase drug should not be
used in ophthalmology?
2. What antidotes can be used for treatment of
different poisoning.
3. Complete the table:
poison Antidotes
Irreversible AcHe-inhibitors
Atropine
Pilocarpine
Physostigmine
Tubocurarine chloride
Succinylcholine

41. Questions
4. How does atropine influence on eyes?
5. How does ganglionic blocker influence on
blood pressure?
6. How to manage shrooms intoxication with
muscarine?

42. Questions
7. Dilated pupils, sensitivity to light, blurred vision,
tachycardia, loss of balance, headache, rash,
flushing, severely dry mouth and throat, slurred
speech, urinary retention, constipation, confusion,
hallucinations, delirium, and convulsions… what
plant is able to cause these symptoms?
8. The Indigenous Polynesians use curare for
hunting (they apply this poison on their arrows)
and eat the prey. Why does not poisoning occur?