Cholinoergic drugs

1. 1

2. PHARMACOLOGY
‫األدوية‬ ‫علم‬
Dr. Ahmed Al- AKYDY
Assoc. Prof. Pharmacology & Therapeutics

3. Cholinoceptor - Activating
(Parasympathomimetic/or cholinomimetic)
Drugs
Cholinergic Drugs

4. Learning Outcomes
 Upon the completion of this lecture, the student should be able to:
1) Discuss the uses, drug actions, general adverse reactions,
contraindications, precautions, and interactions of the cholinergic drugs.
2) Discuss ways to promote an optimal response to therapy, how to manage
common adverse reactions, and important points to keep in mind when
educating the patient about the use of cholinergic drugs

5. Acetylcholine
Bethanechol
Carbachol
Methacholine
Cevimeline
Pilocarpine
Muscarine
Arecoline
Phosphates
Dyflos [Diisopropylflurorophosphate
(DFP)]
Isoflurophate
Echothiophate
Malathion
Parathion
Soman, Sarin, Tabun
 Mimic the effects of ACh
 Classified into 2 groups:
Non-covalent
Inhibitors
Edrophonium
Rivastigmine
Donepezil
Galantamine
Tacrine
1.
2.
A. B.
2.
1.
Carbamates
Physostigmine
Neostigmine
Pyridostigmine
Ambenonium
Demecarium

6. A. Direct-acting (Cholinoceptor agonists)

7. A. Choline esters:
 Poorly absorbed & poorly penetrated into the CNS b/c they are hydrophilic.
 Differ markedly in their susceptibility to hydrolysis by ChE→ have long duration of
action than ACh.
Clinical use
Selective
effector
organ
Hydrolysis
by ChE
R
Drug
 No clinical use
 Non
Yes (++++)
M, N
o ACh
 Glaucoma (miosis → ↑ aqueous
humor outflow → ↓ IOP
 CVS
 GIT
 Bladder
No
N > M
o Carbachol
 Postpartum/or postoperative
paralytic ileus
 Nonobstructive urinary retention
 Neurogenic atony & megacolon
 Xerostomia (dry mouth)
 GIT
 Bladder
No
M
o Bethanechol
 PVD
 Paroxysmal tachycardia
 Dx of asthma
 CVS
Yes (+)
M
o Methacholine
Xerostomia
Sjogren's syndrome
No
M
o Cevimeline

8. B. Alkaloids: well absorbed from most sites of administration
Clinical use (s)
ChE sensitivity
R
Drug (source & actions)
 Open-angle glaucoma
 Xerostomia
 Sjogren's syndrome
 Breaking adhesions
between the iris and the
lens (+ mydriatic)
 Reversing pupillary
dilatation after refraction
testing
No
M
o Pilocarpine
• Alkaloid (Pilocarpus plant)
• Tertiary amine → crosses to
the CNS
• Potent stimulator of
secretions
• Onset of action: rapid
• DOA: short
• Adm.: ophthalmic, oral
 An active ingredient of poisonous mushroom (Amanita muscaria)
 Has no therapeutic application
o Muscarine
 An alkaloid obtained from areca nut, has M &N actions
o Arecoline
 Adverse effects of Cholinoceptor agonists:
 SLUD syndrome: salivation, lacrimation, urination, defecation
 Flushing, hypotension, bradycardia, bronchospasm, GI disturbances (nausea,
vomiting, abdominal pain, diarrhea), CNS disturbances, & pulmonary oedema
(systemic pilocarpine)
 Contraindication: hyperthyroidism b/c the body reacts to hypotension by releasing
NE → AF

9. B.Indirect –Acting Cholinomimetic drugs
4. Inhibition of
ACh
degradation
(ChE inhibitors)
2. ↑ ACh
release
(Cisapride)
1. ↑ ACh
Biosynthesis
 ↑ the availability of
ACh to stimulate
cholinergic receptors
3. Inhibition
of ACh
reuptake
 ↑ Release of ACh in cholinergic nerve endings of GI tract
 Also act as 5-HT4 receptors agonist
o ↑Motility of esophagus, stomach, duodenum, small intestine, & colon
 Metabolized by CYP3A4
 Used in the treatment of GERD b/c it ↑pressure in LES

10. B.Anticholinesterases (Anti- ChE) agents
 Mechanism of action:
 Bind to & inhibit ChE enzyme → ↑ ACh in synaptic space → stimulates M & N
receptors →↑ cholinergic effects (non selective agents)
1. Short-acting ChE inhibitor
 Edrophonium
• A quaternary ammonium compound
• More selective action on skeletal muscles
• Moderate affinity for AChE
• IV: rapid onset, & short duration of action
(5 –15 min), d/t rapid renal elimination
2. Long –acting ChE inhibitor
 Donepezil, Rivastigmine, Galantamine,
Tacrine
 Readily cross the BBB (lipophilic)→
inhibit ChE in the CNS
 Longer durations of action
A.Reversible
1) Non-covalent inhibitors  Myasthenia gravis:
 An autoimmune disease,
manifested by diplopia (double
vision) & ptosis (lid droop) ,
difficulty speaking & swallowing,
& extremity muscle weakness.
 Caused by antibodies that
degrade & ↓ number of NM
receptors of NMJ → ↓
interaction with Ach
 Treatment: ChE inhibitors,
immunosuppressant drugs/
removal of thymus gland/ removal
of immunoglobulins from
plasmapheresis.

11. Demecarium
Pyridostigmine
Ambenonium
Neostigmine
Physostigmine
 Synthetic
 Natural alkaloid (
Physostigma
venenosum)
 Source
 Quaternary ammonium
 Poor (more polar) → no
centrally & topically effective
 Tertiary amine
 Good → both central &
peripheral effects,
including topical effects
 Passing
BBB
 4-6 h
 3-6 h/or 4-8 h
 0.5- 2 h
 2- 4 h
 DOA
 Skeletal muscle, GIT, GUT >
CVS/ or eye
 Eye, GIT, bladder
 Selectivity
3. Intermediate-acting ChE inhibitors (Carbamates)
 Adverse effects of Anti- ChE agents
 SLUD, bradycardia, hypotension, tremors, bronchospasm, GI tract distress
 CNS disturbances (with physostigmine, but not with neostigmine)
 Hepatotoxicity (tacrine)
 Cholinergic crisis (overdose)

12.  Clinical use of Anti- ChE agents “reversible”
1) Eye:
o Glaucoma —physostigmine (rare) b/c it ↑ cataract formation on chronic use
o Reversing of pupillary dilatation after refraction testing
o Breaking adhesions between the iris & the lens (+ mydriatic)
o Diagnosis & treatment of accommodative esotropia (demecarium)
2) Myasthenia gravis: as diagnosis & acute treatment (edrophonium)/or as Long-
term treatment (neostigmine, pyridostigmine, ambenonium)
3) Alzheimer’s disease: ↓ the rate of loss of cognitive function, but not underlying
cause/or progression of the disease.
4) Postoperative urinary retention & paralytic ileus.
5) Drug poisoning
o Atropine poisoning: physostigmine, is preferred as antidote, b/c it has both
central & peripheral actions, slow IV injection (it may cause bradycardia).
o Curare/or nondepolarising neuromuscular blockers poisoning:
edrophonium/or neostigmine (DOC) by IV/or IM

13. B.Irreversible
 Pentavalent phosphorus compounds
 High lipid soluble, rapidly absorbed from unbroken skin, mucous membranes of
lung, gut & conjunctiva
 Bind covalently via its phosphate group to esteratic site
of ChE → irreversibly inhibit ChE →↑ ACh at M & N
receptor sites
 The phosphorylated enzyme slowly releases one of its
alkyl groups → aging → ChE becomes resistant to
reactivation by chemical reactivators → restoration its
activity requires the synthesis of new enzyme molecules
 OP compounds were developed as nerve gases &
insecticides (most)/or as clinical use (rare)
A. Clinical use agents:
 Echothiophate:
– Has a quaternary nitrogen group that binds also to the anionic site of ChE.
– Duration of action: 100 h → intense miosis
– Administration: topical (ophthalmic drops/or ointment)
– Uses: chronic & resistant cases of glaucoma (Obsolete)
 Long -acting ChE inhibitors (organophosphates)

14. B. Insecticide compounds:
– Malathion: relatively safe for mammals & birds b/c it is metabolized by other
enzymes to inactive products → use as ectoparasiticide
– Parathion: commonly used in agriculture & not detoxified effectively in
vertebrates → important toxicity for all animals & farm workers.
C. Chemical weapon agents (nerve gases): used exclusively in warfare & terrorism
CNS manifestations
N manifestations
M manifestations
 Headache
 Restlessness
 Confusion
 Ataxia
 Convulsions
 Coma
 Death: d/t respiratory
failure & CV collapse
 Skeletal muscles:
o Twitchings
o Muscle weakness
o Muscular fasciculation
o Muscular paralysis
 Eye: ciliary spasm, marked
miosis
 CV: bradycardia, hypotension
 RS: bronchoconstriction,
↑secretions
 Glands: sweating, salivation,
lacrimation
 GIT: involuntary defecation
 UT: involuntary urination
1) Acute OP poisoning
 Signs & symptoms
 Diagnosis: history of exposure, signs & symptoms, & estimating ChE activity in
the blood (often↓)

15.  Treatment of acute OP poisoning
A. General supportive measures:
 Termination of exposure: removal of all contaminated clothing, copious
washing of contaminated skin/or mucous membranes with water
 Gastric lavage: should be continued till the returning fluid is clear.
 Maintenance of a patent airway
 Artificial respiration, & administration of oxygen
 Treatment of shock (establish IV line)
 Control convulsions: diazepam (5–10 mg), slow IV injection
B. Specific antidotes:
 Atropine:
o Required to antagonize & control signs of muscarinic excess.
o Administered: (IV)
• Large doses (2 mg ) repeated every 5- 10 min till the patient is fully
atropinized (fully dilated, nonreactive pupils, flushed skin, tachycardia) ─ up to
200 mg/d.
• Maintenance doses: may be required for 1–2 Wks.
 ChE reactivators:
 Oximes: Pralidoxime (2- PAM), obidoxime

16.  Bind with high affinity to anionic site →
dephosphorylate ChE enzyme at the esteratic site →
reactivate it.
 Administered IVI, loading dose (30 mg/kg/20 min),
followed by 8 mg/kg/h continuous infusion till
recovery
 Should be administered before the phosphorylated
enzyme undergoes ‘aging’ & becomes resistant to
reactivation.
 Preventive therapy of acute OP poisoning:
 Pyridostigmine + atropine (autoinjection syringes)
to protect soldiers & civilians.
B. Delayed toxicity of OP: neurotoxicity (delayed
neuropathy with demyelination of axons)

17. 17
Thank you
Any question?