Download 7. Cholinergic drugs

Asmah Nasser, M.D.
M1
Secretory
glands
salivation, stomach acid, sweating, lacrimation
M2
Heart
Decreases heart rate  bradycardia
M3
Smooth
Contraction of smooth muscles (some) 
muscle
diarrhea, bronchospasm, urination
(GI/GU/Resp)
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
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Classification and examples of direct and
indirect acting Cholinergic agonists
Brief discussion of few of the above
examples
Pathophysiology, diagnosis, and
Management of
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Myasthenia gravis and tensilon test
Glaucoma
Alzheimer's disease
Organo Phosphorus compound poisoning
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Heart: Cardiac suppressant…Bradycardia,
hypotension,
Eye: Miosis, cycloplegia, facilitates aqueous
humour drainage, lacrimation
Bronchospasm
Excess secretion from glands….salivary, bronchial,
lacrimal glands etc…..
GIT /bladder… smooth muscle contraction and
relaxation of sphincters…, increased motility,
diarrhea, vomiting , increased micturation (urinary
urgency)
Often called parasympathomimetic drugs,
because their action mimics the action of the
PSNS commonly
 Also called as Cholinergic drugs or
cholinomimetric
Cholinergic agonists are two types :
1. Direct acting
2. Indirect acting
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They act by binding directly to cholinoceptors
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Acetylcholine (Synthetic analogue of ACH)
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Carbachol
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Bethanechol
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Pilocarpine (naturally occurring alkaloid)
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They act through inhibition of Acetyl
cholinesterase enzyme….so increases
Acetylcholine level in the synapse
Reversible:
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Neostigmine
Physostigmine
Pyridostigmine
Edrophonium
Tacrine
Danopezil
•Irreversible :
Ecothiophate
Malathion
Parathion
Sarin
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It is a quaternary ammonium compound so
Cannot penetrate the membrane
Does not have any therapeutic importance,
because of multiplicity of actions & rapid
inactivation by acetylcholinesterases
It has both Muscarinic & Nicotinic actions
Neurotransmitter for pre-ganglionic neuron
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Not hydrolyzed by acetylcholinesterases
It has strong Muscarinic action & no Nicotinic action
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
An alkaloid, lipid soluble & is stable to hydrolysis by
cholinsterases It has Muscarinic activity only .
Actions-
When applied locally to cornea Produces rapid
moisis & contraction of ciliary muscle produces of
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.
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Cholinesterase inhibitors. Can be reversible
or irreversible.
Reversable:
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Neostigmine
Physostigmine
Edrophonium
Tacrin
Danopezil
Irreversible
◦ Malathion and Parathion
◦ Sarin
◦ Ecothiopate
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Neostigmine in M.gravis
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Physostigmine in Glaucoma, atropine overdose
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Ecothiopate in glaucoma
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Edrophonium in M.gravis to test
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Tacrin, Danopezil in Alzheimer's
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Malathion, Parathion as insecticides
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An autoimmune process causes production of
antibodies that decrease the number of functional
nicotinic receptors on the postjunctional end plates.
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Frequent findings are
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Double vision…. diplopia,
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Drooping of eyelids…. ptosis,
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Dysarthria ……Difficulty in speaking
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Dysphagia …..difficulty swallowing,
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Difficult in Daily routines
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Day passes, limb weakness increases.
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Difficulty in respiration Severe disease may affect all the
muscles, including those necessary for respiration.
Death
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Immunosuppressant drugs
Thymectomy
Acetyl Cholinesterase inhibitors
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Neostigmine
Pyridostigmine
Ambenonium
Edrophonium
Other supportive measures
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Neostigmine Has a strong influence at the
neuromuscular junction
Pyridostigmine: Has a longer duration of action
than neostigmine
Ambenonium :Available only in oral form;
cannot be used if patient is unable to swallow
tablets
Edrophonium: Diagnostic agent for myasthenia
gravis and to diffrentiate myasthenic and
cholinergic crisis (Tensilon test )
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Clinical situations in which severe myasthenia
(myasthenic crisis) must be distinguished from
excessive drug therapy (cholinergic crisis) usually
occur in very ill myasthenic patients
If excessive amounts of cholinesterase inhibitor
have been used, patients may become
paradoxically weak because of nicotinic
depolarizing blockade of the motor end plate.
Small doses of edrophonium (1–2 mg
intravenously) will produce no relief or even worsen
weakness if the patient is receiving excessive
cholinesterase inhibitor therapy.
On the other hand, if the patient improves with
edrophonium, an increase in cholinesterase
inhibitor dosage may be indicated.
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A progressive disorder involving neural
degeneration in the cortex
Leads to a marked loss of memory and of the
ability to carry on activities of daily living
Cause of the disease is not yet known
◦ ?????? There is a progressive loss of ACh-producing
neurons and their target neurons
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Tacrine
◦ Side effect: HepatoToxicity
◦ First drug to treat Alzheimer’s dementia
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Rivastigmine
◦ Available in solution for swallowing ease
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Donepezil
◦ Has once-a-day dosing advantage
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Only Ecothipate is used clinically in
Glaucoma. This is the long acting drug used
in glaucoma
◦ Rest of the drugs are used as pesticides or war
gases or poisons: Malathion and Parathion
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The dominant initial signs are those of
muscarinic excess: miosis, salivation, sweating,
bronchial constriction, vomiting, and diarrhea.
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Central nervous system involvement usually
follows rapidly, accompanied by peripheral
nicotinic effects, especially depolarizing
neuromuscular blockade.
(1) maintenance of vital signs—respiration in particular may be
impaired;
(2) decontamination to prevent further absorption—this may
require removal of all clothing and washing of the skin in
cases of exposure to dusts and sprays; and
(3) Atropine parenterally in large doses, given as often as
required to control signs of muscarinic excess stimulation .
(4)Therapy often also includes treatment with pralidoxime
(Acetylcholinesterase reactivator)
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Irreversible cholinesterate inhibitor.
LONG acting
Used in Glaucoma
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Direct/indirect acting cholinergic drugs
actions, adverse effects, toxicity features of
OP poisoning
In OP poisoning atropine used to reverse
only the muscarinic effects..
Pralidoxime used to reactivate the enzyme
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Miosis
Excessive salivation
Bradycardia
Bronchospasm
Abdominal cramps, vomiting, diarrhea,
urination
Sweating
Asmah Nasser, M.D.
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About 70 million people are affected
Worldwide
◦ 10% of these (~7 million) are blind from glaucoma
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US data: > 40 yrs of age, 3 million
about 120, 000 Americans are blind from it.
Most common cause of blindness among
Black-Americans.
50% of all patients, are not aware they have it,
until late
Types of Glaucoma:
1. Open Angle Glaucoma – Excessive production of
Aqueous Humour
2. Closed Angle Glaucoma – Outflow obstruction of
Aqueous Humour
Two Therapy aimed at:
1. Reduce (Production, Synthesis or Secretion)
Dorzolamide, Acetazolamide, Timolol, Betoxolol and
Apraclonidine
2.Facilitate the drainage: Pilocarpine, Carbachol,
Ecothiopate ,Mannitol and Latanoprost
Courtesy : Katzung
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reduces IOP by reducing vitreous volume by
inhibiting the enzyme carbonic anhydrase
Reduces the secretion/synethesis
◦ Timolol topical eye drops Non-selective β
blockade
◦ Betaxolol eye drops Selective β1 blockade
Reduces the synthesis
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Mannitol
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Acetazolamide (oral), Dorzolamide (topical ) :
reduces the synthesis of aqueous humour,
inhibits the enzyme carbonic anhydrase
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α2 receptor agonist (apraclonidine 1%, topical
drops).
1.
Pilocarpine, Carbachol, Ecothiopate and
Physostigmine :Causes Ciliary muscle contraction,
increases Irido-corneal angle and open trabecular
meshwork.
2.
Prostaglandins : Latanoprost : increase the outflow
through uveoscleral meshwork
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Excessive β adrenergic receptor mediated
production and secretion of aqueous humor
from the ciliary body epithelium.
Best treated with betablockers
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Results from obstruction of canal of
Schlemm through which aqueous humor
was supposed to be filtrated out .
Caused by
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Mydriatics : Anti-cholinergic drugs
Antidepressants : SSRI drugs
Treatment: Pilocarpine, Carbachol , ecothiopate
and physostigmine