CHOLINERGIC AGONISTS
DIRECT ACTING
Choline esters Alkaloids
Acetylcholine (M+N) muscarine
methacholine(M) pilocarpine(M)
carbachol(M+N)
bethanechol(M)
1. ACETYLCHOLINE
· not used pharmacologically
· bcz of very short half life
· immediately destroyed by
butyrylcholinesterases in plasma. also known as
psuedo or non specific cholinesterases
· will produce diffused action (ganglia,
neuroeffector site of postganglionic fibers, NM
junction)
· lacrimation, diaphoresis, salivation,
bronchoconstriction, tracheobronchial
secretion, GIT secretion, increased motility,
defecation, micturition, bradycardia(M2),
hypotension(NO mediated)
2. BETHANICOL
· resistant to ChE because acetate is replaced by
carbamate
· poor lipid soluble
· bcz of addition of methyl group does not bind
with N receptors, thus more specific
USES
· Activates bowel and bladder
· non obstructive Urinary retention, post
operative and post partum urinary retention
· chronic hypotonic bladder
· congenital megacolon
ADRs
bradycardia, bronchoconstriction, flushing,
generalized symptoms
CONTRAINDICATION
Peptic ulcer, COPD, IHD, Parkinsons disease
3. CARBACHOL
· Carbamate, no methylation
· due to this M+N activation
· not used systemically bcz of intense stimulation
of autonomic ganglia
· only used for eyes as a second line or last line
agent
· it causes stimulation initially and then
depression
· acts on ciliaris muscles to decrease IOP
4. METHACHOLINE
· to check bronchial hyper reactivity via
inhalation
5. PILOCARPINE
· stable with AChE
· long half life
· used topically
· contract sphincter pupillae and ciliary muscles
· used in xerostomia, sjogren syndrome
INDIRECT ACTING AGONIST
REVERSIBLE IRREVERSIBLE
CARBAMATES ALCOHOL ORGANOPHOSPHATE
Neostigmine Edrophonium parathion
physostigmine malathion
pyridostigmine Ecothiophate
ambenonium
rivastigmine
Important terms
Organophosphate aging
A process whereby the organophosphates, after
binding to cholinesterases, is chemically modified
and becomes more firmly bound to the enzyme.
Myathenic crises
in patients with Myasthenia, an acute worsening of
symptoms bcz of increase in no. of antibodies,
usually relieved by increasing dose of cholinesterase
inhibitors.
Cholinergic crises
The clinical condition of excessive activation of
cholinoceptors.
MECHANISM OF ACTION
Bind with cholinesterases----undergo hydrolysis----
alcohol portion is released----acidic
portion( carbamate ion or phosphate ion) released
more slowly while preventing binding and hydrolysis
of endogenous ACh.
After 2-8h carbamates are released by
cholinesterases
Organophosphates are long acting.they form
extremely stable phosphate complex with the
enzyme.
Note: Cholinesterase inhibitors donot have
significant actions at uninnervated discs e.g
vascular endothelial cells
1. Physostigmine
· have carbamate group
· tertiary amine
· more lipid soluble, less polar
· plant origin, alkaloid
· absorb from GIT, cross BBB(produce toxicity in
CNS), most ganglia are embededin fat, so more
penetration
· form labile bond like neostigmine , which can be
broken and enzyme can restart its action
USES
· non obstructive urinary retention, post
operative and post partum urinary retention
· Glaucoma in combination with pilocarpine
· to treat toxicity of atropine,
phenothiazine(antipsychotic drug), Tricyclic
antidepressants, by increasing ACh
concentration which replaces atropine through
competitive antagonism
Side effects
· Convulsions bcz of CNS over stimulation
· paralysis bcz of over stimulation of Nicotinic
receptors
· Collapse of Cardiovascular system
2. Neostigmine
· synthetic
· Quaternary amine, less lipid soluble as
compared to physostigmine
· most autonomic ganglia are embeded in fat so
less penetration
· more specifically act on neuromuscular junction
even better than physostigmine
· so, in order to stimulate Nm receptor
neostigmine is better than physostigmine
USES
· Myasthenia (weakness) Gravis ( serious),
autoimmune disorder, antibodies against
acetylcholine receptors, which cause
internalization of receptor as well as block them
on postganglionic nerve terminal
· Lambert Eaton syndrome, antibodies against
voltage gated calcium channel
· antidote for tubocurarine
· stimulate bladder and GIT
side effects
generalized cholinergic stimulation, salivation,
bronchospasm etc.
3. Pyridostigmine
· Prolong acting
4. Edrophonium
· alcohol, quaternary amine
· easily detach from cholinesterase enzyme
· short acting (10-20min) & rapidly absorbed
· used in diagnosis of myasthenia gravis
· Tensilon test
· also used in diagnosis of myasthenic crises and
cholinergic crises
· Atropine is antidote
5. Parathion and malathion
· both are prodrugs
· upon biotransformation , they produce active
components i.e paraoxon, malaoxon
· mostly used in pesticide and insecticide
· pralidoxime antidote, must be given before
aging
· pralidoxime is synthetic pyridinium compound
that can reactivate inhibitrd
acetylcholinesterases
· presence of charged group allows it to approach
an anionic site on th enzyme where it displaces
the organophosphate and regenerate the
enzyme
Side effects
convulsions, respiratory and CVS depression
