Synthesis, Storage, Release, Metabolism, receptors pharmacological action of Ach and classification of Parasympathomimetic drugs

1. Amit kumar
Assistant Professor

2.  Parasympathomimetics or cholinomimetics.
 Stimulate parasympathetic nervous system.

3. CHOLINERGIC AGONISTS – Directly Acting Drugs
Choline esters Alkaloids
 Acetylcholine Muscarine
 Methacholine Pilocarpine
 Carbachol Arecoline
 Bethanechol
 Miscellaneous – Tremorine, Oxotremorine, Cevimeline

4. Reversible
 Carbamates Acridine
 Physostigmine (Eserine) Tacrine
 Neostigmine
 Pyridostigmine
 Edrophonium
 Rivastigmine, Donepezil
 Galantamine
Irreversible
Organophosphates Carbamates
 Dyflos (DFP) Carbaryl (SEVIN)
 Echothiophate Propoxur (BAYGON)
 Parathion , Malathion
 Diazinon (TIK-20)
 Tabun, Sarin, Soman

5. • It is the prototype drug of this group.
• Chemically, it is the acetic acid ester of choline.
• Acetylcholine (ACh) was first identified in 1914 by Henry Hallett Dale for its
actions on heart tissue.
• It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name
Vagusstoff because it was released from the vagus nerve.

7.  Nicotinic & muscarinic receptors subtypes.
 Nm & Nn – nicotinic receptors
 M1,M2, M3,M4,M5- muscarinic receptors

8. NM
• Location & Function
neuromuscular junction,
• depolarization of muscle end plate
– contraction of muscle
• Nature ligand gated ion ch.
• Opening of Na, K, ch.
• PTMA, Nicotine- agonist
• Tubocurarine, Alpha
Bungarotoxin- antagonist
NN
• Location & Function
Autonomic ganglia
• Adrenal medulla
• CNS
• Nature ligand gated ion ch.
• Opening of Na, K,Ca, ch.
• DMPP, Nicotine
• Hexamethonium, Trimethaphan

10. Heart :
 Negative chronotropic- decrease in HR
 Negative inotropic- decrease force of contractility & CO
 negative dromotropic- decrease conduction velocity & increase in
refractory period.
 The ventricular myocardium has muscarinic receptors but no innervations,
can exhibit decrease in contractile strength but only to exogenously
administered Ach.

11.  Blood vessels : arteries have M3receptors but no
parasympathetic innervations.
 Vasodilatation due to release of EDRF- fall in BP
 Fall in BP- Baroreceptor reflex, resulting in compensatory
sympathetic discharge at heart-tachycardia.
 Veins have neither parasympathetic innervation nor M receptors.

12.  EYE- circular muscles, ciliary
muscles, lacrimal gland possess
M3 receptors.
 Circular muscles- miosis
 Fall in IOT.
 Ciliary muscles-
accommodation
 Lacrimation

13.  LUNGS - bronchoconstriction, increased bronchial secretion.
 GIT-increase in GI motility & tone, relaxation of sphincters (defecation),
increase gastric acid secretion (M1).
 Urinary bladder - contraction of detrusor muscle & relaxation of sphincter
– urination
 Salivary glands- increase salivation
 Pancreas- acini cells ( M3)- increase pancreatic secretion.

14.  Sweat glands- sweating,
innervation is sympathetic in origin but cholinergic in character.
 CNS- stimulation
ataxia, restlessness, behavior disturbances (nicotinic effect) Tremors &
convulsions- (muscarinic effect)

15. Bethanechol:
 Not hydrolyzed by true & pseudo
cholinesterase- long t1/2
 Has mainly muscarinic actions (git,
urinary bladder), lack nicotinic
effects.
 Treatment of
postoperative/postpartum
nonobstructive urinary retention,
neurogenic bladder.
 Postoperative paralytic ileus, git
atony (non obstructive)
 xerostomia

16.  Methacholine :
slowly hydrolyzed by true
cholinesterase was occasionally used to
terminate PSVT
 Carbachol
 Not hydrolyzed by Cholinesterase.
 Miotic -use

17.  PILOCARPINE
 Pilocarpine It is obtained from the leaves of
Pilocarpus Jaborandi and other species.
 Tertiary amine , crosses BBB
 It has prominent muscarinic actions and also has
mild nicotinic action at ganglia (Nn).
 Highly toxic for systemic use- pulmonary
edema.

18. Uses:
 Glaucoma
 to counteract mydriatic
effect to break adhesions
 xerostomia

19.  It is found in betel nut.
 Has muscarinic as well as nicotinic
actions.
 It also has prominent CNS effect.
 Has been tried in dementia as an
enhancer of cognitive functions.
 But not found useful—has no
therapeutic use.

20.  It occurs in poisonous mushrooms
 Has only muscarinic actions.
 It is not used therapeutically but is of toxicological
importance

21. Reversible
Carbamates Acridine
Physostigmine (Eserine) Tacrine
Neostigmine
Pyridostigmine
Edrophonium
Rivastigmine, Donepezil
Galantamine
Irreversible
Organophosphates Carbamates
Dyflos (DFP) Carbaryl (SEVIN)
Echothiophate Propoxur (BAYGON)
Parathion , Malathion
Diazinon (TIK-20)
Tabun, Sarin, Soman

22.  Anticholinesterases (anti-ChEs) are agents which
inhibit AChE, protect ACh from hydrolysis—produce
cholinergic effects.
 Some anti ChEs have additional direct action on
cholinergic receptors.

24.  Cholinesterase drugs bear a structural resemblance to Ach.
 Carbamates combine with anionic and esteric sites of AChE.
 This complex is less readily hydrolyzed than AChE-Ach complex.
 It results in a temporary inhibition of the enzyme.
 This inhibition prolongs the duration of action of Ach released in the synaptic
cleft.
 The half-life of reactivation of carbamylated enzyme (about 30 min) is less than
that of synthesis of fresh enzyme protein.

25.  Physostigmine: naturally occurring alkaloid, a
tertiary amine, lipid soluble, crosses BBB, highly toxic ,
limited use.
use- reversal of mydriasis, prevent adhesions, glaucoma.
Ophthalmic preparation is not available in India available
in US as Eserine (0.25 &0.5% eye drops)
 Synthetic Quaternary compounds-
neostigmine,edrophonium, pydridostigmine,
distigmine, ambenonium etc

26.  Do not cross BBB
 Intensify the actions of Ach at motor end plate.
 Also have direct agonist action at Nm receptors
.

28. Tacrine: lipid soluble, crosses
BBB, longer DOA, in
Alzheimer’s disease, not used
now due to hepatotoxicity.
Rivastigmine: cerebroselective
Donepezil
Gallantamine
Memantine

29.  As miotic:
1.In Glaucoma
2. To reverse the effect of mydriatic
3. To prevent/break the adhesions between iris & lens or iris & cornea
 Myasthenia gravis
 Postoperative paralytic ileus/urinary retention
 Postoperative decurarization
 Cobra bite
 Belladona poisoning
 Anticholinergic drug overdosages
 Alzheimer’s disease

30.  Myasthenia gravis is an autoimmune disorder affecting about 1
in 10,000 population.
 Due to development of antibodies directed to nicotinic
receptors (NM) at the muscle endplate → reduction in
number of free NM cholinoceptors to 1/3 of normal or less and
structural damage to the neuromuscular junction → weakness
and easy fatigability on repeated activity, with recovery after
rest.

32.  Neostigmine and its congeners improve muscle contraction
by allowing ACh released from pre junctional endings to
accumulate and act on receptors over a larger area, and by
directly depolarizing the endplate.

33.  Diagnostic tests for myasthenia gravis
(a) Ameliorative test: edrophonium 2–10 mg injected
slowly i.v. improves muscle strength only in
myasthenia gravis and not in other muscular
dystrophies.

34.  Treatment is usually started with neostigmine
15 mg orally 6 hourly; dose and frequency is
then adjusted according to response.

35.  Diflos, ecothiophate, parathion, malathion,
diazinon, carbamate derivatives
 They phosphorylate the esteric site of AChE
irreversibly by forming a covalent bond.
 After phosphorylation, the AChE becomes
inactive and very stable ( resistant to
hydrolysis).
 The recovery of AChE therefore depends on its
new synthesis, which may take few weeks.
 The phosphorylated AChE enzyme can undergo
process of ageing which means that within a period
of 1-2 hrs, the AChE- drug complex undergoes
molecular rearrangement and become
completely resistant to hydrolysis.

36.  Accidental, suicidal,
homicidal
 Insecticides & pesticide
 They are highly lipid
soluble , rapidly
absorbed through
mucous membranes
and even trough
unbroken skin.

38.  Termination of further exposure- removal of clothes,
washing of skin
 Gastric lavage
 Maintain patent airway
 Supportive measures – maintain BP, hydration, control
of convulsions
 Specific antidotes: Atropine
 Cholinesterase reactivators (pralidoxime, obidoxime,
diacetylmono-oxime(DAM)

39. Atropine
 Blocks the muscarinic effects due to
excess acetylcholine
 Competitive inhibitor
 2mg iv repeated every 10-15 min
until signs of atropinization appear.
Cholinesterase reactivator (oxime):
Pralidoxime
Obidoxime
Diacetyl-monoxime
HL-07- serine (nerve gas-antidote)
 1-2g given by slow i.v. infusion
over 15-30 min.

40.  Pralidoxime attaches to
anionic site of AChE.
 Its oxime group now lie close
to phosphorylated esteric
site.
 The oxime-phosphonate
complex diffuses out, leaving
the regenerated AChE enzyme
in an active form.
 Reactivation is no longer
possible if enzyme undergoes
the process of ageing.

41.  In case of carbamate poisoning (propxur) all oximes are
ineffective as carbamates attach to anionic as well as
esteric site of AchE.
 Pralidoxime & obidoxime do not cross BBB, hence cannot
reactivate the AChE inhibited in brain.
 In this regard DAM has advantage, can cross BBB.

42. THANK YOU