1. Parasympathomimetics are drugs that mimic the effects of acetylcholine. They are classified as direct-acting cholinergic agonists or indirect-acting anticholinesterases. 2. Direct agonists like carbachol and methacholine directly activate cholinergic receptors. Indirect anticholinesterases like neostigmine, pyridostigmine and edrophonium inhibit acetylcholinesterase and prolong the effects of endogenous acetylcholine. 3. These drugs have therapeutic uses for various conditions like myasthenia gravis, glaucoma, urinary retention and postoperative ileus by strengthening muscle weakness or increasing parasympathetic effects. Their effects are

1. PARASYMPATHOMIMETI
CS
Dr. Yash N. Panchal
Resident Doctor
Pharmacology Department
AMC MET Medical College
10/01/2022

2. Acetylcholine
History
Features
Synthesis
Storage
Release
Metabolism
Cholinergic
Agonists
Classification
Synthetic esters
Natural alkaloids
Miscellaneous
Anticholinesterases
Reversible Anticholinesterases
Hydrolysis of Ach
Irreversible Anticholinesterases
OP Poison

3. • In 1867, Adolf Von Baeyer resolved the structures
of choline and acetylcholine and synthesized them
both, referring to the latter as "acetylneurin" in the study.
• Acetylcholine was first noted to be biologically active in
1906 by Reid Hunt.
• In 1914, Arthur J. Ewins was the first to extract Ach
from nature, he identified it as a Blood pressure
decreasing component.
• H. H. Dale and O. Loewi in
1936 won Nobel Prize in
Physiology for the studies
of Ach and Nerve impulses.

4. Acetic
acid
ester of
choline
Prototype
drug
Rapid
Hydrolysi
s by
AchE
Non-
specific
action

6. • Choline transport inside the nerve terminal is
rate-limiting step.
• Reaction of Ach. Synthesis is carried out by
CHAT (Choline acetyl-transferase).
• Choline transport is blocked by the
HEMICHOLINIUM group of drugs.
• Acetyl CoA is produced in Mitochondria from
Pyruvate by PDH.

7. Once formed, Ach is actively
transported in vesicle by VAT
(Vesicular associated
transporter)
Active transport of Ach is
blocked by Vesamicol
ATP and certain Peptides are
stored as co-transmitters.

8. • Arrival of Action potential causes influx of Calcium ions, thus
triggering release of Ach by Exocytosis.
• Exocytosis involves interaction between Synaptobrevin and
Syntaxin, resulting in fusion of the vesicle and nerve ending
membrane.
• It promotes opening of pore toward extracellular space and release
of Ach
• Botulinum toxin enzymatically alters Synaptobrevin and prevents
release of Ach, in botulism death occurs from respiratory paralysis
• Local anesthetics and Tetrodotoxin affects sodium channel.

10. • Is by enzyme – Acetylcholinesterase to choline and acetic acid
• Choline is recycled in the synthesis of Ach.
• Cholinergic synapse is rich in AchE.
Features True AchE Pseudo AchE
Location All cholinergic sites,
RBC, Placenta, Gray
matter
Plasma, Liver,
Intestine
Hydrolysis of Ach Very fast Slow
Methacholine Slower than Ach Not hydrolyzed
Benzoyl choline Not hydrolyzed Hydrolyzed
Butyryl choline Not hydrolyzed Hydrolyzed
Succinyl choline Not hydrolyzed Hydrolyzed

11. Pseudo-cholinesterase
• is synthesized in the liver.
• Commonly found in plasma, liver, and intestine.
• Hydrolyze Benzoyl choline,
Butyryl choline,
Succinylcholine.
• Genetic variations are commonly seen with this enzyme
• Atypical pseudo-cholinesterase slowly hydrolyze succinyl-choline ( a
skeletal muscle relaxant drug) and exhibit prolonged apnea.

14.  CVS
• Parasympathetic innervation in the Heart is up to Sa node, Atria,
and AV node, but not below, the ventricular myocardium has
muscarinic receptors but no innervation
• At the SA node, Atria, and AV node, there are M2 receptors
• Effect of M2 receptor activation :
1 At SA node – Decrease in Heart rate ( negative chronotropic )
2 At Atria – Decrease in the force of contraction ( negative ionotropic )
3 At AV node – Decrease in the conduction velocity and increase in
the refractory period

15.  Blood Vessels
• Arteries have no parasympathetic innervation, but M3 receptors
• If cholinomimetic is given externally, a transient but a market fall in
blood pressure is observed - due to vasodilatation by EDRF ( = NO,
released by adjacent endothelial cells )
• Fall in blood pressure evokes compensatory Baroreceptor reflex,
resulting in equivalent compensatory sympathetic discharge at the heart.
• As a result, Ach administration by IV route initially causes
bradycardia, followed by tachycardia.
• Systemic veins have neither parasympathetic innervation nor M-
receptors.

16. • Circular muscle of iris, Ciliary muscle of the eye, and Lacrimal
gland M3 receptors.
• Radial muscle of the iris and eyelid smooth muscles have no
Parasympathetic innervation.
• Ach causes
1 – Miosis – Contraction of circular muscle of the iris
2 - Accommodation for near vision – Contraction of Ciliary muscle
3 – Reduction in Intraocular pressure – By the opening of the pore of
the canal of Schlemn, that facilitates aqueous humor drainage
4 - Lacrimation

17.  Salivary gland :
• Salivary glands have M3 receptors, stimulation of which produces
salivation.
• It is Watery saliva, due to vasodilatation.
 Sweat gland :
• Sweat gland also possesses M3 receptors, activation of which leads
to an increase in Sweating.
• The innervation is sympathetic but cholinergic in character

18.  Lung :
• Bronchial smooth muscle and mucous gland possess M3 receptors.
• Stimulation of it leads to bronchoconstriction and increase bronchial
secretions
 Gastrointestinal tract
• GIT smooth muscles, sphincters and gastric glands all have M3
receptors.
• Gastric parietal cell have M1 receptors.
• M3 stimulation leads to increase in the motility and tone of GIT smooth
muscle, relaxation of sphincters and increased secretions from the gastric
glands (defecation).

19.  Urinary Bladder :
• Both detrusor muscle, and sphincter have M3 receptors
• Stimulation causes contraction of detrusor and relaxation of sphincter
voiding of urine occurs
 Pancreas :
• Acinar cell have M3 receptors, stimulation of it causes secretion of
Pancreatic juices
• There is no effect on β cell of islet of Langerhans.
 Male Sex organs :
• These have M3 receptors, Vascular bed of erectile tissue is dilated, while
venous sphincter are closed Erection occurs.
 Central Nervous System :
• There are complex stimulatory effect is seen ; tremor and convulsion
(muscarinic effects), and agitation, restlessness (nicotinic effects)

20.  Stimulation of Nm receptors at Neuromuscular junction
results in skeletal muscle contraction.
o Prolonged activation results in fasciculations and paralysis
of muscle.
 Stimulation of Nn receptor in Brain, (Presynaptically located
Nn receptors ), leads to release of Glutamate and Dopamine.
 Activation of Nn receptors at Autonomic ganglia provides the
transmission of impulse through it and firing of postganglionic
neurons.
 Nn activation at Adrenal medulla facilitate release of
Epinephrine (circulatory catecholamine).

21. • The term Cholinomimetic means the drugs which mimic the action
of Ach
DIRECTLY ACTING :
Bind directly to and activating
cholinergic receptors
INDIRECTLY ACTING :
Inhibit Acetylcholinesterase and
indirectly increasing
concentration of Ach.

23.  Carbachol, and Methacholine are obsolete
 Bethanechol :
• Totally resistant to hydrolysis by true and pseudo
cholinesterase.
• Has Muscarinic effects , particularly on GIT, and GUT, but is devoid
of nicotinic effects.
• Use :
1 – To reverse atony of bladder and to combat urinary retention, as in
post-operative, post-partum, and in neurogenic bladder.
For, Acute condition – 2.5 mg S.C
For, Chronic case – 10-15 mg orally OD, with meal, until automatic

24. 2 - To treat GIT atony or paralytic ileus as in post-partum, and post-operative
conditions
- To expel gases from intestine prior to radiological investigation
Dose – 10-20 mg orally TDS
3- To treat Xerostomia; as an alternative to Pilocarpine.
 Precautions :
Should not be given I.V, because sudden rise in its plasma concentrations
may lead to Cardiovascular collapse.
 Contraindications :
Hyperthyroidism, Peptic Ulcer,
Bronchial Asthma , Myocardial infarction

25. Muscarine
Amanita
muscaria
Non-specific
muscarinic effects
– Not used
clinically
Muscarine poison – Atropine 1-2 mg IM, every 30
minutes, and adequate supportive measures of respiration
and circulation

26. Arecoline
• Alkaloid obtained from Areca plant.
• Non-specific muscarinic effect- not used clinically.
Pilocarpine
Pilocarpus
Jaborandi
leaves

27. • Tertiary amine – cross BBB
• Has dominant muscarinic (Mainly on M3 receptors of the eye and salivary
gland) and mild nicotinic (Nn) action.
• Too toxic for systemic use (Pulmonary edema).
• Use :
1- Ophthalmic use – For treatment of Open-angle glaucoma
as a 0.5%-4% solution, the effect lasts for 4-8 hours
- To counteract atropine induced Mydriasis
- To break adhesions between iris and lens in Iridocyclitis
2 – As Sialagogue – 5-10 mg orally given to stimulate salivary secretions in
Patients after laryngeal Sx Post radiotherapy

28. CEVIMELINE
• Used orally 30 mg, TDS to treat Xerostomia in patients undergoing cancer
chemotherapy and in Sjogren syndrome
TREMORINE & OXOTREMORINE
• Are synthetic Tertiary amines
• Not used clinically
• Used as investigative research tools to stimulate Parkinsonism like
symptoms in the animal model.

30. • vvvv
Natural alkaloids
Physostigmine
Galantamine
Synthetic
quaternary
ammonium
compounds
Neostigmine
Pyridostigmine
Rivastigmine
Edrophonium
Tacrine
Donepezil
Ambenonium
Demecarium

31. • Short acting
Edrophonium
• Intermediate acting
Physostigmine
Neostigmine
Pyridostigmine
Rivastigmine
• Long acting
Organophosphates

32. 1- Positively charged nitrogen of Choline and
Acetoxy group of acetic acid
2- Acetylcholinesterase enzyme
• Anionic site – Carboxyl group of Glutamate amino acid
- Is the binding site
• Esteratic site – Hydroxyl group of Serine amino acid
- Is the catalytic site

33. • Esteratic site is stimulated by histidine
• Hydrolysis of Acetylcholine :
1- Positively charged nitrogen of quaternary ammonium compound of Choline
attracts towards carboxyl group of glutamate residue of acetylcholinesterase
2- Carbon molecule of acetoxy group of acetic acid of Ach forms a bond to the
hydroxyl group of serine residue of Esteratic site
3- Choline is separated, that is recycled in biosynthesis of Ach
4- Ester link is formed, and the enzyme is acetylated
5- The acetylated enzyme is subject to hydrolysis, and becomes free

35. • Reversible anticholinesterases drugs bear a structural
resemblance to Ach
• The may bind at Anionic site, Esteratic site, or both.
• Thus formed complex is less readily hydrolyzed than
Ach-AchE complex
• Resulting in temporary inhibition of the enzyme,
because AchE regeneration is now taking longer time
• This inhibition prolongs the duration of action of Ach.

37. • Non-carbamate, synthetic quaternary ammonium compound
• Short acting (10-20 minutes).

38. • Here weaker Hydrogen bond is formed at the anionic site,
Esteratic site is free.
• Thus prevents binding of Ach at anionic site
• Reason for a shorter duration of action :
A weaker hydrogen bond is broken easily ( and so no hydrolysis is
required by Acetylcholinesterase in the case of Edrophonium )
• Edrophonium is eliminated by renal route
• Not used clinically, due to its shorter duration of action.

39. • AKA Edrophonium test
• Used to diagnose Myasthenia gravis
• Why Edrophonium?
1 - Can not cross BB, no central side effects
2 - Shorter acting (10-20 minutes)
3 - Rapid onset of action (10-30 seconds)
• Myasthenia gravis :
o Auto-immune disorder with the production of IgG antibody against
Nm receptors
o Resulting in muscle fatigue and weakness
o Characterized by ptosis, diplopia, slurring of the speech, difficulty in
swallowing, weakness of extremities

41. Edrophonium chloride 1-2 mg IV is given for initial safety checking
Look for potential adverse effects (Hypotension, Bronchoconstriction,
Cholinergic crisis)
If no serious adverse event is observed
Give 5-8 mg IV Edrophonium
Check for muscle strength
Improved Non-improved
Myasthenia Gravis Other than Myasthenia
Gravis

42. • Obtained from dried seeds of Physostigma venenosum.
• Being tertiary amine, it is highly lipid-soluble.
• Shows better absorption in all body compartments, including CNS.

43. • It has prominent Muscarinic effects (M1 TO M3 receptors), also activate
autonomic ganglia, but the effect on Nm receptor is negligible
• Being highly toxic, it has limited use.
• Therapeutic uses :
Ophthalmic use
 It resembles those of Pilocarpine
 Used in 1 - In Open-angle glaucoma
2 - To reverse Atropine induced Mydriasis
3 - In Iridocyclitis
 More potent than Pilocarpine, but very toxic, so is rarely used
 Ophthalmic preparations not available in India, and some other countries
 Available in the USA as 0.25% to 0.5% eye drops under generic name
ESERINE

44. Belladonna (Atropine ) Poisoning
 Specific antidote for : Atropine (Datura) poison
: Tricyclic antidepressants poison
 Reason – Being tertiary amine, can cross BBB and can antagonize central
as well as peripheral toxicity.
 Give an initial low dose of 0.5-1 mg IM to diagnose Atropine poison
If usual Parasympathetic symptoms (Flushing, Sweating, Salivation,
Lacrimation) are not observed, it could be a case of Atropine poison
Treatment is done by giving 2 mg IV or IM Physostigmine
 Parenteral preparation as 1mg/ml injection for IM/IV use available only in
the USA as ESERINE

45. Galantamine
• Natural alkaloid, and inhibitor of Cerebral Ache
• In addition, it has also weak agonistic action on nicotinic receptors
Tacrine
• Lipophilic acridine compound that interacts with ChE in a manner similar
to Edrophonium
• Being lipophilic, can cross BBB, and by increasing Ach levels, it was found
to produce symptomatic relief in Alzheimer’s disease
• But, not used due to Hepatotoxicity
Donepezil
• Centrally acting anti-AchE that has produced cognitive and behavioral
improvement in Alzheimer’s disease.

46. • Being quaternary compounds, these are least absorbed and don’t
cross BBB.
• At low doses, moderately prolong and intensify the actions of Ach
at the motor endplate.
• Resulting in the strengthening of muscle weakened in case of
Myasthenia Gravis
Curare-like drugs
Cobra-bite
• Also possess, direct agonist action at Nm receptors, that contribute
to their effectiveness in the treatment of Myasthenia Gravis.

47. Neostigmine
• Commonly used in the treatment of Myasthenia Gravis
• No central side effects
• Also used in the treatment of Cobra bite
Postoperative paralytic ileus
Atony of bladder
Pyridostigmine
• Resembles neostigmine in all respects
• Is dose to dose less potent, and longer-acting, less frequent dosing
is required in Myasthenia Gravis

48. • Duration of action of :
Edrophonium – 10 - 20 minutes,
Neostigmine – 0.5 – 2 hours,
Pyridostigmine – 3 – 6 hours,
Ambenonium – 4 – 8 hours

49. 1 – Myasthenia Gravis
• Once the diagnosis is confirmed, treatment is started with any
reversible Anticholinesterase agent of the intermediate duration
of action
Neostigmine – 15-30 mg, orally, in divided doses or o.5-2.5 mg IM/SC
Pyridostigmine – 60mg, orally TDS
Ambenonium 2.5-5 mg, 6 hourly, orally
• Sustained release preparations of Pyridostigmine are also available.
• Longer acting AchE inhibitors are not used, because the dose
requirement in this disease changes too frequently

50. • Muscarinic side effects – Flushing of the face
Salivation
Sweating
Lacrimation
Abdominal cramps
Bronchoconstriction
Nicotinic side effects - Muscle fasciculation
Twitching
muscular weakness
Tremor
• Treatment – Atropine 0.5 mg S.C given
( Neostigmine toxicity itself is identified by its muscarinic
manifestations, Hence non judicious use of Atropine may mask its muscarinic
side effects and patients may undergo cholinergic crisis)

51. 2 – Paralytic ileus and Atony of Urinary Bladder
• Neostigmine 0.5-1 mg S.C is used
• Longer acting, Distigmine can also be used with a dose of 5 mg.
3 – Glaucoma
• 0.25% to 0.5% solution of Demecarium is applied topically in the eye, twice
a week.
• Demecarium is longer acting congener of Neostigmine.
4 – Treatment of Curare poison and Cobra bite
• Neostigmine 0.5-1 mg I.V or Edrophonium 10 mg I.V along with atropine
reverses muscle paralysis

52. ORGANOPHOSPHATES
CARBAMATES
Parathion Carbaryl
Malathion Propoxur
Ecothiophate Aldicarb
Diazinon
Dyflos (DFP)
Nerve Gases – Tabun
Sarin
Soman
• Parathion – Pro-drug
Metabolized to Paraoxon – Active metabolite

53. • Quaternary ammonium compound – cant cross BBB
• Its local irritancy is also very low
• It’s 0.25% to 0.5% aqueous solution is available and used as Miotic and for
the management of glaucoma
• Longer acting, and keep IOP decreased for one to two weeks.
• Its Ophthalmic preparations are not available in India due to associated risks
CARBARYL
• Has low toxicity from dermal absorption, and used topically for the control
of Head Lice, and as Shampoos

54. • These have a labile group, that is attached to PHOSPHORUS by Sulphur
or Oxygen atom
Fluoride in Dyflos Organic group in
others

55. • Phosphorus group interact with – OH of Serine residue
• Phosphorylate Serine residue
by forming a Strong Covalent bond
• During this process labile group
is released
• Remaining part of the drug is
attached Covalently to Esteratic site of
AchE
• Phosphorylated AchE is resistant
to Hydrolysis
(= Longer Acting)

56. • Ecothiophate – Having quaternary ammonium group with Positively
charged Nitrogen
Nitrogen interact with the Anionic site
Hence, slow hydrolysis still occurs, so the action is not
strictly irreversible, although drug is longer acting

57. • Initially Organophosphorus – AchE complex is reversible
• With time (1-2 hours), this complex undergo Molecular
rearrangement
Loss of One Organic group (Alkyl or Alkoxy) occurs
Leaving behind, more stable Mono alkyl-Mono alkoxy –
Phosphoryl - AchE complex
Such complex is totally resistant to Hydrolysis
• Dyflos are more prone to ageing than others

58. • Op poisoning is due to Organophosphorus used as insecticides, and
nerve gases
• Occurs most commonly as a suicide attempt in farming areas, and
less commonly by accident.
• Exposure can be from drinking, breathing in the vapors, or skin
exposure, and these are non-polar with high lipid solubility, so
rapidly absorbed

59. Muscarinic manifestations Nicotinic
Manifestations
Diarrhea Fasciculation of
Skeletal muscle
Urination
Miosis
Bronchoconstriction CNS Manifestations
Lacrimation
Salivation Ataxia
Bronchoconstriction Restlessness
Hypotension Tremor
Bradycardia

60. • Aim :
1 – To re-activate acetylcholinesterase enzyme
2 – To counteract muscarinic and central side effects
Reactivation of Acetylcholinesterase
• Oximes
– Pralidoxime (2-PAM – Pyridine-2-aldoxime methyl
chloride)
- Obidoxime
- DAM – diacetyl monoxime

61. • Pralidoxime – Are quaternary ammonium compounds with positively
charged nitrogen ion
- Possess oxime group ( -NOH)
- Anionic site is vacant in case of OP poison
• Mechanism – Positively charged Nitrogen attracts towards anionic
site and binds
Oxime group which is in close proximity of
Phosphorylated AchE attracts Phosphate group
Transfer of Phosphate group to Oxime group occurs
Oxime-Phosphate group is diffused out, leaving regenerated AchE in
active form

63. • Shortcomings in the use of Oximes as an antidote to OP
Poisoning :
1- Reactivation of phosphorylated AchE is no longer possible if it has
undergone aging, this holds true for all Oximes as well
2 – Pralidoxime and Obidoxime cant cross BBB and so cant reactivate
AchE Inhibited in the brain
• DAM can cross BBB
3 – Oximes are ineffective in case of Poisoning by Carbamates
• Carbamates bind to Esteratic and Anionic site, so anionic site is not
available to bind for Oximes
• Rather contraindicated as it has weak anti-ChE activity.

64. • Initially, Atropine is administered In a dose of 2 mg IV every 10-15
minutes
until muscarinic symptoms disappear.
• Thereafter, Pralidoxime in a dose of 1-2 gm is given by slow IV
infusion over 15-30 minutes to reactivate AchE.
• General supportive measures are provided are :
Removal of Contaminated clothes
Gastric lavage
Respiratory support
Convulsion control by Diazepam

65. • Repeated exposure to certain fluorine-containing and triaryl
organophosphates - Polyneuritis and
- Demyelination
after a latent period of days to a week
• Sensory disturbances occurs first, followed by muscle weakness
and depressed tendon reflexes – lower motor neuron paralysis
• In the second phase, Spasticity, and Upper motor neuron paralysis
occurs
• Recovery takes many years.

66.  Goodman, Louis S., Alfred Gilman, Laurence L. Brunton,
John S. Lazlo, and Keith L. Parker. 2017. Goodman &
Gilman's the pharmacological basis of therapeutics. New
York: McGraw-Hill.
 Ritter, J. (2020). Rang and Dale's pharmacology (Ninth
edition) Edinburgh: Elsevier.
 Tripathi, K. D. (2018). Essentials of medical
pharmacology (8th ed.). Jaypee Brothers Medical.
 Principles of Pharmacology by H. L. Sharma and K. K.
Sharma; Paras Medical Publishers, New Delhi.2018