Cholinergic system full including ANS introduction for MBBS theory class

1. ANS

2. NervousSystem
Central nervous
system
Peripheral nervous
system
Somatic system
Autonomic nervous
system
Enteric nervous
system
Supply skeletal muscle(NMJ)
Main neurotransmitter is Ach
Myelinated nerve fibers
(Visceral/Vegetative /
Involuntary NS)
Supply visceral organs
except – Muscle
Sympathetic NS Parasympathetic NS
Origin Dorsolumbar
(T1, To L2)
Cranio-Sacral(CN-III,VII,IX,X,S2-
S4)
Post ganglionic NT NA(Major) ACh
F(X)- Tackling Stress n emergency
fight & Flight
rest & digest,
Maintain homeostasis of body

3. Enteric Nervous system:-
Highly organized collection of neurons whose cell bodies lie within the
wall of the GIT.
Comprises of :-
1. Myentieric plexus-located b/w circular & longitudinal muscle layer
of the GIT. Control GI motility
2. Meissner plexus:- Found in submucosal layer of the gut.Regulate
GI secretion & body fluid homeostasis
Enteric neurons receive Preganglionic parasympathetic fibers and
postganglionic sympathetic fibers
Most of the viseral organs are supplied by both Sympathatic & para-
sympathetic system except-
1.Blood vessle, Spleen,Sweat gland and hair follicle receive only
sympathetic innervations
2.Ciliary muscle, gastric & pancreatic gland- para sympathatic

4. Brain stem or spinal cord
Gangilionic transmitter


Neuroeffector transmitter
Effector organ
Preganglionic neuron
Postganglionic neuron
Nicotinic receptor (Nn)
Adrenergic or cholinergic
receptors

6.  Drugs that stimulate the parasympathetic nervous
system.
 Performs maintenance activities, rest & digest
(Adrenergic system fight & flight)
 Neurotransmitters-
 Cranio-sacral outflow-Parasympathomamitic
Cholinergic nerves

Acetylcholine

8. Nicotinic Receptors
(Activated by nicotine
M2
(Heart &
SM)
Gi M3
(Glands,
SM
Gq M4
(Gi)
M5
(Gq)
NM
(Neuromuscular
junction)
NN
Autonomic
ganglia,
Adrenal
medulla &
CNS
Muscarinic Receptors
(Activated by muscarine)
Cholinergic Receptors: Receptors Activated by ACh
M1
(Nerve Cells)
Gq
Stimulate
Contraction
Stimulation
Ligand gated
ion channelsIP3
/DAG
Cytosoli
c Ca2⁺ :-
CAM,M
LCK,CC
PK

9. Parasympathetic Nervous System (Craniosacral Outflow)
Genitalia - M
Bladder-M3
Large Intestines
Kidney
Bile Ducts
Gallbladder
Small Intestines-M3
Stomach-M3, M1
Bronchi/Bronchial
Glands-M3
SA & AV Node-M2
Sphincter Muscle of Iris
Ciliary Muscle-M3
Lacrimal Gland
Submaxillary &
Sublingual
Glands
Parotid Gland
M3

10. M1 Secretory
glands
salivation, stomach acid, sweating, lacrimation
M2 Heart Decreases heart rate  bradycardia
M3 Smooth
muscle
(GI/GU/Resp)
Contraction of smooth muscles (some) 
diarrhea, urination, bronchospasm
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

11. Na+
Choline
CHT
Acetyl CoACholine
ATP+ Acetate+Co En-A
Acetyl Co En-A
Acetylcholine
Choline acetyl
transferase(CAT)
Ca++
ACh
H+
Vesicle
ACh

M receptor
VAT
Acetylcholinesterase
N receptor
Hemicholinium
Vesamicol
Botulinum toxin
Acetate+ choline

12. Synthesis-
(1.) Ach is synthesis in the cytoplasm from Acetyle-Co A and choline
through the catalytic action of enzyme choline acetyle transferase
(CAT).
(2.)Choline is transported from the ECF into neuronal terminal by a
sodium dependent membrane choline transporter. This is the rate
limiting step in Ach synthesis
(3.) ACh is transported into the storage vesicle by another carrier called
Vesicle associated transporter (VAT)
(4.) Storage-Storage of Ach is accomplish by the packaging of
“quanta” of Ach molecule
ACh is stored in vesicles along with other potential cotransmitters (Co-
T) such as ATP and VIP at certain neuroeffector junctions.
(5.) Vesicles are concentrated on the inner surface of the nerve terminal
facing synapse through the interaction of SNARE protein also called
VAMP’s-synaptotagmin.

13. (6.)Release-
Release of ACh and the Co-T occurs on depolarization of the nerve
ending , which allows the entry of Ca2+ through voltage-dependent
Ca2+ channels.
(7.)When Action potential reaches the nerve terminal and tigger
sufficient influx of Ca++ ions via N-Type Ca++ channel.
(8) Ca++ interact with VAMP’s on the vesicle membrane and triggers
fusion of vesicle membrane with the terminal membrane and opening
of a pore into the synapse resultant exocytotic expulsion into
the synaptic cleft
Fate- No uptake .Vary rapidly hydrolysis by true & pseudo-
cholinesterase into choline
Steps Inhibitors
Synthesis Uptake inhibited by
hemicholinium (inhibit
CHT)
Storage Inhibited by Vesamicol
Release Botulinum toxin,
LA(procaine),low
Ca++,Streptomycin
Fate Inhibited by
Anticholinesterase

14. Cholinesterase:-
Two types
1.True cholinesterase/specific :-
Site:- Cholinergic neuron, ganglia, RBC’s,NMJ
Rapidly hydrolyses Ach & also a cholinester, methacholine
Function:-Termination of ACh action
2.Pseudocholinesterase/Non specific/Butyrylcholinesterase :-
Site:- Plasma, liver, glial cells.
Ach but not does not hydrolyse methacholine
Function:- Hydrolysis of ingested esters

15. Cholinergic Drugs
Directly Acting
(Activate receptor
directly)
Indirectly Acting
(Increase the availability
of Ach by Ach.esterase
inhibition)
Acetylcholine
Bethanechol
Methacholine
Carbachol
Esters of choline Alkaloids
Pilocarpine
Muscarine
Cevimeline
Nicotine
Cytisine
Lobeline
Dry mouth
Amanita muscaria (muscarine)
Amanita phalloides
(phalloidine)

16. Indirectly Acting
(Increase the availability of Ach
by Ach.esterase inhibition)
Reversible Irreversible
Lipid soluble
Physostigmine
Rivastigmine
Tacrine
Donepezil
Galantamine
Water soluble
Neostigmine
Pyridostigmine
Edrophonium
Organophosphates
Malathiaon
Parathiaon
Echothiophate
Dyflos
Diazinon
Tabun
Sarin
Soman
Carbamates
Carbaryl(Sevin)
Propoxur(Baygon)

17. Acetylchloline
Prototype drug
Not effective orally destroyed by HCl of stomache
Produces muscarninc & nicotinic effects by interecting with respective
receptors on the effector cells
Not effective parenterally- destroyed by choline esterase enzyme
Action:-
1.Muscarinic actions 2.Nicotinic actions
Choline-esters
Choline esters including Acetylcholine,carbachol ,bethanechol
Pharmacokinetics:-
 Quaternary ammonium compounds, charged,
 Highly water soluble.
 Poorly absorbed and poorly distributed into most tissues.
 Hydrolyzed in the GIT and not active by the oral route.
 They differ in their susceptibility to hydrolysis by cholinesterase.

18. Drug Effects of Cholinergic Agents
“SLUDGE”
• Salivation
• Lacrimation
• Urinary incontinence
• Diarrhea
• Gastrointestinal cramps
• Emesis

19. 1.Muscarinic actions:-
Eye:-
On topical Administration- No action because of poor penetration
through tissues
Ach
+
M3-receptor
Contract the sphinter
Papillae(Miosis)
Contracts the cilliary muscle
(Spasm of accommodation)
Opens the trabecular meshwork around the canal of
schlemm
Facilitates drainage of aqueous humour & reduce IOP in glaucomatous eye

22. Light reflex- when bright light is directed into eye
, the pupil constrict- pupillary light reflex

23. Bronchi:-
•Contracts bronchial smooth muscle(Bronchospasm)
•↑Tracheobronchial secretions
•Contraindicated – Asthma
CVS:-
Heart:- Inhibitory action in SA node–open K+ channel –Hypepolarization
Ach
M3 receptor
M2 receptor
Ach
↓ ↓ HR- negative chronotropic Effect
↓ ↓ FOC-Negative Inotropic effect
↓ ↓ A-V conduction-Negative dromotropic effect

24. Blood Vessels:-
Ach stimulate M3 receptor in blood vessels
Release of NO(EDRF)
Vasodilatation ↓BP
Smooth Muscle:-
a. GIT:- stimulate M3 receptor
↑ Tone of the gut
↑ Peristaltic movements
↑ GI secretion
Relaxes the sphinter may cause defecation.

25. Urinary bladder:-
Contracts the detrusor muscle (M3 receptor )
 Relaxes the trigonal sphinter( Causes urination)
Exocrine gland:- (M3 receptor)
↑ salivation, lacrimation, sweat, bronchial , gastric & other
gastrointestinal secretion

26. Nicotinic action:-
1.Autonomic ganglia:-
Higher dose causes dangerous muscarnic effect especialy on heart
High dose of Ach stimulate both the sympathetic as well as the
parasympathetic ganglia causing trachycardia & rise in bp.
2.Skeletal muscle :-
High dose – twitching ,fasciculation followed by prolong
depolarization of NMJ & paralysis
3. CNS:- no action as it poor penetration through the BBB

27. Bethanechol
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-M3 receptor,
Neurogenic bladder
Gastroparesis

28. 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.
 Now a days (Pilocarpine+ Beta blockers)- combination use
Pilocarpine

29. Indirect Cholinergic drugs/ Anticholinesterase
Muscarinic
Receptor
Nicotinic
Receptor
cholinesterase
Some of anticholinesterases have additional direct action on cholinergic receptors
e.g. neostigmine
Acetylcholine
Choline Acetate
Anticholinesterases

30. CHEMISTRY
Anti ChE esters of carbamic acid or
derivatives of phosphoric acid
 Generic formula of
Carbamate Organophosphate
O R2
O R2
R1-O-C-N R1-P
R3 R3

31. Mechanism of Action
Reaction of ACh with ChE:
ChE has two active sites:
* Anionic site: Try, Glu, Tyr
* Esteratic site: Glu, His, Ser
(esteratic
site)
(anionic
site)

32. OH
O
Acetylated enzyme
Free enzyme & Acetate
+H2O
STEP 1
STEP 2
STEP 3
Free enzyme & ACh
E-S complex
OH
OH (-) (-)
(-)(-)

33. Reaction of ChE with Anti ChE:
a. Reversible Anti ChE
› Reversible Anti ChE are structurally similar
to ACh
› Except Edrophonium-bind to A site(shorter
acting drug-10 min)

34. OH
OH
O
OH
(-)
(-)
(-) (-)
STEP1
STEP2
STEP3
E-S Complex
Carbamoylated
enzyme
Free enzyme & carbamate
Free enzyme
+H2O

35. b. Irreversible Anti ChE
 All irreversible Anti ChEs (OPs) bind to
the esteratic site of the enzyme covalently
 Except Ecothiophate

36. OH O(-) (-)
Free enzyme & OP
Phosphorylated enzyme

37. Physostigmine
(Eserine)
Neostigmine
Source Natural alkaloid Synthetic
Chemistry Tertiary amine Quaternary ammonium
Oral absorption Good Poor
Applied to eye Useful Not useful
Direct action on
NM receptor
Absent Present
Prominent effect
on
Autonomic effectors Skeletal muscle
Important use Miotic-in galucoma
Belladonna
poisoning(Antidote)
Myasthenia gravis
Curare poisoning
PO-urinary retention
PO-paralytic ileus
Dose 0.5-1 mg oral/ parenteral
0.25 % eye drop
0.5-2.5 mg i.m /s.c
15-30 mg orally

38. PYRIDOSTIGMINE
• Quaternary ammonium compound
• Preferred drug over neostigmine in Myasthenia
gravis-( longer duration of action )
• Orally: tab. 60mg, as pyridostigmine bromide

39. Edrophonium
• Quaternary ammonium compound
• Rapid onset of action(5-15 min)
• Short duration
• Uses :
To differentiate between myasthenic
and cholinergic crisis

40. Rivastigmine Donepezil Galantamine Tacrine
Nature Carbamate Carbamate Natural
alkaloid
Acridine
Lipophilic Yes Yes Yes Yes
Reversible Yes Yes Yes Yes
Cholinestera
se
Inhibitor Inhibitor Inhibitor
Agonist:
Nicotinic
receptor
Inhibitor
Cerebro
selective
Yes Yes Yes Yes
Uses -
Alzheimer
disease
Yes Yes Yes Now not
used
Duration Long acting Long acting Short acting
twice daily
-------

41. Classification of Irreversible
Anti-ChEs compounds based on uses
• Dyflos (DFP)
• Ecothiophate
Therapeutical
use
• Parathion
• Malathion
• Diazinon(TIK-20)
• Carbaryl(SEVIN)
• Propoxur
(BAYGON)
Insecticides
• Tabun
• Sarin
• Soman
Nerve
gases

42. Echothiophate
• Organophosphorus compound
• Quaternary nitrogen structure
• Long acting miotics
• Slowly hydrolyzed
• 0.025-0.25% solution

43. Parathion and Malathion
• Organophosphorus compound
• Poisoning
• Uses:
-Agricultural
-Household insecticides

44. • An autoimmune process causes production of antibodies that
decrease the number of functional nicotinic receptors on the
postjunctional end plates.
• Difficult in Daily routines
• Day passes, limb weakness increases.
• Difficulty in respiration Severe disease may affect all the muscles,
including those necessary for respiration.
• Death
Myasthenia gravis

45. Diagnosis of M. Gravis
1. Ameliorative Test / Tensilon test → I.V.
Edrophonium
(To distinguish M. Gravis from cholinergic crisis)
(1 – 2 mg)
Improves skeletal Worsen skeletal
muscle activity
Muscle activity
↓ ↓
M. Gravis Cholinergic crisis

46. • Sensitive test for M. Gravis – Anti : NR antibodies
detection in plasma( positive in 85-95 %)
• Most sensitive test for M. Gravis-single fiber
electromyography (SFEMG) (positive upto 95 %)
• Most specific test for M. Gravis – Muscle biopsy
2. Provocative Test → By d-Tubocurarine (Q)

47. Treatment
• Anticholinesterases: neostigmine or neostigmine
substitutes as pyridostigmine and ambenonium (oral).
• Atropine (oral) to avoid the undesired muscarinic actions.
• Adjuvant drugs as ephedrine (facilitates NM transmission
and dilates blood vessels of skeletal muscles) and
caffeine (stimulates skeletal muscles) may be added.
• Immunosuppressive drugs as glucocorticoids (cortisol) and
azathioprine may be needed.
• Surgical treatment: thymectomy may be performed.
• Plasmapheresis in severe cases.

48. Glaucoma:-
Glaucoma is a chronic progressive optic neuropathy caused
due to imbalance between rate of formation of aqueous
humor by the ciliary epithelium and the rate of drainage
conditions which lead to damage of optic nerve with loss
of visual function ’’
• Intraocular pressure(IOP):- more than 21
mmHg
(Normal range – 10-21 mmHg)
( pressure in vascular supply of patient’s retina with
hypoxic damage to retina, very fragile neural tissue,
causes Blindness)

49. Narrow angle glaucoma:-
1.Short acting miotics:-
Pilocarpine (DOC),
physostigmine,
carbachol.
2.Dehydrating agents (osmotic agents):-
Mannitol,
magnesium sulphate,
isosorbide
3.Carbonic Anhydrase Inhibitors:
dorzolamide
acetazolamide
4.Alpha 2 agonists:-
Brimonidine
Wide angle glaucoma:-
1. Muscarinic agonists-
Physostigmine0.25-0.5%)T,,
Carbachol, bethanechol,
Pilocarpine(0.5%-4%)T ,
Neostigmine, demecurium
2. Sympathomimetic
(α-Agonists)- Adrenaline,dipivefrine
α2-Agonists :-Apraclonidine, Brimonidine
Sympathetic Depressants:-
β-Blockers:- timolol,
Betaxolol, levobunolol, carteolol
3. Carbonic Anhydrase Inhibitors:-
Dorzolamide, brinzolamide,
acetazolamide, dichlorophenamide
4.PGF2α-analogues:-
latanoprost,
travoprost,
bimatoprost
DRUGS USED IN GLAUCOMA

50. Other ophthalmologic uses:
Counteract the effects of mydriatics
Break adhesions between iris & lens or iris & cornea

51. Postoperative paralytic ileus & Atony of Urinary
Bladder:
Neostigmine methyl sulfate, sc or Orally for post
operative paralytic ileus
Neostigmine bromide orally for Atony of Urinary
Bladder
Curare Poisoning:
Neostigmine & Edrophonium-preferred drugs
Along with atropine to block Muscarnic effects

52. Snake venom(cobra bite) poisoning:
Neostigmine along with atropine is administered-
Atropine slow (iv)-prevent respiratory paralysis
Neostigmine iv/sc
Belladonna poisoning:
Physostigmine intravenously (Specific Antidote)

53. Used in other drug overdosages:
Tricyclic antidepressants , Phenothiazines &
antihistaminics
Physostigmine

54. Alzheimer’s Disease:
• The most prevalent cause of dementia with Ageing
• Atrophy of cortical & sub-cortical areas is associated with
deposition of -amyloid protein in a form of plaques
• Accumulation of Aβ initiate inflammation
• Inflammatory mediators like IL-1,IL-6
• Ultimately leads to apoptosis
slowly progressing degenerative disorder
Primarily affects cholinergic neurons in the brain
Produces progressive loss of memory & cognitive functions

55. Enlargement ventricles
Diminished hypothalamus
Thin brain cortex
Alzheimer's disease

56. Treatment:
1. Donepezil (Aricept)—
 said to delay progression of the disease by up to 55 weeks.
 Has once-a-day dosing advantage
 Does not cause liver toxicity.
2. Galantamine (Reminyl)—newest kid on the block
3. Rivastigmine (Exelon) long acting. Twice a day
dosing. Available in solution for swallowing ease
4. Tacrine (Cognex)—First drug to treat Alzheimer’s
dementia
Side effect:-
HepatoToxicity . Elevated liver enzymes.
within 18 wks. > in women.

57. ADVERSE EFFECTS:
• sweating
• salivation
• Nausea
• Vomiting
• Abdominal cramps
• Bradycardia
• Diarrhoea
• Tremors
• Hypotension

58. Anticholinesterase poisoning:
The effects of acute intoxication
Muscarinic effects
Nicotinic effects
Central effects

59. A farmer while spraying an insecticide develop
profuse sweating, muscle weakness and
bronchospasm and is admitted immediately to the
hospital. On examination, his pulse rate is 60
beat/min and the pupils are constricted. He is
suspected to have insecticide poisoning.
Q-1: What type of insecticide could have caused this
poisoning? Explain.
Q-2: How do you confirm the diagnosis?
Q-3: Outline the management of this poisoning?

60. SYMPTOMS OF ANTICHOLINESTERASES POISONING
Muscarinic Nicotinic
(On higher dose)
CNS
  All secretions
S → Salivation
L → Lacrimation
U → Urination
D→Defecation
G → GIT-Diarrhea
E → Excess Sweating
 Bradycardia
 Muscular
fassiculations
 Muscular
paralysis
 Respiratory
arrest
(Cause of
death)
 Tachycardia &
 Headache
 Convulsions
 Loss of
consciousness

61. Treatment of Poisoning
General Rx. Specific Rx.
 Wash skin and
mucus membrane
 Gastric lavage
 Maintain airways,
breathing, and
circulation
 Control of
convulsions
Atropine (Q) (2 mg i.v. every 10
min)
|
 Till dryness of mouth begins
 Highly effective in counteracting
Muscarinic symptoms, but
not muscular paralysis, as it is
nicotinic action
 It is drug of choice in both
Organophosphates
&Carbamates poisoning(Q)
 Glycopyrrolate → Similar
outcomes like atropine by using
continuous infusion
Cholinesterase
Reactivators (Oximes)
 Use only in
organophosphate
poisoning. (Q)
 Oximes are :
- Pralidoxime (PAM)
- Obidoxime
- Diacetyl monoxime
(DAM)

62. Mechanism of action of oximes
Acts by reactivating Cholinesterase enzyme.
Ach E has two sites
i. Esteric site → active site
ii.Anionic site
 In organophosphate poisoning esteratic site of cholinesterase
is phosphorylated and anionic site is free.
 Phosphorylated cholinesterase reacts very slowly with water.
 However, if more reactive OH groups in the form of oximes
are provided, reactivation occurs more than a million times
faster.
 Oximes attach to anionic site and provide more reactive OH
groups.

63. Oximes are not use in carbamates poisoning,
because they are not bind to anionic site, which is
already occupied in carbamates poisoning, rather
oximes are contraindicated due to weak
anticholinesterase activity, may worsen the
condition.

64. 64
Agents affecting the availability of acetylcholine
Botulism toxin:-
Protein exotoxin produced by gram-negative
anaerobe Clostridium botulinum
Toxin is specific to strain: A, B, Ca, Cb, D, E, F, G.
lethal dosehuman is 10-9mg/kg; 50% mortality
Binds to the presynaptic membrane of cholinergic neurons preventing
the exocytosis of acetylcholine.
BOTOX® - type A (1990)
MYOBLOC® - type B (2001)
Treatments :-
•dystonia (involuntary rhythmic muscle spasms)
•excessive sweating
•headaches
•muscle spasticity
•pain
•crossed eyes
•blepharospasm

65. Black widow spider venom - a-latrotoxin
causes clumping of synaptic
vesicles at presynaptic
membrane along with
premature release of
acetylcholine
-bungarotoxin
premature release of acetylcholine
180 amino acids; multi-subunited
Agents affecting the availability of acetylcholine:-
Krait venoms

66. Disease Drug of Choice
Cobra bite Neostigmine
Myasthenia
Gravis
Pyridostigmine
Diagnosis of MG Edrophonium
Belladonna or
atropine
poisoning
Physostigmine
Curare poisoning Neostigmine

67. Q1. Classify cholinesterase inhibitors. Describe pharmacological actions, therapeutic
uses and the adverse effects of Neostigmine.
Q2. Describe the toxicity and the management of:- Organophosphorous poisoning
Q3. Write short notes on:- Cholinergic receptors
Q4. Explain why:-
1. Neostigmine is useful in myasthenia gravis
2.Acetylcholine is not used therapeutically
3. Physostigmine is preferred over Neostigmine in the treatment of atropine/
dhatura poisoning
4. Edrophonium and not Neostigmine is used for the diagnosis of myasthenia gravis
Q5. Describe the pharmacological basis of use of:-
1.Pilocarpine and Physostigmine in glaucoma
2. Oximes in organophosphorous poisoning
3. Physostigmine in dhatura poisoning
4. Edrophonium in the diagnosis of myasthenia gravis
Q6. Discuss the management of:
Myasthenia gravis
Pesticide poisoning

69. Introduction:-
Also called:-Muscarinic Receptor antagonist,
Parasympatholytics, Atropinic Drugs, Cholinolytics
Drugs that competitively block or inhibit the actions
of acetylcholine (ACh) in the parasympathetic
nervous system.
These drugs also block actions on autonomic
effectors and in the CNS exerted through muscarinic
receptors.
• On higher concentration anticholinergics also block
nicotinic receptors generally referred to as
“Ganglion blockers” and “Neuromuscular blockers”.

70. Anticholinergic
Agents
Neuronal type
(Nn)
Muscle type
(Nm)
Antinicotinic
agent
Anti muscarinic
agent
70

71. Classification
 Natural alkaloids:
1. Atropine
2. Hyoscine(Scopolamine)
 Semi-Synthetic derivatives:
1. Homatropine and its salts
2. Atropione methonitrate
3. Hyoscine butyl bromide
4. Hyoscine methyl bromide
5. Ipratropium bromide
6. Tiotropium bromide
7. Oxitropium bromide
71

72. Synthetic Compounds:
 Mydriatrics:
1. Cyclopentolate
2. Tropicamide
 Antisecretory- antispasmodics:
 Quaternary compounds:
1. Propantheline
2. Oxyphenonium
3. Clidinium
4. Pipenzolate methyl bromide
5. Isopropamide
6. Glycopyrrolate
7. Drotaverine
72

73.  Tertiary amines:
1. Dicyclomine
2. Valethamate
3. Pirenzepine
 Vasico selective:
1. Oxybutynin
2. Flavoxate
3. Tolteridone
 Antiparkinsonian drugs:
1. Trihexyphenidyl(benzhexol)
2. Benztropine
3. Procyclidine.
4. Biperiden.
73

74. Tropane alkaloids
•Atropine
Atropa belladonna L.
(deadly night shade)
Cura bulgara (Ivan Raev)
•Scopolamine (Hyoscine)
•Solanine

75. HISTORY
Prototype drug for anti-cholinergic drugs
Tertiary amine, Alkaloid of belladona plants
Obtained from Atropa belladona or
Datura stramonium

76. Datura stramonium Hyoscyamus niger

77. Conti….
Naturally occurring atropine is l-hyoscyamine,
responsible for antimuscarinic activity.
Isolation of atropine by Mein in 1831.

78. CHEMISTRY
Atropine and Scopolamine are esters, formed by an
aromatic acid, tropic acid and complex organic bases.
Atropine differs from Scopolamine by an ‘o’ atom bridge
between the carbon atoms designated as 6 and 7
Scopolamine
Atropine

79. Mechanism of action:
• Atropine competitively block the muscarinic
effect of ACh- competitive antagonism.
ACh M Receptor Atropine
• Atropine causes reversible blockade of
cholinomimetic agents at M receptors
(competitive blockade)
79

80. Atropine
( )

81. Atropine
Actions
↓↓ secretion of exocrine gland
GIT:-
↓ motility of gut relieves
spasm
Constipation
Control tremors
& rigidity of Parkinsonism
glandCNS
CVS
Initial bradycardia
(with low dose )
Tachycardia
Eye
Passive mydriasis
Cycloplegia
Loss of light reflex
Respiratory
System
Relaxes the bronchial
smooth
Muscle but dries up all
the secretions
↓ ↓ tone of detrusor
muscle
↑ tone of trigonal
sphincter
Urinary retention
Functional capacity of bladder
increases

83. Pharmacological actions:
1)CNS:-
Atropine – CNS stimulant
Scopolamine (l – hyoscine ) – more cross BBB than atropine
(All anticholinergic drugs ↓ vestibular pathways to CNS because
Ach is a mediator in this. So drugs which having anticholinergic
property+ cross CNS=anti-motion sickness properties)
i.e. – anticholinergics, antihistaminic,
* Due to amnesia & CNS depressant action – scopolamine induces
“twilight sleep”..has been used as “lie detector ” or “truth serum”
Low doses Atropine------ only peripheral effects (cant cross BBB)
Therapeutic doses Atropine- stimulates vagal, respiratory(RC) and
vasomotor centre(VMC)
83

84.  By reducing cholinergic overactivity in basal ganglia, it supresses
rigidity and tremor associated with parkinsonism.
Central anti-cholinergics- benztropine, benzhexol , biperiden – DOC in
drug induced parkinsonism
ACh
DA 84
Toxic doses - cerebral excitation becomes still more prominent
leading to , restlessness ,irritability, disorientation, hallucination
and delirium.
Still larger doses- stimulation is followed by depression,
leading to circulatory collapse, coma and respiratory failure
leading to death

85. 2) CVS:
ON THE HEART – M2
• Atropine : Small doses(0.4-0.6mg): Bradycardia
(Due to blockade of presynaptic Muscarinic autoreceptors on
vagal nerve ending ).
• Large doses(above 1mg): Tachycardia- by blocking
vagal effects on M2 receptor on the SA node
• Contraindicated:- coronary artherosclerosis,
hyperthyroidism ,cardiac insufficiency
(initial bradycardia before the effects of peripheral
vagal block- useful in the treatment of
Bradycardia, asystolia)

86. ON BLOOD VESSELS:
• BP------ ↑ B.P
Tachycardia and VMC stimulation
• VERY HIGH DOSES- has cutaneous vasodilatation
especially in upper portion of body. and histamine
release- ↓BP
• Use in ↑ vagal tone condition i.e. vasovagal attack,
hypersensitive carotid sinus massages, Digitalis
poisoning
• No consistent effect on BP & cardiac contractility-
cholinergic impulse doesn’t play role in vascular tone
maintenance

87. Atropine on
topical
administration
Paralysis of ciliary
muscle
Passive
mydriasis
Cycloplegia-loss
of near vision
paralysis of
sphincter pupillae
3. Eye:-
Photophobia
Loss of accommodation

88. 88

89. • Loss of light reflex.
 Longest acting- Atropine (because tightly bound to M receptor)
 Most potent-Hyoscine – action last for 3-7 days
 Decrease in lacrimal secretion results in “Dry or sandy eyes.”
 Conventional systemic doses of atropine have little ocular effect(48-
72 hrs )
 Locally applied atropine produces ocular effects for 7-12 days
 Used where ciliary tone is very high .e.g.- children (T)
89

90. light reflex
90

91. Accommodation
91
The process by which an
image is kept in sharp
focus , when the gaze
is shifted from far
object (beyond 40 cm)
to a near object

92. 4. Respiratory system:
• Inhibit the secretions & mucociliary clearance
• These also reduce laryngospasm during general anaesthesia.
• Bronchodilatation
• Inflammatory mediators increase vagal activity in addition to their direct
action on bronchial muscle and glands.
92

93. 5. GI tract:-
Gastric secretions:-
Antispasmodic agents –
↓Normal tone Amplitude of contraction & Secretion of the
gut
• Atropine reduces the basal secretions of gastric acid by 40
to 50%.
• The concentration of acid is not necessarily lowered because
secretion of HCO3
–as well as that of H+ is blocked.
• Vagal stimulated secretions and GI responses are inhibited
to a lesser extent by these drugs.
93

94. • Atropine will inhibit the component of acid secretion that
results from muscarinic stimulation of enterochromaffin
cells (histamine secretors) and parietal cells (acid secretors).
• Inhibition of Salivary secretion.
• Motility:- increases the sphincter tone leading to
constipation
• Biliary tract: Atropine exerts a mild Anti-spasmodic action
on the gallbladder and bile ducts in humans.(relaxes the
smooth muscle of gall bladder)
94

95. 6. Genitourinary tract:
Retention of urine
 Functional capacity of bladder increases
95
↓↓ tone
↓↓ Amplitude
↓↓ Frequency
detrusor muscle
Trigonal Sphincter ↑↑tone
M3

96. 7. Sweat glands
Thermoregulatory sweating is suppressed by
atropine.(Atropine fever).
Inhibits sweating +n of temp.regulation centre
Rise in body temperature at higher doses
Atropine
96

97. 8. Local anaesthetic:
• Atropine has mild anaesthetic action on the
cornea.
97

98. 9.Miscellaneous drugs possessing
significant antimuscarinic effects:
• Antihistamines(diphenhydramine,promethazine,
orphenadramine)
• Antipsychotics(chlorpromazine, thioridazine,haloperidol)
• Tricyclic Antidepressants (amitryptyline,imipramine)
• Disopyramide.
• Pethidine.
98

99. 10. Smooth muscles:-
All visceral smooth muscles with parasympathetic inervation are
relaxed (M3-blokade).
GIT :- ↓Tone and amplitude.
Spasm may be reduced, constipation may occur.
Peristalsis is only incompletely suppressed because it is primarily
regulated by local reflexes and other neurotransmitter (serotonin,
encephalin etc.).
Atropine causes bronchodilation and reduced airway
resistance, specially in asthma patients. Inflammatory
mediators (histamine, PGs and kinins) increase vagal
activity in addition to their direct action on bronchial
muscle and glands. Atropine attenuates their action
by antagonizing the reflex vagal component.
It has a relaxant action of ureter and urinary bladder.
Urinary retention can occur in older man with prostatic
hyperplasia.

100. Pharmacokinetics:-
Absorption:- rapidly from GIT.
Passage across BBB is somewhat restricted.
Metabolism:- 50% by liver
Excretion:-unchanged in urine.
t1/2 3–4 h.
Hyoscine is more completely metabolized and has
better BBB penetration.
Some rabbits have a specific atropine
esterase which degrade atropine very rapidly.

102. 1.CARDIAC VAGOLYTIC
As an initial treatment to block excessive vagal
tone in patients with acute myocardial infarction.
Excessive vagal tone causes sinus bradycardia
or A.V block
prevents further clinical deterioration by restoring H.R.
Dosing must be judicious.
Low dose cause bradycardia( M1 blockade).
Higher dose cause tachycardia (M2 blockade).
Useful in reducing severe bradycardia
and syncope

103. 3.Ophthalmic:-
 Refraction testing- (mydriasis + Cycloplegia )
Diagnostic purpose:- Short acting drug use to avoid SE.Topicamide-3-
6hrs
Therapeutic purpose:- longest acting drug
Atropine- locally applied.
Systemic dose – (48-72hr.) less ocular effect
Advantage of Local application:-
 Action lasts for 7-12days-because tightly bound to Muscarinic
receptor
 More local effect, less systemic effect
Use in iritis, irido-cyclitis- to prevent adhesion b/w iris & lens or iris &
cornea
Alternative drug- Homatropine
Contraindicated – Glaucoma

104. 3. IN ORGANOPHOSPHATE
POISONING
Dose:- 2-4 mg atropine i.v every 10 to 15 min till
atropinization symptoms occur.
Treat for 1-2 weeks.
No effect on peripheral muscular paralysis.
Antagonizes tracheobronchial, salivary secretions,
bronchoconstriction and bradycardia.
Larger doses are needed to antagonize CNS
effects.

105. 4. TO TREAT REVERSIBLE
ANTICHOLINESTERASE
OVERDOSE
Dose:- 0.5 mg s.c to antagonise
pyridostigmine.
Blocks only Muscarinic effect of ACh
Useful early in therapy of myasthenia
gravis.
Tolerance develops with long term
therapy

106. 5. USED IN ANAESTHESIA
Used to block responses to vagal reflexes induced by surgical
manipulation.
Non-irritant anaesthetics to bronchi are better preferred now.
Glycopyrrolate- As pre-anaesthetic medication
Quaternary ammonium compound – only peripheral effect
Advantages of using as PAM-
A. To prevent bradycardia during anaesthesia
B. To prevent laryngospasm by ↓ Respiratory secretion
C. To prevent Aspiration pneumonia by ↓ Salivary & respiratory
secretion

107. 6. IN POSTOPERATIVE
DECURARIZATION
Competitive neuro muscular block (d-
tubocurarine) is used to relax the skeletal muscle.
Decurarization :-
neostigmine 0.2-2.0 mg i.v + atropine.

108. 7. TO TREAT COBRA BITE
Cobra venom has a curare like neurotoxin.
Neostigmine + atropine prevents
respiratory paralysis.
Primary treatment is specific antivenom
serum.

109. 8. TO TREAT EARLY
MUSHROOM POISONING
Amanita muscaria (muscarine) Amanita phalloides
(phalloidine)

110. Mushroom poisoning (Mycetism)
Early type / muscarine type(< 30- 60 min)
Muscarinic Atropine+ Muscarinic
Causative organism:-
By Inocybe & Cytocybe
Sp.
Muscarinic excess
i.e. Lacrimation, Bradycardia,
Hypotension
Rx-
DOC- is Atropine
(1-2 mg IM every 30 min )
Causative organism:-
Amanita muscaria
It contain not only muscarine
but also other alkaloids,
Including Antimuscarinic agents
May produce signs of atropine is contraindicated
Rx-
Mainly supportive,
Benzodiazepines,penicillin,thioctic acid,silibin
Delayed type/ phalloidin
type

111. Delayed type/ phalloidin type
Causative organism:-
Amanita phalloides , lepiota and galesina sp.
Most serious
Accounts for > 90% of fatal cases
Principal toxins:-
Ametoxins:- α- amanitin
ß- amanitin
MOA:- Inhibit RNA polymerase-II → Block RNA synthesis
Cell death of GIT mucosa, kidney & liver
Symptoms:- initial symptoms include Abdominal cramp
symptoms free interval followed by renal &
hepatic manifestation
Rx- Mainly supportive & thioctic acid
DEATH (Within 4-7 days)

112.  Atropine derivatives like -
9. COPD & Bronchial Asthma
Ipratropium Bromide Tiotropium Bromide
M1=M2=M3 More selective for M3 receptor
T1/2- 4hrs so,dose needed-
TID,QID
T1/2-24hrs So OD
 Both Quaternary compound-administered by MDI or nebulizer
90% dose swallowed after inhalation but not absorb in systemic
circulation
Most useful in vagal related pathology .e.g- COPD>Asthma
Selected for respiratory system because doesn’t ↓ mucociliary
clearance like atropine
USE- prophylactically – action take 30-60 min so not use in acute con.
↓ tracheo-bronchial secretion so useful in rhinorrhoea associated with
Allergic rhinitis

113. 10.Renal & Biliary colic:-
Atropine + morphine
• Atropine by relaxing the smooth muscle of gall
bladder increases the intrabiliary capacity
• Also incompletely suppress peristalsis
11.GI colic & symptomatic treatment of
diarrhea:-
Dicyclomine – synthetic antimuscarnic agent + prominent
Antispasmodic effect (M3-blocked)
Other GIT related use:- pirenzepine ,telenzepine – use in
peptic ulcer

114. 12.Urinary disorders:-
M3 receptor blockers-
1.Condition causing over reactive bladder,i.e.
→Spastic paraplegia,
→neurogenic bladder (bladder incontinence)
2.In nocturnal enuresis (children)- ↑ functional capacity of
bladder
E.g,-
 Oxybutynin- oldest drug, less selective
 Tolterodine-Most selective
 Fesoterodine- Prodrug, Active is tolterodine

115. Traspium-Don’t cross CNS,so less side effect
Solifenacin & darifenacin- most selective in which
darifenacin has maximum selectivity for M3
receptor
Flavoxate- Directly acting muscle relaxant,
Analgesic,weak anti-cholinergic & weak anesthetic
Drotaverine –Non anticholinerg drug so devoid of
anticholinergic side effects but good anti-
pasmodic.

116. Benzhexol, Benztropine, Biperidine-centrally acting anti-
cholinergics
• Drug induced parkinsonism.
• Antimuscarinic agents improve tremor and rigidity but
have little effect on bradykinesia.
USES:-
Iatrogenic Parkinsonism:- anti dopaminergic drug induced
Idiopathic parkinsonism: useful in the management of
mild-to-moderate symptoms of the PD.
Advantage:-
• Main action –centrally so minimal peripheral action
• cheaper and better tolerated then L-dopa
Adverse effect:- Dry mouth,constipation,drowsiness

118. BELLADONA / ATROPINE
POISONING
Children are highly susceptible.
Manifestations due to exaggerated
antimuscarinic actions.
Specific antidote is physostigmine, tertiary
amine alkaloid, antagonizes central and
peripheral toxicity of atropine.
Diagnosis- smaller dose of physostigmine
0.5-1 mg i.m
Treatment- 2 mg physostigmine i.v/i.m

119. ANTIMUSCARINIC
SYMPTOMS
Opposite effects of acetylcholine
Xerostomia
Mydriasis
Cycloplegia, Photophobia
dry eye
increased heart rate
increased body temperature

120. Cont…
dry warm skin and/or flushing
difficulty emptying our bladder
Constipation
IN CNS
Headaches
Confusion
Agitation
Euphoria
Memory problems
respiratory depression

122. IN NARROW ANGLE
GLAUCOMA
People with narrow iridocorneal angle.
Atropine causes passive mydriasis, worsening
the drainage of aqueous humor.

123. IN PROSTATIC
HYPERTROPHY
In elderly male prostatic hypertrophy patients
muscarinic blockade cause urinary retention.

124. IN PYLORIC STENOSIS
Pyloric stenosis is a narrowing of the pylorus.
The muscles of the pylorus are thickened,
prevents the stomach from emptying into the
small intestine.
Atropine worsens gastric emptying in pyloric
stenosis patients.

126. Absorption of drugs delayed because of delayed
gastric emptying.
digoxin, tetracyclin absorption
Antacids interfere with absorption of
anticholinergics.
Antihistamines, TCAs, phenothiazine, pethidine
have anticholinergic property Additive side
effects.
MAO inhibitors interfere with metabolism of
anticholinergic antiparkinsonian drugs
Delirium occurs.