CHOLINERGIC_VV VHVJJ HVJ VHJ VJH VHJVDRUGS.ppt

G GH GH VG V

1. CHOLINERGIC DRUGS

2. CHOLINERGIC DRUGS
Drugs acting on cholinergic nerves or tissue
they innervate to either mimic or block action
of Acetylcholine
Mimic by either acting directly on cholinergic
receptors or blocking Acetyl cholinesterase (AchE)
Block by either binding to receptor or competing
with Ach for binding with the receptors

3. CHOLINERGIC NERVES
Release Acetylcholine at nerve endings
O N
+
CH
3
O
H
3C
CH
3
CH
3

4. CHOLINERGIC NERVES IN-
Nervous System
Central Nervous System
(cortical & subcortical
region of Brain)
Peripheral Nervous System
ANS
Somatic NS
(Involuntary)
regulates activities
of smooth muscle
& glandular
secretions
(Voluntary)
Sensory
Afferent
Motor
Efferent
to skeletal muscle
(Neuromuscular
junction)
Ach
Sympathetic
Nervous System
Parasympathetic
Nervous System

5. Ach as Neurotransmitter
Ach serves as Neurotransmitter at-
1.Preganglionic & postganglionic nerve endings of
parasympathetic nervous system
2. Preganglionic & Few postganglionic (salivary glands)
nerve endings of sympathetic nervous system
3. All autonomic ganglia & skeletal muscle end plate region
(Neuromuscular junction)

6. Physiological Actions of Ach
Cardiac inhibition (-ve chronotropic & -ve
ionotropic action on heart)
Peripheral Vasodilation
Constriction of Pupil (miosis)
Constriction of bronchi
Increased salivation, increased flow of secretary
glands
Contraction & peristaltic action on GIT & urinary
tract
Stimulation & maintenance of tone of skeletal
muscle

7. SYNTHESIS, STORAGE,RELEASE &
METABOLISM
Muscarnic
receptor
Nicotinic
receptors
Choline + Acetyl-CoA
ChAT
Ach
Ach
Ach
Ach
AchE
AchE
Glucose
Pyruvate
Coenzyme A
SYNTHESIS
STORAGE
Ach
RELEASE
Synaptic cleft
Ach
Ach
Ach
Acetyl
Cholinesterase
Choline + Acetate
DISPOSAL
UPTAKE

8. RECEPTOR SUBTYPES
M
uscarnic
R
eceptors

(G-Protein coupled receptors)
M
1-Neural (activate PLC)
M
2-Cardiac (Inhibit Adenylate
cyclase)
M
3
-Glandular (activate PLC)
M
4
(Inhibit Adenylate cyclase)
M
5 (activate PLC)
O
CH
2 N(CH
3)
3
H
H
H
CH
3
OH

9. Responses mediated by muscarnic
receptors
HEART Atria
A-V node
Heart rate
A-V nodal conduction
EYE Contraction of sphincter muscle
of iris and ciliary muscle
GASTROINTESTINAL
TRACT
Tone, motility & secretion
URINARY BLADDER
Relaxation of sphincter
SECRETARY GLANDS
(Sweat, bronchial, salivary glands)
Secretion

10. RECEPTOR SUBTYPES
NICOTINIC RECEPTORS
(Ion Channels)
N
N
CH
3
Responses mediated by nicotinic receptors
Autonomic ganglia (N
2
)Depolarization
Adrenal medulla Secretion of adrenaline
NM junction (N
1
) Depolarization of
motor end plate

11. CHOLINERGIC STEREOCHEMISTRY
Gauche conformation-preferred
N
H
H
H
AcO
H

12. SAR OF A
ch
Ach – ester of choline with acetic acid,
- stable in acidic solutions,
- hydrolyzed by AchE enzymes,
- exhibits its actions through Muscarnic &
Nicotinic receptors

N
CH
3
CH
3
CH
3
CH
2
CH
2 O C
O
CH
3
Onium
Ethylene
bridge
Ester (Acetyl) gr
gr

13. SAR
Onium group
Essential for intrinsic activity for
both Nicotinic and Muscarnic receptors
Affinity as detecting & directing gr
Binds with –vely charged aspartic acid residue
in 3
rd
helix
Trimethylammonium gr-optimal gr for activity
Phosphonium,Sulfonium,Arsenonium isosteres
& substituents larger than methyl gr on N-
Increases size of onium,diffuse +ve
charge,sterically interfere with proper drug
receptor interaction-decrease the activity

N
CH
3
CH
3
CH
3
CH
2
CH
2 O C
O
CH
3
Onium
Ethylene
bridge
Ester (Acetyl) gr
gr

14. SAR
Ester group
Form Hydrogen bonds with threonine &
asparagine residue
Presence of Acetyl gr is not as critical as that
of the size of the molecule
Bulky substituents on terminal C atom –
antimuscarnic action
O N
+
CH
3
O
H
3C
CH
3
CH
3

15. SAR
Ethylene bridge (chain between N & O)
Binds with receptors thr hydrophobic
forces(Hydrophobic packets on 4,5,6,& 7 helices of
receptor)
Its change affects chemical stability
Five atom rule- For maximum muscarnic activity,
Quarternary ammonium gr should be followed by five
atoms
Shortening & lengthening of chain-decrease muscarnic
action
-substitution-decrease muscarnic activity
β-substitution –decrease nicotinic activity
β-substitution-decreased rate of hydrolysis

O N
+
CH
3
O
H
3C
CH
3
CH
3

16. A
ch-receptor binding

Receptor contains three binding
sites
1.Anionic site (Region for ionic
bonding)
2.Esteratic site (Region for H-bonding)
3.Region for hydrophobic binding

17. CHOLINERGIC AGONISTS
(CHOLINOMIMETICS)
On structural basis, they are divided
into-
1. Acetylcholine and synthetic choline
esters
2. Naturally occurring and synthetic
alkaloids
3. Cholinesterase inhibitors
(Anticholinesterases)
4. Ganglionic stimulants

18. SAR
of CHOLINOMIMETICS
Onium-
Trimethylammonium gr-
essential
Replacing N for P, S, As-
decrease activity
Methyl on N by larger alkyl-
decrease activity
Two methyl gr and one larger
alkyl on N –good activity


Ethylene bridge-
Five atom rule
Substitution on α,β-carbon-
decrease activity
β –methyl-good muscarnic
activity
α –methyl-good nicotinic
activity

19. Acyl group-
 Higher homologue of acetyl- decrease activity
 Aromatic and higher acid- show antagonistic activity
 Terminal CH3 replaced with NH2- Potent cholinergic
acting on Nicotinic & muscarnic receptors
 Interprosthetic distance between O and methyl-play imp
role-should be optimum
Thus, O of ether, ketone, ester, acetyl- identical for
receptor
 Size imp than acyl group
 Ether oxygen- imp for muscarnic action
 Oxygen replaced by Sulphur- decrease activity, thus H-
bonding exists
 Ester gr.not essential for activity-n-
alkyltrimethylammonium shows activity, thus size rather
than functional gr is necessary for intrinsic activity

20. CHOLINOMIMETCS
N
N
O
O
pilocarpine
O
O
N
+
methacholine
N
+
OH
2N
O
carbachol
N
+
OH
2N
O
bethanechol

21. CHOLINESTERASE INHIBITORS
N
H
N
N
NH
C
O O
N
H
3C CH
3
H
2C CH
3
H
2C
O
C
O
CH
3
O
H
Ser
CH
2
O H
Im
1
Im
2
Tyrosine
(Cationic site)
Anionic site
Esteratic
site
CHOLINESTERASE & ACETYL CHOLINE

22. ANTICHOLINESTERASES
ANTICHOLINESTERASES
REVERSIBLE IRREVERSIBLE
1.Natural
Physostigmine
2.Synthetic
Neostigmine, Pyridostigmine
Ambenonium, Demecarium
Edrophonium etc
Organophosphorous
Esters e.g.Isofluorphate,
Malathion, Parathion
Antidote- Pralidoxime

23. ANTICHOLINESTERASES

H
3C C O
O
CH
2CH
2 N
CH
3
CH
3
CH
3
H
2O
AchE
CH
2CH
2 N
CH
3
CH
3
CH
3
HO
CH
3COOH
Acetyl---
E +
+
+
Ach E.Ach E-A E +CH
3COOH
k
+1
k
-1
k
2
-choline
k
3
Carbamyl---
E +CX E.CX E-C E +C
k
+1
k
-1
k
2
k
3
-X
Phosphoryl---
E +PX E.PX E-P E +P
k
+1
k
-1
k
2
k
3
-X

24. REVERSIBLE INHIBITORS
O
NH
O
N
N
PHYSOSTIGMINE
•In solution hydrolyzed to methyl
carbamic acid and eseroline
•
Solutions are stable at pH 6
•Inhibiting property vary with pH
•Poor carbamylating agent
•Reversible inhibitor
•Protonated form is responsible for
Activity
•Uses- in Glaucoma, as antidote for
Atropine poisoning, in Alzheimer’s
Disease
•Used as Salicylate, sulfate

25. N(CH
3)
3
O CN(CH
3)
2
O
NEOSTIGMINE
(m-hydroxyphenyl)trimethylammonium
bromide dimethyl carbamate
Solutions are stable
Rapid hepatic metabolism
Activity does not vary with pH
Also stimulates skeletal muscles
Greater miotic action
Fewer and less unpleasant side effects
Greater chemical stability
Uses- in myasthenia gravis,
intestinal atony, as antidote to
Nondepolarizing NM blocking gents
Used as Bromides and Methyl sulfates

26. N
CH
3
O CN(CH
3)
2
O
PYRIDOSTIGMINE
3-hydroxy-1-methylpyridinium bromide
dimethylcarbamate
One fifth as toxic as neostigmine
Metabolized to 3-hydroxy-N-methylpyridinium
Use- in myasthenia gravis
[Oxalylbis(iminoethylene)]bis [(o-chloro
benzyl)diethylammonium] dichloride
Prolonged duration of action, fewer side effects
Absorbed poorly due to quaternary N
Use- in myasthenia gravis

CH
2
Cl
N CH
2CH
2
C
2H
5
C
2H
5
H
N C
O
H
2C
Cl
NCH
2CH
2
C
2H
5
C
2H
5
H
NC
O
2Cl
AMBENONIUM CHLORIDE

27. O
O
C N
CH
3
(CH
2)
10
(CH
3)
3N
Br
OCN
CH
3
(CH
3)
3N
Br
O
DEMECARIUM BROMIDE
(m-Hydroxyphenyl)trimethylammonium bromide
decamethylenebis[methylcarbamate]
Diester-comparable to bis-prostigmine
Potent
Long acting miotic
Used to treat wide angle glaucoma

28. NH
3C CH
3
C
2H
5
OH
Cl
EDROPHONIUM
o Ethyl(m-hydroxyphenyl)
dimethylammonium chloride
o Reversible inhibitor
o More rapid onset and shorter
duration of action if given parenterally
o
Specific anticurare agent
o Not useful as antidote for
depolarizing blocking agent
o Also show direct cholinomimetic
effect on skeletal muscle
o Use- potential diagnostic agent for myasthenia gravis
N
NH
2
HCl
TACRINE
1,2,3,4-Tetrahydro-9-aminoacridine
(THA)
Use- in the treatment of mild to moderate
Alzheimer’s dementia

29. IRREVERSIBLE INHIBITORS
ORGANOPHOSPHOROUS ESTERS
HIGHLY TOXIC FOR HUMANS
INHIBIT BOTH AChE AND BuChE
LONG ACTING
NERVE POISONS
USED IN WARFARE AND AS
AGRICULTURAL INSECTISIDES
ENZYME REACTIVATORS (2-PAM)

30. SAR
P X
R
2
R
1
A
Where R1= alkoxyl
R2= alkoxyl, alkyl,
or tertiary amine
X = a good leaving gr
(e.g.F, CN, thiomalate
p-nitrophenoxy)

31. P
O
F
iC
3H
7O
iC
3H
7O
ISOFLUORPHATE
Diisopropyl phosphorofluoridate
P O P
O O
OC
2H
5
OC
2H
5
OC
2H
5
OC
2H
5
TETRAETHYLPYROPHOSPHATE (TEPP)
P O
P
O O
OC
2H
5
OC
2H
5
OC
2H
5
OC
2H
5
HEXAETHYLTETRAPHOSPHATE (HETP)
OP
O
OC
2H
5
OP
O
OC
2H
5
P
O
C
2H
5O
C
2H
5O
S N
CH
3
CH
3
CH
3CH
2CH
2
ECHOTHIOPHATE
(2-Mercaptoethyl)trimethylammonium iodide
S-ester with O,O-diethyl phosphorate

32. P
C
2H
5O
C
2H
5O
S
O
NO
2
PARATHION
O,O-diethyl O-p-nitrophenyl phosphorothioate
P
CH
3O
CH
3O
S
S
HC
CH
2
COOC
2H
5
COOC
2H
5
MALATHION
2-[(dimethylphosphinothioyl)thio]-butanedioic
acid diethyl ester
N CH NOH
CH
3
Cl
PRALIDOXIME CHLORIDE (2-PAM)
2-Formyl-1-methylpyridinium chloride oxime

33. CHOLINERGIC BLOCKING AGENTS
Parasympathetic
postganglionic nerves
in smooth muscles
All activated by
Acetylcholine but
blocked by
selective
antagonists
Selective antagonist-
Atropine
Sympathetic and
parasympathetic
Autonomic ganglia
Selective antagonist-
Hexamethonium
Neuromuscular
junction in skeletal
muscles
Selective antagonist-
d-Tubocurarine
BLOCKS THE ACTION OF Ach
Peripheral cholinergic receptors at

34. Two approaches-
1. Drugs inhibit synthesis and release of Ach
2. Drugs block Ach from reacting with receptor
Anticholinergic action- dependent upon ability of compound to
reduce number of free receptors that can
interact with Ach and the rate of drug
receptor interactions
Agonist- has high affinity and intrinsic activity (efficacy)
Antagonist- has high affinity but no intrinsic activity (efficacy)

35. CHOLINERGIC BLOCKING AGENTS
PARASYMPATHETIC
POSTGANGLIONIC
BLOCKERS
GANGLIONIC
BLOCKERS
NEUROMUSCULAR
BLOCKERS

36. PARASYMPATHETIC
POSTGANGLIONIC BLOCKERS
These are also called as-
ANTIMUSCARNIC DRUGS
ANTICHOLINERGIC DRUGS
PARASYMPATHOLYTIC DRUGS
CHOLINOLYTIC DRUGS

37. SAR OF
anticholinergics
Atropine as a prototype
Anticholinergics are structurally similar to Ach but
contains additional substituents to enhance binding
to the cholinergic receptors
Classification-
1. Solanaceous alkaloids & synthetic analouges
2. Synthetic aminoalcohol esters
3. Aminoalcohol ethers
4. Aminoalcohols
5. Aminoamides
6. Miscellaneous
7. Papaveraceous

38. C
A
B
C
CHAIN N
A,B= bulky gr e.g.
cycloalkyl, aromatic etc.
C = H, OH, carboxamide
•Chain- ether,ester, hydrocarbon moiety
•Quaternary or tertiary Nitrogen
•A & B – One aromatic gr for vander waal
interactions
One cycloalkyl or hydrocarbon gr for
hydrophobic interactions
•C- H, OH, carboxamide for H-bonding with
receptor

39. PROTOTYPE
ATROPINE
N
O C
O
CH
CH
2OH
ATROPINE- Ester of tropic acid with tropine (tropanol)
SCOPALAMINE- Ester of tropic acid with scopine

40. SAR
Cationic Head
Quarternary N-essential
Tertiary N-gets protonated at physiologic
pH
Larger(upto butyl) substituents on N-
parasympathomimetc action & thus
antagonist
Carbocholines-hydrophobic binding is
important
Hydroxyl gr
Suitably placed alc.OH gr enhances
muscarnic action
Hydrogen bonding
Position of OH gr relative to N critical-2 to
3 A
o
ATROPINE
N
O C
O
CH
CH
2OH

41. Esteratic gr
(Acyl gr)
Ester gr- imp for effective binding
Acyl gr-smaller-agonist
medium-partial agonist
larger-antagonist
Ethers, aminoalcohols show activity, thus
ester not necessary
Cyclic
substitution
oImportant for hydrophobic binding with
receptors
oAt least one cyclic gr is necessary
oAryl & diaryl substituted acetic acid-good
anticholinergic activity
oTriphenyl substituted-no action
oAromatic acid-less anticholinergic and
more local anesthetic activity
ATROPINE
N
O C
O
CH
CH
2OH

42. THERAPEUTIC USES
Muscarnic blockade results in
 Mydriatic effect, cycloplegia
 Antispasmodic effect
 Antisecretary effect
Uses-

As mydriatic During lens fitting, in inflammation of iris, ciliary organs
& choroid
As antispasmodicAtropine-Neurotropic (block nerve transmission)
Papavarine- Musculotropic (depress muscle cells directly)
Peptic ulcers Antacids preferred
Anticholinergic + CNS depressants
Parkinson’s
disease
To decrease activity of cholinergic neurons in basal
ganglia

43. S
olanaceous Alkaloids & synthetic
a
nalogues
•Causes inhibition of parasympathetic nervous system ans
stimulation of higher nervous centres
•Brings about multiple actions
•Nonspecific blockade of autonomic functions, thus
adverse effects
•
Scopalamine- CNS depression (sedation)
1.(-)Hyocyamine
2.Atropine [(±)Hyocyamine]
3.Scopalamine (Hyoscine)

44. Chemistry
Esters of bicyclic aminoalcohols (3-hydroxytropane) with tropic
acid


3α-tropanol
3α -Hydroxytropane

HO N
TROPINE
12
3
4 5
6
7
8
N
H
3C
OH
1
2
3
4
5
6
7
♦ Exists in chair form, can exist in boat form

♦
Shows optical activity due to rigidity

♦
Trans-3α axial OH (Tropine)

♦
Cis-3β equatorial OH (Pseudotropine)

45. PSEUDOTROPINE
3β-Tropanol
SCOPINE
6:7 β-Epoxy-3α-tropanol
N
H
3C
OH
1
2
3
4
5
6
7
N
H
3C
OH
1
2
3
4
5
6
7
O
Tropine like axial orientation of esterified –OH gr is important
For antimuscarnic action

46. OH
O
OH
*
TROPIC ACID
N
H
3C
O
1
2
3
4
5
6
7
C
O
C
H
CH
2OH
ATROPINE
N
H
3C
O
1
2
3
4
5
6
7
C
O
C
H
CH
2OHO
SCOPALAMINE
*Asymmetric carbon atom
Isomers differ in activity
(-)Hyocyamine more active
than (+)isomer

47. Structural modifications
Modifications in tropic acid-
o Tropic acid portion is highly specific for action
o Other acid- Decreased Neurotropic action
May have increased Musculotropic action
Quaternarization of Nitrogen in amino alcohol with a methyl halide-
o Change in the activity
o Decrease in activity if alkyl gr on N is larger than methyl due to
decrease in affinity for anionic site on receptor (due to electronic
repulsion of groups & steric interference)
o Result in blocking of parasympathetic ganglia
o Increased curariform activity (in high doses)
o Decreased absorption- thus erratic and unpredictable activity

48. Other drugs
N
CH
3
OC
O
CH
OH
. HBr
HOMATROPINE HBr
N
CH
3
OC
O
CH
OH
. Br
HOMATROPINE METHYLBROMIDE
CH
3

49. N
CH(CH
3)
3
OC
O
CH
CH
2OH
. Br
IPRATROPIUM BROMIDE
CH
3
3-(3-Hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-
(1-methyethyl)-8-aza-bicyclo[3.2.1]octane bromide

50. AMINOALCOHOL ESTERS
Esters synthesized in order to-
● reduce undesirable effects of solanaceous alkaloids
● achieve specific cholinolytic action i.e. to separate useful
activities like antispasmodic, antisecretory, mydriatic and

cycloplegic
 Modification in the prototype atropine
◊ Replacement of Tropic acid
◊ Introduction of Quaternary Nitrogen
◊ Simplification of aminoalcohol

51. SAR
Tropic acid Replaced with mandelic acid
Acid portion provided with large hydrophobic
area rather than steric requirements for
antispasmodic action
Quaternary ‘N’Increase antispasmodic activity
But shows curariform activity at high doses
Simplification of
aminoalcohols
Bicyclic tropine replaced by monocyclic
aminoalcohols
Cyclic aminoalcohols are required
Aminoalcohol esters
Antispasmodic
Mydriatic
Aminoalcohol ethers
And aminoalcohols
Antiparkinsonian
ATROPINE
N
O C
O
CH
CH
2OH
Spasmophoric group

52. C
OH
C
O
O
N
CH
3
Br
CLINIDIUM BROMIDE
3-Hydroxy-1-methylquinuclidinium bromide
benzilate
C
C
H
OH
O
O CH
2CH
2
N
CH
3
CH
3
HCl
CYCLOPENTOLATE
2-(Dimethylamino)ethyl 1-hydroxy
-a-phenylcyclopentane acetate HCl
C
O
O CH
2CH
2
N
C
2H
5
C
2H
5
HCl
DICYCLOMINE
2-(Diethylamino)ethyl bicyclohexyl-1-
carboxylate HCl
C
C
H
OH
O
O
N
CH
3
CH
3
CH
3
CH
3
HCl
EUCATROPINE HCl
1,2,2,6-tetramethyl-4-piperidyl mandelate HCl

53. C
C
O
OH
O
CH
3CH
3
Br
MEPENZOLATE
3-Hydroxy-1,1-dimethylpiperidinium bromide
benzilate
N
C
O
O CH
2CH
2 N CH
3
C
2H
5
C
2H
5
O
Br
METHANTHELINE
Diethyl(2-hydroxyethyl)methylammonium bromide
xanthene-9-carboxylate
C
C
O
OH
O
N
CH
3
CH
3
Br
GLYCOPYRROLATE
3-Hydroxy-1,1-dimethylpyrrolidinium bromide
a-cyclopentylmandelate
C
C
OH
O
O
CH
2
N
N
H
3C
HCl
OXYPHENCYCLIMINE
(1,4,5,6-Tetrahydro-1-methyl-2-pyrimidinyl)methyl
a-phenylcyclohexaneglycolate monoHCl

54. C
O
O CH
2CH
2 N CH
3
i-C
3H
7
i-C
3H
7
O
Br
PROPANTHELINE
(2-Hydroxyethyl)diisopropylmethylammonium bromide
xanthene-9-carboxylate

55. AMONOALCOHOL ETHERS
Used as an antiparkinsonian drugs
Closely related to antihistaminics
(Diphenhydramine)
Two carbon chain between Nitrogen and Oxygen
function is essential

56. C
O
H
ORPHENANDRINE CITRATE
N,N-Dimethyl-2-(o-methyl-a-
phenylbenzyloxy)ethylamine citrate
CH
2CH
2 N
CH
3
CH
3
CH
3
C
CH
2COOH
HO COOH
CH
2COOH
C
O
H
N
CH
3
CH
3SO
3H
BENZTROPINE MESYLATE
3a-(Diphenylmethoxy)-1aH,5aH-tropane
methanesuphonate
-Anticholinergic,antihistaminic,
local anaesthetic properties
-No CNS stimulation
-Sedative effect
-used in aged patients
-Low antihistaminic action
-high anticholinergic action
-No sedation
-More central inhibitory effect
than peripheral effect
-Reduce rigidity but not tremor
-used as adjunct to other drugs
-low side effects

57. AMINOALCOHOLS
# Structural characteristics-
1.bulky group in the vicinity of hydroxyl group
2.cyclic amino functional group
3.γ-aminopropanol arrangement with three carbons intervening
between hydroxyl & amino function
# Carboxyl gr of esters are replaced by hydroxyl gr as a
prosthetic group
# Tertiary amines in nature (can cross BBB)
# Used for paralysis agitans
# Quaternization increases antispasmodic & antisecretory
action and destroys antiparkinsonian action

58. C
CH
2CH
2
OH
CH
2
N
BIPERIDEN
a-5-Norbornen-2-yl-a-phenyl-1-piperidinepropanol
C
CH
2CH
2
OH
N
HCl
PROCYCLIDINE HCl
a-Cyclohexyl-a-phenyl-1-pyrrolidinepropanol HCl
C
CH
2CH
2
OH
N Cl
TRIDIHEXETHYL CHLORIDE
(3-Cyclohexyl-3-hydroxy-3-phenylpropyl)
triethylammoniumchloride
C
2H
5
C
2H
5
C
2H
5
C
CH
2CH
2
OH
TRIHEXYPHENIDYL HCl
a-Cyclohexyl-a-phenyl-1-piperidinepropanol HCl
N HCl

59. AMINOAMIDES
Polar amide group replaces polar hydroxyl group
C
CH
2CH
2 N CH
3
i-C
3H
7
i-C
3H
7
I
ISOPROPAMIDE IODIDE
C
O
NH
2
(3-Carbamoyl-3,3-diphenylpropyl) diisopropyl
methylammonium iodide
C
C
CH
2OHH
O
N
C
2H
5
CH
2 N
TROPICAMIDE
N-Ethyl-2-phenyl-N-(4-pyridylmethyl)hydracrylamide

60. MISCELLANEOUS
N
CH
3
CH
3
CH
3SO
4
DIPHEMANIL METHYLSULPHATE
4-(Diphenyl-methylene)-1,1-dimethylpiperidinium
methylsulfate
CH
2CH N
C
2H
5
C
2H
5
S N
HCl
ETHOPROPAZINE
10-[2-(Diethylamino)propyl]phenothiazine
monohydrochloride
CH
3
N
CH
3O
CH
3O
CH
2
OCH
3
OCH
3
PAPAVARINE HCl
6,7-Dimethoxy-1-veratrylisoquinoline HCl

61. SYNTHESIS OF CARBACHOL
HO
N
+
Cl
-
CHOLINE CHLORIDE
COCl
2
Phosgene
in chloroform
-HCl
O
N
+
Cl
-
C
O
Cl
CHOLINE CHLOROFORMATE
CHLORIDE
NH
4OH
N
+
OH
2N
O
Cl
-
CARBACHOL CHLORIDE

62. N
+
OH
2N
O
Cl
-
CARBACHOL CHLORIDE
Cl
HO
2-CHLOROETHANOL
+
Cl
O
Cl
PHOSGENE
NH
2
O
O
Cl
2-CHLOROETHYL CARBAMATE
NH
3
O
O
Cl
Cl
2-CHLOROETHYL CHLOROFORMATE
+
N
TRIMETHYL AMINE

63. GANGLIONIC BLOCKERS
Autonomic Ganglia-
Parasympathetic ganglia
Sympathetic ganglia
Stimulation by Ach –depolarization and
ganglionic transmission of nerve impulse
Stimulation of ganglia by Ach- produces triphasic
response in sympathetic ganglia

64. Ach
Ach
Ach
Dopamine

65. Result of ganglionic blockers on organs
Organ Predominant
system
Result of
blocking
Cardiovascular system
HeartParasympathetic Tachycardia
ArteriolesSympathetic Vasodilation
VeinsSympathetic Dilation
Eye
IrisParasympathetic Mydriasis
Ciliary structureParasympathetic Cycloplegia
GI tract Parasympathetic Relaxation
Urinary bladder Parasympathetic Urinary retention
Salivary glands Parasympathetic Dry mouth
Sweat glands Sympathetic Anhidrosis

66. Depolarizing
blockers
Nondepolarizing
blockers
Competitive Non competitive
Ganglionic blockers

67. SAR
Bistrimethylammonium polymethylene salts
(CH
2)
n
N(CH
3)
3
N(CH
3)
3
n= 5 or 6 Active ganglionic blocker
(Feeble curariform activity)
n= 9 to 12 Weak ganglionic blocker
(strong curariform activity)
Critical distance of about 5 to 6 carbon atoms between
onium centres- essential
Thus pentamethylene and haxamethylene compounds are
active

68. Uses
Little usefulness as Diagnostic and
therapeutic agents in peripheral vascular
diseases
Treatment of Hypertension
Drawback-
Parasympathetic blockade
Constipation
Orthostatic hypotension
Development of tolerance
Contraindications in many disorders

69. (+)-1,3-Dibenzyldecahydro-2-oxoimidazo[4,5-c]thieno[1,2-a]-thiolium-2-oxo-10-
bornanesulfonate
HC
N
CH
CH
N
CH
2
C
O
S
H
2C
H
2C CH
2
CH
2H
2C
Trimethaphan camsylate
•Exists in ionic form, short duration of action, produce
prompt ganglion blocking action.
•Used in neurosurgical procedures
and in hypertensive emergencies only.
•Produce direct vasodilation, Ineffective orally, given IV

70. NHCH
3
CH
3
CH
3
CH
3
Mecamylamine HCL
N,2,3,3-Tetramethyl-2-norbornanamine hydrochloride
 Dual antagonist
 Powerful in action (similar to hexamethonium)
 Adv:- absorbed rapidly & smoothly from GI tract
 Rarely used due to orthostatic hypotension

71. NEUROMUSCULAR BLOCKERS
Block transmission of Ach at motor end
plates
Possess curariform / curarimimetic action
Anatomic Feature- Bare nerve endings at
the neuromuscular junction
Uses:-1.as adjuvants in surgical anesthesia
2.In orthopedic procedures for
corrections of dislocations &
alignment of fractures

72. NM
BLOCKERS
Depolarizing
e.g. Decamethonium
Succinyl choline
Nondepolarizing
e.g. Tubocurarine
Dimethyl
tubocurarine
Pancuranium, Gallamine

73. Curare and Curare alkaloids
N
H
3CO
O
R
1
CH
3
OH
O
N
H
3C
R
2
OH
OCH
3
Cl
Cl
Ia R
1
= R
2
= CH
3
Ib R
1
= H, R
2
= CH
3
Ic R
1
=CH
3, R
2
= H
Tubocurarine

74. Botanical source- Chondodendron tomentosum
(Menispermaceae)
(+) Tubocurarine chloride and (+)
Dimethyltubocurarine Iodide
Diquarternary gives better blocking action than
monoquarternary
Ib is tubocurarine
Ic is isotubocurarine

75. Tubocurarine Chloride
oNondepolarizing
oAction reversed by administration of AchE
inhibitors like Neostigmine or Edrophonium
oIn large doses, respiratory embarrassment
(artificial respiration)
oIn high doses, may produce non competitive blockade
oIneffective orally(inadequate absorbtion), given IV
oBinds to receptor for 1 millisec.
oEffect lasts for 2 hrs, Half life – 89 min
Metocurine Iodide
O, O’ –dimethylchondrocurine diiodide
Curare extracted with methanolic KOH
4 times active than tubocurarine
Adv:- Less effect on respiration

76. Synthetic Compounds
Atracurium Besylate
2.5 times more potent than d-tubocurarine
Short duration of action
Metabolized rapidly & nonenzymatically to give
laudanosine and other small quaternary compound
with no activity
Undergoes Hoffman elimination reaction
Antidotes- Neostigmine, edrophonium &
pyridostigmine
Undergoes enzymatic decomposition of ester to yield
quaternary alcohols and acids

77. N
+
O
O
O
O
O
O
S
O
O
O
-
N
+
O
O
O
O
O
O
S
O
O
-
O
2-(2-carboxyethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-
veratrylisoquinoliniumbenzenesulfonate pentamethylene ester

78. Doxacurium Chloride
•Exists in 10 stereoisomeric forms
•All 3 trans compounds are active
•Long acting
•No vagolytic activity
•Used in surgical anaesthesia

79. 1,2,3,4-tetrahydro-2-(3-hydroxypropyl)-6,7,8-trimethoxy-2-methyl-1-(3,4,5-
trimethoxybenzyl) isoquinolinium succinate
N
OCH
3
H
3CO
H
3CO
(CH
2)
3OC(CH
2)
2CO(CH
2)
3
CH
2
CH
3
OCH
3
OCH
3H
3CO
O
N
OCH
3
OCH
3
OCH
3
H
2C
H
3C
OCH
3
H
3CO OCH
3
O
2Cl

80. Gallamine Triethiodide
OCH
2CH
2N (C
2H
5)
3 I
OCH
2CH
2N (C
2H
5)
3 I
OCH
2CH
2N (C
2H
5)
3 I
[v-Phenethyl-tris(oxyethylene)tris[triethyl
ammonium] triiodide
Strong vagolytic effect
Cumulative effect
Persistent depolarization at
high doses
Antimuscarnic action
Binds with greater affinity with
M
2 receptors than M
1 receptors
Hence vagolytic
Contraindicated in myasthenia
Gravis
Antidote- Neostigmine

81. Mivacurium Chloride
Mixture of three stereoisomers
Trans-trans, cis-trans, cis-cis (1/10 th active)
Short acting
AchE inhibitors as antidotes- prolong the
action rather than reversing

82. 1,2,3,4-tetrahydro-2-(3-hydroxypropyl)-6,7-dimethoxy-2-methyl-1-(3,4,5-
trimethoxybenzyl) isoquinolinium chloride,(E)-4-octadionate
N
HH
2C
OCH
3
H
3CO OCH
3
H
3CO
H
3CO
CH
3
CH
2CH
2CH
2OCCH
2CH
2C=CCH
2CH
2COCH
2CH
2CH
3
N
H CH
2
OCH
3
OCH
3H
3CO
OCH
3
OCH
3
H
3CO O
H
H
2Cl

83. Pancuronium Bromide
•Synthetic but based on natural alkaloid
malouetine
•5 times potent than d-tubocurarine
•No histamine releasing and ganglion blocking
activity
•Little effect on circulatory system
•Action blocked by AchE inhibitor & K ions
•
Action increased by inhalation anaesthetics
•May produce prolonged NM block
•
Used in patients for mechanical ventilation

84. N
N
CH
3
CH
3
OCCH
3
O
H
H
3CCO
O
2Br .H
2O
2,16-Dipiperidino-5-androstane-3,17-diol diacetate dimethobromide

85. Pipecurarium Bromide
Similar to Pancurarium
Long acting
CH
3
CH
3
N
N
N
N
OCCH
3
O
H
H
3CCO
O
2Br .2H
2O
4,4'-(30(-17-Dihydroxy-5-androstan-216-ylene)bis[1,1-
dimethylpiperazinium]dibromide diacetate
CH
3
H
3C
H
3C
CH
3
H
H

86. Vecuronium Bromide
Monoquaternary analogue of Pancuronium
Unstable in acids, undergo hydrolysis in aq. solutions
CH
3
CH
3
N
N
OCCH
3
O
H
H
3CCO
O
1-(317-Dihydroxy-2-piperidino-5-androstan-16-yl)-1-methyl
piperidinium bromide diacetate
H
H
H
H
H
CH
3
Br

87. Succinyl choline
oStable in acids, unstable in alkali
oShort duration of action
oRapid recovery due to rapid hydrolysis
oLarge dose- temp respiratory depression
oAction not antagonized by AchE inhibitors (prolonged)
oUse as muscle relaxant
oIV drip
oNot to be used with Thiopental sodium
HO
O
N
+
O
O