Anticholinergics

1. CHEMISTRY
OF
ANTICHOLINERGICS
Mrs.Akanksha Gupta
Assistant Professor
Department of Pharmaceutical Chemistry
UnitedInstituteofPharmacy

2. ANTICHOLINERGIC DRUGS
• Drugs that directly inhibit pharmacological
response of Ach are known as Anticholinergic
agents.
Acetylcholine (Ach)

3. CLASSIFICATION
• Natural Alkaloids – Atropine , Hyoscine.
• Semisynthetic derivatives - Homatropine, Atropine
methonitrate , Hyoscine butyl bromide , ipratropium bromide
• Synthetic Compounds –
• Mydriatics – Cyclopentolate , Tropicamide.
• Antisecretory-antispasmodics :
A) Quarternary compounds:
Propantheline, Oxyphenonium, clidinium, Pipenzolate methyl
bromide, Isopropamide, Glycopyrrolate.
B)Tertiary amines : Dicyclomine , Oxybutynin, Flevoxate,
Pirenzepine, Telenzipine.

4. CLASSIFICATION
• Antiparkinsonian : Trihexyphenidyl,
Procyclidine, Biperiden , Benztropine.
• Other drugs with anticholinergic properties
• Tricyclic Antidepressants
• Phenothiazines
• Antihistaminics
• Disopyramide

5. Muscarine antagonist/antispamodics
•These drugs block the response of Ach in the muscarine receptor by
competitively binding to it and inhibiting any response.
• They have opposite pharmacological response of Ach i.e if Ach
agonist slows heart rate then Ach antagonist speeds heart rate or if Ach
relaxes bladder then it antagonist constricts it
• Their medical use is in
– in Smooth muscle spasm
– in cold n flu (to reduce nasal secretion)
– previously in ulcer (but now replaced by H2 antagonist and
proton inhibitors)
– Overactive bladder (too much urination)
– Motion sickness
– Treat organophosphate poisoning (still doesn’t work in aging and
doesn’t treat respiratory failure)
– Parkinson (brain disease where nerves start degrading and
person slowly goes crazy)

6. SAR Of Anticholinergics
• Atropine was the first drug of this type and was
used to generate SAR. It was noted that unlike
Ach, the terminal ester carbon in Atropine
had a bulky substituent. This was considered
important and modifications were done there

7. General framework of Anticholinergics
1) The R1 or R2 groups must be carbocyclic or
heterocyclic, but if both are cyclic it gives maximal
antagonist potency. The rings may be same or different.
One of it generally aromatic and other is saturated ring or
olefinic group (ie it has a C-C double bond)
• Rings may be same or different
•The benzene could be any type
Cyclohexane (non-aromatic
carbocyclic or pyridine (aromatic
heterocyclic)
or Pyrrolidine (non-aromatic
heterocyclic
Nsubstituent
R1
R3
R2 C X (CH2)
n

8. 2)The R3 group:
hydrogen, hydroxyl (-OH) , hydroxymethyl (-CH2OH),
amide or a component of the R1 and R2 group. Best
potency is seen with hydroxyl or hydroxymethyl (this
hints that the oxygen group must be participating in H
bond)
Hydrogen Hydroxyl Hydroxymethyl
Amide
Component of R2 and R3

9. 3) The X is mostly ester in most potent derivatives
but it can be a ether oxygen or absent completely
Mostly ester Or else ether Or absent completely

10. 4) The N substituent can be both quaternary ammonium
salt or tertiary amine with different alkyl groups. Most
potent derivatives have quaternary ammonium salt. The
alkyl group is not restricted to only methyl (as in SAR of
Ach agonist). It can be ethyl, propyl or isopropyl.
Quaternary
form is most
potent
Alkyl = methyl
Alkyl = ethyl Alkyl = isopropyl

11. 5) The distance between the ring substituted carbon and
nitrogen is not fixed i.e it can vary
The no. of alkyl units between that carbon and
nitrogen can vary from 2-4, with most potency in case of
two CH2 units.
2 CH2 units is
best distance
2 CH2 units (don’t
count O or N, just C)
3 CH2 (don’t count double or
triple bonded carbon. Only
count single carbons)

12. summary
R3
• The R1 or R2 groups must be carbocyclic or
heterocyclic
• The R3 group can be hydrogen, hydroxyl (-OH),
hydroxymethyl (-CH2OH), amide or a component of
the R2 and R3 group
• The X is mostly ester in most potent derivatives but it
can be a ether oxygen or absent completely
• The N substituent cab be both quaternary ammonium
salt or tertiary amine with different alkyl groups
• The distance between the ring substituted carbon and
nitrogen is not fixed but maximum potency requires
about 2 carbon units
R1
R2 C X (CH2) N substituent

13. Contrast between SAR of Ach agonist and
antagonist
A) Nitrogen group
• In agonist the N can only be quanternary but
• In antagonist N can be both quanternary or
tertiary
Methacholine

14. B) Ethylene group
• In agonist the no of ethylene is fixed at only 2
but
• In antagonist no of ethylene can range from 2- 4
Bethanecol
carbamat
e

15. C) Selectivity
• In agonist the methyl substitution in ethylene group
controls selectivity of muscarinic or nicotinic but
• In antagonist no such feature is present. Still It only
antagonizes muscarinic only
Methacholone
Muscarinic selective

16. D) Ester group or X group
• In agonist ester is not needed and can be
removed but an Oxygen must exist in it’s
place
• In antagonist ester is not needed and can be
removed but an Oxygen need not exist in it’s
place

17. H3C O CH2 CH2 N(CH3)3
H3C CH2 CH2 N(CH3)3
Ether
O
H2N O
O
CH2 CH2 N(CH3)3
Mostly ester
Oxygen in place
of ether
Oxygen absent
Ester
Ketone

18. E) Rule of five and terminal carbon
In agonist rule of five is followed and terminal carbon is
bonded to Hydrogens
In antagonist, rule of five is not followed and the terminal
carbon is bonded to two bulky ring groups
Methachilone

19. Atropine NCH3
O
O C CH
CH2OH
• It is anticholinergic that blocks muscarinic receptors
• It is an alkaloid extracted from Solanaceae plant and was the first
anticholinergic.
• It is an ester of tropine and tropic acid and used as a sulphate Salt in
racemic form.
• At therapeutic does it can penetrate the brain and stimulate the CNS
• Uses
– Treat Bardycardia
– Reduce secretion before surgery
– Treat Iritis (painful inflammation of eye)
– Organophosphate poisoning (only to decrease muscarinic action, not an
antidote like PAM)
• MOA – It competitively binds to muscarinic receptor and
antagonizes it thus blocking all cholinergic effects

20. • It is anticholinergic that blocks muscarinic
receptors
Scopolamine O
 It is an alkaloid extracted from Solanaceae plant
• It is used as salt hydrobromide salt in enantiopure (-) form
• At therapeutic does it depresses CNS
• Uses
– Treat Iritis (painful inflammation of eye)
– Treat Parkinson
– Treat Motion sickness
• MOA - It competitively binds to muscarinic receptor and antagonizes
it thus blocking all cholinergic effects
NCH3
O C
O
CH
CH2OH

21. Dicyclomine
• It is an anticholinergic that blocks muscarinic
receptors
• It is a weaker antagonist than atropine and doesn’t
stimulate the brain
• Uses
– treat intestinal hypermotility (causes constipation and diarrhea
and decreased opportunity for the absorption of nutrients)
– irritable bowel syndrome (a disorder in large intestine that causes
cramping, abdominal pain, bloating, gas)
• MOA - It competitively binds to muscarinic receptor
and antagonizes it thus blocking all cholinergic
effects

22. Synthesis
CH2CN
Phenyl acetonitrile
Br
H2C CH2 CH2 CH2 CH2 Br
-2HBr
CN
Cyclohexane derivative
1,5-Dibromopentane

23. Oxidation
COOH
HO CH2 CH2 N
C2H5
C2H5
HCl
i)
ii) Reduction
C O CH2 CH2 N
C2H5
C2H5
O
.HCl
Dicyclomine Hcl

26. Nicotinic antagonist
• Nicotinic Antagonist competitively bind to nicotinic
receptors and block nicotinic response which results in
blockade of skeletal muscle contraction i.e paralysis
• There are two types
– Neuromuscular Blockers
– Ganglionic Blockers
(We will only discuss the first)

27. Neuromuscular Blockers
• The first Neuromuscular Blockers was extracted from
the plant cucare which contained Tubocuraine.
Therapeutic application
• As an Adjunct to general Anesthetic ,(general Anesthetic are
drugs that makes you unconscious for surgery) they lower the
dose of Anesthetic thus lowering side effects and promoting
post anesthetic recovery time and Correct bone dislocation
• 2 types
– Non-depolarizing (desired property)
– Depolarizing (undesired property)
CLASSIFICATION
Bisquaternaryamines
Succinylcholine,Pancuronium,Atracurium
Mono quaternaryamines
D‐Tubocurarine,Vecuronium,Rocuronium

28. Structure ActivityRelationships
Containatleastone+vechargedquaternaryamine(4C atomsattachedto
nitrogen)likeAch
Bridgingstructureinbetweentwoaminesislipophilicand determinespotency
10‐12 carbonbridgebetweentwonitrogensisoptimalfor maximalneuromuscular
blockade.

29. SAR
N
H3C
• Two quaternary ammonium salts separated by 10-12
carbon units is the only known general requirement. This
follows from the observation that nicotinic receptor has
two cationic site
• H3C CH3
H3C CH3
CH2 N CH3
10
Decamethonium bromide

31. Atropine sulphate- Atropine is a medication used to treat certain
types of nerve agent and pesticide poisonings as well as some types of
slow heart rate and to decrease saliva production during surgery.
Scopolamine hydrobromide- it is used to treat motion sickness and
postoperative nausea and vomiting.
Homatropine hydrobromide- It is used in eye drops as a cycloplegic
(to temporarily paralyze accommodation), and as a mydriatic (to dilate
the pupil).
Ipratropium bromide- It is used to treat the symptoms of chronic
obstructive pulmonary disease and asthma.
Tropicamide- it is a medication used to dilate the pupil and help with
examination of the eye.
Cyclopentolate hydrochloride- It is commonly used as an eye drop
during pediatric eye examinations to dilate the eye (mydriatic) and
prevent the eye from focusing/accommodating

32. Orphenadrine citrate- It is used to treat muscle pain and to help with motor
control in Parkinson's disease
Procyclidine hydrochloride- It is used in patients with parkinsonism and
akathisia, and to reduce the side effects of antipsychotic treatment given for
schizophrenia.
Tridihexethyl chloride- it is used to treat acquired nystagmus or peptic ulcer
disease.
Isopropamide iodide- It is used in the treatment of peptic ulcers and other
gastrointestinal disorders involving hyperacidity (gastrointestinal acidosis) and
hypermotility.
Ethopropazine hydrochloride- it is a phenothiazine derivative used as an
antiparkinsonian agent that has anticholinergic, antihistamine, and
antiadrenergic actions
Dicyclomine hydrochloride- it is a medication that is used to treat spasms of the
intestines such as occur in irritable bowel syndrome.

33. Clidinium bromide- It may help symptoms of cramping and
abdominal/stomach pain by decreasing stomach acid, and slowing the
intestines.
Glycopyrrolate- In anesthesia, glycopyrronium injection can be used as a
before surgery in order to reduce salivary, tracheobronchial, and pharyngeal
secretions, as well as decreasing the acidity of gastric secretion.
Propantheline bromide- it used for the treatment of excessive sweating
(hyperhidrosis), cramps or spasms of the stomach, intestines (gut) or bladder,
and involuntary urination (enuresis).
Benztropine mesylate- it is a medication used to treat a type of movement
disorder due to antipsychotics known as dystonia and parkinsonism.