1. DR BADAR UDDIN UMAR
MBBS, MPhil
Senior Lecturer, Pharmacology
1

2.  Classify parasympathetic blockers with suitable
examples
 Classify antimuscarinic drugs based on their uses with
suitable examples
 List and describe the pharmacological actions of
atropine
 Discuss the rationale for using drugs blocking the
muscarinic actions of ACh
 Discuss the clinical features and drug treatment of
atropine poisoning
2

3.  Cholinergic receptors can be divided into two
types –
• muscarinic and
• nicotinic
 Muscarinic receptors originally were
distinguished from nicotinic receptors by the
selectivity of the agonists muscarine and nicotine
respectively

4.  In tissues innervated by postganglionic
parasympathetic neurons
 In presynaptic noradrenergic and
cholinergic nerve terminals
 In non-innervated sites in vascular
endothelium
 In the central nervous system

5.  There are 5 subtypes of muscarinic
receptors M1, M2, M3, M4, and M5
 They mediate their effects through -
 G proteins coupled to -
 Phospholipase C (M1,3,5),
Potassium channels (M2,4)

6. Muscarinic Acetylcholine ReceptorsMuscarinic Acetylcholine Receptors
MM11 MM22 MM33 MM44 MM55
DistributionDistribution Cortex,Cortex,
hippocampushippocampus
HeartHeart ExocrineExocrine
glands, GIglands, GI
tracttract
NeostriatumNeostriatum SubstantiaSubstantia
nigranigra
AntagonistsAntagonists AtropineAtropine
DicycloverineDicycloverine
TolterodineTolterodine
OxybutyninOxybutynin
IpratropiumIpratropium
PirenzepinePirenzepine
Mamba toxinMamba toxin
MT7MT7
AtropineAtropine
DicycloverineDicycloverine
TolterodineTolterodine
OxybutyninOxybutynin
IpratropiumIpratropium
GallamineGallamine
AtropineAtropine
DicycloverineDicycloverine
TolterodineTolterodine
OxybutyninOxybutynin
IpratropiumIpratropium
DarifenacinDarifenacin
AtropineAtropine
DicycloverineDicycloverine
TolterodineTolterodine
OxybutyninOxybutynin
IpratropiumIpratropium
Mamba toxinMamba toxin
MT3MT3
AtropineAtropine
DicycloverineDicycloverine
TolterodineTolterodine
OxybutyninOxybutynin
AgonistsAgonists AcetylcholineAcetylcholine
Xanomeline,Xanomeline,
CDD-0097CDD-0097
AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine
G proteinG protein GGααq/11q/11 GGααi/oi/o GGααq/11q/11 GGααi/oi/o GGααq/11q/11
IntracellularIntracellular
responseresponse
PhospholipasePhospholipase
CCββ
AdenylylAdenylyl
cyclasecyclase
inhibitioninhibition
PhospholipasePhospholipase
CCββ
AdenylylAdenylyl
cyclasecyclase
inhibitioninhibition
PhospholipasePhospholipase
CCββ

7.  In sympathetic and parasympathetic
ganglia
 In the adrenal medulla
 In the neuromuscular junction of the
skeletal muscle
 In the central nervous system

8.  There are two subtypes of nicotinic receptors
NM and NN
 The NM nicotinic receptor mediates skeletal
muscle stimulation
 The NN nicotinic receptor mediates
stimulation of the autonomic ganglia
[agonists and antagonists at this site are
sometimes called ganglionic agonists and
ganglionic blockers]

9.  Nicotinic receptors are ligand - gated ion channels
 Their activation results in a rapid increase in
cellular permeability to sodium and calcium
 nAChRs are directly coupled to cation channels
 They mediate fast excitatory synaptic transmission
at the neuromuscular junction, autonomic ganglia,
and various sites in the central nervous system
(CNS)

10.  Muscle and neuronal nAChRs differ in their
molecular structure and pharmacology
 They are pentameric arrays of one to four distinct
but homologous subunits, surrounding an internal
channel
 The α subunit has binding sites for ACh.
 Agonist binding induce a conformational change
that opens the channel
 Antagonist may bind to these sites but do not elicit
the conformational change

13. 13

14. Parasympatholytics
Natural Belladonna
Alkaloids
Semisynthetic and Synthetic
Products of Belladonna alkaloids
Atropine
Hyoscine
l-hyoscyamine
Tertiary amines Quaternary amines
•Dicyclomine hydrochloride
•Oxyphencyclimine hydrochloride
•Homatropine hydrobromide
•Cyclopentolate hydrochloride
•Tropicamide
•Atropine methobromide
•Atropine methonitrate
•Hyoscine butyl bromide
•Methantheline bromide
•Porpantheline bromide
•Mepenzolate bromide
•Ipratropium bromide
•Oxyphenonium bromide
14

15. Therapeutic uses Name of drugs Clinical Applications
Motion sickness drugs Scopolamine • Prevention of motion sickness
Postoperative nausea and
vomiting
Gastrointestinal disorders Dicyclomine
Glycopyrrolate
Methantheline
Propantheline
Clidinium
Oxyphenonium
• Irritable bowel syndrome
• Minor diarrhea
Mydriatic and cycloplegic Atropine
Scopolamine
Homatropine
Cyclopentolate
Tropicamide
• Retinal examination
• Prevention of synechiae after
surgery
Respiratory (asthma,
COPD)
Ipratropium
Tiotropium
• Prevention and relief of acute
episodes of bronchospasm
15

16. Therapeutic uses Name of drugs Clinical Applications
Urinary Oxybutynin
Darifenacin
Solifenacin and
Tolterodine (Tertiary amines
with somewhat greater
selectivity for M3 receptors )
Trospium (Quaternary amine
with less CNS effect)
• Urge incontinence
• Postoperative spasms
Cholinergic
poisoning
Atropine • Mandatory antidote for severe
cholinesterase inhibitor
poisoning
Pralidoxime • Usual antidote for early-stage
(48 h) cholinesterase inhibitor
poisoning
16

17.  Muscarinic antagonists (parasympatholytic
drugs) are competitive antagonists of ACh at
muscarinic receptors
 Their chemical structures usually contain ester
and basic groups in the same relationship as
ACh, but
 They have a bulky aromatic group in place of the
acetyl group
Muscarinic antagonists are sometimes called parasympatholytic
because they block the effects of parasympathetic autonomic discharge
17

18. 18

19. Atropine:
 Atropine is the prototype drug of this group
 It is an alkaloid, found in the deadly nightshade
(Atropa belladonna)
 Tertiary amine
 Ester of tropic acid
19

20.  The deadly nightshade (Atropa belladonna)
contains mainly atropine
 The thorn apple (Datura stramonium) contains
mainly scopolamine
 The Hyoscyamus niger contains Scopolamine
(Hyoscine)
 These are tertiary ammonium compounds that
are sufficiently lipid-soluble to be readily
absorbed from the gut or conjunctival sac
20

21.  They also penetrate the blood-brain barrier
 The quaternary derivative of atropine,
atropine methonitrate, has peripheral actions
like atropine but, lacks central actions [can not
cross BBB]
 Ipratropium [a quaternary ammonium
compound] is used by inhalation as a
bronchodilator
21

22.  Cyclopentolate and tropicamide are tertiary amines
developed for ophthalmic use and administered as eye
drops
 Pirenzepine is a relatively selective M1 receptor
antagonist
 Oxybutynin, tolterodine and darifenacin (M3-
selective) are new drugs that act on the bladder to
inhibit micturition, and are used for treating urinary
incontinence
 They produce unwanted effects typical of muscarinic
antagonists, such as dry mouth, constipation and blurred vision
22

23. ATROPINE
23

24. 24

25.  Used as a homicidal poison
 Atropa:
 Atropos: Goddess in Greek Mythology
 Atropos, Clothos & Lachesis….. 3 sisters
 Atropos cuts with shears the web of the life span
and woven by her sisters Clothos & Lachesis
25

26.  Bella donna:
 Italian meaning: Beautiful Lady
 Once fashionable female practice of using the
extract of the plant to dilate the pupils…. Process
of making herself attractive
26

27. 27

28. Atropine is an antagonist drug-
 It blocks all the muscarinic receptors of Ach in
the body & antagonizes the effects of Ach
 Antagonism is reversible
 So, the effects are opposite to Muscarinic effects
of Ach
28

29. 29

30. Inhibition of secretions:
 Very low doses of atropine inhibits salivary, lacrimal,
bronchial and sweat gland secretions producing dry
mouth and skin
 Gastric secretion is only slightly reduced
 Mucociliary clearance in the bronchi is inhibited, so
that residual secretions tend to accumulate in the
lungs
 Ipratropium lacks this effect
30

31. DOSE (mg) EFFECTS
0.5 Slight cardiac slowing; some dryness of mouth; inhibition of sweating
1 Definite dryness of mouth; thirst; acceleration of heart, sometimes
preceded by slowing; mild dilation of pupils
2 Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils;
some blurring of near vision
5 Above symptoms marked; difficulty in speaking and swallowing;
restlessness and fatigue; headache; dry, hot skin; difficulty in
micturition; reduced intestinal peristalsis
10 Above symptoms more marked; pulse rapid and weak; iris practically
obliterated; vision very blurred; skin flushed, hot, dry, and scarlet;
ataxia, restlessness, and excitement; hallucinations and delirium; coma
31

32. Effects on heart:
 Biphasic action
 Atropine causes transient initial
bradycardia due to stimulation of dorsal
nucleus of vagus ( with very low doses;
due to a central action)
 Larger doses cause progressively
increasing tachycardia by blocking
cardiac mAChRs (up to 80-90
beats/min) in humans
32

33.  This is because there is no effect on the
sympathetic system, but only inhibition of the
existing parasympathetic tone
 This is most pronounced in young people (often
absent in the elderly)
 The response of the heart to exercise is unaffected
33

34.  Arterial blood pressure is unaffected, because
most resistance vessels have no cholinergic
innervation
 Large doses cause vasodilatation of the skin
blood vessels specially in the blush area
-‘atropine blush’
34

35. Effects on the eye:
 It dilates the pupil (mydriasis)
 Light reflex is lost
 Relaxation of the ciliary muscle causes paralysis of
accommodation (cycloplegia), so that near vision is
impaired
 Intraocular pressure may rise (unimportant in
normal individuals but can be dangerous in patients
suffering from narrow-angle glaucoma)
35

36. Pupil
Normal Dilated

37. Effects on the gastrointestinal tract:
 Gastrointestinal motility is inhibited by atropine
 Atropine is used in pathological conditions in
which there is increased gastrointestinal motility
(M3 selective agents may be preferable)
 Pirenzepine, owing to its selectivity for M1
receptors, inhibits gastric acid secretion
37

38.  Bronchial, biliary and urinary tract smooth muscle
are all relaxed by atropine
 Reflex bronchoconstriction (during anaesthesia) is
prevented, whereas bronchoconstriction caused by
histamine and leukotrienes is unaffected
 Biliary and urinary tract smooth muscle are only
slightly affected
 Precipitate urinary retention in elderly men with
prostatic enlargement
38

39.  Atropine stimulates CNS followed by depression
 Medulla and higher cerebral centers are stimulated
 With therapeutic doses there is mild vagal excitation
 Large doses produce marked central stimulation
leading to:
• Restlessness
• Irritability
• Disorientation
• Hallucinations
• Delirium
39

40.  Later; depression occurs leading to coma and death
due to medullary paralysis
 Atropine has anti tremor activity in Parkinson’s
disease
 It prevents motion sickness either by acting centrally
or peripherally
 It counteracts central excitatory actions of
physostigmine and OPCs and
 Reduces electrical activity of brain
40

41.  Adjunct for anaesthesia (reduced secretions,
bronchodilatation)
 Anticholinesterase (OPC) poisoning
 Bradycardia
 As antispasmodic in Gastrointestinal hypermotility
 In ophthalmology used topically
• as a mydriatic (to examine the retina, optic disk)
• Treatment of acute iritis, iridocyclitis, keratitis etc.
• Used alternately with a miotic to break or prevent adhesions
between iris and lens
41

42.  Nocturnal enuresis
 Hyperactive bladder
 Motion sickness
 Parkinson’s disease
 Hyperhidrosis
 Mushroom poisoning
 Antidiarrheal
 Pulmonary obstructive disease
42

43.  Ipratropium and Tiotropium are used in the treatment of
chronic obstructive pulmonary disease
 They are less effective in most asthmatic patients
 These are often used with inhaled long-acting β2
agonists
• Ipratropium is administered four times daily via a metered-
dose inhaler or nebulizer
• Tiotropium is administered once daily via a dry powder
inhaler
 Ipratropium is used in nasal inhalers in rhinorrhea
associated with the common cold or with allergic or
non-allergic perennial rhinitis
43

44.  Once widely used for the management of peptic
ulcer
 Can reduce gastric motility and the secretion of
gastric acid
 But antisecretory doses produce pronounced side
effects like-
• such as xerostomia, loss of visual accommodation, photophobia,
and difficulty in urination
 Patient compliance in the long-term is poor
 Pirenzepine, Telenzepine
44

45.  Diarrhea associated with irritation of the
lower bowel [mild dysenteries and
diverticulitis]
 Dicyclomine hydrochloride [weak
muscarinic receptor antagonist] also has
nonspecific direct spasmolytic effects on
smooth muscle of the GI tract
 It is occasionally used in the treatment of
diarrhea-predominant irritable bowel
syndrome
45

46.  Effects on the eye are obtained by topical
administration
 They cause mydriasis and cycloplegia
 Mydriasis is necessary for thorough
examination of the retina and optic disc and
in the therapy of iridocyclitis and keratitis
 The mydriatics may be alternated with
miotics for breaking or preventing the
development of adhesions between the iris
and the lens
46

47.  Complete cycloplegia may be necessary in
the treatment of iridocyclitis and choroiditis
and for accurate measurement of refractive
errors
 Homatropine hydrobromide a semisynthetic
derivative of atropine, Cyclopentolate
hydrochloride and Tropicamide are used in
ophthalmological practice
47

48.  Overactive urinary bladder
 Lower intravesicular pressure
 Increase capacity, and
 Reduce the frequency of contractions by
antagonizing parasympathetic control of the
bladder
 They also may alter bladder sensation during
filling
48

49.  Enuresis in children, particularly when a
progressive increase in bladder capacity is
the objective
 To reduce urinary frequency and increase
bladder capacity in spastic paraplegia
49

50.  Oxybutynin (DITROPAN)
 Tolterodine (DETROL)
 Trospium chloride (SANCTURA)
 Darifenacin (ENABLEX)
 Solifenacin (VESICARE) and
 Fesoterodine (TOVIAZ);
50

51.  Limited clinical utility
 Used only in coronary care units for short-term
interventions or in surgical settings
 Initial treatment of patients with acute
myocardial infarction in whom excessive vagal
tone causes sinus bradycardia or AV nodal
block
51

52.  Sinus bradycardia is the most common
arrhythmia seen during acute myocardial
infarction
 Atropine may prevent further clinical
deterioration in cases of high vagal tone or AV
block by restoring heart rate to a level
sufficient to maintain adequate hemodynamic
status and to eliminate AV nodal block
52

53.  Dry mouth
 Blurred vision
 Tachycardia
 Constipation
 Urinary hesitancy and retention
 Atropine poisoning
53

54.  Occur through accidental
or deliberate ingestion of
berries or seeds of
belladonna or from over
treatment with high doses
 Characterized by:
• Dryness of mouth,
dysarthria, dysphagia
• Blurred vision and
photophobia
• Hot, dry and flushed skin
• Hyperpyrexia
• Tachycardia (weak and
rapid pulse)
• Palpitation
• Urinary difficulty
• Restlessness, excitement,
hallucinations, delirium
followed by
• Depression and death
from respiratory failure
• Convulsions may occur
54

55.  Gastric lavage
 Physostigmine as antidote – slow i.v. injection 1- 4
mg (0.5 mg in children)
 Diazepam for sedation and control convulsions
 Artificial respiration
 Ice bags and alcohol sponge to reduce fever
55

56.  Glaucoma
 Elderly males with enlarged prostate
 Paralytic ileus
 Ulcerative colitis
 Gastroesophageal reflux
 Tachycardia
 Cardiac insufficiency
56

57. 57

58. Property Subgroup
M1 M2 M3
Primary
locations
Nerves Heart, nerves,
sm. muscle
Glands, sm.
muscle,
endothelium
Antagonists Atropine
Pirenzapine
Telenzepine
Dicyclomine
Trihexyphenidyl
Atropine
Gallamine
Methoctramine
Atropine
4-DAMP
Darifenacin
Solifenacin
Oxybutynin
Tolterodine
Atropine does not distinguish among the 3 subtypes of Muscarinic
receptors
Other antagonists are moderately selective for one or another subtypes of
receptors 58

59.  Classify main classes of parasympathetic blockers
 Classify antimuscarinic drugs based on their clinical
uses with suitable examples
 Describe the pharmacological actions of atropine
based on the distribution of muscarinic receptors
 Discuss the contextual rationale for using drugs
blocking ACh
 Discuss the clinical features and drug treatment of
belladonna (atropine) poisoning
59

60. 60