Pharmacology PPT

1. Muscarinic Receptor
Antagonists
Dr. CHINTAN DOSHI

2. Synonyms
 Parasympatholytics
 Anticholinergics
 Antimuscarinic drugs
 Muscarinic receptor antagonists
More precise terms
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22-Mar-14

3. Classification
 Natural Alkaloids :
• Atropine
• Scopolamine (Hyoscine)
 Semisynthetic Derivatives :
• Homatropine
• Atropine methonitrate
• Hyoscine methylbromide
• Benztropine
• Ipratropium bromide
• Tiotropium bromide
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4.  Synthetic compounds :
a) Mydriatics :
Cyclopentolate, Tropicamide
b) Antisecretory – Antispasmodics :
i. Quaternary compounds :
• Propantheline, Oxyphenonium, Clidinium,
• Glycopyrrolate, Isopropamide, Pipenzolate
ii. Tertiary amines :
• Dicyclomine, Valethamate, Pirenzepine
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22-Mar-14

5. c) Vasicoselective :
• Oxybutynin, Flavoxate, Tolterodine
• Solifenacin, Darifenacin, Fesoterodine,
• Trospium chloride
d) Antiparkinsonian :
• Trihexyphenidyl (Benzhexol), Procyclidine, Biperidine
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22-Mar-14

6. Other groups of drugs having
Antimuscarinic property
 Antihistamines :
• Diphenhydramine, Promethazine, Orphenadrine
 Antipsychotics :
 Phenothiazines :- Chlorpromazine, Thioridazine
 Butyrophenones :- Haloperidol
 Tricyclic Antidepressants :
• Amitryptiline, Imipramine
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22-Mar-14

7. Chemistry
 Naturally occurring alkaloids obtained from Solanaceae plants
family
 Atropine :
 l - hyoscyamine dl - hyoscyamine
 Source : Atropa belladona or Datura stromonium
 Scopolamine :
 l – hyoscine
 Source : Hyoscyamus niger
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8. Pharmacodynamics
 Mechanism of Action :
• Compete for the common binding site on muscarinic
receptors (M1 to M5)
• Competitive antagonism
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9. M 1
Ganglia :depolarization
Gastric Glands :secretion
CNS -
learning memory, motor
function
M 2
HEART - inhibitory
action
↓HR
↓ AV conduction
↓ atrial contractility
M 3
Visceral smooth
Muscle - Contraction
Iris : pupil constriction
Cilliary muscle: contraction
Glands – secretion
Vascular endothelium:
Vasodilatation due to NO
GPCR

10. Pharmacological Effects
&
Therapeutic Uses
22-Mar-14
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11. Central Nervous System
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12.  Atropine :
• Low dose : - No detectable effects
• Therapeutic dose : - Mild stimulation of Medullary
centres
• Higher dose : - Stimulation of higher cerebral centres
• Toxic dose : - More prominent central excitation
- Restlessness, Irritability, Disorientation,
Hallucinations, Delirium
22-Mar-14
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13.  Scopolamine :
• Low dose : - CNS Depression
• Therapeutic dose : - Drowsiness, Amnesia, Fatigue,
Dreamless sleep, (↓ REM),
Suppression of Vomiting centre
22-Mar-14
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14. Therapeutic uses :
 Motion Sickness :
• Disturbed body equilibrium Vestibular
pathway Nauseating signals to vomiting centre
• Scopolamine (0.6 - 1.0 mg s.c.)
• Transdermal patches behind ear steady state release of
scopolamine
• As prophylaxis
• Available preparation : BUSCOPAN 10 mg tablet
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15.  Parkinson’s Disease :
• ↑ Cholinergic activity in basal ganglia
• Muscarinic antagonist + Dopaminergic drug
More effective result than one drug alone
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16.  Diagnosis of Alzheimer’s disease :
• Low dose of short acting muscarinic antagonist Tropicamide
into eye of patient with suspected Alzheimer’s disease
• Marked dilatation of pupil
• Due to changes in receptors sensitivity associated with
disease
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17. Eye
22-Mar-14
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18. Effects
(1) Mydriasis :
Blockade of M3 receptors on circular muscle of iris
Constriction of muscle & increased pupil size
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19. (2) Cycloplegia / Paralysis of Accommodation :
Blockade of M3 receptors on ciliary muscles of lens
Tightened suspensory ligaments of lens
Lens flattened & fixed for distant vision
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20. (3) Raised I.O.P. :
• In elderly, or shallow anterior chamber, or narrow angle
glaucoma
• Iris falls back over canal of Schlemm
• Obstruction of drainage of aqueous humour
(4) Decreased Lacrimation :
• Blockade of M3 receptors
• Dry / Sandy eyes 22-Mar-14
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21. Therapeutic Uses
(A) As Mydriatic :
• For complete Ophthalmoscopic examination
• Ciliary paralysis & Mydriasis is needed for measurement of
refractive error, &
• Mydriasis is needed for examination of retina
• Used when both of the above functions are needed
• Otherwise, only α -adrenoceptor agonist (Phenylephrine)
22-Mar-14
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22. (B) To prevent adhesions in inflammatory conditions of eye:
• Alternated with miotic drug e.g. Pilocarpine
• Prevents adhesions between anterior surface of lens & iris in
Iridocyclitis, iritis, uveitis, etc.
• Longer acting (e.g. Homatropine) is preferred
22-Mar-14
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23.  (c)Therapeutic
 long lasting mydriatic-cycloplegic and local anodyne (pain
relieving) action on cornea
 Treatment of
 Iritis
 Iridocyclitis
 Choroiditis
 Keratitis
 Corneal ulcer
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24. Cardiovascular system
22-Mar-14
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25. Effects
 Heart :
 Tachycardia.
 Due to blockade of M2 receptors on the SA node
 Abbreviates refractory period of A-V node and facilitates A-V
conduction
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26.  Blood vessels :
• They have muscarinic receptors but no parasympathetic
supply
• No effect on blood pressure
• However, Cholinomimetic induced fall in BP is easily blocked
by atropine
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27.  Atropine Flush :
• Higher dose of atropine
• Histamine release or Direct compensatory activity to permit
the radiation of heat to decrease atropine fever
• Dilatation of cutaneous blood vessels, especially of face
• Atropine flush
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28. Therapeutic uses
 To counteract reflex vagal cardiac slowing or asystole :
• e.g.- injection of contrast media during cardiac catheterization
 Heart block :
• Digitalis toxicity
 Sinus bradycardia with M.I. :
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29. Respiratory Tract
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30. Effects
• Smooth muscles & Secretory glands have parasympathetic
innervation by M3 receptors
• Atropine inhibits the secretions of nose, mouth, pharynx,
bronchi
• Reduce laryngospasm during G.A.
 Disadvantages :
• Drying of mucous membranes
• ↓ Mucociliary clearance
• Mucous plugs airway obstruction infection
22-Mar-14
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31. 22-Mar-14
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Muscarinic
Antagonists
β2 Adrenergic
Agonists

32.  Advantages of newer drugs :
Ipratropium bromide
Tiotropium bromide
 Less drying effects on sputum
 No inhibition of mucociliary clearance
 Antagonize the bronchoconstriction induced by histamine,
bradykinin, PGF2α
 Block indirect effects of inflammatory mediators released
during asthma attack
22-Mar-14
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33. Ipratropium
 Aerosol / solution to inhale
 Maximal response over 30 – 90
min
 Lasts for 4 – 6 hours
 Blocks all the subtypes of
muscarinic receptors
• Presynaptic M2 receptor
blockade
↑ ACh release
counteracts its M3 receptor
blockade effect
Tiotropium
 Dry powder
 Slower onset
 Lasts 24 hours, Once daily
dosing
 Selective for M1 & M3 receptors
low affinity for M2
Minimal effect on presynaptic
M2 receptor blockade
No ACh release
22-Mar-14
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34. Therapeutic uses
 Bronchial Asthma & COPD :
• Ipratropium & its congeners are used
• Preferred in COPD, as parasympathetic tone is most
important factor in COPD
 Acute attack of asthma :
• Nebulized ipratropium + beta-2 adrenoceptor agonist
22-Mar-14
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35.  Preanaesthetic Medication :
• To ↓ bronchial secretions
• To prevent vagal effects on heart
• Advantage :
 Scopolamine –
 CNS depressant ( amnesia, tranquillisation )
 Glycopyrrolate –
 Less tachycardia
 More decrease in secretions (bronchial & salivary)
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36. Gastrointestinal Tract
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37. Effects
 Salivary secretion :
• Decreased
• Mouth becomes dry
• Swallowing, talking becomes difficult
 Gastric secretions :
• ↓ basal acid output by 40 – 50 %
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38. Therapeutic uses
(1) Peptic Ulcer :
• Before H2 histamine blockers & Proton pump inhibitors were
available,
• Antimuscarinic drugs had been used
• e.g.- Pirenzepine
22-Mar-14
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39. (2) As Antispasmodics :
• Conditions : - intestinal colic - traveler’s diarrhea
- dysentery - irritable bowel syndrome
- Renal colic -Spastic constipation
-Pylorospasm
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40. (3) To reduce excessive salivation :
• Conditions : - Heavy metal poisoning
- Parkinson’s disease
• Drugs : - Dicyclomine
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41. Sweat Glands
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42. Effects
 M3 receptors antagonism
• Thermoregulatory sweating is suppressed
• Adult - skin becomes dry, hot
- atropine fever at toxic dose
• Age < 5 yrs - atropine fever at therapeutic doses
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43. Genitourinary Tract
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44. Effects
 Relaxation of Smooth muscles of ureters & urinary bladder
Slow voiding ( urinary retention )
 Lowering of intravesicular pressure
 Increased capacity
 Reduce frequency of contraction
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45. Therapeutic uses
 Dicyclomine :
• Renal colic
• Ureteral muscle spasm
 Oxybutinin:
• M3 selective
• Bladder spasm after urologic surgery
• Involuntary voiding in neurologic disorders
• Improves bladder capacity
• Metabolized by CYP3A4
22-Mar-14
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46. Miscellaneous uses of Antimuscarinics
 Treatment of mushroom poisoning
 To treat muscarinic side effects of neostigmine
 To treat organophosphorus poisoning, to reverse muscarinic
side effects
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47. Side effects & toxicity
 Dryness of mouth
 Dilated pupil
 Photophobia
 Dry, flushed and hot skin
 Palpitation
 Constipation
 Precipitation of glaucoma
 Decreased bowel sounds
 Difficulty in swallowing
 Difficulty in micturition
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48. CNS symtoms
 Excitement,
 Psychotic behaviour,
 Ataxia,
 Delirium,
 Dreadful visual hallucinations
 Convulsions and coma occur only in severe poisoning
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49. Contraindications
 Narrow iridocorneal angle
 Benign prostatic hyperplasia In elderly
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50. Management of Atropine Poisoning
 Diagnosis :
• Physostigmine ( 1 mg i.m. )
If NO typical salivation, sweating, lacrimation
Diagnosis confirmed
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51. Treatment
 Supportive measures :
• Maintenance of airway, breathing, circulation
• Gastric lavage
 Definitive treatment :
• Physostigmine 2 mg i.v. or i.m. Repeated as needed
• Diazepam to prevent convulsions
22-Mar-14
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52. 22-Mar-14
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53. 22-Mar-14
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All of the following are actions of
muscarinic
antagonists except:
(a) Decreases gastric secretion
(b) Prolongs A-V conduction
(c) Decreases tracheobronchial
secretions
(d) Causes contraction of Spchinter
muscle of iris

54.  A patient presented in emergency with tachycardia,
hyperthermia, bronchial dilatation and constipation.
The person is likely to be suffering from overdose of:
 (a) Atropine
 (b) Organophosphorus compound
 (c) Mushroom
 (d) Paracetamol
22-Mar-14
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55. Drug of choice for mushroom poisoning is:
(a) Atropine
(b) Physostigmine
(c) Adrenaline
(d) Carbachol
22-Mar-14
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56.  Which of the following drugs increases gastro-intestinal
motility?
 (a) Glycopyrrolate
 (b) Atropine
 (c) Neostigmine
 (d) Fentanyl
22-Mar-14
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57.  Atropine can cause:
 (a) Decreased cardiac output
 (b) Heart block
 (c) Hypertension
 (d) Mydriasis
 (e) Sweating
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58.  Which of the following drug is commonly used in
 narcoanalysis?
 (a) Atropine sulfate
 (b) Scopolamine hydrochloride
 (c) Phenobarbitone
 (d) Morphine
22-Mar-14
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59. All of the following drugs are used for the
treatment of
urinary incontinence except:)
(a) Oxybutynin
(b) Ipratropium
(c) Darifenacin
(d) Tolterodine
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60.  Intramuscular injection of atropine causes initial
bradycardia. The reason for this effect being seen is:
 (a) Stimulation of medullary vagal centre
 (b) Stimulation of vagal ganglia
 (c) Blockade of M2 receptors of SA nodal cells
 (d) Blockade of muscarinic autoreceptor on vagal nerve
 endings
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61.  Which one of the following drugs does not produce
 central anticholinergic syndrome?
 (a) Atropine sulphate
 (b) Glycopyrrolate
 (c) Antihistaminics
 (d) Tricyclic antidepressants
22-Mar-14
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62.  Short acting mydriatic used in fundoscopy is:
 (a) Atropine
 (b) Homatropine
 (c) Cyclopentolate
 (d) Tropicamide
22-Mar-14
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63.  All of the following are anticholinergics, except:
 (a) Ipratropium bromide
 (b) Dicyclomine
 (c) Atropine
 (d) Amphetamine
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64.  The main mechanism of hyperpyrexia induced by
 atropine includes:
 (a) Vasodilation
 (b) Inhibition of sweating
 (c) Through central actions
 (d) Increase in basal metabolic rate
22-Mar-14
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65.  You are being asked to give your expert opinion
as a toxicologist regarding an effective antidote for
belladonna poisoning. Which of the following agents
would you suggest?
 (a) Neostigmine
 (b) Physostigmine
 (c) Pilocarpine
 (d) Methacholine
22-Mar-14
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