Anticholinergic drugs -Atropine : Pharmacological action, Pharmacokinetic, ADR and therapeutic uses. Atropine substitute and their therapeutic uses.

1. Dr. Kiran G. Piparva,
Assistant professor, Pharmacology,
All India Institute of Medical Science (AIIMS), Rajkot.
Date: 12/02/21

2. Learning objectives….
• Classification of anticholinergic drugs
• Pharmacological actions
• Pharmacokinetics
• Side effects of Atropine
• Drug drug interaction
• Atropine substitutes

3. Cholinergic Receptors blockers
Muscarinic receptors (Nm) Nicotinic receptors
(Nn) (Nm)
Anticholinergic drugs: Drugs are which blocks the actions of Ach action of on
autonomic effectors and in the CNS exerted through muscarinic receptors.
Though nicotinic antagonists also block certain actions of ACh, they are generally
referred to as ‘ganglion blockers’ and ‘neuromuscular blockers’

4. ANTICHOLINERGIC DRUGS
Antimuscarinic agents (Nm) Antinicotinic agents (Nn)
Ganglionic blockers Neuromuscular blockers
(NN blockers) (NM blockers) Skeletal muscle relaxants
 Anticholinergic drugs- Antimuscarinic drugs
 Neuromuscular blockers- Skeletal muscle relaxants
Ganglionic blockers- NOT USED

5. Hyoscine niger

7. • Cimetropium
bromide
• Isopropamide

8. • Atropine- Racemic mixture
• Atropine- Competitive antagonist of Ach
• Atropine - Don’t differentiate between
M1, M2, M3, M4 subtypes
• Wide spread actions on multiple system
Atropine – Mechanism of Action

10. Atropine – Pharmacological action
CNS (M1): Atropine- less entry → stimulation of CNS -medullary centers
- High dose- excitation, disorientation, hallucination
Hyoscine - freely enters → depression of CNS
↓ of vestibular excitation- emesis –Antimotion sickness
CVS (M2): Tachycardia due to ↓ vagal tone
- Facilitation of AV conduction
- Blood Pressure – minor change

11. SMOOTH MUSCLES (M3 block)
GIT
 Relaxation- relieve
spasm
No effect on peristalsis-
Impact on local mediators
(5-HT, Enkephalin)
Constipation (S/E)
Biliary tract
Weak relaxation
Urinary
↓ tone of ureter
↓tone of fundus→
↓contraction (prostate)
Urinary retention (S/E)
 Bronchi
 Relaxation
Bronchodilation
 Drying of secretion
 Mucus plug

12. EYE

14. Eye

15. Active mydriasis:
• Contraction of dilator pupillae
(Radial muscle)
• Don’t affect accommodation
• Light reflex present
• ɑ1 adrenergic drugs
Passive mydriasis:
• Relaxation of Sphinctor pupillae
• Don’t affect accommodation
• Light reflex absent
• Antimuscarinic drugs

17. Exocrine glands: ↓ secretions
↓ Salivary ≥ Sweat ≥ Bronchial ˃˃ Lacrimal ≥ Gastric
• Dry skin/ eye- difficulty in talking and swallowing √
• Gastric secretion– only volume decreases- mild action & at higher dose

18. Body temperature: ↑ at higher dose : ↑ Thermostat + ↓ Sweating
Local anaesthetic action: Mild anesthetic action on cornea only
Sensitivity of different organ and tissues to atropine-
Saliva, Sweat, Bronchial secretion > Eye > Bronchial muscle, Heart>
Smooth muscle of intestine, bladder> gastric glands

19. Pharmacokinetics of Atropine
• Atropine- poor blood brain barrier
• Hyoscine- better blood brain barrier penetration
• Dose of Atropine available: 0.6-2mg I.M., I.V.
1-2 % topically eye drop
• Combination of atropine and analgesic and antipyretics are banned
in India .

21. Atropine side effects

24. Part 2: Atropine substitutes

25. Atropine substitutes……
• Why there is need of atropine substitute ?
- Nonspecific action
- Ocular side effects- mydriasis, Cycloplegia
- Difficulty in micturition: urinary retention
- Drying of skin & difficulty in swallowing
- Constipation

26. Quaternary ammonium atropine substitute
• Poor absorption from G.I. track
• Poor penetration into cornea
• Poor penetration into brain
• Slower elimination –longer acting
• Higher nicotinic blocking property
• At high dose- Nm blockage occurs

27. Part 2 Atropine substitutes….

28. Atropine substitutes:
1. Antispasmodic antisecretory
2. Respiratory
3. Vesicoselective
4. Ophthalmic
5. Antiparkinsonian

29. Atropine substitutes:
1. Antispasmodic antisecretory antimuscarinic:
2. Respiratory antimuscarinic: Ipratropium bromide, Tiotropium bromide
Tertiary Amine:
Dicyclomine,
Valethamate,
Pirenzepine
Quaternary compound (GOCCIP):
Glycopyrrolate, Oxyphenonium, Clinidium,
Cimetropium bromide, Isopropamide,
Propanthaline (GOCCIP)

30. 3. Vesicoselective antimuscarinic:
Oxybutynin, Flavoxate, Tolterodine, Deriphenacin, Solifenacin
4. Ophthalmic antimuscarinic:
Homatropine, Tropicamide, Cyclopentolate
5. Antiparkinsonian antimuscarinic:
Trihexyphenidyl, Benztropine, Benzhexol.

31. • Hyoscine butylbromide: Esophageal and gastrointestinal spastic conditions:
PREP: 10 mg tab, 20 mg/ml inj.
• Atropine methonitrate: Abdominal colic and hyperacidity
• Propantheline: peptic ulcer and gastritis
• Use has declined due to availability of H2 blockers which are more efficacious.
• Oxyphenonium: Similar to propantheline, recommended in peptic ulcer and gastric
hypermotility
1. Antispasmodic Antisecretory (Quaternary amine)drugs
Gastric spastic
condition
Hyperacidity

32. • Clinidium/ Isopropamide: Hyperacidity, Nervous dyspepsia, irritable
bowel syndrome (IBS) and other G.I. disturbances especially associated
with mental and emotional disorder.
• Cimetropium bromide: especially for IBS –dryness of mouth is
commonest side effect
• Glycopyrrolate: Exclusively used for preanaesthetic medication
during anesthesia

33. 1. Antispasmodic (Tertiary amine)drugs
• Dicyclomine: Anticholinergic, antispasmodic, antiemetic with few atropinic side
effects. Used in Abdominal colic, dysmenorrhea and irritable bowel, morning
sickness and motion sickness.
 Not recommended below 6 months of age.
• Valethamate: visceral anti-spasmodic: (urinary, biliary and intestinal colic)+
Hasten dilatation of cervix when the same is delayed during labor.
• Pirenzepine: peptic ulcer: use is declined due to availability of H2 blocker

34. 2. Respiratory antimuscarinic drugs……..
1. Ipratropium bromide
2. Tiotropium bromide

35. Ipratropium bromide
• Advantages of ipratropium bromide over atropine
- It has selective action on bronchial smooth muscle >secretion
- Don’t depress mucociliary clearance
• Advantages over sympathomimetic (bronchodilator)
- Gradual onset and late peak-good for regular prophylactic use
- Acts on receptors on larger bronchioles.
• COPD: higher parasympathetic tone so ipratropium bromide is more
effective in COPD than in bronchial asthma.
• ADR: less- dryness of mouth, scratching sensation in trachea, bad taste
and nervousness
• 250ug/ml, 2 puffs , 3-4 times daily.

36. Tiotropium bromide
• Tightly binding to
M1/M3- Longer acting
• High bronchial selectivity
• Less ADR- Not absorbed
from respiratory and G.I.
mucosa

37. 3. Vesicoselective anticholinergic(M3/ M1 selective)
• Oxybutynin
• Tolterodine
• Flavoxate
• Darifenacin
• Solifenacin
Therapeutic use
• Detrusor instability- urinary frequency and
urge incontinence
• Post prostatectomy vasical spasm
• Neurogenic bladder
• Nocturnal enuresis
• Spina bifida

38. • Oxybutynin/ Flavoxate:
• M3/M1 selectivity
• Oral: anticholinergic side effect
Intravesical instillation: few side effect
• Tolterodine
• Selective M3 - less ADR (M1 –dryness of
mouth - other anticholinergic action)
Metabolized by CYP3A4
Dose reduction with CYP34 inhibitors
CYP3A4 inhibitors:
Clarithromycin, erythromycin,
diltiazem, itraconazole,
ketoconazole, ritonavir, grapefruit
• Derifenacin/ Solifenacin: M3 selective, long t1/2 - 24hrs by SR preparation

39. Drotaverine:
• Non anticholinergic antispasmodic
• M/A:
PDE-4 (phosphodiesterase-4 inhibitors) inhibitors- increases cAMP/cGMP
• Use:
Intestinal/biliary and renal colic, IBS
• ADR:
- No anticholinergic side effect
- Headache, dizziness, constipation, flushing
- fall in BP (I.V.)

40. 4. Mydriatics
• Limitation of Atropine :
Potent and long lasting mydriatic and cycloplegic – subject is visually
handicap.
• Short acting agents:
Homatropine
Cyclopentolate
Tropicamides

41. Mydriasis Cycloplegia Remarks/ADR
Atropine
30-40 minutes 1 week
Visually handicap for 1 week
Undesirable for refraction
testing
Homatropine (10times
less potent)
45- 60 minutes 1-3days Accommodation recovers in
2 days
Cyclopentolate 30-60 minutes 1 day
Potent and rapidly acting
Transient behavioural
abnormalities in children
Tropicamide
20-40minutes
3-6hrs,
unreliable
cycloplegia
Best for refraction error
testing and short acting
mydriatic for fundoscopy

42. Therapeutic uses of Atropine/ atropine substitute
• Antisecretory
• Antispasmodic
• Bronchial asthma
• Mydriatic and cycloplegic
• Cardiac vagolytic
• Central action
• To antagonize muscarinic effects if drugs and poisons

43. 1. Antisecretory
1. Preanesthetic medication:
- Irritant GA - check increased salivary and tracheobronchial
secretion
- Along with halothane –vagal slowing- NA mediated ventricular
arrhythmias
- prevent reflex laryngospasm
- Prevent vasovagal attack
2. Pulmonary embolism
- reduces pulmonary secretions
3. Antiparkinson: to check excessive sweating or salivation
4. Peptic ulcer: NOT USED

44. 2. antispasmodic
Intestinal colic –abdominal cramps
Spastic constipation, IBS, Pyolorspasm, Nervous dyspepsia
Renal colic – Opioid/NSAID better
To relieve urinary urgency/frequency – increases bladder capacity
Dysmenorrhoea – Not effective

45. 3. Bronchial asthma, COPD
• COPD: reflex vagal activity Bronchoconstriction Bronchodilation Anticholinergic
increased secretion
• Oral route: ADR- drying up of secretion, mucus plug- alveolar collapse
• Inhalation route: NO ADR
• Slow onset- long duration- suitable for regular prophylactic use
• Acute exacerbation of asthma/COPD: in combination with sympathomimetic through
nebulizer
• Ipratropium bromide - OD
• Regular intake reduces episodes of COPD exacerbation

46. 4. Ophthalmic use: Mydriatic & Cycloplegic

47. 4. Ophthalmic use: Mydriatic & Cycloplegic
• Diagnostic:
• Refraction error testing: both
mydriasis & cycloplegia both required
• Best- tropicamide –faster and stronger
action
• For children- atropine/cyclopentolate
• For fundoscopy: only mydriasis is
required
• sympathomimetic preferred
• Therapeutic:
• Irits/ iridocyclitis/ chorioiditis/
keratitis / corneal ulcer
• Atropine
• Long lasting mydriatic-cycloplegic
• Local anodyne action on cornea
• Rest to intraocular muscles- cut down
painful spasm
• Along with miotics- break adhesion
between iris and lens

48. 5. Cardiac vagolytic
• Increased vagal tone (myocardial infraction / digitalis toxicity) - sinus
bradycardia, partial heart block
• Only in selected cases.

49. 6. Central action
• Parkinsonism:
• Central anticholinergic used in “ Drug induced
parkinsonism”
• Motion sickness:
• Most effective – hyoscine, Dicyclomine(2nd option)
• Start before journey
• Prophylactic use: 0.2mg oral –action last 4-6hrs
• TDS: applied behind pina 4hrs before journey-
protect 3 days

50. 7. To antagonize muscarinic effects of drugs and poisons…
• In mashroom poisoning
• To reverse muscarinic action neostigmine for mysethenia gravis,
decurarization, cobra envenomation.

51. Belladonna poisoning
• Overdose /overconsumption of seeds / barriers of belladonna/
dhatura plant
• Children
• Symptoms: exaggerated pharmacological
action of atropine- 7Ds
• Diagnosis: Methacholine/neostigmine-
fail to produce muscarinic action
• Rx: Symptomatic Mx only
• Gastric lavage
• Patient should be kept in dark quite room
• Cold sponging
• ABC management – no ChE effective- more ADR

52. •Rapid fire….
• Atropine produces active mydriasis or passive mydriasis?
• Atropine induced cycloplegia last for????
• Best substitute for Irritable bowel syndrome???
• Best substitute for preanesthetic medication??
• Best short acting mydriatic?
• Mydriatic of choice in pediatric?
• Non anticholinergic smooth musce relaxant?
• Y anticholinergic is better for COPD than BA?
• Drug of choice for motion sickness?