pharmacology drugs acting at autonomic nervous system

2. TOPICS
History
Classification
Muscarinic antagonist
Pharmacological actions
Therapeutic uses
Toxicity

3. INTRODUCTION
 These agents block cholinergic receptors thereby inhibit cholinergic
transmission hence these agents are also called as parasympatholytics.
 Are they specific?
 Yes, these drugs are somewhat specific
 these drugs can block specifically either muscarinic receptors or nicotinic
receptors.

4. History
• Roman empire and middle ages
– Deadly nightshade shrub: Linnaeus : Atropa belladonna
• Datura stramonium
– In India – Use of Jimson weed – roots and leaves – burnt –
smoke was inhaled by asthmatics.
• Mein – 1831- isolated atropine in pure form
• Bezold and Bleobaum – 1867 – showed that atropine
blocked the cardiac effects of vagal stimulation.
• Heidenhain – 1872 –atropine prevented salivary
secretion produced by the stimulation of the chorda
tympani.

5. BELLADONNA EYES MYDRIASIS

6. Atropa belladonna
Hyoscyamus
niger
Datura
stramonium

7. SOURCES
AT R O P I N E
Atropa belladona
Atropa acuminata
Datura stramonium
S C O PA L A M I N E
Hyoscyamus niger
Scopola carniolica

8. Anti-muscarinic agents
Natural Alkaloids
• Atropine(d,l-hyoscyamine)
• Scopolamine (l-hyoscine)
Semisynthetic
Derivatives
• Homatropine
• Atropine methionitrate
• Hyoscine methylbromide
• Benztropine
• Ipratropium bromide
• Tiotropium bromide
Synthetic Derivatives
• Eucatropine
• Cyclopentolate
• Tropicamide
• Dicyclomine
• Flavoxate
• Oxybutynin
• Pirenzepine
• Telenzepine
• Trihexyphenidyl
• Procyclidine
• Tolterodine
• Glycopyrrolate
• Propantheline
• Oxyphenonium
• Clidinium
• Pipenzolate
• Drotaverine
• Valethamate

9. Tertiary and Quaternary derivatives
Tertiary
• Atropine
• Scopolamine
• Homatropine
• Benztropine
• Eucatropine
• Cyclopentolate
• Tropicamide
• Dicyclomine
• Flavoxate
Quaternary
• Atropine methionitrate
• Hyoscine methylbromide
• Ipratropium bromide
• Tiotropium bromide
• Propantheline
• Oxyphenonium
• Glycopyrrolate
• Clidinium
• Pipenzolate
• Valethamate
• Oxybutynin
• Pirenzepine
• Telenzepine
• Trihexyphenidyl
• Procyclidine
• Drotaverine
• Tolterodine

10. CLASSIFICATION

11. MUSCARINIC ANTAGONISTS
• Muscarinic receptors are further classified into
M1 to M5
• drugs may produce either selective or non-
selective block
• we can divide this category further into
Non-selective muscarinic antagonists
Selective muscarinic antagonists

12. Atropine
Scopolamine
Dicyclomine
Cyclopentolate
Tropicamide
Ipratropium
Tiotropium
Solifenacin
Oxybutynin
Tolterodine
Benztropine
Trihexyphenidyl
NON-SELECTIVE MUSCARINIC ANTAGONISTS

13. SELECTIVE MUSCARINIC ANTAGONISTS
Selective cholinergic antagonists are available on
M1, M2 and M3 receptors.
• M1 antagonist
• Pirenzepine
• M2 antagonist
• Gallamine
• M3 antagonist
• Darifenacin

14. STRUCTURE-ACTIVITY RELATIONSHIP
Tropine
Tropi
c acid
Scopine
Mandeli
c acid

15. MECHANISM OF ACTION
Competitive
antagonism
Reversible
(surmountable)
blockade
Competition of
atropine and
scopolamine with
acetylcholine for
the muscarinic
receptor

16. ABSORPTION
T E R T I A R Y
A N T I M U S C A R I N I C D R U G S
Absorbed rapidly from the GI
tract and conjunctival
membrane
When applied in suitable
vehicle, some are even
absorbed across the skin
 Scopolamine: transdermal patch
in the post-auricular region
Q U A T E R N A R Y
A N T I M U S C A R I N I C D R U G S
only 10-30% is absorbed
after oral
administration
 Decreased solubility of the
charged molecule
 Less readily penetrate the
conjunctiva of the eye

17. DISTRIBUTION
T E R T I A R Y A N T I -
M U S C A R I N I C D R U G S
Atropine and other tertiary
agents widely distributed in
the body
Significant levels are achieved in
CNS within 30 min to 1 hr
Scopolamine is rapidly and fully
distributed into the CNS
where it has greater effects
than most others
Crosses placental barrier and
secreted in milk and saliva
Q U A T E R N A R Y A N T I -
M U S C A R I N I C D R U G S
Quaternary
derivatives are
poorly taken up
by the brain and
therefore free of
CNS effects

18. METABOLISM & ELIMINATION
Atropine has a t1/2 of ≈4 hours
 Hepatic metabolism accounts for the elimination of about half of a dose
 Remainder is excreted unchanged in the urine.
Rabbit – Atropine esterase – tolerate large doses without toxicity

19. PHARMACOLOGICAL ACTIONS

20. EFFECTS OF ATROPINE IN RELATION TO DOSE
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

21. EYE
• Just like muscarinic agonists, these drugs act on two muscles in the
eye.
 Constrictor muscle
 Ciliary muscle
• Relaxation of this muscle by muscarinic antagonists produce pupilary
dilatation.
• ciliary muscle is required for adjustment of the lens with respect to the
distance of the object
 Ciliary muscle paralysis
 Loss of accommodation – cycloplegia
Both atropine and scopolamine produced this effect.
 Long duration of action
 Pupillary and accommodation reflex recover 7-12 days after.

26. Other short acting drugs are preferred as mydriatic
Sympathomimetic drugs also cause pupillary dilation without cycloplegia
Alpha adrenoceptors stimulants drugs
• Phenylephrine – short lasting mydriasis sufficient for fundus examination
Opposing effect: that can partially or fully reverse the effect of atropine
• Pilocarpine
• Choline esters
• Physostigmine
• Isoflurophate (DFP)
Contraindications:
 Narrow angle glaucoma

27. THERAPEUTIC USES
Mydriasis
 Examination of retina and optic disc and for refractive errors
 Therapy of iridocyclitis and keratitis
Cycloplegia
 In Rx of iridocyclitis and choroiditis
 Measurement of refractive errors
 Young – long acting mdriatics + cycloplegia preferred
 Adults- short acting drugs preferred

28. In therapy of iridocyclitis
 Adminstered alternately with miotics
 Long lasting preparations like Homatropine
 To break/prevent adhesions between iris and lens
 Complete cycloplegia is necessary in treatment of iridocyclitis &
choroiditis
 If complete cycloplegia is required
atropine or scopolamine preferred >> cyclopentolate or
tropicamide

29. ANTI-MUSCARINIC DRUGS USED IN
OPHTHALMOLOGY
Drug Duration of Effect
(days)
Usual
Concentration (%)
Ocular side
effects
Atropine 7–10 0.5–1
Scopolamine 3–7 0.25
Homatropine 1–3 2–5 Photosensitivity,
blurred vision
Cyclopentolate 1 0.5–2
Tropicamide 0.25 0.5–1

30. GLANDS
All the glandular secretions are inhibited.
• Salivary secretions
• Lacrimal secretions
• Sweat secretion
• Bronchial secretions
• Gastric secretions
Reduction of salivary secretion leads to dry
mouth and reduction of lacrimal secretions leads
to blurred vision
therapeutic uses
Drug induced salivation
 Heavy metal poisoning
 Parkinson disease

31. Clinical Relevance – Sialorrhoea
Sialorrhoea is drooling or excess saliva that cannot be controlled. There
are two mechanisms by which this can occur:
1. Lack of swallowing – resulting in saliva pooling in the mouth.
This is typically due to neuromuscular dysfunction such as
cerebral palsy, Parkinson’s disease or Motor Neuron Disease.
1. Increased secretion of saliva – which is typically due to
medication. It is often noted within the treatment of Alzheimer’s
disease or myasthenia gravis, as treatment of both conditions
involves the use of anti-cholinesterases.

32. MANAGEMENT
• depends on the cause
• involves treatment of any reversible factors.
• For example, drug regimes may need to be changed or even stopped depending
on the severity.
• Behaviour modification may be necessary in terms of learning methods to help
clear the pooled saliva.
• In severe cases
• anticholinergic medication can be used.
• Belladona alkaloids
• Synthetic tertiary amine derivatives like DICYCLOMINE are very effective
• Side effects
• If nothing else is successful radiation
• injection of botulinum toxin or
• surgery may be considered.

33. HEART

34. So they show
+ve ionotropic effect
+ve chronotropic effect
The decrease in the heart rate leads to tachycardia. Since they produce
tachycardia, they can be indicated in sinus bradycardia. Atropine is particularly
used for this condition.

35. CARDIOVASCULAR SYSTEM
Effects of increasing
doses of atropine on
heart rate compared
with muscarinic
receptor occupancy
in humans
Parasympathomimetic
effect of low-dose
atropine is attributed
to blockade of
presynaptic M1
receptors that
suppress
acetylcholine release
normally

36. Usual clinical dose
(0.4 to 0.6 mg)
Larger dose
Receptor action M1 M2
mechanism Inhibition of pre synaptic
M1  inc. Ach release
SA and AV node
Effect 1. Bradycardia
2. 4-8 beats pre min.
1. Tachycardia
2. 35-40 beats per
min.

37. PHARMACOLOGICAL ACTIONS
Effect on young – high  due to high vagal tone
Effect in elderly  lower  due to less vagal tone
Effect on rhythmicity
 Prevents or abolishes bradycardia or asystole caused by choline esters, ache
inhibitors
Effect on conduction
 Facilitate AV node conduction  removal of vagal influence on the heart and
increase ventricular rate
 E.g in
1. Atrial fibrillation
2. II degree heart block
3. In digitalis toxicity
4. In complete heart block

38. Antimuscarinic agent Preparations
Atropine
Oral: 0.4, 0.6 mg
tablets
Parenteral: 0.05, 0.1,
0.3, 0.4, 0.5, 0.8, 1
mg/mL for injection

39. PHARMACOLOGICAL ACTIONS
Circulation
 In clinical doses, when given along with choline esters
 When given alone
 In toxic and occasionally in therapeutic doses: atropine flush

40. BRONCHIOLES
These drugs block M3 receptors on bronchioles and produce bronchodilatation.
Bronchial secretions are also inhibited which is useful in asthma.

41. Respiratory System
Pharmacological Actions
• Broncho-dilation and decrease in tracheobronchial secretion
• Reduction of mucous secretion and mucociliary clearance
• Inhibits broncho-constriction caused by infl. Mediators
• Belladona alkaloids  decreases secretions caused by irritant
anaesthetics like diethyl ether
– Side effects: decrease mucus secretion and clearance  mucus plugs
obstruction
• Quarternary ammonium derevatives have minimal inhibitory effect
on mucociliary clearance

42. THERAPEUTIC USES
A D V A N T A G E S O F
I P R A T R O P I U M
• No effect on
mucociliary clearance
• Inhalational –
decreased systemic
side effects
• Longer acting – can
be given once daily
• Can be used as
adjunct to pulm.
Rehab. In increasing
exercise intolerance
T H E R A P E U T I C U S E S
COPD & Asthma
 Used along with
adrenergic receptor
agonists
Decrease the
rhinorrhea
associated with the
common cold or
with allergic and
nonallergic rhinitis

43. Antimuscarinic agent Duration
of action
Preaparations
Ipratropium 4-6hrs Aerosol: 200 dose metered-dose
inhaler(18mcg/puff).
Solution for nebulizer:
0.02%(500mcg/vial).
Nasal spray: 0.03, 0.06%(21,
42mcg/spray).
Tiotropium 24hrs Aerosol: 18 mcg tablet for inhaler

44. SMOOTH MUSCLE ( GIT)

45. GI TRACT
T H E R A P E U T I C
U S E S
To facilitate endoscopy and gastrointestinal radiology
by relaxing gastrointestinal smooth muscle
Once used in management of peptic ulcer disease
 Pirenzepine and telenzepine were used
Antispasmodic
Antisecretory
 Mild dysenteries and diverticulitis

46. Once most widely used for management of peptic ulcer disease.
Anti secretory doses produced – S/E- dry mouth, loss of visual accomodation,
photophobia, and difficulty urination
This reduced patient compliance
Pirenzepine
 Similar in structure to imipramine
 It is tricyclic antidepressant
 Selective for M1 receptors (also M4)
 Inhibition of gastric acid secretion by Neural stimuli > muscarinic agoinsts
Telenzepine
 Analogue of pirenzepine
 Higher potency
 Selective for M1 receptors

47. Antimuscarinic agent Preparations
Pirenzepine Oral: 50mg tablets
Telenzepine Oral: 3mg tablets
Dicyclomine Oral: 10, 20 mg capsules;
20 mg tablets; 10 mg/5 mL
syrup
Parenteral: 10 mg/mL for
intramuscular injection
Glycopyrrolate Oral: 1, 2 mg tablets Parenteral: 0.2 mg/mL for
injection

48. GENITO-URINARY SYSTEM

49. GENITO-URINARY TRACT
• Relaxes smooth muscles of ureter and bladder wall
and slows voiding
• lower intra-vesicular pressure
• increase capacity
• reduce the frequency of contractions
• alter bladder sensation during filling
• This effect is achieved only after the inhibition of
salivation, lacrimation & blurring of vision
• Mediated by multiple receptor subtypes M2 < M3
P H A R M A C O L O G I C A L A C T I O N S

50. GENITO-URINARY TRACT
T H E R A P E U T I C U S E S
1. Motor Urge (Hypertonic) Incontinence:
• This is the most common incontinence in elderly
• Etiology. Involuntary rises in bladder pressure occur from idiopathic detrusor
contractions that cannot be voluntarily suppressed
• Urge incontinence can be linked to
• stroke,
• Parkinson's disease,
• multiple sclerosis and
• other health conditions
• which interfere with the brain's ability to send messages to the bladder via the spinal
cord.
• These conditions can affect a person's ability to hold and store urine.

51. Motor Urge (Hypertonic) Incontinence:
Management.
1. Anticholinergic medications
i. Oxybutynin [Ditropan] 5mg BD oral
ii. Dicyclomine 10-20 mg BD
iii. Solifenacin 5-10 mg BD oral
iv. Tolterodine 2 mg BD oral
v. Fesoterodine
vi. Flavoxate 200 mg TDS oral
2. Non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit detrusor
contractions;
3. Tricyclic antidepressants;
4. Calcium -channel blockers
Newer addition for the
t/t of urge incontinence
Mnemonic
SOFT
bladder
Therapeutic uses

52. 2. Stress incontinence
• Involuntary loss of urine
• With coughing and sneezing
• No urine lost at night
Treatment:
a) Medical therapy
- some success with duloxetine (yentreve) (SNRI)
b) Surgical therapy
Therapeutic uses

53. DRUGS - INHIBIT/PROMOTE VOIDING

54. 3.Rx of enuresis in children
- by lowering intra-vesicular pressure, increasing
capacity and reducing frequency of contractions
4.Used to reduce urinary frequency in spastic
paraplegia and to increase capacity of bladder
5. To relieve spasm after urological surgery
Prostatectomy

55. 6. Used to reduce involuntary voiding in patients with neurological
disease
- Children with menigomyelocele – Oxybutynin orally or can be
instilled via catheter
7. Propiverine is a newer anticholinergic drug used for the treatment
of
 urinary urgency,
 frequency and
 urge incontinence,
 all symptoms of overactive bladder syndrome.
 It is a muscarinic antagonist.
 A modified release preparation is also available, taken once
daily.

56. NONPROPRIETAR
Y NAME
t1/2 (HOURS) METABOLISM &
ELIMINATION
PREPARATIONS DAILY DOSE
(ADULT)
Oxybutynin 2-5 CYP3A4 Immediate
Release
10-20 mg
Extended Release 5-30 mg
Transdermal
patch
3.9 mg
Topical gel 100 mg
Tolterodine 2-9.6 CYP2D6, CYP3A4 IR 2-4 mg
6.9-18 ER 4 mg
Trospium chloride 20 KIDNEYS IR 20-40 mg
35 ER 60 mg
Solifenacin 55 CYP3A4 IR 5-10 mg
Darifenacin 13-19 CYP2D6, CYP3A4 ER 7.5-15 mg
Fesoterodine 7 ER 4-8 mg

57. OTHER SMOOTH MUSCLE
Biliary Tract
Mild antispasmodic action
Not effective to prevent the spasm induced by
opioids
Sweat Glands and Temperature
Inhibits the activity of sweat glands
Skin becomes hot and dry
Sweating may be depressed enough to raise body
temperature

58. CENTRAL NERVOUS SYSTEM

59. CENTRAL NERVOUS SYSTEM

61. LDT/PPT (Ach)
Dorsal raphe/ locus
ceruleus
Inhibit wakefulness
Promotes REM
sleep
Thalamus
Inhibit slow sleep
wave spindles
Causes cortical
arousal
In both WAKEFUL
and REM sleep
Pontine reticular
formation
Ach released in to
the PRF causes
Promotes onset of
REM
pedunculopontine tegmental (PPT) and laterodorsal tegmental nucleus (LDT)

62. CENTRAL NERVOUS SYSTEM
Atropine : action on CNS is dose dependent
 Therapeutic doses
 Minimal effects, mild stimulation of the parasympathetic medullary centres
 With toxic doses
 Central excitation
 With still larger doses:
 Stimulation followed by depression
Scopolamine
 Crosses BBB, has prominent central effects at low therapeutic doses;
 CNS depression, amnesia
 also causes euphoria
 In severe pain, same doses cause excitement
P H A R M A C O L O G I C A L
A C T I O N S

63. Parkinson disease
Adjunct to levodopa
Motion sickness
Given prophylactically
Therapeutic uses

64. Antimuscarinic
agent
Preparations Usual daily dose
Scopolamine Oral: 0.25 mg tablets Parenteral: 0.3,
0.4, 0.6, 1 mg/mL
for injection
Transdermal patch:
delivers ≈0.5mg over
72hrs
Benztropine Oral: 0.5, 1, 2 mg
tablets
Parenteral:
1mg/ml for
injection
1–6mg
Biperiden Oral: 2mg tablets Parenteral:
5mg/ml for
injection
2–12mg
Trihexyphenidyl Oral: 2, 5mg
tablets
Sustained release:
5mg capsules
6–20mg

65. Other uses
• Uses in Anesthesia
– Blocks vagal reflexes induced by surgical
manipulation of viscera
– In anaesthetic premedication, atropine, and
hyoscine block the vagus and reduce mucosal
secretions; hyoscine also has useful sedative and
amnestic effects

66. ORGANOPHOSPHORUS POISONING
The use of atropine in large doses for the
treatment of poisoning by anticholinesterase
organophosphorus insecticides.
1-2 mg of atropine sulfate
I.V every 5-15 min until signs of effect appear
Acute effects of op poisioning last for 24-48
hrs

67.  Cholinesterase regenerator compounds
 PAM or pro-2-PAM
 Diacetyl monoxime
 The oxime group (=NOH) has very high affinity for
phosphorous atom
 These drugs cannot hydrolyse if the complex has aged
 Ageing involves breaking of one of the oxygen-
phosphorous bonds of the inhibitor
 further strengthens the phosphorus – enzyme bond

68. In mushroom poisoning :
 Rapid onset type:
 Characterized by early signs of muscarinic excess – nausea, vomiting,
diarrhea, urinary urgency, vasodilation, reflex tachycardia, sweating,
salivation and broncho-constriction
 Inocybe genus mushrooms causes rapid type poisioning
 Parenteral atropine 1-2 mg
 Delayed type
 Amanita phylloides
 A.virosa
 Atropine is of no value

69. CONTRAINDICATIONS
Include
Urinary tract obstruction
GI obstruction
Uncontrolled (or susceptibility to attacks of) angle-
closure glaucoma.
Benign prostatic hyperplasia.

70. Atropine poisoning
• Atropine has wide margin of safety
• Lethal dose
– Children: 10-20mg
– Adults: 80-130mg
• Scopolamine is more toxic than atropine
• Poisoning may also occur following ingestion
of natural sources.

71. Adverse effects

72. Signs and symptoms

73. diagnosis
• Intravenous injection of the anticholinesterase
agent physostigmine may be used for
confirmation.
• If physostigmine does not elicit the expected
salivation, sweating, bradycardia, and
intestinal hyperactivity, intoxication with
atropine or a related agent is almost certain.

74. Contd…
• If Poison ingested
– Gastric lavage
– Universal antidote
– Muscarinic effects- counteracted by IV Physostigmine 1-
4mg(adult), 0.5-1mg(children), repeated at intervals till
satisfactory control
– Restlessness, delirium- Diazepam
– Dark room to alleviate photophobia
– Catherization for urinary retention
– Tepid sponging for pyrexia
– Good nursing care, oxygen, artificial ventilation (when
necessary)

75. Toxicology of drugs with antimuscarinic
properties
• Histamine H1 receptor antagonists
(promethazine, diphenhydramine)
• Phenothiazines (chlorpromazine and
thioridazine)
• Tricyclic antidepressants (protriptyline and
amitriptyline)
– block muscarinic receptors, and in sufficient
dosage, produce syndromes that include features
of atropine intoxication.

76. • In addition, overdose with suicidal intent is a
danger in the population using
antidepressants.
• Fortunately, most of the newer
antidepressants, selective serotonin reuptake
inhibitors and newer antipsychotic drugs have
more limited anticholinergic properties.

77. Summary
• Muscarinic receptor antagonists have a wide
variety of therapeutic uses:
– Treatment of overactive bladder
– COPD
– Increased GI motility
– Ophthalmology
– OP poisioning

78. References
• HL Sharma & KK Sharma’s “Principles of
Pharmacology” 3nd edition
• Goodman & Gilman’s “The Pharmacological Basis of
Therapeutics”
• Rang & Dale’s “Pharmacology” 8th edition
• Katzung’s “Basic and Clinical Pharmacology” 14th
edition
• R.S. Satoskar’s “Pharmacology and
Pharmacotherapeutics” 23rd edition
• KD Tripathi’s “Essentials of Medical Pharmacology” 7th
edition

79. THANK YOU