cholinergic antagoinsts

1. Cholinergic Antagonists
1

2.  Antimuscarinic agents (muscarinic blockers)
 Ganglionic blockers
 Neuromuscular blockers
2

3. 3

4. Antimuscarinic Agents
4

5. 5

6. 6

7. 7

8. ....
8

9. • Antimuscarinic Agents
– These agents block muscarinic receptors , causing
inhibition of all muscarinic functions
– These drugs block the few exceptional
sympathetic neurons that are cholinergic, such as
those innervating sweat glands
– Are beneficial in a variety of clinical situations
– Do not block nicotinic receptors....means ??? No
nictinic receptor adverse effect
• A number of antihistaminic and antidepressant drugs
also have antimuscarinic activity
9

10. • Atropine
– A tertiary amine belladonna alkaloid
– Atropa belladonna, or deadly nightshade, and in
Datura stramonium
– Has a high affinity for muscarinic receptors, where
it binds competitively, preventing acetylcholine
from binding to those sites
– Atropine acts both centrally and peripherally.
– Its general actions last about 4 hours except when
placed topically in the eye, where the action may
last for days
10

11. 11

12. 12

13. Atropine actions
• Tissues most sensitive to atropine are the
salivary, bronchial, and sweat glands
• Secretion of acid by the gastric parietal cells is
the least sensitive
13

14. • Eye
• Atropine blocks all cholinergic activity on the
eye, resulting in
– Persistent mydriasis (dilation of the pupil)
– Unresponsiveness to light, and cycloplegia
(inability to focus for near vision)
– In closed angle glaucoma it may rise pressure
dangerously
• GI
– Reduce activity of GI...is used as antispasmodic
– Acid secretion is not significantly reduced so?
14

15. Atropine
• Urinary system
– reduce hypermotility states of the urinary bladder
• Occasionally used in enuresis (involuntary voiding of urine)
among children
• Cardiovascular
– Divergent effect
– At low dose ... decreased cardiac rate (bradycardia)
– Higher dose .....cardiac rate increases modestly
– Arterial BP is unaffected
– Block vasodilation
• Secretions
– Atropine blocks the salivary glands, producing a
drying effect on the oral mucous membranes
(xerostomia)
15

16. • CNS
– Minimal stimulant effects on the central nervous
system
– A slower, longer-lasting sedative effect on the
brain
– Toxic dose
• Cause excitement, agitation, hallucinations, and coma
16

17. 17

18. Atropine
• Therapeutic uses
• Ophthalmic
– Permits the measurement of refractive errors
without interference by the accommodative
capacity of the eye......
• Antispasmodic
– Atropine is used as an antispasmodic agent to
relax the GI tract and bladder
18

19. Atropine ..
Therapeutic uses…
• Antidote for cholinergic agonists
– Atropine is used for the treatment of overdoses of
cholinesterase inhibitor insecticides and some
types of mushroom poisoning
• Antisecretory
– The drug is sometimes used as an antisecretory
agent to block secretions in the upper and lower
respiratory tracts prior to surgery
19

20. Atropine
Pharmacokinetics
• Atropine is readily absorbed, partially
metabolized by the liver, and eliminated primarily
in the urine.
• It has a half-life of about 4 hours.
Adverse effects
• Depending on the dose, atropine may cause dry
mouth, blurred vision, sandy eyes, tachycardia,
and constipation
• In older patients ..... it may exacerbate an attack of
glaucoma, may induce urinary retention
• CNS.... restlessness, confusion, hallucinations, and
delirium, which may progress to depression, collapse of
the circulatory and respiratory systems, and death
20

21. 21

22. Scoplamine
• Similar effect with atropine...but
scoplamine is has greater action on the
CNS and longer duration of action
• Actions:
• Scopolamine is one of the most effective
anti motion sickness drugs available
• Also has the unusual effect of blocking
short-term memory
• In contrast to atropine, scopolamine
produces sedation, but at higher doses it
can produce excitement instead.
• Scopolamine may produce euphoria and is
subject to abuse
22

23. Scoplamine
• Therapeutic uses
– Limited to prevention of motion sickness (for
which it is particularly effective) and to blocking
short-term memory
23

24. Ipratropium and tiotropium
• A quaternary derivative of atropine
• useful in treating asthma in patients who are
unable to take adrenergic agonists
• also beneficial in the management of chronic
obstructive pulmonary disease
• It is inhaled for these conditions
• Because of positive charge, it does not enter
the systemic circulation or the CNS, isolating
its effects to the pulmonary system
24

25. • Tropicamide and cyclopentolate
• These agents are used as ophthalmic solutions
for similar conditions as atropine (mydriasis
and cycloplegia)
• Their duration of action is shorter than that of
atropine; tropicamide produces mydriasis for 6
hours and cyclopentolate for 24 hours
25

26. • Pirenzepine and a more potent analog,
telenzepine
– Reduce gastric acid secretion with fewer adverse
effects than atropine and other less selective
agents
26

27. 27

28. Summery of clinical use
• CENTRAL NERVOUS SYSTEM DISORDERS
– Parkinson's Disease
– Motion Sickness
• OPHTHALMOLOGIC DISORDERS
– Accurate measurement of refractive error in uncooperative patients
– Ophthalmoscopic examination of the retina is greatly facilitated by
mydriasis
• RESPIRATORY DISORDERS
– Preoperative medication
– Asthma ,COPD
• CARDIOVASCULAR DISORDERS
– Management of vasovagal attack
– Hyperactive carotid sinus reflexes
• May experience faintness or even syncope as a result of vagal discharge in response
to pressure on the neck, eg, from a tight collar
– Idiopathic dilated cardiomyopathy
28

29. Summery ...
• GI
– Rarely for PUD
– Travellers diarrhoea ,hypermotility
– Usually combined with an opioid antidiarrheal
drug: atropine + diphenoxylate (e.g Lomotile )
• GU
– Provide symptomatic relief in the treatment of
urinary urgency caused by minor inflammatory
bladder disorders
29

30. Summery ..
GU..
• Oxybutynin(M3 selective ) and Trospium(non
selective ), Darifenacin and solifenacin (greater
selectivity for M3 )
– Is used to relieve bladder spasm after urologic surgery
– Help in reducing involuntary voiding in patients with
neurologic disease
• Tolterodine,( M3-selective ) is available for use in
adults with urinary incontinence
• Propiverine newer antimuscarnic used to reduce
incontinence in institutionalized elderly patients
30

31. Summery ....
• CHOLINERGIC POISONING
–To reverse the muscarinic effects
–A tertiary (not quaternary) amine drug must
be used (preferably atropine)
• So that both the central and peripheral Sx are
reversed
31

32. Antimuscarinics :contraindication
 Contraindications in this case are
relative not absolute
• In patients with glaucoma(closed angle )
• In elderly ( caution should be there) but
–Avoid if with prostatic hyperplasia
• Pts with peptic ulcer....especially the non
selective ones
–Because they delay gastric emptying and
increase symptoms in patients with gastric
ulcer
32

33. 33

34. Ganglionic stimulating/blocking drugs
34

35. Ganglionic stimulating drugs
Nicotine
• The ultimate response of any one system represents the
summation of stimulatory and inhibitory effects of nicotine
• E,g nicotine
• Increases HR
– Excitation of sympathetic or paralysis of
parasympathetic cardiac ganglia
• Decreases HR
– Paralysis of sympathetic or stimulation of
parasympathetic cardiac ganglia
• Effect on chemoreceptors on carotid and aortic bodies plus
the brain plus cardiovascular reflex
• Nicotine elicits a discharge of epinephrine from the adrenal
medulla, which accelerates heart rate and raises blood
pressure
35

36. Nicotine..
Peripheral nervous system
• Initially of transient stimulation and
subsequently of a more persistent
depression of all autonomic ganglia
• On adrenal medulla ..small doses evoke
and large doses prevent catecholamine
release
• NMJ….stimulant effect is largely obscured
by the rapidly developing paralysis
36

37. Nicotine ….
• Stimulate a number of sensory receptors
–Mechanoreceptors that respond to stretch
or pressure of the skin, mesentery, tongue,
lung, and stomach
–Chemoreceptors of the carotid body
–Thermal receptors of the skin and tongue;
and
–Pain receptors
37

38. Nicotine ..
CNS
• Nicotine markedly stimulates the CNS
• Low doses produce weak analgesia; with higher
doses, tremors leading to convulsions at toxic
doses are evident
• The excitation of respiration is a prominent action
of nicotine
• Stimulation of the CNS with large doses is followed
by depression, and death results from failure of
respiration owing to both central paralysis and
peripheral blockade of muscles of respiration
• Induces vomiting by both central and peripheral
actions
38

39. Nicotine ..
GI tract
–Increased tone and motor activity of the
bowel
–Nausea, vomiting, and occasionally diarrhea
are observed following systemic absorption
of nicotine in an individual who has not
been exposed to nicotine previously
• Endocrine gland
–Initial stimulation of salivary and bronchial
secretion then inhibition
39

40. Nicotine..
Pharmacokinetics
• Nicotine is readily absorbed from the respiratory
tract, buccal membranes, and skin
– Severe poisoning has resulted from percutaneous
absorption.
• Relatively strong base …..so????….
• Nicotine in chewing tobacco, because it is
absorbed more slowly than inhaled nicotine, has
a longer duration of effect
• The average cigarette contains 6 to 11 mg
nicotine and delivers about 1 to 3 mg nicotine
systemically to the smoker
40

41. Nicotine …
• Dosage forms
– A gum (nicotine polacrilex, NICORETTE)
– Transdermal patch (NICODERM, HABITROL,
others)
– A nasal spray (NICOTROL NS), and
– A vapor inhaler (NICOTROL INHALER)
The objective
To obtain a sustained plasma nicotine
concentration lower than venous blood
concentrations after smoking
41

42. Nicotine …
• Approximately 80% to 90% of nicotine is
altered in the body, mainly in the liver but also
in the kidney and lung…..cotinine is the major
metabolite
• Half-life following inhalation or parenteral
adm..is 2hrs
• Eliminated mainly in kidney ..rate of excretion
decreases when urine is alkaline
• Milk .. the milk of heavy smokers may contain
0.5 mg/L.
42

43. Nicotine ..
Acute nicotine poisoning
• Fatal dose in adult 6.5–13 mg/kg
• Smoking tobacco usually contains 1% to 2%
nicotine
• The gastric absorption of nicotine from
tobacco taken by mouth is delayed because of
slowed gastric emptying, …so vomiting caused
by the central effect of the initially absorbed
fraction may remove much of the tobacco
remaining in the GI tract
43

44. Nicotine …
Sign and symptoms of poisoning
• Nausea, salivation, abdominal pain, vomiting,
diarrhea, cold sweat, headache, dizziness,
disturbed hearing and vision, mental confusion,
and marked weakness
• Faintness and prostration ensue; the blood
pressure falls; breathing is difficult; the pulse is
weak, rapid, and irregular; and collapse may be
followed by terminal convulsions
• Death may result within a few minutes from
respiratory failure
44

45. Nicotine …
Therapy
• Vomiting may be induced, or gastric lavage
should be performed
• Alkaline solutions should be avoided
• A slurry of activated charcoal is then passed
through the tube and left in the stomach
• Respiratory assistance and treatment of shock
may be necessary
45

46. Ganglionic Blockers
• Act on the nicotinic receptors of both
parasympathetic and sympathetic autonomic
ganglia
• These drugs block the entire output of the
autonomic nervous system at the nicotinic
receptor
• Are nondepolarizing, competitive antagonists
except nicotine
46

47. Ganglionic blockers …
• Effect depends on knowing which division of
the autonomic nervous system exercises
dominant control of various organs
47

48. 48

49. Organ system effect of ganglionic
blockers
• Reading assignment
49

50. 50

51. Therapeutic use and toxicity
• The responses observed are complex and
unpredictable, making it impossible to achieve
selective actions
Therefore, ganglionic blockade is rarely used
therapeutically
• Mecamylamine :to reduce nicotine craving
• Trimethaphan:in treatment of hypertensive
emergencies and dissecting aortic aneurysm
– Controlled hypotension
51

52. 52
Neuromuscular Blocking Drugs

53. Neuromuscular Blocking Drugs
• Block cholinergic transmission between
motor nerve endings and the nicotinic
receptors on the neuromuscular end plate of
skeletal muscle
• These neuromuscular blockers are structural
analogs of acetylcholine, and they act either
as
– Antagonists (nondepolarizing type) or
– Agonists (depolarizing type) at the receptors on
the end plate of the neuromuscular junction
53

54. 54

55. …
• Neuromuscular blockers are clinically useful
during surgery for
– Producing complete muscle relaxation, without
having to employ higher anesthetic doses to
achieve comparable muscular relaxation
– Higher doses of anesthesia may produce
respiratory paralysis and cardiac depression,
increasing recovery time after surgery
• Agents are also useful in facilitating
intubation as well
55

56. Nondepolarizing (competitive) blockers
56

57. Nondepolarizing …
• Curare
– A generic term for various South American arrow
poisons
– Has been used for centuries for immobilizing and
paralyzing wild animals used for food
57

58. Nondepolarizing…..
• Include Tubocurarine, Atracurium,
Mivacurium, Pancuronium, Vecuronium,
Rocuronium, and Rapacuronium
• Are all reversible antagonists of Ach at NMJ
• d-tubocurarine is the prototype drug in this
group.
58

59. Nondepolarizing….
• Classified
• Based on duration of drug action
– Long acting
• D-tubocurarine, metocurine, pancuronium, and
doxacurium
– Intermediate acting
• vecuronium and atracurium, Rocuronium
– Short acting
• mivacurium
59

60. • Based on chemical nature
– Natural alkaloids or their congeners
• D-tubocurarine, alcuronium
– The ammonio steroids
• Pancuronium..newer vecuronium and rocuronium
• Pancuronium has No histamine release but blocks
muscarinic receptors …vagal blockade and tachycardia
– The benzylisoquinolines
• Atracurium, mivacurium ( metabolized by plasma
esterases)
• Devoid of vagolytic and ganglionic blocking actions but
show a slight propensity for histamine release
• Important in pts with renal failure
60

61. Nondepolarizing ….
• Mechanism of action
• At low dose
– Competitive blockers ..at motor end plate
• At high doses
– Nondepolarizing blockers can block the ion
channels of the end plate…in a fashion w/c is non
competitive
– This leads to further weakening of neuromuscular
transmission, and it reduces the ability of
acetylcholinesterase inhibitors to reverse the
actions of nondepolarizing muscle relaxants
61

62. Nondepolarizing ….
• Not all muscles are equally sensitive to blockade
by competitive blockers
1st Small, rapidly contracting muscles of the face
and eye are most susceptible and are paralyzed
first, followed by the fingers
2nd the limbs, neck, and trunk muscles are paralyzed
3rd the intercostal muscles are affected, and lastly,
the diaphragm muscles are paralyzed
• Recovery in the reverse order
• Those agents (for example, tubocurarine,
mivacurium, and atracurium), which release
histamine, can produce a fall in blood pressure,
flushing, and bronchoconstriction
62

63. Nondepolarizing…
Effect on the autonomic ganglia and muscarinic
sites
• Tubocurarine
– partial blockade probably is produced both at
autonomic ganglia and at the adrenal medulla, which
results in a fall in blood pressure and tachycardia.
• Pancuronium shows less ganglionic blockade at
common clinical doses
• Atracurium, vecuronium, doxacurium,
pipecuronium, mivacurium, and rocuronium are
even more selective
63

64. Nondepolarizing…
• Pharmacokinetics
All NM blockers are injected intravenously..slowly
and poorly absorbed orally
Poor membrane penetration
Do not enter cell or BBB…so ???
Many of the drugs are not metabolized
– For example, tubocurarine, pancuronium, mivacurium,
metocurine, and doxacurium are excreted in the urine
unchanged
– vecuronium and rocuronium are deacetylated in the
liver, and their clearance may be prolonged in patients
with hepatic disease
64

65. 65

66. Nondepolarizing ….
• Therapeutic uses:
–As adjuvant drugs in anesthesia during
surgery to relax skeletal muscle
–To facilitate intubation as well as during
orthopedic surgery
66

67. Nondepolarizing (competitive)
blockers
• The choice of an agent will depend on how
quickly muscle relaxation is needed and on
the duration of the muscle relaxation
67

68. 68

69. 69

70. 70

71. Nondepolarizing (competitive)
blockers
• Adverse effects:
– In general, agents are safe with minimal side effect
• Drug interactions
Cholinesterase inhibitors (competative)
– Can overcome the action ...but with increasing
dosage they cause depolarizing block
– Neostigmine, pyridostigmine, edrophonium
– Sugammadex (not competitative, doesn’t
increase Ach level)
• Can rapidly inactivate steroidal neuromuscular blocking
drugs by forming an inactive complex, which is excreted
in the urine
71

72. Drug interactions..
Halogenated hydrocarbon anaesthetics
Potentiation …. By
–Nervous system depression at sites proximal
to the neuromuscular junction
–Increased muscle blood flow
–Decreased sensitivity of the postjunctional
membrane to depolarization
isoflurane (most); sevoflurane, desflurane,
enflurane, and halothane; and nitrous oxide
(least) (anesthatics)
72

73. Drug interactions ..
Aminoglycoside antibiotics
– E.g gentamicin or tobramycin inhibit acetylcholine
release from cholinergic nerves by competing with
calcium ions
Calcium-channel blockers
– may increase the neuromuscular block of
tubocurarine and other competitive blockers as
well as depolarizing blockers
73

74. Drug interactions …
• Other drugs with significant interaction for
both
• trimethaphan , opioid analgesics, procaine,
lidocaine, quinidine, phenelzine, phenytoin,
propranolol, magnesium salts, corticosteroids,
digitalis glycosides, chloroquine,
catecholamines, and diuretics
74

75. Toxicology
• Prolonged apnea, cardiovascular collapse,
those resulting from histamine release, and,
rarely, anaphylaxis
75

76. Depolarizing agents
• Mechanism of action
–Attach to the nicotinic receptor and acts like
acetylcholine to depolarize the junction
–Unlike acetylcholine, which is instantly
destroyed by acetylcholinesterase, the
depolarizing agent persists at high
concentrations in the synaptic cleft,
remaining attached to the receptor for a
relatively longer time and providing a
constant stimulation of the receptor
76

77. Depolarizing agents
Phase I
• The depolarizing agent first causes the
opening of the sodium channel associated
with the nicotinic receptors, which results in
depolarization of the receptor
– This leads to a transient twitching of the muscle
(fasciculations)
– Because excitation-contraction coupling requires
end plate repolarization ("repriming") and
repetitive firing to maintain muscle tension, a
flaccid paralysis results
77

78. Depolarizing agents
Phase II
• Continued binding of the depolarizing agent
renders the receptor incapable of transmitting
further impulses. With time, continuous
depolarization gives way to gradual
repolarization as the sodium channel closes or
is blocked
– But the repolarized channel is resistance to
depolarization
78

79. 79

80. 80

81. Depolarizing agents
Actions
• The respiratory muscles are paralyzed last
• Succinylcholine
– Initially produces short-lasting muscle
fasciculations, followed ,within a few minutes, by
paralysis
– Does not produce a ganglionic block except at
high doses,
– But it does have weak histamine-releasing action
81

82. Depolarizing agents
Therapeutic uses:
• succinylcholine is useful when rapid
endotracheal intubation is required during the
induction of anesthesia (a rapid action is
essential if aspiration of gastric contents is to
be avoided during intubation)
– Because of its rapid onset and short duration of
action
• It is also employed during electroconvulsive
shock treatment
82

83. Depolarizing agents
Pharmacokinetics
• Succinylcholine is injected intravenously.
• Its brief duration of action (several minutes)
results from redistribution and rapid
hydrolysis by plasma cholinesterase
• It therefore is usually given by continuous
infusion
83

84. Depolarizing agents
Adverse effect
• Malignant Hyperthermia:
• Mostly when a depolarizing agent is used with
anesthetic ..
• Halogenated hydrocarbon anesthetic with
succynlchoine
• Uncontrolled release of Ca from sarcoplasmic
reticulum is the initiating step
• Susceptibility is related to an autosomal
dominant trait(defect in ryanodine receptor,L-
type calcium channel), is associated with certain
congenital myopathies such as central core
disease… 84

85. Depolarizing agents
Malignant hyperthermia
• Clinical feature includes
–Contracture
–Rigidity, and
–Heat production from skeletal muscle
resulting in severe hyperthermia,
accelerated muscle metabolism, metabolic
acidosis, and tachycardia
85

86. Depolarizing agents
Malignant hyperthermia
Treatment
– Administration of dantrolene(IV), which blocks
release of Ca2+ from the sarcoplasmic reticulum
of muscle cells, thus reducing heat production and
relaxing muscle tone
– Rapid cooling, inhalation of 100% oxygen, and
control of acidosis should be considered
86

87. ....
• Apnea:
Administration of succinylcholine to a patient who
is genetically deficient in plasma cholinesterase or
has an atypical form of the enzyme can lead to
prolonged apnea due to paralysis of the
diaphragm
• Hyperkalemia:
Succinylcholine increases potassium release from
intracellular stores.
This may be particularly dangerous in burn patients or
patients with massive tissue damage in which
postassium is been rapidly lost from within cells
In patients with congestive heart failure who are
receiving digoxin or diuretics
87

88. …
Other adverse effects
• Increased intraocular pressure
• Increased intragastric pressure
• Muscle pain
88

89. Common adverse effect to both
Respiratory paralysis
• Treatment
– Should be by positive-pressure artificial
respiration with oxygen and maintenance of a
patent airway until recovery of normal respiration
is ensured
– With the competitive blocking agents, this may be
hastened by the administration of neostigmine
methylsulfate (0.5 to 2 mg intravenously) or
edrophonium (10 mg intravenously, repeated as
required)
89

90. …
• To reverse other toxic effect
– Neostigmine to reverse skeletal muscle blocking
action but may aggravate hypotention,and may
induce bronchospasm
– Atropine to reverse muscarinic stimulation
– Antihistamines
90

91. ….
Contraindication/caution
• In patients with
– Non traumatic rhabdomyolysis
– Ocular lacerations,
– Spinal cord injuries with paraplegia or
quadriplegia, or muscular dystrophies
91

92. 92

93. Summery of clinical use of
Neuromuscular Blocking Drugs
• Surgical relaxation
• Tracheal intubation
• Control of ventilation
– In critially ill patients who have ventilatory failure
from various causes (eg, severe bronchospasm,
pneumonia,chronic obstructive airway disease)
• Treatment of convulsions
93

94. Others
• Many drugs and toxins block neuromuscular
transmission by other mechanisms
• Interference with the synthesis or release of
ACh
Include
• Vasamicol,hemicholinim,Botulinium toxin
• But most of these agents are not employed
clinically except botulinium toxin
94

95. • Reading assignment
– Botulinium Toxin
95

96. …
Botulinium Toxin
• Administered locally into muscles of the orbit in
the management of ocular blepharospasm
(abnormal contraction of the eye lid muscles )and strabismus
(Abnormal alignment of one or both eyes)
• Has been used to control other muscle spasms
and to facilitate facial muscle relaxation
• Injected into the lower esophageal sphincter to
treat achalasia
• Other spasms :hemifacial spasms, adductor
spasmodic dysphonia, oromandibular dystonia,
cervical dystonia
96

97. 97

98. …
• Non muscular use of Botulinium toxin
– Hyperhidrosis of the palms and axillae
– Chronic migraine
98