PARASYMPATHMIMETICS

1
PARASYMPATHMIMETICS
PARASYMPATHMIMETICS
PARASYMPATHMIMETICS
2
CHOLINOMIMETICS, MUSCARINIC AGONISTS,
CHOLINOCEPTIVE AGONISTS

• A) Direct Parasympathomimetics
• 1-Choline Esters
• a- Acetylcholine b- Methacholine.
• c-Carbachol. d-Bethanechol.
•   2-Cholinomimetic Alkaloids
• a- Pilocarpine. b-Muscarine.
• c-Arecoline. d. oxotremorine

3

• B) Indirect Parasympathomimetic
  (Anti-Cholinesterases)
• They inhibit cholinesterase enzymes ( and
  include both TRUE and Pseudocholinesterasea).
• They causes an accumulation of the endogenous
  A.Ch. leading to the stimulation of both the
  Muscarinic and Nicotinic receptors to provide the
  corresponding actions.

4

• 1-Reversible Anti-Cholinesterasees
• a- Quaternary Alcohols Edrophonium.
• It is not a substrate for the Enzyme.
• b- Carbamate Derivatives.
• Are Substrate for the Enzyme.
• -Physostigmine.
• -Neostigmine.
• - Pyridostigmine .

5

• 2-Irreversible Anti-Cholinesterases
  (Organophosphorus Compounds)
• Non-competitive Irreversible inhibition of
  enzyme.
• a. Di- isopropyl flurophosphate (DFP )
• b. Echothiophate, used as eye drops in the
  treatment of glaucoma

6

• c. Tetraethyl pyrophosphate (TEPP)
• d. Nerve gases ( Tabun, Sarin Soman )
• e. Agricultural Insecticides ( Parathion,
  Malathion Fenthion)
• f. Metrifonate used in treatment of urinary
  bilhaziasis

7
A- Choline Esters

• 1- Acetylcholine
• Synthesis
• a- Active Uptake of Choline by Cholinergic
  Varicosity (Rate Limiting Step)
• N.B. hemicholinium Inhibits Neuronal Uptake of
  Choline.
• b- In Mitochondria of Cholinergic Nerve Terminal
  (Varicosity)
• Acetate Co. A ATP ? Acetyl Co. A
  ADP
• c-In Cytoplasm of cholinergic Nerve Ending
  (Varicosity)
• Choline Acetyl Co.A ? Acetylcholine
  Co.A 

8

• Absorption and Fate
• a. ACh is ineffective orally and be given
  parenterally.
• b. Rapidly hydrolyzed in the blood and tissues
  to choline and acetic acid by the enzyme
  cholinesterase.

9

• Types of cholinesterase
• There are two types of cholinesterase
• a. True cholinesterase
• - occurs in the CNS , red blood cells and in all
  cholinergic structures.
• - it is responsible for the hydrolysis of ACh
  released at the cholinergic sites.

10

• b. Pseudocholinesterase
• It occurs in the liver and plasma.
• It hydrolyzes drugs with structural similarity to
  Ach.
• - The enzyme has two active sites, the anionic
  site ( containing glutamate ) and the estratic
  site which contains serine amino acid

11

• Properties of Ach
• Very short duration of action because of its
  rapid hydrolysis by both enzymes.
• Not used as a drug.
• Not be given orally.

12
Pharmacological Actions of Acetylcholine

• There are two main actions called 1- Muscarinic
  actions
• 2- Nicotinic actions.

13
Muscarinic actions
14

• 1 - Actions on The Cardiovascular System
• A- On the heart
• a- Negative Chronotropic ? ? SAN ? decreases
  The heart rate (Bradycardia).
• b- Negative inotropic on Atrium (decreases the
  force of contraction).
• c- Negative Dromotropic ( ? A-V
  Conduction).This will reduce the cardiac output

15

• B- On the blood vessels
• A.Ch. Non - innervated muscarinic receptors
  on Intact Endothelium ? releases Endothelium
  Derived Relaxing Factor (EDRF, Nitric Oxide) ?
  increases the cGMP levels ? vasodilatation.
• C. Blood pressure
• Caues fall in blood pressure as a result of
  the bradycardia and vasodilatation.

16

• The induced vasodilatation of both peripheral
  and systemic blood vessels leads to
• a- Reduction of the systemic ABP
• b- Reduction of the PVR
• c- Reduction of the blood flow to some organs
  e.g. kidney and the liver

17

• 2- Actions on Gastrointestinal tract
• a- Motility Stimulation
• b- Sphincters Relaxation
• c- Secretions Increase

18
(No Transcript)
19

• 3- Urinary bladder (Evacuation)
• a- Detrusor Muscle Contraction (
  urination)
• b- Sphincters Relaxation (
  urination)

20
(No Transcript)
21

• 4- Eye
• a- Circular Muscles ( M3) Contraction (
  Miosis)
• b- Ciliary Muscles (M3) Contraction for near
  vision ( to see the near objects)

22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
(No Transcript)
26
(No Transcript)
27

• 5- Glands
• Sweat, salivary and lacrymal Stimulation to
  increase secretions.
• 6- Lung
• a- Bronchial Muscles Contraction (
  Bronchoconstriction)
• b- Bronchal glands Stimulation ( Increased
  secretions)

28
(No Transcript)
29
(No Transcript)
30
(No Transcript)
31
Nicotinic Actions
32

• 1-Stimulation of Autonomic Ganglia and Adrenal
  Medulla (Nn)
• a. Acetylcholine stimulates the autonomic
  ganglia, resulting the release of noradrenaline
  from the sympathetic nerve endings .

33

• b. Stimulation of the adrenal medulla release of
  adrenaline and noradrenaline .
• This effect is blocked by the ganglionic
  blockers, hexamethonium

34

• 2- Motor end plate (Nm)
• Acetylcholine induces muscle twitching.
• This effect is blocked by the neuromuscular
  junction blocker decamethonium and flaxedil.

35
Acetylcholine reversal In presence of atropine
high doses of acetylcholine produce an increase
in blood pressure instead of a decrease.
36
Therapeutic uses of Ach

• Not used therapeutically because of
• a. Its multiplicity in action,
• b. Its rapid inactivation by cholinesterase
  enzymes.
• c. Being ineffective orally.
• Except during cataract , it produces immediate
  brief miosis

37
2- Synthetic Cholinomimetic esters

• They are characterized by
• 1. More stable than ACh
• 2. More selective than Ach
• 3. Have longer duration of action
• 4. Active orally and parentrally

38

• They can be prepared either by
• 1. B-methylation, increases the muscarinic
  activity.
• 2. Addition of carbamate increases the
  stability and resist the enzymatic hydrolysis.

39

• Properties
• 1- ALL are quaternary ammonium compounds
• 2- More specific.
• 3- Less metabolised Hence have longer duration
  of action and Effective Orally.
• 4- NEVER be injected I.V. or I.M. ? toxicity is
  abolished by ATROPINE.

40

• Contraindicated in
• a- Bronchial asthma ?(Bronchospasm and
  increased secretion).
• b- Peptic Ulcer ? (?Gastric Acid
  Secretions).
• c- Angina Pectoris ? (Hypotension ?
  reduction of coronary blood Flow).
• d- Thyrotoxicosis ? (Atrial
  Fibrillation).

41

• Therapeutic Uses of methacholine
• 1. Paroxysmal atrial tachycardia
• 2. Raynaud's disease
• 3.Diagnosis of atropine (Belladonna) toxicity
• How? Because Normally when injected,
• It causes colics, salivation, lacrimation,
  sweating.
• These symptoms do not appear in case of
  atropine toxicity

42

• Uses of carbachol
• Used for treatment of Glaucoma and cataract
  extraction.
• Uses of Bethanechol ( Urecholine )
• 1. Paralytic ileus
• 2. Post operative retention of urine, in
  absence of mechanical obstruction
• 3. Gastric atony
• 4. Glaucoma

43
A- Methacholine

• a- Its nicotinc actions are not clear
• b- It has longer duration of action
• c- Its muscarinic actions are more
  prodominent on the cardiovascular system than on
  GIT and urinary bladder.

44

• B- Carbamylcholine ( Carbachol)
• a- It has a longer duration of action
• b- Its nicotinc action is nearly similar to
  Ach
• c- Its muscarinic actions are more
  prodominent on the eye , urinary bladder and GIT.
• C-Bethanechol ( Urecholine)
• It is completely similar to that of carbachol
  , but the main difference is that it does not
  have nicotinic actions.

45
II- Cholinomimetic Alkaloides
46
II- Cholinomimetic Alkaloides Pilocarpine

• Pilocarpine is a direct prasympathomimetic
  tertiary amine.
• a. It is a naturally occurring alkaloid obtained
  from Pilocarpus jaborandi leaf.
• b. It is readily absorbed from the GIT.
• c. Inactivated by cholinesterase enzyme .

47

• d. It has longer duration of action.
• e- Passes the B.B.B (Avoids in Parkinsonism).
• f- Excreted in urine.

48
Pharmacological actions

• A. Eye
• Locally in the eye as eye drops, it produces
• a. Miosis
• b. Contraction of the ciliary muscle leading
  to accomodation for near objects
• c. Decreases the intra-ocular pressure.

49

• B. Exocrine glands
• Increases the secretion of the exocrine
  glands especially salivary (sialagogue action)
  and sweat (diaphoretic action)
• Smooth muscles . C
• It increases the tone and motility of the GIT,
  urinary bladder and bronchoconstriction.

50

• Therapeutic uses
• 1. Treatment of glaucoma, the drug of choice in
  the emergency of the increased IOP in both open
  and closed angel glaucoma.
• 2. To counteract the mydriatic effect of
  atropine, homatropine and eucatropine .

51

• 3. Alternately with mydriatics to break adhesions
  between the iris and lens
• 4. To stimulate salivation in dry mouth (
  xerostomia)
• 5. Treatment of atropine overdosage.

52
(No Transcript)
53
(No Transcript)
54
(No Transcript)
55
(No Transcript)
56
(No Transcript)
57
(No Transcript)
58
(No Transcript)
59
(No Transcript)
60
(No Transcript)
61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
ANTICHOLINESTERASES
65
(No Transcript)
66

• They are indirectly acting cholinomimetics.
• They block the enzymatic hydrolysis of
  acetylcholine, by inhibition of
  acetylcholin-esterase and plasma
  pseudocholinesterase.
• They increase the local acetylcholine
  concentrations and Accumulation of the endogenous
  A.Ch. inducing both the Muscarinic and
  Nicotinic actions.

67

• 1-Reversible Anti-Cholinesterasees
• They weakly inhibit acetylcholinesterase by
  reversible association with the anionic site and
  hindering access to acetylcholine
• 2-Irreversible Anti-Cholinesterases
  (Organophosphorus Compounds)
• These agents act by covelantly phosphorylating
  the hydroxyl group of serine on the enzyme.

68

• 1. Reversible anticholinesterases
• a. Short acting
• Edrophonium
• it is mainly used for diagnostic
  purposes
• b. Medium acting
• - Physostigmine
• - It is a natural alkaloid). (tertiary
  amine).
• - Absorbed from the GIT and pass the BBB
  producing central stimulation.

69

• - Neostigmine (prostigmine), has a direct
  stimulant effect on skeletal muscles.
• - Pyridostgmine
• - Tacrine, Donepezil, Rivastgmine, galantamine (
  3ary amines in Alzheimer)
• - Ambenomium , - Demecrium and - Benzyrinium.

70

• Mechanism of action
• A. Short acting
• Compete with ACh for the active sites on the true
  and pseudocholinestrases .
• Bind to the anionic site of the enzyme with ionic
  bond so they have brief and short duration.

71

• B.Medium acting
• - They bind to the anionic site and estratic
  site of the enzyme.
• - The carbamylated enzyme has a slower rate of
  hydrolysis and recovery.
• - The duration of action of these drugs is
  relatively longer.
• Neostgmine 2-4 h, Pyridostgimine 3-6 h.

72

• 2. Irreversible anticholinesterases (Organic
  phosphate esters)
• a. Diisopropylflurorophosphate (DFP)
  (Isoflurophate)
• b. Tetraethylpyrophosphate
• c. Ecothiophate
• d. Insecticides e.g. parathion
• e. Nerve gases e.g. sarin, tabun and soman.

73

• Mechanism of action
• 1. They bind to the serine OH group in the
  estratic site .
• 2. The inactivated phopshorylated enzyme is
  very stable.
• 3. The recovery of the enzyme activity depends
  on the synthesis of new one.

74

• It takes few weeks ( Reactivation of the
  non-aged enzyme may be occurred by cholinesterase
  reactivator. pralidoxime (PAM).
• 4. War gases and pesticides interact only with
  the estratic site of the enzyme and have no
  anionic.
• Ecothiophate which binds also to the anionic
  site.

75
Pharmacological actions

• I. Muscarinic actions
• 1. Cardiac muscles bradycardia and decrease
  conductivity
• 2. Smooth muscles
• a. Eye iris miosis due to contraction of
  circular muscles
• ciliary muscles contraction and
  accommodation for near vision.

76

• b. Bronchi bronchoconstriction and
  stimulation of secretion
• c. GIT increase tone and motility and
  stimulation of gastric secretions
• d. Urinary bladder evacuation of the bladder
  and urination.
• 3. Exocrine glands Stimulation of sweat,
  salivary and lacrymal secretions.

77

• II. Nicotinic actions
• Skeletal muscles
• These drugs potentiate the action of Ach on
  the muscle by their anticholinesterase activity.
• 2. Autonomic ganglia no marked effect.

78

• III. Effect on the CNS
• Tertiary compounds as physostigmine, tacrine
  and donepezil pass the blood brain barrier.
• They produce symptoms of CNS stimulation as
  restlessness, insomnia, tremors and convulsions
  followed by depression.

79

• These effects are
• - Due to the activation of the muscarininc
  receptors.
• - Antagonized by atropine.
• - Greater with irreversible anticholinesterase
  compounds.

80
Therapeutic uses
81

• 1. Diagnosis and treatment of myasthenia gravis
• 2. Treatment of glaucoma (eserine, demecarium)
• 3. Teatment of postoperative paralytic ileus and
  urine retention (benzpyrinium)
• 4. Antidote for atropine poisoning
• 5. Alzheimer (tacrine and donepezil)
• 6. To counteract the mydriatic effect of
  homatropine and eucatropine
• 7. Alternatively with mydriatic to break adhesion
  between iris and lens.

82

• 1. Diagnosis and treatment of myasthenia gravis
• What is myasthenia gravis?
• Myasthenia Gravis mean "Grave muscle weakness." 
• Myasthenia gravis is a auto-immune disorder,
  characterized by progressive muscle fatigue and
  weakness.
• Usually involves muscles around the eyes, mouth,
  throat and limbs.

83

• A. A disease of impaired neuromuscular
  transmission.
• B. Characterized by weakness and rapid
  fatigability of the skeletal muscle, drooping of
  the upper eye lid (ptosis).
• C. Usually occurs between age group of 20 and 40,
  and more common in women.
• D. This disease affects 12000 individuals,
  100,000 case in USA.

84
(No Transcript)
85
(No Transcript)
86
(No Transcript)
87
(No Transcript)
88
(No Transcript)
89

• Etiology
• 1. Autoimmune disease, due to the presence of
  antibodies against Ach receptor protein.
• 2. The presence of circulating curare-like
  substances.
• 3. A defective rate of synthesis of
  acetylcholine.
• 4. Excessive amount of acetylcholinesterase in
  the neuromuscular junction.

90
(No Transcript)
91
Myasthenia gravis occurs when the immune system
makes antibodies that damage or block many of the
muscle's acetylcholine (ACh) receptors on the
surface of muscle cells. This prohibits ACh from
binding to the damaged receptors and acting on
the muscle, which reduces muscle contractions,
leading to weakness and fatigue.
92
(No Transcript)
93
Antibody (Y-shaped) binds and reduces the number
of acetylcholine receptorand makes the
transmission of the signal difficult
There are enough number of acetylcholine
receptortransmitting the signal from the nerve
to the muscle.
94
(No Transcript)
95
(No Transcript)
96

• A.Diagnosis of Myasthenia gravis
• Administration of edrophonium (IV) which is a
  short acting anticholinesterase.
• B.Treatment of Myasthenia gravis
• a. Anticholinesterases
• Neostigmine
• It has a direct action on the muscle. It is used
  in combination with atropine to block the
  unwanted muscarinic effects.

97

• Pyridostgmine (Neostgmine substitutes, mestinone)
• Ambenonium More selective on the skeletal
  muscles, effective orally, longer duration of
  action (advantage over neostgmine)
• b. Azathioprine ( immunosuppressant agent).
• c. Thymectomy
• d. Plasma exchange
• e. Prednisolone ( as corticosterids)

98

• 2. Treatment of glaucoma (eserine, demecarium)
• 3. Teatment of postoperative paralytic ileus and
  urine retention (benzpyrinium)
• 4. Antidote for atropine poisoning
• 5. Alzheimer (tacrine and donepezil)
• 6. To counteract the mydriatic effect of
  homatropine and eucatropine
• 7. Alternatively with mydriatic to break adhesion
  between iris and lens.

99
II- Parasympatholytics
II- Parasympatholytics
II- Parasympatholytics
100

• . These are drugs that block the peripheral
  muscarinic receptors.
• . They inhibit the muscarinic actions of acety
  -lcholine and other parasympathomimetics.
• They include
• a-Naturally occurring Belladonna alkaloids
• e.g. Atropine, Hyoscine ( Scopolamine)
• b- Atropine substitutes

101
I. Atropine

• Pharmacological Actions of Atropine
• 1. Actions on the smooth muscles
• A. Eye
• B. Bronchi
• C. Gastrointestinal tract
• D. Urinary tract
• E. Blood vessels
• F. Exocrine Glands

102

• A. Eye
• Local application of atropine in the eye or its
  systemic administration produces
• a. Mydriasis due to paralysis of the constrictor
  pupillae muscle containing M3 receptors ( passive
  mydriasis)
• b. Paralysis of the ciliary muscle (cycloplegia)
  leading to loss of accomodation to near objects.

103

• c. Increased intra-ocular tension due to closure
  of the canal of Schlemm and obstruction of the
  spaces of Fontana
• d. Loss of the light reflex
• e. Inhibition of lacrimation
• The duration of action of atropine following its
  local application to the eye is 7 10 days.

104

• B. Bronchi
• Bronchodilation and reduction of bronchial
  secretion
• C. Gastrointestinal tract
• a. Reduction of tone and motility of the GIT
• b. Reduction of gastric secretion (volume and
  total acid content)

105

• D. Urinary tract
• a. Ureter antispasmodic
• b. Urinary bladder relaxation of the detrusor
  muscle, contraction of the sphincter and trigone
  leading to retention of urine.

106

• E. Blood vessels
• a. Therapeutic doses do not produce significant
  action on the blood vessels and blood pressure
• b. Toxic doses dilatation of cutaneous blood
  vessels especially those in face area (Atropine
  flush).

107

• F. Exocrine Glands
• - Reduction of salivary secretions producing dry
  mouth
• - Reduction of the Lachrymal secretion
• - Reduction of sweating producing dry skin and
  arise of body temperature (atropine fever) and
  is usually observed after toxic doses of atropine.

108

• 2. Action On The Central Nervous System
• Stimulant Actions
• a. Stimulation of the respiratory center causing
  respiratory stimulation
• b. High doses stimulate the Cerebral cortex
  leading to restlessness, hallucinations and
  delirium.
• This central excitation is followed by
  depression

109

• Depressant Actions
• a- Decreased tremors and rigidity, so can be
  used in treatment of parkinsonism
• b- Inhibits vomiting centers Antiemetic action

110

• 3. Cardiovascular system
• Heart
• Small doses bradycardia due to blockade of M1
  receptors on the inhibitory prejunctional neurons
  thus increasing the release acetylcholine.
• b. Large doses produce tachycardia due to
  blocking of the postsynaptic M2 receptors

111

• Therapeutic uses
• 1- Preanesthetic medication
• Half an hour before general anesthesia
• a. Decrease salivary and bronchial secretions
• b. Protect the heart from excessive vagal tone
• c. Counteract the inhibitory effect of
  morphine on the respiratory center

112

• 2- Antispasmodic in cases of intestinal , biliary
  and renal colics
• 3- In case of Heart block due to myocardial
  infarction , over dose of digitalis or
  propranolol.
• 4- Treatment of severe bradycardia

113

• 6- Hyperhidrosis (excessive sweating)
• 7- locally in the eye
• a. In cases of iris and corneal ulcer to
  prevent the adhesions
• b. In alternations with miotics to breakdown
  recent adhesions between the iris and lens

114

• 8- Antidote to parasympathomimetics poisoning
  e.g. organophosphorus poisoning.
• 9- In case of Parkinsonism
• 10- To treat Peptic ulcer
• 11- Bronchial asthma however, it has the
  disadvantage that the sputum becomes viscid and
  more difficult to expel.
• 12- Nocturnal enuresis

115

• Side Effects
• 1. Dryness of mouth , blurred vision and
  tachycardia
• 2. Retention of urine may occur in patients with
  enlarged prostate
• 3. Acute glaucoma may be precipitated
• 4. In children, cutaneous vasodilatation with
  flushing of the skin and elevation of body
  temperature

116

• Contraindications
• 1. It can precipitate an acute attack of
  glaucoma.
• 2. Patients with enlarged prostate as atropine
  may precipitate urine retention.

117

• 2. Hyoscine (Scopolamine)
• 1. It has a CNS depressant effect and usually
  causes drowsiness and euphoria.
• 2 .It has a depressant action on vestibular
  function and is useful in the management of
  motion sickness and Meniere disease.

118

• 3. It produces amnesia and was used with
  morphine to produce a state of twilight sleep
  during delivery.
• 4. In parkinsonism, hyoscine has antitremor
  activity therefore reducing tremors

119
Synthetic Atropine substitutes

• 1- Mydriatic Atropine substitutes
• They have shorter duration of action
• 1. Homatropine
• 2. Eucatropine
• 3. Cyclopentolate
• 4. Tropicamide

120

• 2- Antisecretory Antispasmodic Atropine
  substitutes
• Propantheline,
• Oxyphenonium,
• Hyoscine butylbromide
• Glycopyrrolate,
• Dicyclomine

121

• They are used for treatment of spasms of the GIT,
  bile duct and urinary tract
• Pirenzepine telenzepine these drugs are
  selective M1 receptor antagonists , used in the
  treatment of peptic ulcer.

122

• 3- Antiparkinsonism atropine substitutes
• 1. Trihexphenidyl
• 2. Benztropine (cogentin)
• 3. Biperiden

123

• 4- Decreasing urinary bladder activity
• A. Oxybutynin to relieve bladder spasm after
  urologic surgery and to reduce involuntary
  voiding in patients with neurologic disease.
• B. Tolterodine, an M3- selective antimuscarinic,
  is used in adults with urinary incontinence.
• C. Propiverine

124

• 5- Atropine substitutes used in bronchial asthma
• Ipratropium
• It has more selective bronchodilators effect with
  a lesser action on sputum viscosity.
• It can be used in combination with ?2 agonists as
  a bronchodilators in asthma.