drug acting on parasympathetic system

1. DRUG AFFECTING PARSYMPATHETIC
SYSTEM
The learning outcome or objectives of this lecture are:
1. Describe the anatomical projections of the sympathetic and parasympathetic autonomic
nervous system and features of autonomic neurotransmission.
2. List the steps in the synthesis, storage, release and inactivation of acetylcholine, and drugs
or agents that interface with those processes.
3. Describe the types of nicotinic and muscarinic and explain mechanism of
action of drugs that act on these receptors
4. List the classification of cholinomimetics, parasympatholytic (Anticholinergic) drugs, their
pharmacological activities, uses , adverse effects and contraindications.
Prof. Awad G. Abdellatif
Faculty of Medicine – University of Benghazi

2. Types of Nervous System

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General Features of Peripheral Autonomic Neurotransmission
Membrane Depolarization of
Pre- or Postganglionic Fiber
Calcium Entry into
Varicosity
Exocytosis of NT
Diffusion of NT Across
Neuroeffector Junction
or Synapse
Activation of NT
Receptors
Depolarization of Postganglionic
Fiber or Response of
Effector Cell
Nerve Impulse

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Action Potential
Na+
aab
ACH
Acetylcholinesterase
Na+
Parasympathetic Ganglionic Synapse
Preganglionic neuron Postganglionic neuron
Nicotinic
Receptor

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Action Potential
Na+
ACH
Acetylcholinesterase
Parasympathetic Organ Synapse
K+
G
Effector
Organ
Postganglionic neuron
Muscarinic
Receptor

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Nicotinic Receptors
(Activated by nicotine from tobacco)
M2
(Heart &
SM)
M3
(Heart &
SM)
M4
(SM &
Glands) M5
CNS
(?)
NM
(Neuromuscular)
NN
Autonomic
ganglia,
Adrenal
medulla &
CNS
(Blocked by Trimethaphan)
(Blocked by
Tubocurarine)
Muscarinic Receptors
(Activated by muscarine from Amanita muscaria)
Cholinergic Receptors: Receptors Activated by ACh
1(Nerve Cells)
cilitate impluse
nsmission)

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Formation
of IP3
Formation of
DAG
Release of
Intracellular
Calcium
Activation of
PKC
βγsubunit
Inhibition of
Adenylyl
Cyclase
Opening of
Potassium
Channels
Activation of PLC
Gq
Muscarinic Receptors
βγsubunit
Gi

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PARASYMPATHOMIMETICS
(CHOLINOMIMETICS):
Drugs that facilitate or mimic some or all
of the actions of the parasympathetic
nervous system
Muscarinic
receptor
agonists
Anticholinesterases

16. 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- Indirectelly acting sympathomimetics
(Anticholinesterases)
Alkaloids are not
metabolized by
cholinesterases

17. 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

18. 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.

19. Pharmacokinetic
• All quaternary cholinesters are hydrolyzed by AChE at differing rate and
extent
Ach:ACh is ineffective orally and rapidly hydrolyzed in the blood and tissues to choline and
acetic acid by the enzyme cholinesterase
-Duration of effect of large iv doses is 5-20sec
Methacholine:
-3-times more resistant to hydrolysis than ACh
-Duration of effect is more longer
-sc injection can produce systemic effect
-β methylation reduces affinity towards nicotinic receptors
Carbachol :
More resistant to hydrolysis has nicotinic and muscarinic
actions
Betanechol :
-Duration of action is further prolonged
Resist hydrolysis and has muscarinic activities
Muscarine:
-Absorption is poor
-No penetration into the CNS
-Toxic when ingested as mushroom

20. Types of choline estrase enzymes (CHE)
2. Pseudo AChE
(Butyrylcholinesterase):
• Wide spread, found in blood, liver, glia, tissues
• Main substrate:
-butyrylcholine, ACh is also substrate but,
metacholine is not a substrate
-It hydrolysed other esters as →benzoycholine,
procaine,propanidid (short-acting anaesth.),
succinylcholine(succamethonium)
• Genetic polymorphism:
A genetic defect in this enzyme →↓ in the
hydrolysis of ACh and Succinylcholine
1. True AChE:
• Confined only to:
a. Synapses
b. Cholinergic neuro-effecter
junctions
c. Erythrocytes
d. CNS
• Main substrate: ACh
• MW: 250.000, 4 major subunits
• Methacholine is also substrate,
• But not other esters of ACh
The enzyme has two active sites, the anionic site ( containing glutamate ) and
the estratic site which contains serine amino acid

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22. 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
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
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

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24. 2- Actions on Gastrointestinal tract:
a- Motility : Stimulation
b- Sphincters : Relaxation
c- Secretions : Increase
3- Urinary bladder: (Evacuation)
a- Detrusor Muscle : Contraction ( urination)
b- Sphincters : Relaxation ( urination)

25. 4- Eye :
a- Circular Muscles ( M3) : Contraction ( Miosis)
b- Ciliary Muscles (M3) : Contraction for near vision ( to see the near objects)

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Sympathetic: Contraction of radial muscle produces dilation (mydriasis)
Parasympathetic: Contraction of circular muscle produces constriction (miosis)

28. 5- Glands:
Sweat, salivary and lacrymal : Stimulation to increase secretions.
6- Lung :
a- Bronchial Muscles: Contraction ( Bronchoconstriction)
b- Bronchal glands : Stimulation ( Increased secretions)
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
b. Stimulation of the adrenal medulla release of adrenaline and noradrenaline . This effect
is blocked by the ganglionic blockers, hexamethonium
2- Motor end plate (Nm):
Acetylcholine induces muscle twitching. This effect is blocked by the neuromuscular
junction blocker decamethonium and flaxedil

29. Therapeutic Uses Choline esters:
1.Ach:
As eye drops for ophthalmic examination when miosis is needed
2. 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
3. Carbachol:
Used for treatment of Glaucoma and cataract extraction.
4. Bethanechol ( Urecholine )
1. Paralytic ileus
2. Post operative retention of urine, in absence of mechanical obstruction
3. Gastric atony
4. Glaucoma

30. Cholinergic Drugs
Adverse Effects
Adverse effects are a result of overstimulation of the PSNS
 Cardiovascular
 Bradycardia, hypotension, conduction abnormalities (AV block and
cardiac arrest)
 CNS
 Headache, dizziness, convulsions
 Gastrointestinal
 Abdominal cramps, increased secretions, nausea, vomiting
 Respiratory
 Increased bronchial secretions, bronchospasm

31. Other adverse effects:
(SLUDGE): →
 Salivation
 Lacrimation
 Urinary incontinence
 Diarrhea
 Gastrointestinal cramps
 Emesis
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).

32. Cholinomimetic alkaloids
Pilocarpine:
Natural Alkaloid, of Plant Origin. ,Tertiary amine
Kinetics:
1- Given Orally. & Passes the B.B.B. (Avoid in Parkinsonism)
2- Not affected by Ch.E
2- Excreted in urine.
Actions:
- Partial agonist on muscarinic receptors (m1>m2>m3)
1- Acts selectively on sweat, salivary, lacrimal and bronchial glands secretion
-Less selective on gut
2- Very Weak nicotinic.
Uses:
1. Hair lotion to promote growth of Hair.
2. Miotic Eye Drops
(Miosis + NO Twitches + IOP + Lacrymation).
a. Treatment of Glaucoma.
b. To Counteract Mydriatics. e.g after Fundus examination.
c. Alternatively with mydriatics to cut recent adhesions between iris & lens.
d. To treat dry mouth (Xerostomia).

33. Anticholinestrases
They inhibit Cholinesterases Accumulation of Endogenous
A.Ch
They are classified into:
I-Reversible Anti-Cholinesterasees:
They weakly inhibit acetylcholinesterase by reversible association with the
anionic and estratic site and hindering access to acetylcholine
II-Irreversible Anti-Cholinesterases: (Organophosphorus
Compounds):
These agents act by covelantly phosphorylating the hydroxyl group of serine
on the enzyme.
Mechanism of action of:
I-Reversible anti-cholinestrases:
A. Short acting (edrophonium)::
-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.

34. B.Medium acting (Carbamate deriveatives e,g
Physostigmine, neostgmine and pyridostigmine
- 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.
C. Irreversible anticholinesterases:
(Organic phosphate esters e.g Isoflurophate, tetraethylpyrophosphate, Ecothiophate,
parathione. And Nerve gases as . sarin, tabun and soman)
They:
Bind to the serine OH group in the estratic site forming very stable inacivated enzyme.
N.B:
- The recovery of the enzyme activity depends on the synthesis of new one.
-War gases and pesticides interact only with the estratic site of the enzyme and have
no anionic. Ecothiophate binds also to the anionic site.

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

36. 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.
These effects are:
- Due to the activation of the muscarininc receptors.
- Antagonized by atropine.
- Greater with irreversible anticholinesterase compounds
Therapeutic uses:
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

37. Edrophonium
It is a synthetic, Rapidly acting . Quaternary Alcohol
Kinetic:
1. Given IV (Immediate Onset & Short Duration “5 minutes”)
2. Attaches mainly to the anionic site
But Not substrate for the enzyme (i,e not Hydrolysed by the enzyme).
3. Excreted in Urine Unchanged.
*Actions:
1. Rapidly Reversible Anti-Ch.E. (produces muscarinic & nicotinic
actions)
3. Sk.m. stimulant, more specific than Neostigmine.
3. Ganglion stimulant.
Uses: I.V.
a. Diagnosis of Myasthenia gravis.
b. Differentiation between myasthenic & cholinergic crisis.
c.Curare poisoning (Edrophonium has to be repeated if used
alone)
d. Paroxysmal Atrial Tachycardia (PAT)

38. 2. Carbamate Derivatives: (Slowly acting)
(Physostigmine, Neostigmine& Neostigmine substitute)
a. Attach at both sites of the Enzyme.
b. They are Substrate for the Enzyme.(Hydrolysed slower than A.Ch.)

41. 1. Diagnosis and treatment of myasthenia gravis
Myasthenia gravis is a auto-immune disorder involves impaired neuromuscular
transmission .It is characterized by progressive muscle fatigue, weakness and dropping of
the upper lid (ptosis). It is usually involves muscles around the eyes, mouth, throat
and limbs. Usually occurs between age

46. These are drugs that block the muscarinic receptors. They inhibit the muscarinic
actions of acetylcholine and other parasympathomimetics.
They include:
I- Naturally occurring antimuscarinic drugs:
1- Atropine
2- Scopolamine (hyoscine)
II- Synthetic Antimuscarinic Substitutes
a) Tertiary amines :
1. Propantheline
2. Pirenzepine
3. Dicyclomine
4. Tropicamide
5. Benztropine
6. Oxybutynin
b) Quaternary amines
1. Ipratropium
2. Trospium

47. I. Atropine
Pharmacological Actions of Atropine :
1-Actions on the smooth muscles of:
A.The eye:
-Mydriasis due to paralysis of the constrictor pupillae muscle containing M3
receptors (passive mydriasis)
-Paralysis of the ciliary muscle (cycloplegia) leading to loss of accomodation to
near objects.
- Increased intra-ocular tension due to closure of the canal of Schlemm
- Loss of the light reflex and - Inhibition of lacrimation
The duration of action of atropine following its local application to the eye is 7 – 10
days.
B. Bronchi: Bronchodilation and reduction of bronchial secretion
C. Gastrointestinal tract:
a. Reduction of tone and motility of the GIT

48. 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.
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).
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

49. 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
Depressant Actions:
a- Decreased tremors and rigidity, so can be used in treatment of parkinsonism
b- Inhibits vomiting centers : Antiemetic action
3. Cardiovascular system:
Heart:
a. 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
Therapeutic uses:
1- Preanesthetic medication:
Given half an hour before general anesthesia : so it →
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

50. 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
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
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
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 of body temperature

51. Contraindications
1. It can precipitate an acute attack of glaucoma.
2. Patients with enlarged prostate as atropine may precipitate urine retention.
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’s disease.
3-In parkinsonism, hyoscine has antitremor activity therefore reducing tremors
Synthetic Atropine substitutes
1- Mydriatic Atropine substitutes:
They have shorter duration of action as compared to atropine
1. Homatropine
2. Eucatropine
3. Cyclopentolate
4. Tropicamide
Are used in ophthalmic examinations

52. 2- Antisecretory – Antispasmodic Atropine substitutes:
Propantheline, Oxyphenonium, Hyoscine butylbromide Glycopyrrolate,
Dicyclomine
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
3- Antiparkinsonism – atropine substitutes
1. Trihexphenidyl 2. Benztropine (cogentin) 3. Biperiden
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
5- Atropine substitutes used in bronchial asthma
Ipratropium: It has local effect, and does not inhibit mucoceliary movement
It has more selective bronchodilators effect with a lesser action on sputum viscosity.
It can be used in combination with b2 agonists as a bronchodilators in asthma.

53. Organ
system
Drugs Application
CNS Benztropine,trihexyphenidyl,
biperiden,
To treat parkinson’s disease
manifestations
scopolamine To prevent or reduce motion
sickness
Eye Atropine,homatropine,
cyclopentolate,tropicamide.
To produce mydriasis and
cycloplagia. Cyclopentolate is well
absorbed from conjunctival sac
into the eye
bronchi Ipratropium To cause bronchodilation in
asthma and chronic obstructive
pulmonary diseases
GIT Glycopyrrolate, dicyclomine,
methscopolamine
To reduce transient hypermotality
Genito-
urinary tract
Oxybutynin,
glycopyrrolate,dicyclomine,
tolterodine
To treat transient cystitis,
postoperative bladder spasm, or
incontinence
SUMMARY:

54. TOXICITY OF ANTIMUSCARINIC DRUGS:
Predictable toxicities Unpredictable toxicities
1. Predictable toxicities:
• Blockade of thermoregulatory sweating hyperthermia or Atropine fever
• Tachycardia or arrhythmias
• Most important toxicity in elderly patients include Acute angle closure glaucoma and
urinary retention particularly in pats. of prostatic hyperplasia.
• Constipation
• Blurred vision.
2. Unpredictable toxicities:
a. CNS
• Sedation, amnesia, delirium and hallucination, convulsions. (mad as hatter)
b. Cardiovascular
• Intra ventricular conduction blockade.
• Dilation of coetaneous vessels of arms, head, neck and trunk leading to “Atropine
flush.” (red as beet)

55. .
Treatment of Atropine Poisoning:
1. I.V. Physostigmine to correct Central &
Peripheral Manifestations.
2. Symptomatic treatment: -
- for Convulsions →→→ Diazepam.
- for Coma →→→ Artificial Respiration.
-for Oral Poisoning →→→ gastric lavage
-for fever →→→ Ice page