II.

Autonomic Drugs
 Drugs acting on the parasympathetic nervous system:
1. Cholinergic drugs OR Parasympathomimetics.
2. Anticholinergic drugs OR parasymaptholytics.

 Drugs acting on the sympathetic nervous system:

1. Adrenergic drugs OR symapthomimetics.
2. Adrenergic blockers OR sympatholytics.
1.Drugs acting on
the cholinergic system
6hours
 Introduction
Cholinergic neurons
1. Locations:

1. Preganglionic fibers terminating in

the adrenal medulla.

2. Autonomic ganglia.

3. Postganglionic fibers of parasympathetic

nervous system.

4. Somatic nervous system (voluntary muscles).

 3. Neurotransmission

Na+
Muscarinic
ACH Receptor
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+ Acetylcholine
Action Potential Choline

Na+ H+
ACH Nicotinic
Choline Acetate
Receptor
Choline

Presynaptic neuron
Postsynaptic target
 4. Cholinergic Receptors
(cholinoceptors)
1- Muscurinic Receptors (M or mACh):
 G-protein–coupled receptors (metabotropic receptors).
 Muscarine, an alkaloid in certain poisonous mushrooms.
 There are five subclasses of muscarinic receptors
Subtypes and location(5):
 M1-R in gastric parietal cells.
 M2-R in cardiac cells and smooth muscles.
 M3-R in exocrine glands and smooth muscles.
Intracellular mechanisms
Receptor agonists activate signal
transduction pathways
O CH3

NH3 CH3 C O CH2 CH2 N CH3

CH3
Acetylcholine

M3 muscarinic R

(+) Phospho-
Gq lipase C
PIP2

COOH IP3 Diacylglycerol

Increase Ca2+ Activate Protein

Kinase C

Response
 2- Nicotinic receptors (N or nAch):
Nicotine binds to cholinergic receptors, which called nicotinic
receptors(5subunits).

Location: CNS, adrenal medulla, autonomic ganglia and NMJ.

Sub-Types:

 Nn(1)-R in autonomic ganglia

 Nm(2)-R in skeletal muscles (NMJ).

Intracellular mechanism:

They are Ion-channel R, Na/K channel.

2. CHOLINERGIC
DRUGS.
Parasympathomimetics.
Classification:

A- Direct acting cholinergic drugs:

1. Choline esters: e.g. Acetylcholine, Carbachol

and Bethanechol.

2. Cholinergic alkaloids e.g. Pilocarpine & Nicotine

B- Indirect acting cholinergic drugs:

1. Reversible: e.g. Neostigmine and Physostigmine

2. Irreversible: e.g. Organophosphate compounds

10
Direct acting type

1- ACETYLCHOLINE
 Actions:

1. Muscarinic actions: those produced at postganaglionic

cholinergic nerve endings

2. Nicotinic actions: those produced by stimulation of all

autonomic ganglia and neuromuscular junction.
Muscarinic actions:
1. CVS:
Heart: slow heart rate(Bradycardia and negative chronotropy)
Blood vessels: vasodilator (Due to release of EDRF, NO).
BP: Decreases the blood pressure.

2. GIT (Evacuation of bowel):

Stimulates the tone and motility.
Relaxation of sphincters.
Increase HCl secretion
3. Urinary tract: contraction of Detrusor and relaxation of
Trigone and sphincter--------Evacuation of bladder
4. bronchioles: bronchoconstriction.
5. Eyes:
 Miosis (contraction of circle sphincter muscles of iris).
 Accommodation of near vision (contraction ciliary muscles).
 Reduce Intra Ocuar Pressure(IOP).
6. Exocrine glands: stimulates salivary, gastric, lacrimal, bronchial and sweat gland
secretions
SLUDGE
 Salivation
 Lacrimation
 Urinary incontinence
 Diarrhea
 Gastrointestinal cramps
 Emesis
2- CARBACHOL(M&N)
& Bethanechol (M only)
Therapeutic uses of cholinesters:
Glaucoma, paralytic ileus & retention of
urine(postoperative)

Contraindications of cholinester:
1. Bronchial asthma.
2. Hyperthyroidism.
3. Coronary insufficiency.
4. Mechanical obstruction of the GIT and urinary bladder.
3. PILOCARPINE:
It is natural alkaloid.
Marked Muscarinic actions
Therapeutic uses: GLAUCOMA (emergency.. IOP)
The mechanism: the opening of trabecular
meshwork around schlemm canal (due to
miosis) and  drainage.
Side effects:
CNS disturbance, Sweating and salivation.
INDIRECT ACTING CHOLINOMEMTICS
(ANTICHOLINESTERASE)

ACETYLCHOLINESTERASE (AchE(
 It is an enzyme that cleaves the
acetylcholine into choline and
acetate.
 It is Membrane bound enzyme.

AchE inhibitors are agents that

increase the Ach at the
synaptic space, which interact
with the cholinreceptor (M and
N) in the ANS and NMJ.
I- REVERSIBLE ANTICHOLINESTERASE

CLASSIFICATION:

1. carbamates: they include:

 Quaternary ammonium compounds such as Neostegmine.

 Tertiary ammonium compounds such as Physostigmine.

2. Simple alcohol with quaternary ammonium

group such as Edrophonium. (diagnosis MG)
1- PHYSOSTIGMINE
 Natural.
 Tertiary amine (cross to CNS).
 Actions on N, M in ANS and NMJ
Therapeutic uses: Overdoses of Anticholinergic drug such as
atropine.
2- NEOSTIGMINE
• Synthetic.
• Quaternary nitrogen.
• Not enter to CNS
Therapeutic uses:

1. Management of MYSTHENIA GRAVIS.

2. Reversal of effect of muscale
relaxants e.g. tubocurarine
3. Post operative urine retention
Tacrine.
Donepezil.
Rivastigmine, & galantamine

Use:
Alzheimer disease (a deficiency of cholinergic neurons)
Toxicity of Tacrine : Hepatotoxicity.
Note:
These drugs delay the progression of Alzheimer disease, Not
stop its progression.
II- IRREVERSIBLE ANTICHOLINESTERASE

Organophosphate compounds:
Covalent binding to AChE
They include:
 insecticides: parathion & malathion.
 They are highly lipid
soluble compounds all toxic compounds EXCEPT
Ecothiophate.
Toxicity of organophosphates

Acute toxicity:
 paralysis of respiratory
muscle
 excessive bronchial
secretion
 death.
Chronic toxicity: neuropathy
and demyelination of axons.
Drug Treatment
1. Atropine.

2. cholinesterase reactivator (OXIMES):

 Examples of oximes: pralidoxime

(PAM)

 Dose: PAM is I.V. infusion

1-2g/15-30min.
Summary
Type: Direct Indirect
Reversible irreversible

Chemistry: Choline ester Natural Tertiary Quaternary Organo

Synthetic choline Tertiary amine ammonium phosphates
amine compound

Drugs: Ach Carba Bethane Pilocarpine Physo Neo Ecothiophate

chol chol stigmine stigmine

Receptors Non- Non- Muscurinic Muscurinic Non-selective

selective selective (M3-R)
(M&N)
Site All site: Eye GIT & Eyes Eyes Urinary Eyes
of GIT, GIT & urinary & CNS system &
actions Eyes..etc urinary system Exocrine & GIT muscles
system glands
Clinical Not used Glaucoma Paralytic Glaucoma Glaucoma Myasthenia Glaucoma
uses (prototype) ileus & & gravis, (Ecothiophate)
& Xerostomia Atropine paralytic
Urinary (dry mouth) toxicity ileus
retention & urinary
retention
Contra- • Bronchial asthma. Simple alcohol
indications • Hyperthyroidism. Edrophonium
• Coronary insufficiency. diagnosis
• Mechanical obstruction of the GIT and
urinary bladder MG
 Study Questions
1. If an ophthalmologist wants to dilate the pupils for an eye
examination, which drug/class of drugs is
theoretically useful?
A. Muscarinic receptor activator (agonist)
B. Muscarinic receptor inhibitor (antagonist)
C. Pilocarpine
D. Neostigmine
2. In Alzheimer disease, there is a deficiency of cholinergic neuronal
function in the brain. Theoretically, which
strategy is useful in treating symptoms of Alzheimer disease?
A. Inhibiting cholinergic receptors in the brain
B. Inhibiting the release of acetylcholine in the brain
C. Inhibiting the acetylcholinesterase enzyme in the brain
D. Activating the acetylcholinesterase enzyme in the brain
3. A patient who received a nondepolarizing neuromuscular blocker
(NMB) for skeletal muscle relaxation
during surgery is experiencing mild skeletal muscle paralysis after the
surgery. Which drug could reverse
this effect of NMBs?
A. Pilocarpine
B. Bethanechol
C. Neostigmine
D. Atropine
Part II:
Anticholinergic drugs or
parasympatholytics
 ANTICHOLINERGIC
DRUGS
Anticholinergics fall into two major families:

1. Antinicotinics which include

 Ganglion blockers such as hexamethonium & trimethaphan
 Neuromuscular blockers such as gallamine & tubocurarine.

2. Antimuscarinics include
 Tertiary amines such as atropine, scopolamine & tropicamide.
 Quaternary amines such as propantheline & ipratropium.
Sites of action
ANTIMUSCURINIC DRUGS
Classification
 Natural drugs: e.g. Atropine
 Synthetic drugs: e.g. Ipratrpium
ATROPINE:
 Natural alkaloid from Atropa belladonna
 It is reversible competitive muscurinic blocker
 It is excreted unchanged by kidney 60%.
 Actions
1. Eye: Mydriasis.
 Cycloplegia (loss ability to accommodate).
 Increase the IOP.
2. GIT:
 reduces the gastric motility & secretions
3. Urinary system:
 reduces the hypermotility of
urinary bladder
 urinary retention.
4. CVS:
Tachycardia.
Vasoconstriction.
5. CNS:
Lower dose: sedation.
Higher dose: excitation
and hallucination
6. Secretions:
all secretions of the body are suppressed
 Lacrimal secretion: cause sandy eye.
 Salivary secretion: cause dry mouth
 Sweating secretion: atropine fever.
7. Respiratory system:
 bronchodialtation.
 Reduce secretions.
Adverse effects:
At low doses: dry mouth, blurred vision,
tachycardia and Retention of urine.

Contraindications:
 Glaucoma.
 Bladder outlet obstruction.
 Prostatic enlargement patients.
2- IPRATROPIUM & TIOTROPIUM:
It is quaternary derivative of atropine.
Ipr. short-acting muscarinic antagonist (SAMA).
Tio. long-acting muscarinic antagonists (LAMAs).
 Use: in the acute management of
bronchospasm in asthma and chronic
management of asthma
 3. Scopolamine
 Tertiary amine plant alkaloid.

 Scopolamine has greater action on

the CNS (unlike atropine, CNS effects
are observed at therapeutic doses).

 Longer duration of action as

compared to atropine

4. Benztropine and trihexyphenidyl :

Use: adjunct agent in Treatment of Parkinson disease

5. Oxybutynin (M3-R antagonist):

Use: Management of overactive bladder and urinary incontinence
II- GANGLIONIC BLOCKERS
They act on the nicotinic receptors of both parasympathetic and
sympathetic autonomic ganglia

such as Hexamethonium & Trimethaphan

Nicotine
• A component of cigarette smoke.
• It is without therapeutic benefit and is deleterious to health.
• Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in
stimulation and then in paralysis of all ganglia.
• The stimulatory effects are complex and result from
• increased release of neurotransmitters, due to effects on both sympathetic and
parasympathetic ganglia.
Study question.

Which of the following drugs could theoretically improve asthma

symptoms?

A. Bethanechol

B. Pilocarpine

C. Pyridostigmine

D. Atropine
III.Neuromuscular
junction blockers
Neuromuscular junction
blockers
Two types:
1.Nondepolarizing 2. Depolarizing
(competitive) (noncompetitive)
they include: they include: succinlycholine.

d-tubocurarine (dtc)
binds to the endplate nicotinic
cholinoceptors without exciting
them, acting as a competitive
antagonist towards ACh.
By preventing the binding of
released ACh, it blocks
neuromuscular transmission.
 d-TUBOCURARINE

Source: Curare is the term for plant-derived arrow

poisons of South American natives.
When struck by a curare-tipped arrow, an animal
Therapeutic uses
skeletal muscle relaxant during surgical operations
Side effects: bronchospasm, urticarial and
hypotension
Antidote: cholinesterase inhibitor(neostigmine)
 Drug interactions
1. Cholinesterase inhibitors such as neostigmine: overcome the action of
nondepolarizing NMBs. However, with increased dosage, cholinesterase
inhibitors can cause a depolarizing block due to elevated ACh
concentrations at the end plate membrane. If the NMB has entered the ion
channel (is bound to the receptor), cholinesterase inhibitors are not as
effective in overcoming blockade

2. Halogenated hydrocarbon anesthetics: Desflurane enhances

neuromuscular blockade by exerting a stabilizing action at the NMJ.

3. Aminoglycoside antibiotics: such as gentamicin inhibit ACh release from

cholinergic nerves by competing with calcium ions. (synergism)

4. Calcium channel blockers: CCBs may increase the neuromuscular

blockade of competitive blockers.
SUCCINYLCHOLINE
(SUXAMETHONIUM)

• Like ACh, succinylcholine acts as agonist at endplate nicotinic

cholinoceptors
• It produces muscle relaxation.
• Unlike ACh, it is not hydrolyzed by acetylcholinesterase.
However, it is a substrate of nonspecific plasma cholinesterase
(pseudocholinesterase)
Therapeutic uses:
 Rapid endotracheal intubations.
 During electroconvulsive shock treatment.

Adverse effects:
Hyperthermia, Apnea & Hyperkalemia
Note:
cholinesterase inhibitors are unable to counteract the effect of
succinylcholine.
Summary:
Type Anti-Muscurinic
Chemistry Natural Synthetic Synthetic Synthetic
Tertiary amine Quaternary
ammonium

Drugs Atropine Benztropine Pirenzepine Ipratropium

Clinical uses 1. Organophosphates Parkinson s disease Peptic ulcer COPD

toxicity
2. Pre-anesthetic drug
3. Antispasmodic
Side effects 1. Dry mouth CNS side effects Less side effects Less side effects
2. Dry hot skin
3. Blurred vision
4. Tachycardia.
5. Urinary retention

Contra 1. Glaucoma.
2. Prostatic
indications enlargement
3. Urinary outlet
obstruction
Summary: skeletal muscle relaxants
Type competitive Non-competitive
Drugs D-tubucurarine Atracurium succinylcholine
Chemistry Highly polar Highly polar Ester
Duration of action long intermediate Short
Site of action NMJ
Mechanism of Compete with Ach for N-R Combined with N-R and
action open Na-channel
Depolarization No Yes
Muscle twitching No Yes
Therapeutic uses Adjuvant in Endotracheal intubation
general anesthesia convulsion
Side effects Bronchospasm Bronchospasm Hyperkalemia
Hypotension Arrhythmia
Tachycardia. Glaucoma
Malignant hyperthermia
Sch apnea
MCQ
Case 1:
1. Which of the following 2. A patient develops urinary
drugs could theoretically retention after an abdominal
surgery. Urinary obstruction
improve asthma symptoms? was ruled out in this patient.
A. Bethanechol Which strategy would be
helpful in promoting
B. Pilocarpine urination?
C. Pyridostigmine A. Nicotine.
D. ipratropium B. Acetylcholine
C. Neostigmine.
D. Atropine.
 Case2:
3. A 40-year-old male presents to his family physician
with drooping eyelids, difficulty chewing and
swallowing, and muscle fatigue even on mild exertion.
Which agent could be used to diagnose myasthenia
gravis in this patient?
A. Atropine
B. Edrophonium
C. Pralidoxime
D. Echothiophate
 Case 3:
4. During an ophthalmic surgical procedure, the surgeon
wanted to constrict the pupil using a miotic drug.
However, he accidentally used another drug that caused
dilation of the pupil (mydriasis). Which drug was most
likely used?
A. Acetylcholine
B. Pilocarpine
C. Tropicamide
D. Bethanechol
Reference