PHARMACOLOGY OF CHOLINERGIC DRUGS IN DETAIL.pptx

Pharmacology of
Autonomic Nervous System
(CHOLINERGIC DRUGS)
JYOTIRANJAN ROUL

AUTONOMIC NERVOUS SYSTEM
• The autonomic nervous system is part of peripheral nervous system
that acts unconsciously/ automatically in body.
• It regulates various body functions such as:
• Heart rate
• Digestion
• Regulation of BP
• Regulation of respiration
• Metabolism
• Exocrine and endocrine secretions
• Sexual arousal
• Urination
• Contractions and relaxations of smooth muscles

The autonomic nervous system is divided into three parts:
a) Parasympathetic nervous system [ Major NT is Ach]
b) Sympathetic nervous system [ Major neurotransmitter is
NE]
c) Enteric nervous system

PARASYMPATHETIC NERVOUS SYSTEM
•The parasympathetic nervous system originates in the
sacral spinal cord and medulla, physically surrounding
the sympathetic origin, and works in concert with the
sympathetic nervous system.
•Its main function is to activate the "rest and digest"
response and return the body to homeostasis after the
fight or flight response.
•This system utilises and activates the release of the
neurotransmitter acetylcholine.

Cholinergic receptors are muscarinic and nicotinic
receptors.
•Nicotinic acetylcholine receptors: These are responsive
to nicotine. These are present in skeletal muscles and
autonomic ganglia.
•Muscarinic acetylcholine receptors: These are
particularly responsive to muscarine. These are present
in heart, smooth muscles, blood vessels, different glands
and eyes.

MUSCARINIC RECEPTORS:
Five types of muscarinic receptors are M1, M2, M3, M4, and M5.
• M1 (neuronal): These are G-protein coupled receptors, it activate phospholipase
C and stimulate Inositol Triphosphate (IP3) and Diacylglycerol (DAG) and increase
intracellular calcium level.
• These receptors are present in CNS, gastric glands and salivary glands.
(Function: Gastric secretion, salivary secretion)
Location Function
Autonomic ganglion/junction
(Junction– I)
Activation of post ganglionic
neuron/fiber

• M2 (cardiac): These are G-protein coupled receptors, it act by opening
K+ channels which reduce cyclic AMP (cAMP) level. These are present
in Heart.
(Function: decrease heart rate, decrease force of contraction, decrease
conduction velocity)
Heart rate: chronotropy
Force of contraction: inotropy
Conduction velocity: dromotropy
Location Function
Heart  Decrease force of contraction (Negative Inotropic)
 Decrease heart rate (Negative Chronotropic)
 Decrease conduction (Negative dromotropic)

• M3 (glands, smooth muscles): These are G-protein coupled receptors,
it activate phospholipase C and stimulate Inositol Triphosphate (IP3)
and Diacylglycerol (DAG) and increase intracellular calcium level. These
are present in exocrine glands, GI smooth muscles, eye, and blood
vessel. (Function: Increase Glandular secretions (sweat, saliva,
ocular), Increase motility, vasodilatation
Location Function
GI smooth muscle Contraction of GI smooth muscle
Salivary glands Increase saliva secretion
Lacrimal glands Increase Lacrimal secretion
Gastric glands Increase gatric acid secretion
Urinary tract Contract urinary bladder, produce micturition
Bronchial smooth muscle Contraction
Eye Miosis (contraction of pupil), contraction of
sphincter pupil.

• M4 (CNS): Present in CNS (Function: Enhanced locomotion)
• M5 (CNS): Present in CNS (Function: Not Known
NICOTINIC RECEPTORS
• Two types of nicotinic receptors are present: NM and NN.
• NM: These are the intrinsic ion channel receptors, it act by opening various ion
channels like Na+, K+ and Ca+. It is the part of somatic systems. These are present
in the neuromuscular junction and skeletal muscle. Function: Skeletal Muscle
contraction.
• NN: These are intrinsic ion channel receptors. They act by opening various ion
channels like sodium ion, calcium ion, potassium ion. They are present in the
autonomic ganglion. Function: Stimulation of Autonomic ganglia

• CHOLINOMIMETIC (CHOLINERGIC) DRUGS
• Cholinomimetics (cholinergic/ parasympathomimetics): Drugs those
mimic the effects produced by stimulation of parasympathetic nervous
system. Examples: Acetylcholine (Ach), Pilocarpine, Arecholine,
Muscarine.
Direct acting agents
(Cholinergic agonists)
Indirect acting agents (Anticholinesterases:
Reversible Irreversible
Acetylcholine
Arecholine
Bethanechol
Carbachol
Muscarine
Pilocarpine
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Parathion
Malathion
Ecothiophate
Tabun
Sarin
Soman

Cholinesterase is a family of enzymes present in nervous
tissue, muscle. It hydrolyzes acetylcholine into choline and
acetic acid.
Anticholinesterases are the drugs that inhibit
cholinesterase, resulting in increased levels of ACh
everywhere in the body.

PHARMACOLOGY OF ACETYLCHOLINE (Ach)
• It is in found in both the central nervous system (CNS) and the peripheral
nervous system (PNS).
• It is one of the body's most important neurotransmitters, which are
chemicals used to transmit signals from one cell to another.
• The name acetylcholine is derived from its structure. It is a chemical
compound made up of acetic acid and choline.
• Cholinergic synapses are those in which transmission is mediated by
acetylcholine.
• Acetylcholine is not only the most common chemical messenger, but it
was also the very first neurotransmitter to be identified.
• It was discovered by Henry Hallett Dale in 1914, and its existence was
later confirmed by Otto Loewi. Both individuals were awarded the Nobel
Prize in Physiology/Medicine in 1936 for their discovery.

•SYNTHESIS, STORAGE, RELEASE AND DEGRADATION
•Synthesis: Acetylcholine is synthesized in certain neurons
(mainly cholinergic) from the compounds choline and acetyl-
CoA by enzyme choline acetyltransferase.
•Storage: After its synthesis, acetylcholine is packaged into
storage vesicles and is stored at the nerve ending.
•Release: Acetylcholine is released into synaptic cleft, when an
action potential arrives.
•Degradation: The enzyme acetylcholinesterase converts
acetylcholine into the inactive metabolites choline and acetate.

•Pharmacological actions
•M1 (neuronal): Gastric secretion increases so digestion
enhance.
•M2 (cardiac): Decreases heart rate, decreases force of
contraction, decreases conduction velocity.
•M3 (glands, smooth muscles): Increases glandular secretions
(sweat, saliva, ocular), increases motility, vasodilatation, and
miosis (decrease pupil size).
•M4 (CNS): Enhances locomotion
•NM: Inducesskeletal muscle contraction
•NN: Stimulates Autonomic ganglia

Uses
• Acetylcholine is a drug used as a parasympathomimetic preparation
for intraocular use.
• It is used as miotic during Ocular Surgery.
• It is used in cataract surgery too.
Adverse effects
• Common (ocular) side effects of Acetylcholine include:
• Corneal swelling
• Corneal clouding
• Corneal decompensation
• Rare (systemic) side effects of Acetylcholine include:
• slow heartrate
• flushing
• low blood pressure (hypotension)
• breathing difficulty
• sweating

SHORT NOTE ON PILOCARPINE
Pharmacokinetics
•This drug is readily absorbed from the gastrointestinal tract and
it is not hydrolyzed by cholinesterase enzyme. It is excreted
partly destroyed and partly unchanged in the urine.
Pharmacodynamics
•The drug directly stimulates the muscarinic receptors to bring
about all the muscarinic effects of acetylcholine.
Indications: Glaucoma

CHOLINE ESTERS
• CARBACHOL
• Pharmacokinetics: Carbachol is completely absorbed from the gastro intestinal tract
and is stable towards hydrolysis by cholinesterase enzyme; therefore it can be given
both orally and parenteraly with almost similar dosage.
• Pharmacodynamics: It has similar actions to those of acetylcholine with
pronounced effects on the gastro intestinal tract and the urinary bladder
• Indications: Glaucoma, Retention of urine (postoperative), Paralytic ileus
• Contraindications of Choline Esters
• Bronchial asthma because they may induce bronchial constriction and increase bronchial
secretions
• Hyperthyroidism because of the danger of inducing atrial fibrillation
• Peptic ulcer disease because of the increase in gastric acid secretion
• Coronary insufficiency because the hypertension produced will further compromise coronary
blood flow
• Mechanical intestinal and urinary outlet obstruction.

SHORT NOTES ON PHYSOSTIGMINE
• Pharmacokinetics: This drug is completely absorbed from the
gastrointestinal and is highly distributed throughout the body; it can
pass the blood brain barrier.
• Pharmacodynamics
• Inhibits the enzyme cholinesterase; therefore, it increases and prolongs
the effect of endogenous acetylcholine at the different sites. It has no
direct effect on cholinergic receptors.
• Indications:
• Glaucoma
• Atropine over dosage

SHORT NOTES ON NEOSTIGMINE
• Pharmacokinetics: This drug is poorly absorbed from the gastro
intestinal tract and is poorly distributed throughout the body; it cannot
pass the blood brain barrier.
• Pharmacodynamics: Just like physostigmine, it inhibits cholinesterase
enzyme; but unlike physostigmine, it has a direct nicotinic action on
skeletal muscles.
• Indications:
• Myasthenia gravis
• Paralytic Ileus
• Reversal of effect of muscle relaxants, e.g. tubocurarine
• Post-operative urine retention

MANAGEMENT OF GLAUCOMA
Introduction:
•It is a chronic progressive optic neuropathy caused by a group
of ocular conditions which lead to damage of the optic nerve
with loss of visual function.
•It is the second major cause of blindness. It occurs due to
increase in IOP (Intra Ocular pressure).
•IOP depends on the balance between production and removal
of aqueous humor.

• Classification: According to appearance of the angle, glaucoma is classified into two
types:
• Open angle Glaucoma:
• It is caused by the slow clogging of the drainage canals, resulting in increased intra
ocular pressure.
• It has a wide and open angle between the iris and cornea.
• It is observed in 90 % of glaucoma patients. It is the most common type of Glaucoma.
• It causes slow damage to the optic nerve causing gradual and irreversible loss of
vision.
• Closed angle Glaucoma:
• It is caused by blocked drainage canals, resulting in a sudden rise in intraocular
pressure.
• It is a less common form of glaucoma.
• It has a closed or narrow angle between the iris and cornea.
• It is also called narrow-angle glaucoma.

• Management:
• Open angle Glaucoma Management:
• Timolol Maleate 0.5% twice daily if patient is not asthmatic or not hypertensive, according
to response.
• Latanoprost 0.005 % /Travoprost 0.004 % (Prostaglandin analogues) one drop once daily in
the evening if patient is asthmatic or hypertensive, according to response.
• Acetazolamide 250-1000 mg /day orally can be given.
• Trabeculectomy can be done surgically.
• Closed angle Glaucoma Management:
• Systemic - Intravenous Mannitol 20% 1-2 gm per Kg over ½ an hr.
• Acetazolamide 250-1000mg per day in divided doses should be given.
• One drop of 2% Pilocarpine placed in the eye every 5 min till pupil constricts, then One
drop QID.
• One drop of Timolol Maleate 0.5 % twice daily.

•CLASSIFICATION OF ANTICHOLINESTERASE AGENTS.
Reversible Irreversible
Physostigmine
Neostigmine
Pyridostigmine
Edrophonium
Parathion
Malathion
Ecothiophate
Tabun
Sarin
Soman

•THERAPEUTIC USES OF ANTICHOLINESTERASE AGENTS
•Physostigmine: It is used along with pilocarpine in glaucoma.
It is also used as antidote in belladonna poisoning.
•Neostigmine: It is indicated in myasthenia gravis.
•Pyridostigmine: It is indicated in myasthenia gravis.
•Rivastigmine, donepezil and galantamine: They are used in
Alzheimer’s disease.
•Neostigmine: With atropine to stop respiratory paralysis (cobra
bite).

• A NOTE ON ORGANOPHOSPHATES
•Organophosphates such as echothiophate, isofluorophate, etc.
combine with cholinesterase irreversibly and thus hydrolysis is
very slow.
•They may be used in glaucoma.
•Other organophosphates like Parathion and Malathion are
used as insecticides. Poisoning with organophosphates is an
important cause of morbidity and mortality all over the world.
•It usually results from Occupational exposure as in persons
engaged in spraying insecticides, Accidental exposure, and
Ingestion of any of these compounds with suicidal intent.

• ORGANOPHOSPHOROUS POISONING AND ITS MANAGEMENT
• Organophosphates are used as insecticides, medicines.
• Examples of organophosphates include: Malathion, parathion, diazinon, fenthion,
dichlorvos, chlorpyrifos, ethion, Echothiophate, isoflurophate, Soman, sarin,
tabun, Trichlorfon
• Symptoms of organophosphate poisoning include:
• Increased saliva production
• Increased tear production
• Diarrhea
• Vomiting
• Miosis
• Sweating
• Muscle tremors
• Confusion

• Treatment:
• Treatment of organophosphate poisoning includes atropine (Anticholinergic
activity), pralidoxime (Cholinesterase reactivator), and diazepam
(benzodiazepines).
• The following steps are followed in treatment:
• Rapid treatment is necessary to prevent fatal effect.
• Patient needs to be hospitalized ideally in I.C.U.
• Complete rest to affected individual
• Gastic lavage, Endotracheal intubation for proper respiration to be done
• Atropine sulphate(2 mg IV slowly) and repeated every 10-12 minutes till pupils
are dilated
• Oximes (pralidoxime) I gram in 5 ml distilled water IV. If this is not available,
blood transfusion may need to be considered.
• Frusemide 40-80 mg. IV
• General supportive measures

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