Cholinergic And Adrenergic

Pharmacology

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 Introduction
Brain
CNS
Spinal
cord
Nervous
system Enteric
Rest and
PSNS
Digest
Autonomi
PNS
c
Flight and
SNS
Fear
Somatic

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Involuntary Body Functions Controlled By ANS
• Respiration
• Circulation
• Digestion
• Body temperature
• Metabolism
• Sweating
• Some endocrine glands and secretions
Neuro transmitters in the ANS include; acetylcholine,
norepinephrine(noradrenaline), epinephrine (adrenaline) and
dopamine 3
Body Responses – “rest and digest”
• Dilation of blood vessels in skin
• Decrease heart rate (bradycardia)
• Increase secretion of digestive enzymes
• Constriction of smooth muscle of bronchi
• Increase in sweat glands - cooling
• Contraction of smooth muscles of urinary bladder- Urinary
sphincter relaxation
• Contraction of smooth muscle of skeletal system

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Body Responses of SNS - “flight and fear”
• Dilation of pupils (mydriasis)
• Increase of heart rate, force of contraction and BP
• Decrease in blood flow to non essential organs
• Increase in blood flow to skeletal and cardiac muscle
• Airways dilate andrespiratory rate increases
• Blood glucose level increases
• Decrease in digestion

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Cholinergic Pharmacology

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Definitions
• Cholinergic neuron: a nerve cell which mainly uses the
neurotransmitter ACh to send its messages.
• Cholinergic receptor/cholinoceptor: are receptors that are
activated when they bind to ACh.
• Parasympathomimetic: drug that mimics the action of the
PSNS.
• Cholinomimetic: drug that mimics the action of the Ach.

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Cholinergic Receptors

Cholinergic
receptors

muscarinic Nicotinic

M1 M2 M3 M4 M5 Nm Nn

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• Muscarinic receptors are G-protein coupled
• Primarily located in autonomic effector cells in the heart, eyes,
smooth muscles, and glands of GIT and CNS
• M1,M3 and M5 – Gq
• M2 and M4 – Gi
• Nicotinic repeptors are ligand gated ion channels
• Nm is the muscle type while Nn is the ganglionic type

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Receptor Location Transducer Effects Agonist Antagonist
M1 Autonomic Increased IP3 Modulation of Oxotremorline Pirenzepine
ganglion cells, neurotransmiss ACh
gastric galnds ion
and
CNS(cortex,
hyppocampus,
corpus
startium)

M2 Heart and CNS Increased Slowing of Methacholine Triptramine

potassium heart rate and ACh
efflux conduction
Decreased
cAMP

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M3 Smooth Increased IP3 Contarction of Bethanechol Darifenacin
muscles of Increased smooth ACh
viscera, eyes, cGMP as a muscles and
exocrine resukt of nitric stimulation of
glands and oxide galndular
endothelium stimulation secretions
vasodilation

M4 Smooth Ddecreased ACh

muscles, salivation
secretory
galnds and
CNS

M5 CNS vasodilation ACh

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Receptor type Location Transducer Effects Agonist Antagonist

Nm Skeletel muscle Increased Stimulates Ach, carbachol, Tubocurarine,

end plate sodium influx contarction of suxamethonium atracurium,
skeletal muscle vecuronium,
pancuronium

Nn Autonomic Increased Neuronal Ach, carbachol, Trimethapan,

ganglia sodium influx excitation nicotine mecamylamine,
hexamethonium

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Cholinergic Drugs
• Often called parasympathomimetic drugs, because their action
mimics the action of the PSNS.
• Also called cholinomimetic.
• Stimulate parasympathetic nervous system in same manner as
does acetylcholine
• May stimulate cholinergic receptors directly or slow
acetylcholine metabolism at synapses (affect the enzyme
acetylcholinesterase)
• Cholinergic drugs are two types :
1.Direct acting
2.Indirect acting 13
 Cholinergic
drugs

Direct acting Indirect acting

(cholinergic agonist) (anticholinesterases)

Choline esters Alkaloids Reversible Irreversible

Ach(natural) Pilocarpine Neostigmine

Methacholine Muscarine Pyridostigmin Organophosphorus Carbamate
Physostigmine e
Carbachol Arecholine compounds esters
bethanechol Oxotremorine Distigmine
Rivastigmin
donepezil
Malathion
Parathion
Ecothiopate 14
Diazonin
Direct Acting Cholinergic Agonist

• They act by binding directly to cholinoceptors.

• Direct acting cholinergics are lipid insoluble.
• Do not readily enter the CNS so effects are peripheral.
• Resistant to metabolism by acetylcholinesterase.
• Effects are longer acting than with acetylcholine.

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Drug Effects of Cholinergic Agents
• Cardiovascular effect: Decreased heart rate( Bradycardia),
Vasodilation.
• Stimulate intestine and bladder to Increased gastric secretions,
Increased gastrointestinal motility and Increased urinary
frequency.
• Eyes: Stimulate pupil that is Constriction (miosis), Spasm of
accomodation, Reduced intraocular pressure (increased
outflow).
• Respiratory effects: Bronchial constriction, narrowed airways.
• Increased salivation and sweating.
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• Miosis
• Salivation
• Lacrimation
• Urination
• Bronchoconstriction
• Defaecation
• Decreased heart rate

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Acetylcholine
• One of the main neurotransmitters of the ANS.
• Released at preganglionic fibers of both the sympathetic and
parasympathetic nervous system
• Also released from postganglionic sympathetic neurons that
innervate the sweat glands and from motor neurons that
innervate the skeletal muscles
• It is a quaternary ammonium compound so cannot penetrate
the membrane.
• Does not have any therapeutic importance, because of rapid
inactivation by acetylcholinesterases.
• It has both Muscarinic & Nicotinic actions 18
Acetylcholine Synthesis

Acetyl co-A
Choline +
+ acetylcholine
acetate
Choline

Choline acetyl transaferase Acetyl cholinestarase

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Muscarinic ACh actions
Heart: M2
• SA node hyperpolarization (decrease in rate of diastolic
depolarizaton); reduction in impulse generation and Bradycardia
• AVN and PF; RP is increased, slowing of conduction,
partial/complete heart block
• Atrial fibres: Reduction in force of contraction and RP in fibers
abbreviated, APD increase
• Atrial fibrillation and flutter; nonuniform vagal innervations and
variation in intensity of effect on RP in different atrial fibres
• Decrease in ventricular contractility (less prominent)

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BloodVessels: M3
• Cholinergic innervations is limited: skin of face and neck, fall in
BP and flushing
• Present in all type blood vessel
• Penile erection
Smooth Muscles: M3 All are contracted
• Abdominal cramps, diarrhoea ; due to increased peristalsis and
relaxed sphincters
• Voiding of Bladder
• Bronchial SM contraction; dyspnoea, attack of asthma etc.

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Glands: M3
• Increased secretions: sweating, salivation, lacrimation,
tracheobronchial tree and gastric glands
• Pancreatic and intestinal glands
Eye: M3
• Contraction of circular fibres of Iris; miosis
• Contraction of Ciliary muscles; spasm of accommodation,
increased outflow and reduction in IOP

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Nicotinic Ach actions
 Autonomic ganglia: Both Sympathetic and parasympathetic
ganglia are stimulated, After atropine injection ACh causes
tachycardia and rise in BP
Skeletal muscle: causes contraction of skeletal muscle
 CNS: Does not penetrate BBB, Local injection in CNS –
complex actions (Acetylcholine is not used therapeutically – non
specific)

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Bethanechol
• Not hydrolyzed by acetylcholinesterases
Actions
• Directly stimulates M receptors causing increased intestinal motility &
tone
• It stimulates detrusor muscle of the bladder while trigone & sphincters
are relaxed causing expulsion of urine
Therapeutic Uses:
• Paralytic ileus
• Urinary retentions
• Helpful for postsurgical atony of the bladder and GI tract

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Pilocarpine
• An alkaloid, lipid soluble & is stable to hydrolysis by cholinsterases.
Actions:
• When applied locally to cornea Produces rapid miosis & contraction
of ciliary muscle to produce spasm of accommodation & vision is
fixed at particular distance making it impossible to focus for far
situated objects
Therapeutic Use :
• In Glaucoma it opens trabecular meshwork around schlemm’s
canal to cause drainage of aqueous humor and IOP immediately
decreases.
• Used to reverse mydriatic effects of atropine
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Mushroom poisoning
• Occurs after the ingestion of mushrooms that contain toxins
• Thousands of species of mushrooms, but only 100 species of
mushrooms cause symptoms
• 15-20 mushroom species are potentially lethal when ingested
(As a result of misidentification of the mushroom by an amateur)
• Toxins: Amatoxin, Gyromitrins (monomethylhydrazine),
Muscarine, Muscimol & ibotenic acid, Nephrotoxins
(norleucine), Myotoxins, Immunoactive toxins, Hemolytic toxins
and GI irritants

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Early Onset Mushroom Poisoning
• Occurs ½ to 1 hour – Symptoms are characteristic of Muscarinic
actions
• severe cholinergic symptoms like vomiting, salivation, lacrimation,
headache, bronchospasm, diarrhoea bradycardia, dyspnoea,
hypotension, weakness, cardiovascular collapse, convulsions and
coma
• Antidote is Atropine sulphate ( 2-3 mg IM every hrly till improvement)
Hallucinogenic Type
• Due to Muscimol or ibotenic acid present in A. muscria. Blocks
muscarinic receptors in brain and activate amino acid receptors. No
specific treatment – Atropine contraindicated.

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Late Onset Mushroom Poisoning
• Occurs within 6 - 15 hours
• Due to peptide toxins – Inhibit RNA and protein synthesis
• Irritability, restlessness, nausea, vomiting, bloody diarrhoea ataxia,
hallucination, delirium, sedation, drowsiness and sleep – Kidney,
liver and GIT mucosal damage
• Maintain blood pressure, respiration, Inj. Diazepam 5 mg IM
• penicillin, thioctic acid and silibinin
• Gastric lavage and activated charcoal
• Atropine contraindicated as it may cause convulsions and death
Delayed Onset Type (more than 24 Hours) – Nephrotoxic
syndromes 28
Indirect Acting Cholinergic Agonists
MOA
• They act through inhibition of Acetyl cholinesterase enzyme,
therefore increases Acetylcholine level in the synapse.
• Accumulation of acetylcholine then occurs which enhances the
activation of the nicotinic and muscarinic receptors

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Physostigmine
• Lipid soluble and capable of crossing the blood brain barrier.
• Well absorbed orally, Hydrolysed in liver and plasma by
esterases
• Long lasting action (4-8 hours)
• Penetrates cornea readily on local application in eye -
Muscarinic action on eye causing miosis and spasm of
accommodation on local application

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Uses
• Used as miotic drops to decrease IOP in Glaucoma
• To antagonize mydriatic effect of atropine
• To break adhesions between iris and cornea alternating with
mydriatic drops
• Belladonna poisoning, TCAs & Phenothiazine poisoning
• Alzheimer’s disease- pre-senile or senile dementia
ADRs
• CNS stimulation followed by depression
Atropine is the antidote in physostigmine poisoning.
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Neostigmine
• Lipid insoluble, cannot cross BBB
• Hydrolysed by esterases in liver & plasma
• Short duration of action (3-5 hours)
Uses
• Used in the treatment of Myasthenia Gravis to increase muscle
strength
• Post-operative reversal of neuromuscular blockade
• Post-operative complications such as gastric atony paralytic
ileus, urinary bladder atony
• Cobra snake bite
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ADRs
• Produces twitching & fasciculations of muscles leading to
weakness
• Atropine is the antidote in acute neostigmine poisoning
Donepezil
• Used in the treatment of mild to moderate Alzheimer’s disease.
• Helps to increase or maintain memory and learning capabilities.
Pyridostigmine
• Is the maintenance drug of choice for patients with Myasthenia
gravis.
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Uses Of Indirect Cholinergic Agonists
• Glaucoma – Pilocarpine, Physostigmine
• Edrophonium to test Myasthenia gravis
• Neostigmine and pyridostigmine in treatment of M. gravis.
• Postoperative paralytic ileus – Neostigmine
• Postoperative decurarization – Neostigmine(reverses muscle
paralysis)
• Cobra bite – edrophonium (prevent respiratory paralysis.
• atropine poisoning – Physostigmine (antogonizes both central
and peripheral effects).
• Alzheimer’s Disease – Donepezil, galantamine, tacrine,
rivastigmine.
• TCA, Phenothiazines, overdose – Physostigmine. 34
Side 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, bronchospasms
• Others: Lacrimation, sweating, salivation, loss of binocular
accommodation,

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Organophosphate Poisoning
• Acute toxic effects of irreversible cholinesterase inhibitors
• Leading to Cholinergic crisis which occurs because the
irreversible anticholinesterase poison binds to the enzyme
acetylcholinesterase and inactivates it. Thus, acetylcholine
remains in cholinergic synapses causing excessive stimulation
of muscarinic and nicotinic receptors.
• These agents (OP)are lipid soluble
• Can enter the body via the eye, skin, respiratory system and GI
tract.
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• Examples: organophosphate insecticides (malathion, parathion)
or nerve gases (sarin, tabun, soman)
• These agents cause excessive cholinergic stimulation
(muscarinic) and neuromuscular blockade
Signs and symptoms:
1. Irritation of eye, lacrimation, salivation, tracheo-bronchial
secretions, colic, blurring of vision, defaecation and urination
2. Fall in BP, tachycardia or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory paralysis
4. Irritability, disorientation, ataxia, tremor, convulsions and
coma 
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Treatment
1. Decontamination and termination of further exposure
2. Flushing poison from skin and eyes
3. Activated charcoal and Gastric lavage if needed ( GI
ingestion)
4. Airway maintenance – endotrachial intubation
5. Supportive measures – for BP/fluid and electrolyte
6. Specific antidote – Atropine – 2mg IV every 10 minutes till
pupil dilates and mouth dries i.e. atropinisation (up to 200
mg/day)

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7. To relieve the neuromuscular blockade by nicotinic effects,
give pralidoxime, a cholinesterase reactivator which causes the
anticholinesterase poison to release the enzyme
acetylcholinesterase
Dose: 1-2 gm IV slowly maximum 12 gms/24 hrs and 20-30
mg/kg/hour continuous IV infusion.

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Myasthenia Gravis
• Autoimmune disorder as a result of reduction in number of Nm
receptors caused by development of antibodies directed to
Nicotinic receptors in muscle end plate and Structural damage
to NM junction

• Symptoms: Weakness and easy fatigability, diaphragmatic

paralysis

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