Cholinergic agonists
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Transcript of Cholinergic agonists
CHOLINERGIC AGONISTS
Cholinoceptor-Activating Drugs
Parasymapthomimmetics
Case Scenario
In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.
Cholinergic agonists
Direct Actinga.Alkaloids
Muscarine, Pilocarpine*, Nicotine*, Lobeline*
b.Choline Esters
ACh, Methacholine, Carbachol, Bethanechol
In-direct ActingReversible
Edrophonium, neostigmine, physostigmine, demecarium
Irreversible
Ecothiophate, isoflurophate, Soman, parathion, malathion
Reactivator of acetylcholinesterase ---
Pralidoxime
poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysisby cholinesterase. Acetylcholine is very rapidly hydrolyzed
Methacholine is resistant to hydrolysis, Carbamic acid esters Carbachol and Bethanecholmore resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action.
Lobeline ………………………plant derivative similar to nicotine.
* Tertiary natural cholinomimetic alkaloids
Structural classification ---Indirect acting drugs
1. Simple alcohols bearing a quaternary
ammonium group:
Edrophonium
2. Carbamic acid esters of alcohols bearing quaternary or tertiary ammonium groups :
Carbamates:
Neostigmine, Pyridostigmine, Physostigmine, Ambenonium, Demacarium
3. Organophosphates:
Isoflurophate
Ecothiophate
Cholinergic Neurotransmitter
CHOLINERGIC NEUROTRANSMITTER
ACETYLCHOLINE
SITES WHERE Ach IS RELEASED AS TRANSMITTER:
Preganglionic fibers to adrenal medulla.
Postganglionic fibers of parasympathetic division.
Autonomic ganglia (both sympathetic and parasympathetic)
Neuromuscular junction
Cholinergic Receptors
Nicotinic (nAChR)
Muscarinic (mAChR)
Cholinoceptors are members of either G protein–linked (muscarinic) or ion channel (nicotinic) families on the basis oftheir transmembrane signaling mechanisms.
THREE MECHANISMS BY WHICH BINDING OF NEUROTRANSMITTER LEADS TO A CELLULAR RESPONSE AND EFFECT:
RECEPTORS COUPLED TO A ION CHANNEL
Cholinergic nicotinic receptors
Ions
Change in membrane potential or ionic
concentration in cell.
Ions
RECEPTORS COUPLED TO DIACYLGLYCEROL (DAG) & INOSITOL TRIPHOSPHATE
DAG IP3
Protein phosphorylation & increase in intracellular Ca
Intracellular effect
Cholinergic muscarinic receptor
Mechanism of action of
Indirect acting Cholinergic agonist
Mechanism of Action
ACETATE
ACETYLCHOLINESTERASEACETYLCHOLINE
Ach
CHOLINE
1.Choline + Acetylated Enzyme
H20
2. Acetylated Enzyme Acetate + Enzyme
ACETYLCHOLINESTERASE INHIBITORS
Actions of cholinergic agonist on
various systems
(organ system effects)
EYE:
Contraction of sphincter pupillae
muscle--- pupil constricts (Miosis).
Contraction of ciliary muscle -----------
---- accommodation of lens for
Near vision
CVS:The action of Ach on heart mimic the effects of VAGAL stimulation.
v The normal vagal activity regulates the heart by release of Ach at SA node.
Vasodilatation
SA node:
Atria:
Atrioventricular:
Ventricles: Small decrease in contractile strength.
Decrease in heart rate ( -ve chronotropic effect).
Decrease in force of contraction ( -ve Inotropic effect).
Decrease in rate of conduction in SA & AV nodes ( -ve dromotropic effect).
G.I.T: (increased secretory and motor activity)
Increase salivary secretions
Stimulates intestinal secretions
Stimulates intestinal motility.
Sphincters are relaxed
RESPIRATORY SYSTEM:
Stimulates bronchiolar secretions
G.U SYSTEM:
Increase tone of detrusor muscle
Relaxes sphincter and trigone.
Miscellaneous secretory glands
Stimulate secretion of sweat, lacrimal and nasopharyngeal glands
CNS
vTremors
vHypothermia
v Increased locomotor activity
v Improved cognition
Therapeutic Uses
of
Cholinergic agonist
EYE
Glaucoma Drugs used:Direct acting agonists Pilocarpine
Methacholine CarbacholCholinesterase inhibitors
Physostigmine Demacurium Echothiophate
Isoflurophate
Gastrointestinal and Urinary Tract
Post operative ileus
Congenital megacolon
Postoperative or postpartum nonobstructive urinary retention Reflux esophagitis Sjogren’s syndrome --- Pilocarpine / CEVIMELINE
Most commonly used choline ester:
Most commonly used Cholinesterase inhibitors:
Atony or paralysis of stomach or bowel following surgical manipulation
Bethanecol
Neostigmine
Neuromuscular junction
Myasthenia gravis
Autoimmune diseaseAntibodies against:---------- nicotinic receptors
on post junctional end platesClinical findings: Ptosis, DiplopiaDifficulty in speaking and swallowing Extremity weakness
Treatment of myasthenia gravis
Cholinesterase inhibitors
CHOLINESTERASE INHIBITORS
Diagnostic test for myastheniav EdrophoniumLong term therapy for myastheniavNeostigmine v Pyridostigmine vAmbenonium
Neuromuscular blockage(pharmacological paralysis)
caused by:Nondepolarizing neuromuscular relaxants
DRUGS USED FOR Rx
Neostigmine Edrophonium
HEART
Supraventricular tachyaryhthmiasParoxysmal supraventricular tachycardia
Drug used:
Edrophonium Adenosine / Verapamil / Diltiazem
Antimuscuranic poisoning
Atropine poisoning
Drug Used:
Physostigmine
Why Physostigmine ?why not some other cholinesterase inhibitor
Because
Physostigmine is
naturally occurring
tertiary amine
greater lipid solubility
CNS
Alzheimer's Disease
Drugs Used:
TacrineDonepezilGalantamine Rivastigmine
Alzheimer's disease (AD) or senile dementia of Alzheimer's typeneurodegenerative disease results in: a loss of mental functions due to the: deterioration of brain tissue.
Its exact aetiology (cause) is still unknown
Clinical features
usual first symptom: memory loss. behavioral changes, like confusion, disorientation, sudden periods of defiance, abusive behavior, or violence, etc. in people who have no previous history of such behavior.
Toxicity
Direct acting Muscarinic stimulantsCause predictable signs of muscarinic excess
NauseaVomitingDiarrheaSalivationSweatingCutaneous vasodilatationBronchocontriction Certain Mushrooms contain muscarinic alkaloid ---Treatment is with:Atropine – 1-2 m parenterally
Cholinergic Crises/Poisoning
Medical emergency
Especially in
Rural communities/ cultures --- Use of
Cholinesterase inhibitor (organophosphorus) insecticide
Wild Mushrooms are commonly eaten
Chemical warfare nerve gases
Mushroom poisoning ---Rapid onset (15-30 min), Delayed onset (6-12 hour)
Management of Cholinergic Crises
Decontamination
Activated charcoal
Gastric Lavage.
Atropine (to counter the muscarinic effects)
Mild symptoms of nerve agent (nerve gas) or insecticide exposure:2 mg/0.7 mL by AtroPen auto-injector into midlateral thigh followed by 2 additional 2 mg/0.7 mL (AtroPen) injections given in rapid succession are recommended 10 minutes after receiving the first injection
Pralidoxime (Cholinesterase reactivator) …… to relieve neuromuscular blockage.
v Mark I NAAK, or MARK I Kit, is United States military nomenclature for the "Nerve Agent Antidote Kit". It is a dual-chamberautoinjector
v Brand names: ATNAA (ANTIDOTE TREATMENT - NERVE AGENT, AUTO-INJECTOR) has both the
atropine and the pralidoxime in one syringe injected into the muscles of an outer thigh or into the buttocks.
Diazepam: to control seizures
Mechanical Ventilation - Respiratory paralysis