overview - indirect cholinergic agonism (ache inhibition) - muscarinic antagonism (emphasis on drugs...
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Overview
• - Indirect cholinergic agonism (AchE inhibition)
• - Muscarinic antagonism (emphasis on drugs and organ effects)
• - Nicotine-Ach receptor (emphasis on drugs and therapeutics)
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Indirect cholinergic agonists
Inhibitors of acetylcholinesterase
-Increase acetylcholine concentration and lifetime by inhibiting degradation
-Act by binding to AchE active site causing reversible(non covalent) or long lasting (covalent modification)
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Mechanisms of indirect agonism
- Quaternary alcohols (ephodronium) – reversible binding (limit acetylcholine access)
Non covalent – enzyme-inhibitor complex lifetime (2 - 10 minutes)
- Carbamate esters – neostigmine, physostigmine – reaction with AchE active site
Covalent carbamoylation – enzyme-inhibitor complex lifetime (0.5 - 6h)
- Organophosphates – Parathion, Sarin, Soman - phophorylates AchE active site
Covalent phosphorylation – very stable enzyme-inhibitor complex, days (especially after aging)
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AchE Inhibitors (quaternary alcohols and carbamates)
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Organophosphates
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Aging
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Organ effects/therapeutic uses
• - Effects are due to acetylcholine accumulation and are both sympathetic and parasympathetic
USES Approx DurationALCOHOLS
Edrophonium Myasthenia gravis 5 – 15 minutesarrythmias
CARBAMATES
Neostigmine Myasthenia gravis 0.5 – 2hPyridostigmine Myasthenia gravis 3 – 6hPhysostigmine Glaucoma 0.5 – 2hDemecarium Glaucoma 4 – 6h
Organophosphates
Echotiophate Glaucoma 100 h (> 4 days)
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Treatment of organophosphate poisoning
• 1 - maintenance of vital signs (respiration particularly important)
• 2 - Decontamination (to avoid further absorption)
• 3 - Atropine parenterally (to minimize muscarinic effects) as required
• 4 - Rescue of AchE activity with Hydroxylamines (Pralidoxime, Diacetylmonoxime)
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Muscarinic antagonism
Attropa belladona
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Muscarinic Antagonists
ATROPINE
SCOPOLAMINE
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Muscarinic Antagonists
ATROPINE
SCOPOLAMINE Attropa belladona
- Atropine and Scopolamine are belladona alkaloids (competitive inhibitors)
-Drugs differ in their CNS effects, scopolamine permeates the blood-brain barrier
-At therapeutic doses atropine has negligible effects upon the CNS, scopolamine even at low doses has prominent CNS effects.
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Mechanism of drug action
- Competitively block muscarinic receptors
- Salivary, bronchial, and sweat glands aremost sensitive to atropine
- Smooth muscle and heart are intermediatein responsiveness
- In the eye, causes pupil dilation and difficulty for far vision accomodation
- Relaxation of the GI, slows peristalsis
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History/sources
• Atropa belladona - used in the renaissance• Deadly nightshade - used in the middle ages to produce prolonged
poisoning
Jimson plant leaves burned in India to treat Asthma (1800) purification of atropine (1831)
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Effect of muscarinic inhibitor in the eyePupil dilation vs accomodation
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Effect of muscarinic inhibition in the heart and salivary glands
- Increases the heart rate after a transient bradychardia at the low dose- Diminishes gland excretory function
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Graphic summary of atropine effects
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Organ effect – drug reviewAntidotes
• ORGAN DRUG APPLICATIONCNS Benztropine Treat Parkinson’s disease
Scopolamine Prevent/Reduce motion sickness
Eye Atropine Pupil dilation
Bronchi Ipatropium Bronchodilate in Asthma, COPD
GI Methscopolamine Reduce motility/cramps
GU Oxybutinin Treat transient cystitisPostoperative bladder spasms
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Toxicity of muscarinic antagonists
• “DRY AS BONE, RED AS A BEET, MAD AS HATTER.”
• Dry is a consequence of decreased sweating, salivation and lacrimation
• Red is a result of reflex peripheral (cutaneous) vasodilation to dissipate heat (hyperthermia)
• Mad is a result of the CNS effects of muscarinic inhibition which can lead to sedation, amnesia (hypersensitivity), or hallucination
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Nicotinic – Acetylcholine Receptor
polarizedRelaxation
depolarizedcontraction
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Signaling through Ach-nicotinic receptor(competitive and depolarizing blockers)
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Competitive/depolarizing
CompetitivePhysically blocks Ach binding
INHIBITOR
DepolarizingBinds and locks the receptoropen
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Examples of competitive/depolarizing drugs
Competitive
Tubocurarine Mivacurium
Depolarizing
AchEButyrylcholinesteraseSensitive sites
Succinylcholine
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Clinical uses
• Adjuvant use in surgical anesthesia (muscular relaxation)
• Advantage – much lighter levels of anesthesia required
• Other uses: muscular relaxation for orthopedics (correction of dislocation/alignment of fractures)
• (short duration) – facilitate intubation, laryngoscopy, bronchoscopy, esophagoscopy
• Control of muscular spasms, strabism, hemifacial spasms, oromandibular and cervical dystonia, spasms of the lower esophageal sphincter
• Cosmetic – Bottox (Botulinum toxin A)
• Paralytic action on skeletal muscle
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Agents/Features/Duration
• AGENT CLASS PROPERTY ONSET DURATION Succinylcholine Dicholine ester Depolarization 1 min 5 – 8 min
Tubocurarine Alkaloid Competitive 5 min 80 – 120 min
Atracurium Benzylisoquinoline Competitive 3 min 30 – 60 min
Mivacurium Benzylisoquinoline Competitive 3 min 12 – 18 min
Pancuronium Ammonio Steroid Competitive 5 min 120 – 180 min
Vecuronium Ammonio Steroid Competitive 3 min 60 – 90 min
Hydrolysis by esterases Liver clearance/renal elimination Both
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Precautions/Toxicity
• - Prolonged apnea, cardiovascular collapse
Sequence of paralysis : Eye muscles, Jaw, Larynx, limbs and trunk, intercostal muscles and the dyaphragm
- Generally caused by diminished esterase activity, renal malfunction, liver insufficiency, poor circulatory function.
- Special caution in patients with electrolyte imbalance (K+)
- Antidote : Neostigmine/Ephodronium to increase Ach, and atropine to block Ach muscarinic stimulation.
- Malignant hyperthermia – results from a discharge of Ca2+, exacerbated muscular action – tachycardia, hyperthermia, acidosis and rigidity (mutations of RYR1, central core disease) treated with Dantrolene, preservation of respiration
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Summary
X
TetrodoxinBatrachotoxin
XHemicholiniumBotulinum toxin
XCurare alkaloidsSnake venom α
XAch
HydrolysisAchE inhibitors
XDantrolene
AchpilocarpineMuscarineBethanecholNeostigmine**Edrophonium**
X
** Indirect
AtropineScopolamineTubocurarineMivacurium
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Movie
http://www.youtube.com/watch?v=yd46Hs7pTowNicotine in the brain