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)
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)
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)
AchE Inhibitors (quaternary alcohols and carbamates)
Organophosphates
Aging
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)
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)
Muscarinic antagonism
Attropa belladona
Muscarinic Antagonists
ATROPINE
SCOPOLAMINE
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.
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
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)
Effect of muscarinic inhibitor in the eyePupil dilation vs accomodation
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
Graphic summary of atropine effects
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
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
Nicotinic – Acetylcholine Receptor
polarizedRelaxation
depolarizedcontraction
Signaling through Ach-nicotinic receptor(competitive and depolarizing blockers)
Competitive/depolarizing
CompetitivePhysically blocks Ach binding
INHIBITOR
DepolarizingBinds and locks the receptoropen
Examples of competitive/depolarizing drugs
Competitive
Tubocurarine Mivacurium
Depolarizing
AchEButyrylcholinesteraseSensitive sites
Succinylcholine
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
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
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
Summary
X
TetrodoxinBatrachotoxin
XHemicholiniumBotulinum toxin
XCurare alkaloidsSnake venom α
XAch
HydrolysisAchE inhibitors
XDantrolene
AchpilocarpineMuscarineBethanecholNeostigmine**Edrophonium**
X
** Indirect
AtropineScopolamineTubocurarineMivacurium
Movie
http://www.youtube.com/watch?v=yd46Hs7pTowNicotine in the brain