Transcript Indirect cholinergic agonists

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 Duration
ALCOHOLS
Edrophonium
Myasthenia gravis
arrythmias
5 – 15 minutes
Myasthenia gravis
Myasthenia gravis
Glaucoma
Glaucoma
0.5 – 2h
3 – 6h
0.5 – 2h
4 – 6h
Glaucoma
100 h (> 4 days)
CARBAMATES
Neostigmine
Pyridostigmine
Physostigmine
Demecarium
Organophosphates
Echotiophate
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 are
most sensitive to atropine
- Smooth muscle and heart are intermediate
in 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 eye
Pupil 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 review
Antidotes
• ORGAN
DRUG
APPLICATION
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 cystitis
Postoperative bladder spasms
CNS
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
polarized
Relaxation
depolarized
contraction
Signaling through Ach-nicotinic receptor
(competitive and depolarizing blockers)
Competitive/depolarizing
Competitive
Physically blocks
Ach binding
INHIBITOR
Depolarizing
Binds and locks the receptor
open
Examples of competitive/depolarizing drugs
Competitive
Mivacurium
Tubocurarine
Depolarizing
AchE
Butyrylcholinesterase
Sensitive 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
Competitive
5 min
80 – 120 min
30 – 60 min
Alkaloid
Atracurium
Benzylisoquinoline
Competitive
3 min
Mivacurium
Benzylisoquinoline
Competitive
3 min
12 – 18 min
Pancuronium Ammonio Steroid
Competitive
5 min
120 – 180 min
Vecuronium
Competitive
3 min
60 – 90 min
Ammonio Steroid
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
Tetrodoxin
Batrachotoxin
Hemicholinium
Botulinum toxin
Curare alkaloids
Snake venom α
Dantrolene
AchE inhibitors
Ach
pilocarpine
Muscarine
Bethanechol
Neostigmine**
Edrophonium**
Atropine
Scopolamine
Tubocurarine
Mivacurium
X
X
X
X
X
** Indirect
Movie
http://www.youtube.com/watch?v=yd46Hs7pTow
Nicotine in the brain