Transcript M-cholinoblocker

Autonomic nervous system
Cholinergic agonists
(CHOLINOMIMETICS)
Cholinergic antagonists
(CHOLINOBLOCKERS)
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Functional divisions within the
nervous system
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Efferent neurons of the
autonomic nervous system
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Sympathetic and parasympathetic actions
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Sympathetic ANS
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The 1st neuron of sympathetic division is
located in the thoracolumbar region of the spinal
cord (T1-L3) and the 2nd is disposed either in
the paravertebral, or in the prevertebral ganglia.
Postganglionic non-myelinated nerve fibres
arising from neurones in the ganglia, innervate
most organs of the body
• The neurotransmitter released by sympathetic
nerve endings is noradrenaline.
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Parasympathetic system
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The 1st neuron of parasympathetic system is
located in the brain stem and in the sacral region
of the spinal cord. The preganglionic fibres leave
the central nervous system in the III, VII, IX and
X pairs of cranial nerves and the third and fourth
sacral spinal roots.
• Ganglia are located either in the tissue of
effector organ or near it. The nerve endings of
the postganglionic parasympathetic fibres
release neurotransmitter acetylcholine. All the
preganglionic nerve fibres (sympathetic and
parasympathetic;) are myelinated and release
acetylcholine from the nerve terminals which
depolarizes the ganglionic neurones by
activating nicotinic receptors.
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Cholinergic transmission
Main NT is Acetylcholine (Ach).
A large number of peripheral ANS fibers which
synthesize & release Acetylcholine are called
CHOLINERGIC fibers. They include:
• All pre-ganglionic efferent autonomic fibers.
• Somatic motor fibers to skeletal muscles.
• Most parasympathetic post ganglionic fibers.
• A few sympathetic post ganglionic fibers– to
sweat glands.
Some parasympathetic post ganglionic fibers utilize
nitric oxide or peptides for transmission.
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Cholinergic synapse
• Nerve terminal of
cholinergic fibre contains
numerous vesicles with
neurotransmitter
acetylcholine (ACh) that is
released from presynaptic
membrane.
• Release of acetylcholine
depends on sufficient
influx of Ca 2+, which
occurs under the influence
of action potential.
ATP
negative
feedback
ATP
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Fate of acetylcholine released
by cholinergic fiber
• ACh is released from the nerve into the synaptic
cleft and binds to ACh receptors on the postsynaptic membrane, relaying the signal from the
nerve.
• Ach-esterase, located on the post-synaptic
membrane, terminates the signal transmission
by hydrolyzing ACh.
• The liberated choline is reuptaken by the presynaptic membrane and used for resynthesis of
ACh.
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Cholinergic receptor types
• Two cholinergic
receptor subtypes
have been identified
by selective
agonists: muscarinic
(M-cholinoceptors)
and nicotinic (Ncholinoceptors). At
least 5 subtypes of
muscarinic receptors
(M1 – M5) have
been distinguished.
• There are 3 main
classes of Ncholinoceptors: the
muscle, ganglionic,
and CNS classes.
MUSCARINIC
M1
M2
M3
M4
Eye
Heart
Smooth muscles
Exocrine glands
CNS
NICOTINIC
M5
NM
NN
Ganglions
Carotid sinus
Skeletal muscles
Adrenal glands
CNS
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Muscarinic receptors
• High affinity to muscarine
• M1 – gastric parietal cells, saliva, CNS
• M2 - cardiac cells, smooth muscle,
CNS
Amanita muscaria
• M3 - bladder, exocrine glands, smooth muscle, eye, CNS
• M1&M3 – Gq
• M2 - Gi
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Nicotinic receptors
• High affinity to nicotine
• NM- neuro-muscular junction
• NN – ganglion, adrenal gland
CNS, carotid sinus
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Mechanisms of impulse
transmission
• Muscarinic receptors belong to G-protein
coupled receptors. Transmission of impulses
through M1, M3, M5 cholinoceptors is realized
by phospholipase C, inositol triphosphate and
diacylglycerol
• Stimulation of M2 and M4 cholinoceptors results
in inhibition of adenylate cyclase and decrease in
intracellular cAMP.
• N- cholinoceptors are ion channel coupled. Their
stimulation results in opening of Na+ channels
that causes depolarization.
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Muscarinic receptors
M1
M3
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M-cholinoceptors
Cholinocep
tors
Localization
Effects of stimulation
M2
Heart
Bradycardia, decrease in conduction,
decrease in force of atrial contraction
Relaxation
Smooth muscle
M3
Smooth muscles
Increase in tone, increase in
peristalsis, decrease in sphincter tone
and removal of content,
bronchoconstriction
M1-M3
Exocrine glands
Secretion
Eye
a)miosis
b)spasm of accommodation
c)decrease in intraocular tension
CNS
Stimulation
M1-M5
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N-cholinoceptors
Cholinoc Localization
eptors
Effects of stimulation
NN
Autonomic
Increase in parasympathetic and
ganglia
sympathetic reactions
(parasympatheti
c and
sympathetic)
NN
Adrenal medulla Increase in adrenaline release, increase in
BP
NM
Skeletal muscle
Increase in tone, contraction
Carotid sinus
Reflex respiratory centre stimulation
CNS
Stimulation
NN
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Cholinomimetics
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I. Direct acting
1. Muscarinic agonists (Mcholinomimetics)
Pilocarpine
Oxothermorine
Aceclidine
2. Nicotinic agonists
Lobeline
Dimethylphenylpiperazinum
(DMPP)
3. Muscarinic and nicotinic
agonists
Acethylcholine
Carbachol
II. Indirect acting (muscarinic
and nicotinic agonists –
anticholinesterase agents)
1. Reversible
Neostigmine (Proserinum)
Physostigmine
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Pyridostigmine
Edrophonium
Ambenonium chloride
(Oxazylum)
Galanthamine
2. Irreversible
(Organophosphates)
Echotiophate
Isoflurophate
Arminum
Drugs used in poisoning with
organophosphates
1. Reactivators of
acetylcholine esterase
Pralidoxime
Dipiridoxinum
Izonitrozinum
Obidoxime
2. M-cholinoblockers
Atropine
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Pharmacological effects
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Bradycardia, decrease in blood pressure
Raising the tone of smooth muscles of internal organs
Stimulation of intestinal motility
Reducing sphincter of alimentary canal and bladder
Increased secretory activity of the exocrine glands
Constriction of the pupil of the eye (miosis)
spasm of accommodation
Reducing intra ocular pressure
Relief of pulses in mionevralnomu skeletal muscle
synapse, strengthening their contractility (anticholinergic
drugs)
• Stimulation of the central nervous system (means of
penetrating the blood-brain barrier)
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Main clinical usage
• 1. Glaucoma (Pilocarpine, Physostigmine,
Armine)
• 2. Infants (Neostigmine)
• 3. Postoperative atony of the intestines and
bladder (Neostigmine)
• 4. Paralysis, paresis, neuritis, polyneuritis
(Neostigmine)
• 5. Dusturbances of skeletal muscle contractile
function after cranial trauma, polio and stroke
(Galanthamine hydrobromide)
• 6. Belladonna poisoning (Neostigmine,
Physostigmine, Galanthamine)
• 7. Overdose nondepolarizing muscle relaxants
(Neostigmine)
• 8. Xerostomia (Pilocarpine)
• 9. Respiratory depression (Cititon, Lobeline)
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Side effects of cholinomimetics
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1. Bradycardia
2. Bronchospasm
3. Intestinal cramps, colic, diarrhea
4. Hypersalivation
5. Blurred vision
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Contraindications
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1. Bradycardia, A-V block
2. Asthma
3. Gastric ulcer and 12 duodenal ulcer
4. Epilepsy (Neostigmine)
5.Pregnancy (Neostigmine)
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Direct acting cholinergic agonists
ACETYLCHOLINE
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Direct acting cholinergic agonists
ACETYLCHOLINE
1. Decrease in heart rate and cardiac output
2. Decrease in blood pressure
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Direct acting cholinergic agonists
ACETYLCHOLINE
3. Other actions
4. Clinical use very rare: eye drops to obtain miosis
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Direct acting cholinergic agonists
1.
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3.
4.
Stimulation of atonic bladder
Nonobstructive urinary retention
Neurogenic atony
Megacolon
Ophthalmology
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Direct acting cholinergic agonists
PILOCARPINE
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
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Direct acting cholinergic agonists
PILOCARPINE
1. Secretagoge (sweat, tears,
saliva)
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Jaborandi - what causes
slobbering
2. Sjögren’s syndrome
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Dry mouth, lack tears
3. Glaucoma
Jaborandi (Pilocarpus pennatifolius)
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Direct acting cholinergic agonists
PILOCARPINE
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Mushroom poisoning
 Miosis
 Hyper salivation
 Excessive sweating, lacrimation
 Cold, wet skin
 Bradycardia
 Polyuria
 Diarrhea
 Convulsions
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Indirect acting cholinergic agonists
Reversible
Irreversible
Edrophonium
Neostigmine
Physostigmine
Rivastigmine
Galantamine
Echothiophate
Organophosphates
Arminum
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Mechanism of action
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Reversible
Physostigmine
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
Calabar Bean
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Reversible
Physostigmine
Indications
1. Atony of intestine
2. Atony of bladder
3. Glaucoma
4. Overdose of
ATROPINE,
ANTIPSYCOTICS,
ANTIDEPRESSANTS
Side effects
1. Convulsions
2. Bradycardia
3. Paralysis of skeletal muscle
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Reversible
Neostigmine
1. Quatenary nitrogen
2. Poor adsorbtion
3. Not penetrate BBB
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Reversible
Neostigmine
Indications
Side effects
1. Paralyzes
2. Myastenia gravis
3. Antidote of neuromuscular blocker
TUBOCURARINE
1. Salivation
2. Flushing
3. Decreased BP
4. Abdominal pain
5. Diarrhea
6. Bronchospasm
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Reversible
Neostigmine
1. Bronchial asthma
2. Intestinal inflammation,
obstruction
3. Bladder obstruction
4. Peritonitis
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Reversible
Edrophonium
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4.
5.
Quatenary nitrogen
Poor adsorbtion
Not penetrate BBB
Fast elimination
Duration 10-20 min
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Reversible
Edrophonium
1. Diagnosis of myasthenia gravis
2. Antidote of neuro-muscular
blocker
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Reversible
Rivastigmine
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
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Reversible
Rivastigmine
Alzheimer disease
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Irreversible
Echothiophate
Glaucoma
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Toxicology
Organophosphates
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Toxicology
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal motility
Emesis
Miosis
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Toxicology
1. Reactivation of acetylcholinesterase
• PRALIDOXIME
Not enter BBB
2. M-cholinoblocker
• ATROPINE
 Antimuscarinic only
3. Anticonvulsant
• DIAZEPAM
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CHOLINERGIC BLOCKERS
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Classification of cholinoblockers
• I. M-cholinoblockers (Muscarinic antagonists)
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Natural agents
• Atropine
• Hyoscine /Scopolamine/
• Plathyphylline
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Semisynthetic and synthetic
• Homatropine
• Propantheline
• Methacinum
• Ipratropium bromide /Atrovent/
• Cyclopentolate
• Pirenzepine
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Classification of N-cholinoblockers
1. Ganglion blocking
drugs
• Hexamethonium
/Benzohexonium/
• Hygronium
• Mecamylamine
• Pempidine tosilate
• Trimethaphan
• 2. Neuromuscular
blockers
• a) Nondepolarizing
• Atracurium
• Pancuronium
• Tubocurarine
• Vecuronium
• b) Depolarizing
• Succinylcholine
• Dithylinum
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Mechanism of action
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Parasympatholythics
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Eye
inability to focus for near vision, mydriasis, IOP ↑
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Saliva
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xerostomia
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Bronchi
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bronchodilation, secretion ↓
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Heart
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Rate ↑
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GIT
secretion, peristalsis ↓ sphincter tone ↑
Bladder
detrusor ↓ sphincter tone ↑
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Clinical uses of M-cholinoblockers
• A-V block – Atropine
• Colic, abdominal cramps – Atropine,
Plathyphylline
• Urinary frequency - Oxybutinin
• Preanesthetic medication – Atropine, Hyoscine
• Peptic ulcer – Pirenzepine (selective M1
cholinoblocker)
• Bronchial asthma - Ipratropium bromide
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Clinical uses of M-cholinoblockers
• Therapeutic uses in ophthalmology: in iritis,
keratitis and other inflammatory diseases and
trauma of eye - Atropine
• Diagnostics in ophthalmology – Atropine,
Homatropine, Cyclopentolate
• Prevention of motion sickness - Hyoscine
• Muscarinic poisoning – Atropine
• Organophosphate poisoning - Atropine
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Pharmakokinetics
ATROPINE
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
Atropa belladonna
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Main effects
ATROPINE
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Smooth muscle relaxation
Antisecretory
Dose-dependent effects of atropine
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Therapeutic uses
ATROPINE
1. Ophtalmological tests
2. Spasmolythic (as an
antispasmodic agent to relax
the GIT and bladder)
3. Antisecretory (during dental
operations, tuberculosis, to
block secretions in the upper
and lower respiratory tracts
prior to surgery)
4. Mushroom poisoning
5. Organophosphates poisoning
6. Heart block, bradycardia
7. Resuscitation (asystole)
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Adverse effects
ATROPINE
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Contraindications
ATROPINE
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2.
3.
4.
Narrow-angle glaucoma
Pyloricstenosis
Prostatichypertrophy
Drivers
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Belladonna poisoning
• Dry mouth, difficulties in
swallowing and talking
• Dilated pupil, photophobia, blurred
vision
• Dry, flushed and hot skin
• Difficulties in micturation
• Constipation
• Hypotension, weak and rapid
pulse
• Excitement, psychotic
behavior,delirium, hallucination
• ANTICHOLINESTERASE DRUGS ARE ANTIDOTES
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Pharmakokinetics
SCOPOLAMINE
1. Tertiary nitrogen
2. Good adsorbtion
3. Penetrate BBB
Solanaceae family
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Therapeutic uses
SCOPOLAMINE
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Therapeutic uses
TROPICAMIDE
Eye examination
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Therapeutic uses
IPRATROPIUM
1. Bronchial asthma
2. COPD
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Therapeutic uses
TRIHEXYPHENIDYL
Parkinson’s disease
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Nicotine
• Dose-dependent effect
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Ganglion blocking drugs
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Hexamithonium
Hygronium
Mecamylamine
Trimethaphan
Interfere with postsynaptic transmission of Ach
Block action of Ach on nicotinic receptors
Used rarely
severe adverse effects:
Orthostatic (postural) hypotension, tachycardia, dry-mouth, GIT atony,
urine retention, digestive problems, sexual dysfunction: failure of erection
and ejaculation
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Neuromuscular Blocking Drugs
Nondepolarizing
(competitive)
Atracurium
Pancuronium
Tubocurarine
Depolarizing
(non-competitive)
Succinylcholine
Dithylinum
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Tubocurarine
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Clinical uses of nondepolarizing
myorelaxants
• In surgery
• General anesthesia to produce paralysis, to
permit intubation of the trachea,
• To optimize the surgical field by inhibiting
spontaneous ventilation, and causing
relaxation of skeletal muscles.
• Because the appropriate dose of
neuromuscular-blocking drug may paralyze
muscles required for breathing (i.e., the
diaphragm), mechanical ventilation should be
available to maintain adequate respiration.
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Side effects of nondepolarizing
myorelaxants
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Stimulation of histamine release,
Hypotension,
Flushing,
Tachycardia
Arrest of breathing. Because the appropriate
dose of neuromuscular-blocking drug may
paralyze muscles required for breathing (i.e.,
the diaphragm), mechanical ventilation
should be available to maintain adequate
respiration.
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Succinylcholine
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Succinylcholine
• It has a rapid onset (30 seconds) but very
short duration of action (5–10 minutes)
because of hydrolysis by various
cholinesterases (such as
butyrylcholinesterase in the blood).
• Used in short lasting surgical invasions
• It cause side effects:
 fasciculations (a sudden twitch just before
paralysis occurs).
 post-operative pain
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TOXICITY
1. RESPIRATORY PARALYSIS - neuromuscular blockers induce a
respiratory paralysis. If mechanical ventilation is not provided,
the patient will asphyxiate.
2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia
susceptibility, an autosomal dominant disorder of skeletal
muscle, is one of the main causes of death due to anesthesia.
Depolarizing neuromuscular blocking drugs (succinylcholine)
can trigger malignant hyperthermia.
Malignant hyperthermia is a result of excessive release of Ca2+
from sarcoplasmic reticulum.
• The clinical features of malignant hyperthermia are
hyperthermia, metabolic acidosis, tachycardia, accelerated
muscle metabolism and contructures.
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