Lecture 12: Somatic Flashcards
Botulinum toxin (BOTOX)
most toxic substance known
prevent quantal release of acetylcholine at presynaptic membrane
inhibit fusion of vesicles with the plasma membrane
Rab proteins, V and T snares
Rab binds to GTP and target tethering protein to mediate initial contact between vesicle and target
V and T snares bring membrane close enough with vesicle to initiate fusion
leads to release and diffusion of ACh
Synaptobrevin
V-snares
Synaptotagmin
Ca sensor
Syntaxin & SNAP-25
T-snares
a-latrotoxin
promotes ACh release
enhance transmitter release leads to blockade as result of ACh storage depletion
a and b - Bungarotoxins
a: irreversibly binds and block nAChR - neuromuscular blockade & skeletal damage
b: prevent release of ACh from motor nerve endings
Curare
active ingredient is D-tubocurarine competitive antagonist injection block receptor so ACh cant bind excreted in urine
Non-depolarizing neuromuscular blocking drugs (NMBA)
D-tubocurarine
compete with ACh for binding site on nicotinic receptor
zero efficacy
no depolarization
Problems with D-tubocurarine
small degree of ganglionic blockade lead to respiratory depression
decrease blood pressure caused by release of histamine
onset of action relatively long
cannot use for intubation
How to overcome non-depolarizing block
esterase inhibitor (neostigmine) increase concentration of ACh to outcompete antagonist
but can also activate muscarinic receptor
block muscarinic effect using atropine
Pancuronium
nondepolarizing drug
similar to tubocurarine but no histamine release
m2 ACh receptor antagonism
blocks NE uptake can lead to increase sympathetic tone: increase HR BP
uses:
skeletal muscle relaxant in general anesthesia
facilitate mechanical ventilation
adverse effect:
cardiovascular actions
slow onset (3 min) and duration (86 min)
Vercuronium
less potent at m2 ACh receptor than pancuronium
Rocuronium
NMBA
competitive antagonist
minimal cardiac effects
rapid onset (1 min) with moderate duration
FASTEST onset can be used for incubation
Sugamadex reversal
selectively binds to rocuronium
8 min recovery
Halogenated hydrocarbon anesthetics (Halothane)
enhance neuromuscular blockade
Aminoglycoside antibiotics (Streptomycin)
decrease ACh release from cholinergic fibers by competing with Ca2+
synergy with TUBOCURARINE and other competitive blockers
Ca channel blockers
increase tubocurarine blockade
Depolarizing neuromuscular blocking drugs MOA
- initially activate nACh receptor leads to depolarization (transient twitch of muscles)
- continued binding cause receptor desensitization
- endplate remains depolarized while muscle relaxes
- endplate repolarizes but muscle is still relaxed and endplate unresponsive to stimulation
FLACCID PARALYSIS
Decamethonium
depolarizing blocking drug
two quaternary ammonium linked by simple alkyl chain
Succinylcholine
depolarizing block
two molecules of ACh binds together
cannot be metabolized by acetylcholine esterase but plasma cholinesterase
plasma cholinesterase found in low concentration at NMJ
remains attached to receptor for a long time, constant stimulation and depolarization leads to receptor desensitization
uses: fast onset but short duration given by continuous infusion useful for INCUBATION electroconvulsive therapy
rare adverse reaction:
malignant hyperthermia: combine use with halothane as anesthetic
leads to large Ca release
treated by dantrolene (DHP receptor antagonist) block release of Ca at SR
dantrolene can reduce heat production and muscle tone
Use for neuromuscular block agent
surgery (muscle relaxation without CNS depression)
certain anesthetic can only produce relaxation at high doses therefore dangerous
Incubation
maintaining ventilation during surgery and in ICU patients
reduction of muscle tone
Organophosphorus derivatives
irreversible inactivation of acetylcholine esterase
leads to desensitization of nACh receptor by high level of ACh
neuromuscular blockade - toxic effects
3 Therapeutic use of acetylcholine esterase inhibitor at NMJ
- Antidote for NMDA (tubocurarine and neurotoxins)
- Long acting AChase inhibitor can maintain muscular relaxation and avoid respiratory depression following surgery (neostigmine and edrophonium)
- Symptomatic treatment for myasthenia gravis (muscle weakness)
Myasthenia gravis
autoimmune
nACH receptor are destroyed modulated by antibodies
prevent normal activity
symptoms:
muscle fatigue
difficulty in eye motion
throat muscles fatigue (cannot speak properly)
challenge by using acetylcholine esterase
determine between MYASTHENIA GRAVIS or RECEPTOR DESENSITIZATION
How does acetylcholine esterase challenge and diagnose myasthenia gravis and receptor desensitization?
If myasthenia gravis: burst of ACh can reverse effects of muscle weakness
If receptor desensitization: no or worsen effect because depletion of more ACh, worsen symptoms
Myasthenia gravis treatment
- surgical removal of thymus gland
- corticosteroids, immunosuppressive
- Pyridostigmine + atropine
Ethanol
low dose increase ACh release by action potential
higher dose (legally impaired): decrease release of ACh, muscle relaxes
Caffeine
sensitize muscle so easier to contract
increase intracellular Ca
increase cAMP levels due to PDE inhibiting activity
Dantrolene
block intracellular Ca release
Procaine, tetracaine, lidocaine, bupivacaine
esters and amides local anesthetic
tetracaine more potent, lower TI, longer half life
Local anesthetic MOA
inhibit voltage-gated Na channel
held at inactive conformation at selective tissue
cannot move to open form
decrease pain signalling
