Card Set Information
HAZARDS OF DEEP ANESTHESIA
¢In order to achieve muscle relaxation and
abolition of reflexes sufficient for deep surgery, dangerous levels of
anesthesia are required.
¢This often led to patient death on the
HAZARDS OF LIGHT ANESTHESIA
pt could wake up
TUBOCURARINE - what kind of drug
paralyzing drug or neuromuscular blocking drug
Tubocurarine - mechanism
block neuromuscular junction
The Muscle End Plate has what?
packed with acetylcholine receptors
¢nicotinic acetylcholine receptors
Mechanism of ms contraction at the neuromuscular junction
¢Nerve impulse travels down the nerve
fiber and its branches to the terminal.
¢Depolarization opens presynaptic calcium
channels in membrane → inward calcium flux.
¢Calcium promotes discharge of vesicles
full of acetylcholine from terminal into synaptic cleft
Neuromuscular junction - components
cholinesterase, Voltage-gated Ca2+ channel, Ligand-gated Ca2+ channel, Vesicle filled with Ach
Ligand Gated Ion Channels
: Skeletal Muscle (Single Subtype)
Autonomic Ganglia (NN)
: (Several Subtypes)
CNS: (Multiple Subtypes)
G Protein-linked Receptors
CNS, A Few Sympathetic Sites
Muscurinic receptor are predominantly under parasympathetic control. The exception are
sweat gland under sympathetic control
True or false
THE NICOTINIC ACETYLCHOLINE RECEPTOR:
Ligands at the receptor need to be cations.
Almost all agonists and antagonists to nicotinic Ach recptor are ... compound
quaternary ammonium compounds
THE NICOTINIC RECEPTOR - morphology
¢The receptor is a rosette of five
¢In muscle there are four types, with the α-subunit repeated twice.
¢In nerve there may only be α-subunits, or a mixture of α and β
Tubocurarine (and other curariform drugs) are antagonists at the nicotinic receptor.
Tubocurarine - mechanism
¢They compete with released acetylcholine
to prevent any end plate depolarization being large enough to activate muscle
Tubocurarine cause what kind of paralysis?
flacid in all ms.
Require blocking enough receptor so that the ms become weak and flaccid.
Tubocurarine - dose response curves and explain?
very steep because AP is all or none so it require a lot of drug to stop all or most AP in order for ms to become paralyze
PROBLEMS WITH TUBOCURARINE
¢It blocks autonomic ganglia
Lossof control of blood pressure
¢It affects muscarinic receptors
Loss of parasympathetic control of heart rate
¢It releases histamine
Hypotension and bronchoconstriction
¢Its duration of action is over 30 min
Too long for short procedures such as intubation.
¢Therefore, better drugs had to be
¢High percentage of receptors must be
blocked before any effect on contraction due to receptor reserve
Need to block 70% before any effect
> 90% for full effect
Greatest in the muscles of respiration
Great in muscles of coarse movement (e.g. gastrocnemius)
Least in the muscles of the face and eyes
¢Lack of facial expression and ptosis are
diagnostic of neuromuscular failure.
COMMONLY USED NEUROMUSCULAR (NM)
Curare (d-tubocurarine, original blocker)
Vecuronium (“pure” NM blocker)
Rocuronium (most popular)
Cisatracurium (Hofmann elimination)
Nondepolarizers - mechanism of action
Competitive antagonists of nicotinic receptors
Tend to be slow in onset because need receptor block of 70% before any effect, and
> 90% for full effect
Two structural types:
Structure of nondepolarizer
big so that it will block the neuroms jxn
Structure of depolarizer
look just that Ach so that it cause depolarization but it can't be degraded by normal esterase --> worn out the ms
DEPOLARIZING BLOCKING AGENTS - Succinylcholine
Rapid stimulation of nicotinic receptors
Resistant to acetylcholinesterase, but susceptible to plasma cholinesterase
Initial depolarization of muscle seen as fasciculation and twitches at onset
DEPOLARIZING BLOCKING AGENTS - Voltage-gated sodium channels
are first activated and then inactivated
by the depolarization.
DEPOLARIZING BLOCKING AGENTS - mechanism
¢Inactivated channels must first be
repolarized before they return to resting state and can be activated again.
¢Prolonging the depolarization by using a
relatively longer acting agonist drug prevents return to the resting state.
¢No more action potentials
: muscle is then
paralyzed even though receptors are activated.
Rapid onset – 1 min
Short duration of action (3 – 5 min)
Inactivation of surrounding Na+ channels
(phase 1 block)
achieve long duration of action
Continuous administration leads to long duration (phase II block)
Postoperative muscle pain (from fasciculation
Hyperkalemia (from fasciculation) --> stop the heart
-->Patients with congenital deficiency of plasma cholinesterase experience long lasting block.
OF NEUROMUSCULAR BLOCKERS
¢Ganglionic blockade (curare)
¢Histamine release with isoquinoliniums
¢Changes in heart rate
Tachycardia with steroidals
Bradycardia with succinylcholine
¢Malignant hyperthermia (succinylcholine)
Succinylcholine along cause malignant hyperthermia
rare but possible
Succinylcholine + volatile inhalation anesthetics cause
Malignant hyperthermia - physiological consequence and response
altered ryanodine receptor magnifies Ca2+ release
THERAPEUTIC USES OF NMBs
¢Surgery: nondepolarizers & succinylcholine
¢Intubated patients in ICU: nondepolarizers
¢Joint, bone manipulations: nondepolarizers
¢Laryngospasm: succinylcholine & rocuronium
OTHER AGENTS AFFECTING NEUROMUSCULAR TRANSMISSION
GABAA activation at spinal cord level
¢Presynaptic GABAB activation →↓glutamate release
: CNS acting
¢Botulinum toxin (Botox)
Prevents release of Ach by interfering with neurotransmitter vesicle fusion to presynaptic nerve terminal and thus exocytosis of ACh
GANGLIONIC (NN) BLOCKERS - Trimethaphan
¢Intraoperative blood pressure reduction
GANGLIONIC (NN) BLOCKERS-Mecamylamine
¢Oral drug (lipid soluble)