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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
- operating table.
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
- Nicotinic Receptors
- Ligand Gated Ion Channels
- NMJ (NM): Skeletal Muscle (Single Subtype)
- Autonomic Ganglia (NN): (Several Subtypes)
- CNS: (Multiple Subtypes)
- Muscarinic Receptors
- G Protein-linked Receptors
- Postganglionic Parasympathetic
- CNS, A Few Sympathetic Sites
- Receptor Subtypes: M1-5
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
- ¢This is:
- 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
- ¢Diazepam (Valium)
- GABAA activation at spinal cord level
- Baclofen (Lioresal)
- ¢Presynaptic GABAB activation →↓glutamate release
- Tizanidine (Zanaflex)
- ¢α2 agonist: 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
- ¢Intravenous drug
- ¢Hypertensive emergencies
- ¢Intraoperative blood pressure reduction
GANGLIONIC (NN) BLOCKERS-Mecamylamine
¢Oral drug (lipid soluble)
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