Term
| perception of pain resulting from activation of primary sensory (afferent) nerve fibers by noxious stimuli |
|
Definition
|
|
Term
| potential to cause tissue/cellular damage |
|
Definition
noxious
neurons that respond to noxious stimuli are called nociceptors |
|
|
Term
| transmission of action potential from the periphery to CNS |
|
Definition
afferent
nociceptors are afferent neurons |
|
|
Term
| transmission of action potential away from the CNS to the peripheray |
|
Definition
efferent
motor neurons are efferent |
|
|
Term
| mechanism of voltage gated sodium channels |
|
Definition
the probability of channel opening (Na conduction) is dependent on membrane potential
the Na channels that propagate action potentials are voltage gated
depolarization of the neuron membrane increases the probability of channel opening and Na channel opening causes depolarization (positive feedback)
local anesthetics (LAs) bind voltage gated Na channels and block Na current |
|
|
Term
| physiology of nociception |
|
Definition
[image]
a nociceptor can be activated by 2 main types of stimuli:
one stimulus type comes directly from the causative agent such as high temperature, mechanical, or chemical stimuli
the other type of stimulus comes secondary from cell damage or substances released from nearby cells
1a
direct activation of nociceptors by thermal, chemical, or mechanical stimulation
the neuron reaches threshold and produces an action potential
1b
thermal, mechanical, and chemical stimulus concurrently causes nearby cell damage
damaged cells may leak K into the extracellular space and release bradykinin, serotonin, and prostaglandins all of which promote production of action potentials in nociceptors
2
caused by 1a and 1b
this is "pain" signal conduction to the CNS
3
activated neurons release mediators (substance P, calcitonin gene related peptide (CGRP)) that lower neuron activation threshold, cause dilation
4a
nearby blood vessels dilate, cause mast cell degranulation
4b
mast cells release serotonin and histamine |
|
|
Term
| A-delta fibers and C fibers |
|
Definition
these nerve types not only vary in function but also vary in presence of myelin sheath, conduction velocity, and diameter
the 2 types that conduct patin signals are A-delta and C fibers
type A delta are faster conducting and type C are slower conducting
conduction velocity is dependent on presence of myelin and axon diameter
first pain occurs rapidly and is perceived as "sharp" and localized through A-delta fibers
second pain is delayed and is perceived as "dull" and diffuse through C fibers |
|
|
Term
| USE DEPENDENCY OF LOCAL ANESTHETICS |
|
Definition
[image]
1) resting (closed) - no action potential
2) activated (open) - during action potential
3) inactivated (closed) - action potential termination
LOCAL ANESTHETICS BIND TO THE ACTIVATED AND INACTIVATED STATES
when LAs bind the activated state Na current is decreased
binding of LAs to the inactivated state stabilize the inactivated state
effect of repetitive activity on the block of Na current produced by a local anesthetic in a myelinated axon: the current produced by the pulses rapidly declines = PHASIC INHIBITION
each time the neuron produces an action potential more LA is bound to the Na channels causing more blockage of current
this observation is described as "use dependent" and is a mechanism for selective activity of LAs
note that Na current is lower each time even though LA concentration is constant
the term "phasic inhibition" is sometimes used instead of use dependency when discussing local anethetics |
|
|
Term
|
Definition
the nerve bundle CONTAINS ALL NERVE FIBER TYPES
the types that conduct pain signals are A-delta and C
the LA is injected near a nerve bundle
the LA must diffuse across 3 major membranes composed of connective tissue and endothelial cell layers:
epineurium
perineurium
endoneurium
the LA binds Na channels and blocks action potential conduction
generally the neurons in the outer part of the bundle innervate proximal regions (shoulder, upper arm) and the inner (core) neurons innervate distal regions (hand, fingers), so the consequence of this anatomy is that the proximal regions are affected first by local application of the LA near a nerve bundle
outer neurons = PROXIMAL
inner neurons = DISTAL |
|
|
Term
| structural properties of local anesthetics |
|
Definition
[image]
LIPOPHILICITY
very low then cannot enter cell membrane
if very high then drug trapped in membrane
moderate most potent
ESTER AND AMIDE LINKAGE:
ester bond is less stable (quickly hydrolyzed in tissues and plasma, shorter duration of action)
amide links are more stable |
|
|
Term
| EFFECT OF PH AND INFLAMMATION on LAs |
|
Definition
locasl anesthetics must pass through nerve bundle layers and nerve cell membranes and then bind the cytoplasmic side of the Na channel in order to have effect
[image]
LAs are weak bases with pKa 8-9
the neutral species can cross the membrane readily
the charged species is required for channel binding
generally, low pH such as in area of inflammation will decrease effectiveness of the LA because very little uncharged drug is available to cross the membrane
LAs work best when the pKa-pH is not too large |
|
|
Term
|
Definition
vascularity of the tissue effects the duration of action because the LAs enter peripheral circulation and are carried away from the injection site
based on this principle, a vasoconstrictor (EPINEPHRINE COINJECTION) will increase duration of action and decrease systemic absorption
epinephrine is less effective for more hydrophobic LAs (more lipophilic drugs are retained at injection site)
LAs can cause dilation (inject lidocaine in the tissue and cause dilation, carried away from site of action)
EPI is used with it to cause vasoconstriction to increase duration of action of lidocaine |
|
|
Term
| general unwanted effects of LAs |
|
Definition
LOCAL:
irritation - EPI coinjection can cause tissue damage
local irritation at injection site is common
coinjection of EPI should be avoided in extremities b/c of possible ischemic damage or in patients with poor circulation
SYSTEMIC:
arteriole dilation
NEGATIVE INOTROPIC EFFECT
CNS stimulation initially, followed by CNS depression and respiratory depression
LAs can block any Na channel in the body, so they potentially can have effets on any organ system or tissue
generally, the amide linked LAs have more potential to cause systemic effect
LAs can block cardiac Na channels |
|
|
Term
|
Definition
procaine
benzocaine
tetracaine |
|
|
Term
|
Definition
lidocaine
prilocaine
bupivacaine
ropivacaine |
|
|
Term
|
Definition
introduced in 1905
LOW POTENCY (LOW HYDROPHOBICITY)
hydrophobicity is directly related to the potency of LAs
more hydrophobic drugs will remain at the site of administration longer and bind Na channel more tightly
however, if a drug is extremely hydrophobic then potency will be low
SHORT DURATION
partially due to removal by perfusion at the injection site and the ester bond is rapidly hydrolyzed by tissue and plasma esterases
used for dental procedures
metabolized to PARA-AMINOBENZOIC ACID (PABA)
PABA is a precursor to DNA synthesis in some prokaryotes and sulfonamides are structurally similar to PABA
sulfonamides are competitive inhibitors of PABA
procaine (and tetracaine) could decrease the effectiveness of sulfonammides |
|
|
Term
|
Definition
more hydrophobic
high potency
rapid onset
LONG DURATION OF ACTION
used for spinal block
PABA metabolite |
|
|
Term
|
Definition
no aliphatic amine (exception to general structure)
aromatic amino pKa 2.8
LIMITED TO TOPICAL USE and lozenges
insoluble in water |
|
|
Term
|
Definition
COMMON and wide use
rapid onset
MEDIUM DURATION (1-2 hours)
moderately hydrophobic
liver metabolism
SIDE EFFECTS:
drowsiness, tinnitus, dizziness, twitching
seizures, respiratory depression and coma can occur at high plasma levels
USES:
infiltration anesthesia
peripheral neruve block
epidural
topical
amide intermediate link is resistant to tissue and plasma esterases |
|
|
Term
|
Definition
similar profile as lidocaine, but less CNS effects
causes METHEMOGLOBINEMIA (iron oxidation, limits obstetrical use)
conversion (oxidation) of ferrous Fe (2+) to ferric Fe (3+) caused by prilocaine aromatic ring metabolite
when iron is in ferric state, hemoglobin cannot carry oxygen
fetal circulation more prone to oxidative stress and slower to convert iron back to ferrous state
also complicates newborn assessment
USES:
good choice when EPI contraindicated
compared to other LAs, prilocaine causes far less vasodilation |
|
|
Term
| properties of bupivacaine |
|
Definition
VERY HYDROPHOBIC
very long duration of action
CARDIOTOXIC (VERY SLOW OFF)
USES:
good for spinal, epidural, infiltration anesthesia and peripheral nerve blocks
S-enantiomer (levobupivacaine) less cardiotoxic
less motor neuron block compared to other LAs
all LA drugs have potential for cardiotoxicity, but bupivacaine dissociates from cardiac Na channels very slowly (channels still blocked at end of diastole) |
|
|
Term
| properties of ropivacaine |
|
Definition
close structure to bupivacaine, but LESS CARDIOTOXIC
used for epidural and regional surgical anesthesia |
|
|
Term
| overview of site and mechanism of muscle relaxants |
|
Definition
muscle relaxant - decreases tone in normal or spasmodic muscle
1) neuromuscular junction (nicotinic receptors)
most of the clinically used neuromuscular junction (NMJ) blockers are competitive antagonists of the nicotinic receptor (nondepolarizing blocker)
there is one clinically used muscle relaxant (succinylcholine) that works at the NMJ that is a nicotinic receptor agonist (depolarizing blocker)
2) central nervous system (brain stem, spinal cord)
the CNS muscle relaxants act in multiple sites (decrease motor neuron basal activity, block muscle stretch reflex arc, enhance activity of descending inhibitory neurons and/or decrease activity of descending excitatory neurons)
3) other (ACh release, excitation-contraction coupling)
dantrolene and botulnum toxin work by different mechanisms
dantrolene blocks the ryanodine receptor in the sarcoplasmic reticulum (SR); ryanodine receptor is the Ca release channel in the SR membrane; release of Ca leads to muscle contraction
botulinum toxin binds to vesicle associated protein and inhibits ACh release |
|
|
Term
| the neuromuscular junction |
|
Definition
[image]
A
an alpha motor neuron makes a junction with a group of muscle fibers
B
the axon terminus innervates a specialized area on the group of muscle fibers known as the end plate region
a bouton is a knoblike region of the axon terminal that forms a synapse with the end plate region
C
a close up view of a synapse at the NMJ
the presynaptic vesicles contain ACh
the ACh is released into the synapse and binds the postsynaptic nicotinic receptor
ACh is rapidly hydrolyzed by acetylcholinesterase so the action is very brief
opening of nicotinic receptors causes Na influx and end plate depolarization (end plate potential)
if the end plate potential reaches threshold an action potential is produced
Ca from the SR is released and the muscle contracts |
|
|
Term
| muscle contraction requires accumulation of sufficient concentration of ( ) at the end plate region to depolarize the muscle and reach threshold potential |
|
Definition
|
|
Term
| neuromuscular junction (NMJ) blockers - nondepolarizing |
|
Definition
atracurium besylate
cisatracurium besylate
mivacurium chloride
pancuronium bromide
rocuronium bromide
vecuronium bromide |
|
|
Term
| MOA of nondepolarizing NMJ blockers |
|
Definition
COMPETITIVE ANTAGONISTS at nicotinic receptor
causes skeletal muscle relaxation to complete paralysis (SMALL MUSCLES FIRST)
uses: tracheal intubation, during surgery, and during mechanical ventilation
nondepolarizing NMJ blockers act by cometing for ACh binding on the nicotinic receptor (the effect of these drugs can be overcome/surmounted by acethylcholinesterase inhibitors
these drugs do not depolarize the muscle cell (nondepolarizing)
these drugs are more specific for nicotinic receptors at the NMJ (some have weak-moderate block on ganglionic N and heart M receptors)
small, fast moving muscles are affected first (jaw, eyes) before larger slow moving muscles (limbs, trunk, intercostals)
these drugs allow less inhalation anesthetic to be used during surgery, thereby reducing the cardiovascular and respiratory depression of inhalation anesthetics |
|
|
Term
| nicotinic receptor (ligand gated) |
|
Definition
[image]
the nicotinic receptor is a ligand-gated ion channel comprised of 5 subunits
the receptor has 2 binding sites for ACh
when the channel is in open state there is Na movement from outside to inside the muscle cell (depolarization)
when an action potential is produced in the muscle cell, Ca is released from the SR and then the muscle contracts
the nondepolarizing drugs block binding of ACh to the nicotinic receptor (competitive antagonism) |
|
|
Term
| nondepolarizing NMJ blockers are competitive antagonists: which states do these drugs bind? |
|
Definition
[image]
the nicotinic receptor can exist in 4 states:
nothing is bound
one ACh binding site is occupied
the receptor is bound by 2 AChs
both sites are occupied by Ach but the channel is open
true competitive antagonists bind to the same site as endogenous NTs (inhibits the binding of ACh)
these inhibitors can ONLY BIND TO STATE 1 OR 2 = mutually exclusive binding |
|
|
Term
| ADRs of nondepolarizing NMJ blockers |
|
Definition
HEART (muscarinic)
tachycardia and increased cardiac output (pancuronium)
the main/most concerning ADRs are on the heart
muscarinic receptors found on the heart, these drugs act as antagonists to muscarinic receptors
the autonomic nervous system effect consists of the balance between the PNS and SNS
most of the nondepolarizing blockers have little M receptor antagonism except pancuronium
HISTAMINE RELEASE (mast cell)
flushing
decreased peripheral vascular resistance (tubocuruarine, mivacurium)
histamine release is result of direct effect of drug on mast cells and basophils (tubocurarine and mivacurium cause more histamine release than the other nondepolarizing NMJ blockers)
AUTONOMIC GANGLIA (nicotinic)
effect depends on predominant autonomic tone (i.e. sympathetic in veins, parasympathetic in heart)
the effect of blockage of nicotinic receptors in the autonomic ganglia dependends on the predominant autonomic tone in the particular tissue or organ
for example, there is predominant sympathetic tone in veins, so the effect of nicotinic receptor blockage would be vasodilation
as another example, the heart normally has predominant parasympathetic tone, so effect of nicotinic receptor blockage in ganglia is tachycardia
at therapeutic concentrations nondepolarizing NMJ blockers have very little effect on nicotinic receptors in autonomic ganglia |
|
|
Term
| neuromuscular junction blockers - depolarizing |
|
Definition
|
|
Term
|
Definition
AGONIST at NMJ nicotinic receptor
1) first causes SUSTAINED muscle fiber depolarization (phase I block)
results in muscle relaxation b/c Ca is taken up by the SR after sustained depolarization
2) then muscle repolarizes, but is DESENSITIZED (phase II block)
muscle is relaxed
uses: adjunct to surgical anesthesia, facilitates intubation
succinylcholine is rapidly hydrolyzed by plasma butyrylcholinesterases
at the NMJ, succinylcholine is resistant to AChE (hydrolyzed slower than Ach) |
|
|
Term
|
Definition
hyperkalemia
CARDIAC CONDUCTION EFFECTS
succinylcholine causes flux of K from inside to outside the muscle cell, in turn raising extracellular and plasma K concentration (hyperkalemia)
succinylcholine should be used with caution during circumstance exhibiting elevated plasma K such as trauma or burns
severe hyperkalemia may result in fatal cardiac arrhythmias
malignant hyperthermia (muscle rigidity, hyperthermia)
especially when administered with volatile anesthetics
the initiating event is elevated intracellular Ca resulting from excessive release from the sarcoplasmic reticulum
sudden onset
clinical presentation includes skeletal muscle rigidity and hyperthermia (from high muscle metabolism)
this side effect is dose dependent
patients with central core disease (strong association with ryanodine receptor mutation) carry highest risk of malignant hyperthermia
negative inotropic and chronotropic effects (muscarinic) on heart
lower concentrations of succinylcholine have negative inotropic and negative chronotropic effects on the heart attributed to direct activation of heart muscarinic receptors |
|
|
Term
| skeletal muscle spasticity |
|
Definition
involves overactive stretch reflex or problem with control by descending (upper motor) neuron pathways
skeletal muscle spasticity is caused by hyperactive muscle stretch reflex or problem with descending corticospinal pathways
then centrally acting drugs act in the spinal cord and/or brain stem (not at the NMJ) to reduce muscle tone |
|
|
Term
| centrally acting skeletal muscle relaxants |
|
Definition
baclofen
diazepam
tizanidine |
|
|
Term
| MOA of centrally acting skeletal muscle relaxants |
|
Definition
the mechanism of these drugs is not well understood
1) spinal cord (reflex arc) - reduce stretch reflex
2) higher brain centers - activate descending pathways that inhibit motor neurons that synapse directly with muscle |
|
|
Term
| mechanism of the stretch reflex |
|
Definition
[image]
the spindle senses muscle length (stretch)
when the muscle is stretched the afferent nerves are activated and send action potential to the spinal cord
the efferent nerves (motor neurons) become activated and send action potentials to the muscle fibers causing muscle contraction
this process is the muscle stretch reflex arc
sensory neurons from skin can directly enter the reflex arc in the spinal cord and activate the efferent nerves (this is the basis for automatic reflex that occurs when we touch a hot surface for example) |
|
|
Term
| mechanism of descending inhibitory pathway |
|
Definition
inhibit alpha motor neurons
descending inhibitory neurons reduce basal alpha motor neuron activity (regulates muscle tone)
when this descending inhibitory pathway is damaged increased muscle tone results
most centrally acting drugs enhance activity of descending neuron pathways |
|
|
Term
|
Definition
GABA analogue
selective GABA-B RECEPTOR agonist
increased K conductance, decreased Ca conductance)
thought to hyperpolarize excitatory neurons in the brain and spinal cord (K efflux) and reduce Ca in the presynaptic terminal
MUSCLE RELAXANT AND ANALGESIC
reduce substance P?
adverse effects: somnolence, increased seizure activity
[image]
GABA-B is a GPCR (metabotripic) linked to ion channel conductance (K and Ca) through second messenger system |
|
|
Term
|
Definition
GABA-A receptor agonist
increase Cl conductanse
ENHANCE DESCENDING INHIBITORY INPUT
SUPPRESS REFLEX ARC
ADRs: somnolence
tolerance |
|
|
Term
|
Definition
agonist of ALPHA2 RECEPTORS (presynaptic)
REDUCES ADRENERGIC INPUT to alpha motor neurons
no effect on spinal cord reflex
less anti-hypertension effect than clonidine
ADRs: hypotension, asthenia |
|
|
Term
|
Definition
binds to presynaptic vesicles
inhibits Ach release |
|
|
Term
|
Definition
binds ryanodine receptor
inhibits Ca release from SR
TREATMENT FOR MALIGNANT HYPERTHERMIA |
|
|
