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Anesthesia Pharm Midterm 2 > Physiology of Pain + LA > Flashcards

Physiology of Pain + LA Flashcards

1
Q

Acute pain

A

-usually caused by noxious stimuli (nociceptive pain)
-self limited
-resolves in day to weeks
if not taken care of= chronic pain

Somatic pain:
—superifical= skin or SQ, usually sharp
—deep= muscle or bone, dull
Visceral pain:
internal organ– harder to identify- referred pain

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2
Q

Chronic pain

A
  • persists beyond normal time for acute pain/disease process
  • starts around 6 weeks to 3 months
  • persists 1-6 months or longer
  • nociceptive, neuropathic, cancer, unknown etiology
  • cormac: by the time it gets to chronic pain pathways are remodeled and very hard to decrease pain
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3
Q

Acute or Chronic pain is useful and protective?

A

acute pain: direct result of tissue damage or potential damage and is a symptom

  • well defined
  • protects form tissue damage and allows time for healing
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4
Q

Risk factors from increased post operative pain

A
  • poor pain control experience with prior surgery
  • moderate to severe pain for > 1 month
  • psychologically vulnerable
  • younger patients
  • female
  • workers comp case
  • genetic predisposition: familiar/culture, pharmacogentics
  • diffuse noxious inhibitory control issues
  • —–noxious stimuli active C and A delta fibers
  • —–a mechanism where WDR neurons responsive to pain signals from 1 area may be inhibited by stimuli from another locations
  • chronic opioid therapy (> 2 weeks)
  • tolerance of physical dependence
  • compared to opioid naive patients:
  • —- pain severity 3X higher
  • —- post op opioid use is 3X higher
  • —- if epidural placed– stayed for 3 extra days
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5
Q

Acute pain management

A

Independent predictors for development of Persistent post surgical pain (PPP):

  1. pre operative pain levels
  2. age– younger is worse
  3. Typer of surgery
  4. Preoperative anxiety–high-increased severe pain
  5. Severity of immediate post operative pain
  6. size of incision–larger is worse
  7. gender– females have worse output, no effect in patient

Note:
BMI has inconsistent effects
duration of surgery has no predictable effect
type of anesthesia has no predictable effect

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6
Q

Problems with un/poorly treated post-op pain

A

higher acute post-op pain

  • -increases risk of persistent post surgical pain (PPS)
  • -increases CV complications
  • -increases pulmonary complication
  • -delays discharge
  • -prolongs post operative convalescence and return to work
  • -increases risk of admit after ASC procedures
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7
Q

Model of Pain Transmission

A
  1. Pain impulse enters the dorsal horn
  2. Glutamate or Substance P release allows transmission (intrathecal morphine inhibits the release of substance P into the CSF)
  3. Transmission may be modulated by a descending inhibitory pathway that inhibits excitatory NTM (opioid receptors in SG are probably on substance P terminals and block its releasing producing analgesia)
    - -non opioid inhibitory NTMs: endorphines, serotonins, norepi, glycine, GABA
    - -Norepi is inhibitory transmitter in pain pathway
    - -Clonidine (alpha 2 agonist) produces spinal analgesia
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8
Q

Neuropeptides and pain

A
  • NTM
  • substance P and calcitonin Gene related peptide (CGRP)
  • inflammatory response- arthritic pain
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9
Q

Opioids and pain

A
  • after peripheral inflammation there is an up regulation of the opioid receptors on the peripheral terminals of primary afferent
  • macrophages, monocytes, the lymphocytes all contain endogenous opioids
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10
Q

glutamate and pain

A
  • excitatory NTM
  • receptors found on primary afferent nociceptor terminals
  • injection of glutamate cause hyperalgesia
  • up regulated in joints after inflammation
  • blockade of glutamate receptors reduces pain and hyperalgesia
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11
Q

ion channels and pain

A
  • acid sensing channels-low pH in inflamed tissues

- vanilloid receptor activated by capsaicin and mediates hyperalgesia

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12
Q

Glutamate

A
  • hippocampus, outer layer of cerebral cortex, and SG
  • learning and memory= recall
  • central pain transduction
  • excitotoxic neuronal injury
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13
Q

inotropic glutamate receptors-NMDA

A
  • ligand operated channel opens

- influx of cation (Na+), membrane depolarization occurs

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14
Q

Pain transmission: 3 neuron system

A
  • primary afferent
  • spinothalamic tract (STT)
  • thalamic neuron
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15
Q

Where do pain receptors originate in the skin?

A

-nociceptors originate in the skin, skeletal structures, and viscera

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16
Q

A-delta

A

fast pain- first pain

  • primarily releases glutamate which binds to AMPA and NMDA receptors
    ex: incisional pain
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17
Q

C fibers

A

slow-nagging pain

-primarily release of substance P which binds to NK-1 receptors in the post synaptic membrane

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18
Q

A-delta and C fibers BOTH

A

are stimulated

-A and C fibers both enter dorsal root ganglion and ascend or descend 1-3 segments in the Tract of Lissauer (ToL)

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19
Q

A-delta fibers

A

myelinated, medium speed

  • fast pain, touch, temperature
  • exit TOL enter the dorsal horn and terminate in Rexed’s lamina I and V
  • second order neurons leave RL I and V and cross to the contralateral spinothalamic tract and ascend to the brain
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20
Q

C fibers

A

NON-myelinated, really slow speed

  • slow pain, touch, temperature, post ganglionic SNS**
  • exit TOL and primarily terminate in he Rexed’s Lamina II and III
  • interneurons transmit C fiber impulses from RL I and II to RL V
  • C fiber impulses leaving RL V cross immediately to the contralateral ST tract and ascend to the brain

lamina II and III are also called substance gelatinous

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21
Q

lower motor neuron lesion vs upper motor neuron lesion

A
  • Flaccid paralysis and absent stretch reflex indicates a lower motor neuron lesion/injury
  • Spastic paralysis with accentuated stretch reflex in the absence of skeletal muscle paralysis indicates upper motor neuron injury/destruction
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22
Q

Inhibition of pain signals: A delta

A 
A delta fibers fast/first pain- Na+ channels
-block the sodium channels= disrupt transmission
1st generation:
--carbamazepine
--phenytoin
--valporic acid
2nd generation:
--oxcarbezepine
--lamotrigine
--topiramate

K+ channels also have inhibitory role in nociceptive signal transmission

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23
Q

Inhibition of pain signals: C fibers

A

C fibers slow, dull, aching pain= Ca2+ channels

  • Block calcium channels:
  • -gabapentin
  • -pregabalin

Opioids block the voltage gated Ca2+ channels
-enhance K+ efflux- enhance noradrenergic activity at the dorsal horn which alters the perception of pain, modulates nociceptive pathways (enhances endogenous opioids), and affects mesolimbic dopamine system (reinforcing and rewarding properties)

Remember we are altering the perception of pain, not blocking the pain altogether***

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24
Q 
Important dermatomes to know:
Clavicle
Nipples
Xiphoid
Tibia
Perineum
A 
Clavicle: C4
Nipples: T4
Xiphoid: T6
Tibia: L4-5
Perineum: S2-4
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25
Q

Nerve cell resting potential issues

A
  • inside of neuron is more negatively charged compared to outside
  • inside is primarily K+ ions
  • outside is primarily Na+ ions
  • Na/K pump constantly moves Na+ out and K+ into cells
  • K constantly leaks outward
26
Q

Action potential triggered by something:

A
  • Na channels open, Na+ rushes in, polarity reversed, AP happens, NTM released
  • K+ channels open, K+ in, Na/K pump action, repolarization happens
27
Q

Esters

A

LA: impair nerve signal transmission by blocking voltage gated Na+ channels anywhere

Aminoesters:

  • pseudocholinesterase metabolism except cocaine
  • -ester linkage connects the aromatic ring to the tertiary amine
  • -cocaine, procaine, chloroprocaine, teracaine

Aromatic ring is lipophilic (hydrophobic)
Tertiary amine is hydrophilic (lipophobic)
More hydrophobic compounds are more potent and produce longer blockade than the less hydrophobic ones

28
Q

Amides

A

LA: impair nerve signal tranmission by blocking voltage gated Na+ channels anywhere

Amino-amides (Liver metabolism)
-Amide linkage connects the aromatic ring to the tertiary amine: lidocaine, lignocaine, mepivicaine, prilocaine, bupivicaine, levobupivacaine, etidocaine, ropivacaine

Aromatic ring is lipophilic (hydrophobic)
tertiary amine is hydrophilic (lipophobic)

29
Q

Weak acids bind with ___________

Weak bases bind with __________

A

weak acids bind with + charged ions like Mg, Na, Ca
weak bases bind with - charged ions like Cl- and SO4=

lidocaine hydrochloride and morphine sulfate are weak bases

30
Q

pka & pH are important determinants of LA function: why?

A

pka is the pH at which 50% is ionized and 50% non ionized
pka is different for different LA

pka of Lidocaine is 7.7-7.9
at a pH of 7.5 lidocaine is more ionized (75% ionized) than at 7.7, so less is available to cross membranes
base (lidocaine) + acid (human fluids)= ionized LA (not available to work**)

31
Q

correlation between pka and onset of block

A

generally speaking, the lower PKA means more LA is in non ionized form, and faster onset of block

example:
Benozcaine pka= 3.5, onset of block is about 2 minutes
Procaine pka= 9.1, onset of block is 14-18 min

32
Q

What happens to weak bases as the pH increases?

A
  1. Most LA are weak bases (pka 7.5-9) in solution but salts are weak acids
  2. Weak bases become MORE non ionized as the pH increases
    increased ph= decrease H+ ions= increased non ionized LA= good
  • LA must be in basic form to be unionized and capable of penetrating the cell membrane to block Na+ channels
  • LA will move across membranes faster in a alkylotic patient
33
Q

LAST

A

-LAST will be worse as the patient becomes more acidotic because LA moved into Na+ channels and gets trapped there due to acidosis

34
Q

LA premixed with epi

A
  • are more acidotic (pH 3.5) to prevent breakdown of the pi which increase the ionization of LA
  • therefore, alkalinizing LA solutions with premixed epi may speed onset much more than alkalinizing plain LA solution
35
Q

LA protein binding

A

most LA have very high protein binding (AAG preferred to albumin) but in humans, Alb»> AAG
-must release from protein to cause Na+ Channel block
-protein binding fraction similiar to duration of LA action
(high protein binding= long duration of LA)
*protein binding is dependent on influenced by plasma pH
as pH decreases, bound drug % decreases

bupivacaine > etidocaine > ropivacaine > mepivacaine > lidocaine > procaine > 2-chloroprocaine

36
Q

Why is it important to not let a suspected LAST patient become acidotic?

A
  • the proportion of free LA molecules will increased markedly when patient becomes more acidotic
  • Bupivacaine 95% protein bound normally, decreased 70% with acidosis —- more free drug, more to block Na+ channels in the heart= bad!!!!
  • will not release until intralipids are given
37
Q

Lipid solubility of LA

A
  • the oil:water partition coefficient of a med relates directly to the lipid solubility of that med
  • greater the lipid solubility of a med, the greater than potency of that med
  • so, the greater the oil:water partition coefficient for an LA, the greater the potency of that LA
  • in genreal more lipid soluble a LA, more potent it is
  • increasing the lipid solubility of any LA will increase the potency of the LA AND the duration***
  • protein binding is more important than lipid solubly for duration of action though
38
Q

Blocking the Na+ Channel

A

-peripheral nerves are mixed nerves
-LA placed near a nerve diffuses from the outer surface toward the core via the concentration gradient
fibers in the outer mantle (proximal structures and motor fibers) are blocked first
-if enough drug present it will diffuse into the core and block the distal structures

39
Q

Sequence of action of LA (5)

A
  1. Unionized LA molecules penetrate cell membrane
  2. Becomes ionized
  3. Then bids to Na+ channel
  4. Prevents opening and Na+ inrush
  5. NO Action Potential

blocking na+ channel blocks conduction of nerve impulse propagation to the brain
no pain impulse= no pain sensation=happy patient

40
Q

Onset of Block

A
  • LA as close to nerve as possible=faster onset
  • within nerve sheath is good
  • intraneural and sub-epineural injections result in really fast onset due to proximity of LA to nerve
41
Q

Rate of diffusion across nerve sheath is determined by

A
  • concentration of LA (higher is better)
  • degree of ionized (unionized diffuses faster)
  • hydrophobicity (want it lipophilic)
  • physical characteristics of tissues surrounding the nerve
42
Q

Small fibers vs large fibers

A
  • small fibers block easier than large fibers
  • myelinated fibers block easier than unmyelinated
  • no difference in sensitivity between motor or sensory fibers (a-alpha = a-beta)
  • motor fibers may be blocked before sensory in large nerve trunks due to location in outer portion of nerve bundle
43
Q

Increased lipid solubility

A

-can also increase toxicity and decrease the therapeutic index of LA

44
Q

Duration of a nerve block

A
  • mainly determined by the ability of the LA molecules to stay near the nerve
  • 3 factors determining this:
    1. lipid solubility
    2. vascularity of tissue
    3. presence of vasoconstrictors which prevent vascular uptake of LA molecules
45
Q

Fastest and slowest nerve blocks

A

C fiber is the last fiber to be blocked but the fastest to recover

46
Q

Order of loss of nerve sensations?

A
  1. Autonomic Functions
  2. Pain
  3. Cold
  4. Warmth
  5. Touch
  6. Pressure
  7. Vibration
  8. Proprioception
  9. Motor funtion
47
Q

Desirable properties of LA agent

A
  • reversible conduction blockade
  • compatible w/ vasoconstrictors
  • short (fast) onset
  • non irritating
  • low potential for LAST
  • long duration, possibly short recovery period
  • effective in different delivery modalities
48
Q

Cocaine

A
  • naturally occurring
  • blocks nerve impulses
  • local vasoconstriction d/t inhibition of local norepi reuptake
  • euphoria d/t blockade of dopamine reuptake in CNS
  • good for LA anesthesia in nasal passages and other areas where LA and vasoconstriction desired
49
Q

Procaine

A
  • ester LA: metabolized by circulating pseudocholinesterase
  • first synthetic LA
  • low potency, slow onset, and short duration
50
Q

2-chloroprocaine

A
  • ester LA: metabolized by circulating pseudocholinesterase

- chlorinated procaine, most rapidly metabolized by (pchesterase)

51
Q

Tetracaine

A
  • ester LA: metabolized by circulating pseudocholinesterase
  • longer duration ester
  • more potent, long duration, slowly metabolized, too toxic for use in peripheral nerve blocks, OK for long acting spinals
  • is sometimes mixed with lidocaine & used for peripheral block? toxicity issues *
52
Q

Lidocaine

A
  • amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
  • thereforce hepatic blood flow and liver function are important *
  • rapid absorption parenteral, GI, and respiratory
  • intermediation duration
  • 1.5%-2.0% for most regional blocks for surgery
  • more dilute for pain managment
53
Q

Mepivacaine

A
  • amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
  • intermediate duration
  • pharm similar to lidocaine
  • similar onset, slightly longer duration (3-6 hours)
  • toxic to neonates: NEVER IN OB****
54
Q

Prilocaine

A
  • amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
  • intermediate duration
  • lacks vasodilation, increase Vd, limits CNS toxicity
  • causes methemoglobienmia: usually requires dose of 8mg/kg, if happens treat with methylene blue 1-2 mg/kg
  • uncommon for peripheral nerve blocks
55
Q

Etidocaine

A
  • amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
  • longer duration
  • onset like lido, duration like bupivcaine
  • alkyl substitution on aliphatic group between hydrophilic amine and amide linkage increases lipid solubility which increases potency and increases duration
  • down is prolonged motor block that outlasts sensory block
  • not useful for peripheral nerve blocks
56
Q

Bupivacaine

A
  • amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
  • long duration LA (longer when epi added)
  • slower onset, longer, variable duration
  • –2-3 hours for a spinal dose
  • –12-14 hrs for peripheral nerve block

CARDIOTOXIC:

  • cumulative and&raquo_space; than expected r/t LA potency
  • direct injection of this into medulla will produce ventricular arrhythmias
  • difficult to dissociate this from Na+ channels
  • widely used for p. blocks in dilute concentrations (<0.5%)
  • continuous infusions usually <0.1% c/s opioid
  • careful in OB epidural <0.25%
57
Q

Ropivacaine

A

-amide LA: metabolized in liver by deaklyation of an ethyl group from the tertiary amine
-S-enantiomer of bup= lower toxicity
-slower uptake and thus lower blood levels
-extensive hepatic meatbolism
-less potent than Bup at lower <0.5% (good for peripheral nerve block, NOT GOOD FOR SPINAL)
>0.5%, dense block with slightly shorter duration than bupivicaine
-at 0.75% Ropivacaine, onset is fast, CNs and cardiotoxicity are reduced, and motor block is less than Bup
-ropivacaine is very population for peripheral nerve blocks

58
Q

Levobupivacaine

A
  • another single enantiomer version of bup
  • less well studied than ropivicaine
  • appears to work in similiar fashion to Rop; less toxic than bup; similar onset and duration as Bup
59
Q

Duration of anesthesia or anaglesia longer for blocks?

A

Duration of anesthesia is SHORTER than duration of analgesia

60
Q

LAST

A
  • plasma concentration of LA is determined by:
    1. dose of drug administered
    2. rate of absorption of the drug
    3. SITE of injection
    4. biotransofmation and elimination of the drug from circulation
  • thesame dose of LA injected in different locations and different patients patients will lead to very different peak plasma levels
  • you must consider all factors when determining which drug and dose for your local, regional
61
Q

Blood flow and LA absorption

A
  • from fastest to slowest rates of venous LA:
    1. Intravenous
    2. tracheal
    3. intercostal
    4. caudal
    5. paracervical
    6. epidural
    7. brachial plexus
    8. subarachnoid, sciatic, femoral
    9. SQ
62
Q

LAST: order of symptoms 1-8

A
  1. Drowsiness
  2. Paresthesias in the mouth and tongue
  3. Tinitus, auditory hallucination
  4. Muscular spasm
  5. Seizures
  6. Coma
  7. Respiratory Arrest
  8. Cardiac Arrest

Anesthesia Pharm Midterm 2 (8 decks)

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