Local Anesthetics Flashcards
Review of RMP/Action Potential
Local Anesthetics
Esters and Amides
- Impair nerve signal transmission by blocking VGaNa+C anywhere
- the aromatic ring is lipophilic (hydrophobic)
- the tertiary amine is hydrophilic (lipophobic)
- more hydrophobic compounds are more potent and produce longer blockade than less hydrophobic ones
we want MORE hydrophobic/lipophilic… longer lasting!
Esters
- metabolized by P.cholinesterase (except cocaine)
- one I
Amides
- liver metabolism (therefore hepatic blood flow and function are important!!)
- Two I’s
Review of Ester/Amide Structures
Weak Acid Binding
Weak acids bind with positively charged ions like Na+, Mg++, Ca++
- sodium pentathol is a weak acid
Weak Base Binding
Weak bases bind with negatively charged ions like Cl- and SO42-
- lidocaine hydrochloride and morphine sulfate are weak bases
2 important determinants of LA function:
pH and pKa
pKa
pKa is pH at which 50% is ionized and 50% is unionized
- pKa is different for the different LA
pKa Lidocaine example
- pKa Lidocaine is 7.7 - 7.9
- Standard human pH is 7.35 - 7.45 (7.4)
- At pH 7.4, lidocaine is more ionized (75% ionized) than at pH 7.7 so less is available to cross membranes
- base (lidocaine) + acid (human fluids) = ionized LA
generally speaking… lower pKa means more LA in nonionized form and faster onset of block
Most LA are ____ ____ (pKa 7.5 - 9) in solution but salts are ____ _____.
Most LA are weak bases (pKa 7.5 - 9) in solution but salts are weak acids.
- ketamine, opioids, and benzos are weak bases
Weak bases become ____ nonionized as the pH increases.
MORE
increased pH = decreased H+ ions = increased nonionized LA = good (but bad w babies and ion trapping)
LA must be in the basic form to be unionized and capable of penetrating the cell membrane to block the Na+ channel
Is LAST worse in basic or acidotic patient?
LAST is worse with acidosis because the LA moves into the Na+ channels and gets trapped.
ie: in the heart blocking Na+ channels
How do you increase the ionization of LA?
LA premixed w Epi = more acidic (pH 3.5) which increases the ionization of the LA
*has increased duration but also increased onset time. Inversely, you can mix w bicarb to bring pH up and get more in the unionized form to get a faster onset but shorting acting LA.
LA Protein Binding
LA have high protein binding (A1AG preferred to Albumin) but more albumin exists in the human body.
- LA must release from protein to cause Na+ ch block
- protein binding = duration
- high protein binding = long duration of LA
- as pH decreases, % of bound drug decreases
- protein binding is more important than lipid solubility for duration of aciton
LA protein binding and duration order
Bupivacaine
etidocaine
ropivacaine
mepivacaine
lidocaine
procaine
2-chloroprocaine
Acidosis and the LAST patient
Do not let a suspected LAST pt become acidotic since the proportion of free LA molecules will increase rapidly!
ie: bupivacaine 95% (5% available for action) protein bound normally decreases to 70% w acidosis (30% available for action!) 6x more blockage
Oil:Water Partition Coefficient
is equal to lipid solubility = potency
The greater the oil: water PC for an LA, the greater the potency.
Blocking the Na+ Channel
- peripheral nerves are mixed (motor/sensory)
- LA placed near nerve diffuses via concentration gradient from outer sheath to core
- fibers in outer/proximal/motor are blocked first
Steps of Blocking Na+ Channel
- unionized LA penetrate cell membrane
- become ionized
- bind to Na+ channel
- prevent opening and Na+ inrush
- NO action potential!
- blocking the Na+ ch blocks conduction of nerve impulse to the brain…*
no impulse = no pain
Onset of LA Block
Closer to the nerve = faster onset!
- within the sheath is good, but not on the actual nerve
- intraneural and sub-epineural = faster onset dur to proximity of LA to nerve
- small block faster than large
- myelineated block easier than un
- NO DIFFERENCE in motor vs. sensory
Factors determining rate of diffusion across nerve sheath:
- concentration of LA (higher concentration diffuses faster)
- degree of ionization (UNionized faster)
- hydrophobicity
- physical characteristics of tissue around nerve (ie: more vascular taken up faster and not get to nerve)
Increased lipid solubility… (4 things)
- increases potency
- increases duration
- increases toxicity
- decreases therapeutic index
What 3 factors determine ability of LA to stay near the nerve? (and therefore duration)
1) lipid solubility
2) vascularity of tissue
3) presence of vasoconstrictors (which prevent vascular uptake of LA molecules)
Order of Loss of Nerve Sensations
- Autonomics
- Pain
- Cold
- Warmth
- Touch
- Pressure
- Vibration
- Proprioception
- Motor function
Desireable Properties of LA
- reversible conduction block
- compatible w vasoconstrictors
- rapid onset
- non-irritating
- low potential for LAST
- long duration w short recovery
- effective in different delivery modalities
Cocaine
- ester
- blocks nerve impulses
- local vasoconstriction d/t inhibition of local NE reuptake
- euphoria d/t blockade of dopamine reuptake in CNS
- good for LA in nasal passages (because it is a LA that also vasoconstricts)
procaine
ester
- 1st synthetic LA (synthetics get rid of the SE we don’t want)
- low potency, slow onset, short duration
2-chloroprocaine
ester
- chlorinated procaine, most rapidly metabolized by Pcholinesterase
tetracaine
longest duration ester!
- more potent, slowly metabolized
- too toxic for peripheral blocks but OK for long acting spinals
- sometimes mixed w lidocaine for peripherals
lidocaine
amide
- rapid absorption paernteral, GI, and resp
- intermediate duration
- 1.5-2% for most regional blocks
- more dilute concentrations for pain mgmt
mepivacaine
amide
- intermediate duration
- pharm similar to lido
- similar onset w slightly longer duration (3-6 hr)
- toxic to neonates - NOT used in OB!
prilocaine
amide
- intermediate duration w pharm like lido
- lacks vasodilation, increased Vd (limits CNS toxicity)
- causes methmeglobinemia at 8 mg/kg (tx w methylene blue 1-2mg/kg)
- uncommon in peripheral nerve blocks
etidocaine
amide
- longer duration
- onset like lido, duration like bup
- alkyl sub on aliphatic group between hydrophilic amine and amide increases lipid solubility
- increased lipid solubility = increased potency = increased duration
- downlide is motor block that outlasts sensory!
- not useful for peripheral nerve blocks
bupivacaine
amide
- long duration (longer w EPI)
- slower onset w variable duration (2-3 hours spinal, 12-24 for peripheral)
- cardiotoxic (direct inj into medulla = v-arrhythmias, difficult to dissociate from Na+ ch)
- widely used for peripheral blocks in dilute concentrations of <0.5%
- careful use in OB epidurals (<0.25%)
ropivacaine
amide
- S-enantionmer of bup = lower toxicity, less potent at <0.5%
- slower uptake thus lower blood levels
- extensive hepatic metabolism
- >0.5% dense block w shorter duration than Bup
- at 0.75%, onset is fast, CNS and cardiotoxicity are reduced, and motor block is less than Bup
- popular for peripheral nerve blocks
levobupivacaine
- another single enantiomer of bup
- less toxic than Bup but works in similar fashion w similar duration
LA Percentages
- 25% = 2.5 mg/mL
- 5% = 5 mg/mL
1% = 10 mg/mL
2% = 20 mg/mL
Plasma concentration of LA is determined by what 4 things? (LAST)
- DOSE of drug
- RATE OF ABSORPTION
- SITE of injection
- biotransformation and ELIMINATION from circulation
* same dose injected in different locations in diff patients = diff peak plasma levels!*
Blood flow and LA absorption (I think I can push each bolus Sslowly for safety)
From shortest to fastest:
- IV
- Tracheal
- Intercostal
- Caudal
- Paracervical
- Epidural
- Brachial Plexus
- Subarachnoic, sciatic, femoral
- SubQ
LAST
