Local Anesthetics

Front 1

Mimics LA effects

Back 1

anoxia, mech. trauma, hypothermia, or chem. irritants.

Front 2

Inj. into nerves essentially kills them

Back 2

alcohol or phenol

Front 3

RMP determined by?

Back 3

K+, -70mV

Front 4

dV/dt

Back 4

rate of increase of of permeability to Na+

Front 5

Nerst & Goldman equation?

Back 5

Nerst- formula for determining electrochemical gradient for single ion.
Goldman- multp. ions

Front 6

3 parts to LA?

Back 6

1. Aromatic lipophilic uncharged base (benzene) 2. hydrophilic charged tertiary amine 3. intermediate chain (ester or amide)

Front 7

LA MOA?

Back 7

Inhibits voltage gated Na+ channels. Causes reversible blockade of neural tissue.
At higher conc. can bind to K+ channels.
**LA must be delivered inside cell membrane.

Front 8

Where do LA bind?

Back 8

D4S6 of alpha subunit of Na+ channel

Front 9

Electrophysiologic effects of LA?

Back 9

1. Increased threshold
2. Decreased dV/dt
3. Decreased overshoot
4. Decreased conduction velocity.
**No effect on RMP**

Front 10

Henderson Hasselbach?

Back 10

Equation to calculate the relative fraction of ionized vs. unionized.

Front 11

If the difference b/w pH - pKa is a negative #?

Back 11

The greater proportion of LA is in the ionized form

Front 12

How are LA marketed?

Back 12

As a salt (HCL)

Front 13

Tetrodotoxin?

Back 13

Poison from the puffer fish. Found in the gonads, viscera, & skin of fish. Also found on the skin of the Atelopus (costa rican frog). Binds to Na+ channels on the outside of membrane.

Front 14

In HCL solution LA ionize to ?

Back 14

Quaternary amine and Cl- ion.

Front 15

Stucture -activity relationship of LA?

Back 15

1. pKa b/w 8-10
2. Most LA are charged at physiologic pH
3. Bind to plasma proteins (a1-acid glycoprotein & albumin)
3. Uncharged species penetrates lipid membrane
4. Charged species interacts w/ receptor
5. Increasing alkyl subst. increases lipid solubility & potency
6. Lengthening chain increases potency & toxicity
7. Compounds w/ asymmetrical carbons have optical isomers
8. State dependent blockade

Front 16

Increases lipid solubility & potency?

Back 16

Increasing alkyl subst. on aromatic or tertiary amine

Front 17

Increases potency & toxicity?

Back 17

lengthening chain

Front 18

Substitution of methyl group for butyl group on tertiary amine?

Back 18

Mepivacaine to Bupivacaine

Front 19

State dependent blockade?

Back 19

Higher affinity state when channels are inactivated or when voltageis more positive (frequency & voltage dependence).
Resting nerve is less sensitive to blockade.
Higher frequenvy stimulation = greater degree of blockade.

Front 20

Differential sensitivities of nerves?

Back 20

1. Small fibers more susceptible than larger fibers to be blocked by LA.
2. Unmyelinated fibers more easily blocked.
3. 1st ANS nerves are blocked(1st c-fibers, 2nd. A-delta, then A -gamma, then A-beta, then a-alpha fibers).2nd sensory (temp.), 3rd. motor

Front 21

Critical length achieved/not achieved?

Back 21

blocked/not blocked

Front 22

Block above T5?

Back 22

Cardiac accelerating fibers cause hypotension & bradycardia

Front 23

Block below T5?

Back 23

Block vasomotor tone (b/c SNS is housed in T1-L2) & cause vasodilation

Front 24

Toxicity?

Back 24

1. based on lipophilicity
2. based on absorption & elimination
3. decreased by vasconstrictors
4. related to unbound drug conc.

Front 25

Metabolism of LA?

Back 25

- Bound by plasma proteins & lung tissue
- Esters hydrolyzed by plasma esterases (cholinesterase)

Front 26

Is toxicity a problem for SAB?

Back 26

No. b/c inj. small amts.

Front 27

Is toxicity a problem for epidural?

Back 27

yes. b/c inj. lg. amts

Front 28

Contribute to toxicity?

Back 28

1. vasularity of area
2. volume of LA
3. Conc. of LA

Front 29

Metabolism for Amide LA?

Back 29

Degrades by hepatic endoplasmic reticulum.
- N-dealkylation & hydrolysis
- bound extensively to a1- acid glycoprotein
- lung uptake also important

Front 30

LA CNS effects?

Back 30

- decrease electrical activity of excitable tissue
- low doses = anticonvulsants (raise Sz threshold)
- high doses = CNS effects & may cause sz.

Front 31

CNS effects as plasma levels increase?

Back 31

light-headedness, dizziness, parethesia of sight & sound, tinnitus, circumoral numbness.
- Further increase: disorientation, LOC, & tonic-clonic sz.

Front 32

CC/CNS ratio?

Back 32

ratio of dosage required for CV collpase vs. CNS toxicity.
- lower w/ bupivacaine than etidocaine & lidocaine

Front 33

Potentiates cardiac toxicity?

Back 33

tachycardia

Front 34

Kinetics of bupivacaine?

Back 34

Fast in/slow out.
- fast into cardiac tissue but takes long time to disassociate
- potentiated by hyperkalemia

Front 35

Increases suceptibility for cardiotoxicity?

Back 35

Progesterone. (pregnancy also assoc. w/ decrease plasma proteins = more free drug)

Front 36

Use of 0.75% bupivacaine?

Back 36

Prohibited for EPIDURAL use in the parturient pt.

Front 37

Preservatives in LA?

Back 37

Paraben dervatives (methylparaben) are potent allergens & ilicit IgE response.
- LA containing preservatives may not be used for neuroaxial blockade.
**can cause cauda equina syn.

Front 38

Procaine?

Back 38

- oldest ester, Rapidly metabolized to PABA.
- pKa 8.9
- Poor lipid solubility (can not use topically)

Front 39

2-chloroprocaine?

Back 39

-ester
-produced by Cl- subst. of aromatic ring
- t1/2B = 21sec. (decreased risk of toxicity)
- pKa 9.0 but has a fast onset b/c its 3% (30mg/ml, more molecules)
- preservative problems

Front 40

2-chloroprocaine preservatives & problems?

Back 40

- sodium bisulfite = neural irritaion after SAB.
- ethylenediaminetetracetic acid (EDTA) = back pain/spasm b/c its a chelating agent & pulls Ca2+ out of muscle

Front 41

Tetracaine?

Back 41

- ester
- excellent topical, & used for spinal (1% solution)
- highly lipophilic - rapidly absorbed into blood
- avail. lypophilized
- reconstituted w/ 10% dextrose, CSF, or sterile H2O for SAB.
- 1/2 life 2-3min.
- epinephrine use w/ SAB increases duration by 25%
**Do not administer greater than 80-100mg

Front 42

Cocaine?

Back 42

-ester
-1st agent used for LA
-blocks catecholamine (dopamine & NE) reuptake centrally & peripherally
-hydrolyzed by esterases but also undergoes hepatic metabolism

Front 43

Lidoacine?

Back 43

-amide
-metabolized by mixed fxn oxidases& amidases
-De-ethylation of amino nitrogen leads to monoethylyycine xtlidide (MEGX) & glycine xylidide (MEGX may cause sz.
-toxicity max 500-600mg or 7mg/kg
-acidosis increases toxicity by decreasing protein binding

Front 44

Mepivacaine?

Back 44

- amide
-double ring structure
-not for OB use b/c fetus unable to metabolize double ring structure = prolonged 1/2 life in fetus.
-weak vasoconstrictor
-similar to lido but less toxic

Front 45

Prilocaine?

Back 45

-amide
-lido analog
-assoc. w/ methemoglobinemia
-metabolic product is 3-& 5-hydroxytoludine

Front 46

LA assoc. w/ methemoglobinemia
-metabolic product is 3-& 5-hydroxytoludine

Back 46

Prilocaine

Front 47

EMLA?

Back 47

-Eutectic mixture of LA
-5% prilocaine & lidocaine
-used as topical

Front 48

Bupivicaine?

Back 48

-amide
-potent, long acting, long latency to onset
-differential blockade (sensory w/ min. motor)
-do not see aura of CNS toxicity prior to CV collapse
-fast in/slow out kinetics in heart tissue
-R (+) isomer avidly blocks cardiac Na+ channels & slowly dissociates
-0.75% banned for OB epidural use ONLY!

Front 49

Levobupivacaine?

Back 49

-amide
-S-enantiomer of bupivicaine
-CNS & cardiac toxcity 1/2 of bup.

Front 50

Ropivacaine

Back 50

-amide
-newest LA, pure S(-) isomer
-less motor blockade & less potency than bup.
-arrhythmogenicity intermediate b/w mep. & bup.
-used extensively for epidural/not marketed for spinal

Front 51

How to dose LA?

Back 51

based on kg body wt. although no relationship b/w kg wt & max. conc.

Front 52

Tachyphylaxis w/ LA?

Back 52

-decreased efficacy of repeated doses
-may be r/t changes in pH due to eventual consumption of extracellular buffering capacity by repeat inj. of acidic LA solution

Front 53

Use of NaHO3 w/ LA?

Back 53

- by alkalinization of LA solutions speeds onset & improves quality of block & prolongs blockade by increasing the amt. of free base avail.

Front 54

Clinical correlations?

Back 54

-higher conc. to block thicker nerves
-more drug to block highly vascular areas
-LA poorly effective in infected tissue
-prolong action w/ vasoconstrictors
-speed onset w/ NaHCO3

Front 55

Critical length?

Back 55

-smaller diameter fibers have shorter critical lengths
-axons in mantle usually blocked 1st then then axons in core

Front 56

Vasocontrictors & LA?

Back 56

-5mg/ml is optimal (1:200,000)
-add 0.1ml of 1:1000 to 20ml LA
-caution w/ unstable angina, HTN
-CI w/ OB use (esp. preg. induced HTN) b/c placental insuff.
**every dose is a test dose**