Exam 2 LA

Question 1

Local anesthetics are either ? Or ?

Answer 1

Esters or amides; a hydrophobic tail connected to hydrophilic benzene ring via ester or amide bond

Question 2

Difference bw esters and amids

Answer 2

Esters have shorter DOA and increased systemic toxicity

• differences in stereochemistry can also affect potency and clinical properties
• typically administered as salts to increase stability and solubility

Question 3

Procaine is an ____ and lidocaine is an?

Answer 3

Procaine is ester, lidocaine is the first amide

Question 4

Local anesthetics are what and their pkas are within what range

Answer 4

Weak bases; Pka: 7.5-9 (physiologic is 7.4, so Las are predominantly ionized (LAH+)

Question 5

Describe the Henderson Hasselbach kinetics associated with Local anesthetics

Answer 5

At physiologic pH, most LA are in ionized form. The binding site is on the inner membrane, but need to be in non-ionized (LA + H+) form to cross cell membrane. Inside, the ionized form binds to Na channel

*note: hydrophobic pathway – neutral LA through the membrane

Question 6

The closer the pKA of the drug is to the physioloigic pH (7.4), the higher the concentration of the drug is in what form? What does this mean for the transport and drug action?

Answer 6

Closer the pKA is to physio pH, the higher the concentration of the drug is in the non-ionized form; this increases membrane transport meaning faster onset of action
Ex: Lidocaine (7.8) has faster onset than bupivacaine (8.1); exception is Benzocaine (pka 3.5) that is always in the non-ionized (LA+H) form – topical application only

Question 7

How does inflammation/infection affect membrane transport? How do we overcome this

Answer 7

Decreases membrane transport due to increased acidification (more drug in ionized form) **bicarb makes pH more basic and increases non-ionized drug concentrations and thus LA transport

Question 8

How do local anesthetics work? What is this dependent on?

Answer 8

Block Na channels and inhibit neuronal firing. Extent of block is VOLTAGE/POTENTIAL and TIME/FIRING dependent
High affinity for channels in activated (open) and inactivated states
Low affinity for channels in resting/closed state
Block more effective in rapidly firing axons
Repetitive activity on the block of Na current increases threshold for excitation and opening of channels; Na current into cell decreases progressively and conduction slows till complete block is achieved

Question 9

What LAs are lipophilic? And their rate of action?

Answer 9

Tetracaine, bupivicaine, ropivicaine

*have a faster rate of interaction with the Na+ channel

Question 10

What effect does elevated Ca have on membrane potential/block?

Answer 10

Elevated Ca hyperpolarizes membrane potential; more channels are in resting state; block is DIMINISHED

Question 11

What effect does elevated K have on membrane potential/block?

Answer 11

Depolarizes membrane potneital; more channels in inactivate state; block is ENHANCED

Question 12

Potency of the Local anesthetics is correlated to what? How is it measured?

Answer 12

Potency is correlated to lipid solubility and DOA. Measured as relative to procaine(1). Increased lipid solubility results in increased time at site of action, and hence, increased duration of action

Question 13

What local anesthetics have short vs medium vs long DOA (correlates with potency/lipid solubility)

Answer 13

Short: Procaine (1)
Med: Cocaine (2), Mepivacaine (2), Lidocaine (4)
Long: Tetracaine(16), Bupivicaine (16), Ropivicaine (16)

Question 14

PK of Local anesthetics

Answer 14

Exert their effect at site of application
PK is important for elim and potential SE (CNS, cardiac)
Rapidly diffuse away from the site of application
DOA dep on time at site of action
Toxic effects (CNS, cardiac) are dep on t1/2

Question 15

What is the distribution of local anesthetics (local vs systemic)

Answer 15

Local: hyperbaric (helps sink into skin), isobaric and hypobaric solutions
Systemic: alpha phase (rapid diffusion into highly perfused areas) and Beta phase (delayed diffusion into lesser perfused areas (ie SQ fat)

Question 16

Re systemic absorption; what is it affected by

Answer 16

Dosage
Site of injection (vascular area vs fat)
Drug tissue binding
Chem properties of the drug (lipophilic vs hydrophilic)
Local blood flow (increased blood flow means increased systemic absorption)
Vasoconstricting agents ie Epi (these help decrease diffusion of drug and prolong DOA, decrease systemic abs and systemic toxicity)

Question 17

Metab and excretion of amides

Answer 17

CYP450 metab

Toxicity more likely in pt with hepatic dz or reduced hepatic blood flow

Question 18

Metab and excretion of esters

Answer 18

Rapidly metab by butyrylcholinesterases in the plasma; Mutations can affect metab of ester Las
Renal excretion

Question 19

What factors affect anesthetic action

Answer 19

Differential block: block not limited to intended site
Block noxious stimuli but also motor nerves
May lead to motor paralysis and resp impairment
Diff deg of sensory vs motor nerve inhibition (bupivacaine blocks sensory before motor, etidocaine blocks motor before sensory)
Anatomic Arrangement (effect hits proximal fibers then proceeds to more distal fibers within a nerve bundle
Intrinsic susceptibility of nerve fibers to blocks.
Larger and more myelinated fibers are blocked faster but also less sensitive

Question 20

Explain the intrinsic susceptibility of nerve fibers

Answer 20

Order of senstitivity: Sympathetic >Sensory (pain) > touch > motor

*heavier the myelination, the faster the conduction velocity but the less sensitive to the block

Question 21

General SE and Toxicities of local anesthetics

Answer 21

Cardiovascular: Inhibition of Na and Ca channels
Arrhythmias, vasodilation, hypoTN
Bupivacaine has inc binding to resting cardiac Na channels, slower dissociative times
Cocaine has increased SNS tone
IV lipid administration (lipid sink) may decrease toxicity

CNS: depress cortical inhibitory pathways – sedation, visual/auditory disturbances, nystagmus, convulsions, death

Allergic: PABA metab from esters may cause hypersensitivity rxn

Blood: PRILOCAINE metab may cause METHEMOGLOBINEMIA

PNS: sensory and motor deficit

Localized toxicity: neural injury, transient neuro sx (TNS) linked to use of LIDOCAINE for spinal anesthesia

Question 22

Procaine: type, absorption/metab, duration

Answer 22

First synethtic LA, ester type
Well abs; metab by butyrylcholinesterases
Short DOA
PABA metab – hypersensitivity rxn and inhibit sulfonamide action

Question 23

Procaine (Novocain): forms, use, prep

Answer 23

Used for infiltration anesthesia and nerve blocks

• Lacks topical activity
• Minimal systemic toxicity and no local irritation bc short DOA
• Available with and without epinephrine

Question 24

Tetracaine (pontocain): type, onset/duration, potency/toxicity, use

Answer 24

Ester type
Slow onset (>10min), long DOA (2-3hr)
~16x more potent/toxic than procaine
Severe toxicity with high vol peripheral blocks
OPTHALMOLOGICAL use (retrobulbar)
*spinal anesthesia with 10% dextrose to inc specific gravity; heavier than CSF (hyperbaric)

Question 25

Benzocaine (americaine): type, ionization, transport, use

Answer 25

Ester type
Lipophilic (Pka 3.5), always in non-ionized from
Readily transported through membrane, min binding to Na channel
Topical only – tx sunburn, minor burns, pruritus
FDA – risk of METHEMOGLOBINEMIA

Question 26

Cocaine: type, duration, use, MOA

Answer 26

Ester type
Short acting, naturally occurring alkaloid
Use: topical anesthesia of mucous membranes around URT (reduce dental bleeding)
Inhibits Na channels secondary to increasing DA in CNS and periphery
Prep: 1, 4, 10% for topical application

Question 27

Cocaine: Adverse effects

Answer 27

Tolerance/abuse/OD potential

CNS: euphoria followed by dysphoria and poststimulatory depression

CV: block uptake of catecholamines at adrenergic nerve terminals; tachycardia, vasoconstriction, HTN
Caution in pt with HTN, CVD, or thyrotoxicosis
Caution with drugs that potentiate catecholamines

Question 28

Lidocaine (xylocaine): type, absorption, onset, potency, DOA, activity

Answer 28

Prototype amide drug (AMIDE KINETICS)
Rapid abs; intermediate DOA
Rapid onset of anesthesia
Greater potency and longer DOA than procaine
Moderate topical activity and minimal local irritation

Question 29

Lidocaine (xylocaine): Applications, use, prep

Answer 29

Wide range of applications
Pref for infiltration blocks & epidural anesthesia
NOT pref for spinal blocks – risk of TNS!! (transient neuro sx – transient pain, dysesthesia)
Also used as an antiarrhythmic agent
Prep: with or w/o epi

Question 30

Bupivacaine (Marcaine): type, DOA, use

Answer 30

Amide type
Long DOA, differential block (sensory>motor)
Pref for epidural for preg/labor
Use: Analgesia for post op pain control; spinal anesthesia, infiltration blocks and epidural anesthesia

*more cardiotoxicity than other amides (s enantiomers)

Question 31

SE/risk of Bupivacaine (Marcaine)

Answer 31

Greater cardiotoxicity than other amides (S enantiomers)
Binds to more resting cardiac Na channesl
Dissociates from channels slower than other Las

Question 32

Ropivacaine (Naropin): type, DOA, stereochemistery, solubility

Answer 32

Amide type
Long acting
S enantiomer of Bupivacaine – less lipid soluble and cleared more rapidly than bupivacaine thus less cardiac toxicity

Question 33

Ropivacaine (Naropin): Metab, use

Answer 33

(*note: S enantiomer of Bupivacaine)
CYP3A4 metab (drug interaction potential)
Use: peripheral and epidural blocks
*vasoconstriction at clinical dose (nice benefit)

Question 34

Mepivacaine (Carbocaine): type, DOA, use

Answer 34

Amide type similar to bupivacaine
Intermediate DOA
Perf: peripheral nerve blocks
NOT topical, NOT for labor anesthesia

Question 35

Etidocaine (Duranest) type, DOA, effect/use

Answer 35

Amide type
Long DOA
Inverse differential block (motor>sensory) – not favorable

Question 36

Prilocaine (Citanest): type, DOA, metab, risk

Answer 36

Amide type
Intermediate DOA
Highest rate of clearance of amides
*methemoglobinemia due to metab
Excessive methemoglobin in blood (choc color), SOB, fatigue, dizzy, coma death.
Reverse with methylene blue

Question 37

CI for prilocaine (Citanest)

Answer 37

Pt with cardiac or respiratory dz (remember risk methemoglobinemia)
*largely limited use to dentistry – pearly whites prilocaine

Question 38

Articaine (septocaine): type, DOA/toxicity, use

Answer 38

Amide type, but has additional ester group subject to metab by plasma esterases
*this decreases t1/2 and potential toxicity of Articaien (septocaine) [septocaine is the exception]

*widespread use in dental med bc larger therapeutic window and low potential for systemic toxicity (can inject more later in procedure)

Question 39

Adverse effects of articaine (septocaine)

Answer 39

*remember: amide type LA but has additional ester group – used in dentistry bc safe therapeutic index

SE: rare, but may include dev of persistent paresthesias (3x more likely with w articaine)

Question 40

Dibucaine (nupercainal): type, use, test

Answer 40

Amide type
Used topically in US (spinal anesthetic outside)

Dibucaine # test: measure butyrylcholinesterase activity to differentialte indiv who have mutations and deficiencies (genetic or acquired)
Dibucaine inhibits normal wilde type butyrylcholinesterase; based on deg of inhibition, determine dibucaine #
<80 = deficient butyrylcholinesterase