14 Local Anesthetics

Question 1

Reversible protonation of the tertiary amine group tends to make local anesthetics less charged at more basic pH and more charged at neutral or acidic pH; the neutral base forms are more soluble in lipid environments, whereas the charged acid forms, the more potent species, are more soluble in aqueous environments.

• V ou F

Answer 1

Verdadeiro

Question 2

Aminoesters are metabolized primarily by ___1___, and aminoamides are metabolized primarily by ___2___

Answer 2

1. plasma esterases
2. hepatic cytochrome P450-linked enzymes.

Question 3

Qual a diferenca entre as classes de Anestesicos Locais?

Answer 3

Grupamento amida ou ester na cadeia intermediaria

Question 4

Qual porcao da molecula de AL é lipofilica e qual é hidrofilica?

Answer 4

• Lipofilico: anel aromatico
• Hidrofilico: grupamento amina

Question 5

Quais AL tem pKa mais proximo do pH fisiológico?

Answer 5

Lidocaina > Bupi > Tetracaina > Chloroprocaina

Question 6

Por que a amina terciaria é relativamente hidrofilica?

Answer 6

• Parcialmente protonada e por isso apresenta carga positiva nos limites de pH Fisiológico
• Substituinte alkyl

Question 7

Compounds with a more hydrophobic nature are obtained by increasing the size of the ___1___. These agents are more potent and produce longer-lasting blocks than their less hydrophobic congeners do.

For example, etidocaine, which has three more carbon atoms in the amine end of the molecule than lidocaine, is four times as potent and five times as long lasting when compared in the isolated sciatic nerve.

Answer 7

1. alkyl substituents.

Question 8

The tendency to be protonated also depends on environmental factors, such as: (3)

Answer 8

1. Temperatura
2. Força ionica
3. pH do meio

Question 9

Qual a influencia do pH na tendencia a protonacao do anestésico local?

Answer 9

• Tecidos inflamados, com pH mais baixo, deixam o AL mais protonado e com mais dificuldade de penetrar nos tecidos.

Question 10

Sobre as fibras tipo C, quais as subclasses, localizacao e funcao?

Answer 10

Subclasse sC:

• pos-ganglionar simpatico,
• diversas funcoes autonomicas

Subclasse dC:

• aferente sensorial,
• funções anatómicas, dor, calor, toque

Question 11

Sobre as fibras tipo B, qual a localizacao e funcao?

Answer 11

• Preganglionar simpatica
• Varias funções autonomicas

Question 12

Sobre as fibras tipo C, quais as subclasses, localizacao e funcao?

Answer 12

Fibras 𝛂
* Mm. Eferentes
* Motora

Fibras β
* Aferente de pele e articulacoes
* tatil, propriocepcao

Fibras δ

• eferente de spindles musculares
• tonus muscular

Fibras δ

• Aferente sensorial
• Dor, frio, toque

Question 13

Os nervos em repouso se comportam majoritariamente como “eletrodos de potássio” de acordo com a equacao de:

Answer 13

Nernst

Question 14

Em que momento a fase de despolarização encerra e ocorre a repolarizacao?

Answer 14

• Ate alguns canais de Na se tornarem inativos e canais de K suficientes abrirem para trocar o equilibrio de corrente e resultar em uma corrente líquida para fora, que produz a repolarização da membrana.

This sequence of events continues during the depolarizing phase until some of the Na+ channels have become inactivated and enough of the K+ channels have opened to change the balance of current and result in a net outward current that produces membrane repolar- ization

Question 15

Por que a propagacao de impulsos é unilateral?

Answer 15

A regiao que foi despolarizada esta absolutamente refrataria.

Question 16

Durante o potencial de acao, quais canais se abrem mais rapido?

Answer 16

• Canais de Na

The Na+ channels open faster, and the inwardly directed Na+ current (see Fig. 29.6) depolar- izes the membrane further, thereby leading to opening of more Na+ channels and increasing the inward Na+ current even further (Fig. 29.7).

This sequence of events continues during the depolarizing phase until some of the Na+ channels have become inactivated and enough of the K+ channels have opened to change the balance of current and result in a net outward current that produces membrane repolarization (see Fig. 29.7).

After one action potential, the con- centrations of Na+ and K+ have changed little for the large myelinated fibers but by as much as 10% for the small, nonmyelinated axons. The Na+ ions entering and K+ ions leaving the cell as a result of this process are restored by the Na+/K+ pump.

Question 17

Moderately hydrophobic local anesthetics block faster than either hydrophilic or highly hydropho- bic ones, delivered at the same concentration, for the following reasons: (2)

Answer 17

1. Less bound to tissues than very hydrophobic drugs, but still more permeant than very hydrophilic ones
2. Highly hydrophobic local anesthetics, having higher potencies, are used in lower concentrations and their diffusion controlled rate of onset is correspondingly reduced

Question 18

Which form of the local anesthetic, charged cation or neutral base, is actually responsible for blockade of impulses?

Answer 18

More alkaline solutions of local anesthetics block nerve conduction more effectively.

The rate of inhibition by tertiary amine anesthetics is greater at alkaline than at neutral external pH because membrane permeation, favored by the base over the cationic species, determines the rate of access to the binding site.

Question 19

Como interpretar o grafico em relacao ao potencial de acao e aumento na concentracao de lidocaína?

Answer 19

• As the concentration of local anesthetic applied to the nerve is increased, a decrease in the rate of depolarization and in the peak amplitude of the action potential occurs until the impulse is abolished.
• Sodium currents during one initial depolarization are reduced by subclinical doses of local anesthetic (e.g., 0.2 mM lidocaine) and totally abolished by clinical doses (e.g., 1% lidocaine ≈40 mM).

Question 20

O que é a inibicao Tônica e a inibicao Fásica?

Answer 20

Inibicao frequencia-dependente

• Em condições normais, anestésicos locais bloqueiam parcialmente os canais de sódio quando o nervo está em repouso. Esse bloqueio em repouso é chamado de inibição tônica.
• Porém, se o nervo for estimulado repetidamente em altas frequências (como >5 Hz), cada pulso adicional da despolarização provoca uma inibição incremental dos canais de sódio. Isso acontece porque os canais de sódio voltam a um estado mais suscetível ao bloqueio pelo anestésico durante a estimulação frequente. Esse bloqueio dependente da estimulação frequente é o que se chama inibição fásica.

A lidocaína, por exemplo, entra mais facilmente nos canais que estão frequentemente abrindo e fechando, como ocorre durante estimulação repetida. Dessa forma, em frequências menores, o bloqueio do Na⁺ é apenas parcial (inibição tônica). Mas com estímulos frequentes, os canais de sódio permanecem mais tempo abertos ou inativados, aumentando o contato do anestésico com os canais, reforçando o bloqueio e resultando na inibição fásica.

Question 21

Como a inibicao fásica é revertida?

Answer 21

• Quando a estimulacao é lentificada ou interrompida e as correntes retornam ao nuvem de inibicao tonica observado no potencial de repouso

Question 22

O que é o modelo “receptor modulado”

Answer 22

O modelo do receptor modulado explica que os anestésicos locais têm afinidades variáveis pelos canais de sódio dependendo do estado em que estes se encontram (fechado, aberto ou inativado). Durante a estimulação frequente (e maior despolarização), os canais são mais propensos a estar em estados abertos ou inativados, onde os anestésicos locais se ligam com maior afinidade. Essa ligação não apenas bloqueia a condução de sódio, mas também estabiliza o canal no estado bloqueado.

Pontos-chave do modelo:

• Dependência do estado: O anestésico se liga preferencialmente a canais de sódio abertos ou inativados e tem baixa afinidade por canais fechados.
• Despolarização aumenta a ligação: Quando a célula se despolariza (alta ativação), mais canais se abrem/inativam, permitindo um bloqueio mais eficiente pelos anestésicos.
• Efeito estabilizador: O anestésico estabiliza os estados que impedem o canal de conduzir o íon Na⁺ (bloqueio funcional).

Question 23

A afinidade dos receptores aos anestesicos locais é aumentada pela despolarização de membrana por dois motivos:

Answer 23

• Mais sitios de ligacao se tornam acessíveis durante a ativacao (“guarded receptor model)
• Dissociacao de canais inativos é mais lenta do que de canais em repouso (modulated receptor model)

Question 24

There appears to be a single, albeit complex, binding site for local anesthetics on the Na+ chan- nel, with a “tonic” affinity at rest and increased “phasic” affinity occurring as a result of depolarization. The sodium channel can be influenced by a number of drugs or toxins/ venoms, and the different sites are numbered.

The binding site for local anesthetics is referred to as ___1___, while the outer channel pore, binding site for tetrodotoxin (TTX) or saxitoxin (STX), is referred to as ___2___.

Answer 24

1. Site 9
2. Site 1

Question 25

Em que local especifico do Canal de Na os anestesicos locais se ligam?

Answer 25

* Vestibulo interno do canal de Na fechado

Question 26

Sobre AL e receptores: *In brief, **___1___** delivers the drug to the receptor and charge keeps it there.*

Answer 26

* hydrophobicity

Question 27

Como ocorre a associação e dissociação do anestésico local (LA) em um canal inativado?

Answer 27

* protonacao e desprotonacao da molecula de AL *The closed (inactivated) channel has a more intimate association with the LA molecule, whose favored pathway for dissociation is no longer between S6 segments (the former pore) but now, much more slowly, laterally between segments and then through the membrane, the “hydrophobic” pathway. Na+ ions entering the pore will compete with the LA for a site in the channel, and H+ ions, which pass very slowly through the pore, can enter and leave from the extracellular opening, thereby protonating and deprotonating a bound LA molecule and thus regulating its rate of dissociation from the channel.*

Question 28

Quais as fibras mais suscetíveis a supressao de impulso por AL?

Answer 28

* small myelinated axons (**Aγ motor and Aδ sensory fibers**) are the most susceptible to impulse suppression. *Depois, large myelinated (Aα and Aβ) fibers, and the least susceptible are the small, nonmyelinated C fibers.*

Question 29

Clinically, testing of block efficacy is often performed using methods that target **___1___**, so these findings suggest that loss of temperature or pin-prick discrimination does not guarantee complete and reliable block of all sensory modalities.

Answer 29

1. Aδ sensory fibers

Question 30

Local anesthetic molecules permeate the nerve’s axon membranes and reside there and in the axoplasm. The speed and extent of these processes depend on a particular drug’s **___1___** and on the **___2___** of its base and cation species.

Answer 30

1. pKa 2. lipophilicity

Question 31

One local anesthetic binding site on the Na+ channel may be sufficient to account for the drug’s resting (**___1___**) and use-dependent (**___2___**) actions.

Answer 31

1. tonic 2. phasic

Question 32

The clinically observed rates of onset and recovery from blockade are governed by the relatively slow diffusion of local anesthetic molecules into and out of the whole nerve, not by their much faster binding and dissociation from ion channels. A clinically effective block that may last for hours can be accomplished with local anesthetic drugs that dissociate from Na+ channels in a few seconds. * **V ou F**

Answer 32

Verdadeiro

Question 33

Aminoesters are hydro- lyzed in plasma by cholinesterase enzymes, but the amides undergo enzymatic degradation in the liver. Two exceptions to this trend include:

Answer 33

* Cocaina: ester metabolizado pela carboxylesterase hepatica * Articaina: amida inativada pela carbodilesterase plasmatica

Question 34

Qual metabolito dos aminoesteres que pode induzir alergias?

Answer 34

Acido p-Aminobenzoico

Question 35

Vantagens da Bupivacaina no bloqueio epidural (2)

Answer 35

* Antinocicepcao adequada sem inibicao da atividade motora * Pouca fraqueza muscular

Question 36

The use of epinephrine as a marker for inadvertent intravas- cular injection continues to be sensible, even though false negatives and false positives can occur, such as difficulty in interpretation for specific patient groups as with (3)

Answer 36

1. Parturienetes 2. Anestesia Geral 3. Beta-bloqueadores

Question 37

Efeito da Epinefrina como aditivo a AL (2)

Answer 37

1. prolonga duracao 2. intensifica bloqueio com lidocaína e bupi

Question 38

Efeito da 𝛂2-agonistas como aditivo a AL (1)

Answer 38

1. prolonga efeito * Alto risco de eventos adversos * acao em receptores 𝛂2 e correntes induzidas por hiperpolarizacao

Question 39

Efeito da Buprenorfina como aditivo a AL (2)

Answer 39

1. prolonga efeito 2. elevado NVPO * agonista mi, bloqueio kappa e delta, bloqueio Na-vd

Question 40

Efeito da Dexametasona como aditivo a AL

Answer 40

* prolonga efeito

Question 41

Efeito de ajustes no pH e Carbonatacao como aditivo a AL (2)

Answer 41

1. Acelera o inicio 2. Diminui a concecntracao necessaria *Beneficio incerto*

Question 42

Em que stituacao a mistura de anestesicos locais é adequada?

Answer 42

* Infusao de cateter *The use of catheter techniques for many forms of regional anesthesia makes it possible to begin with a rapid-onset local anesthetic such as lidocaine, mepivacaine, or chloroprocaine and then follow with an infusion of either a shorter-acting or longer- acting local anesthetic thereafter.*

Question 43

Efeitos da gestacao nas propriedades de anestesicos locais

Answer 43

Alteracoes na susceptibiliadades dos nervos a condução de bloqueio (diminuicao do volume do espaco epidural e subaracnoite, influências hormonais) * Diminuir a dose de AL

Question 44

Epinephrine will prolong the duration of infiltration anesthesia by all local anesthetic drugs, although this effect is most pronounced when epinephrine is added to:

Answer 44

* lidocaine

Question 45

Patients frequently experience pain immediately after subcutaneous injection of local anesthetic solutions, in part because of the **___1___** of these solutions, and in part because lidocaine briefly activates **___2___** and **___3___**, causing pain, before sodium channel block subsequently silences the neuron.

Answer 45

1. acidic nature 2. transient receptor potential vanilloid-1 (TRPV-1) channel 3. transient receptor potential ankyrin-1 (TRPA-1) channel

Question 46

With prolonged infusions there is a theoretical potential for delayed systemic accumulation and toxicity. However, the activation of the acute-phase response after trauma or surgery also leads to an increase in **___1___**, which is potent at binding free local anesthetics and decreases the risk of cumulation of free local anesthetic.

Answer 46

1. α-1 acidic glycoprotein

Question 47

The duration of short- and intermediate-acting drugs is significantly prolonged by the addition of **___1___**, but the duration of long-acting drugs is only minimally affected by it.

Answer 47

1. epinephrine (1:200,000)

Question 48

Systemic lidocaine has been extensively investigated over the past 10 years for its potential to inhibit **___1___** receptors. Systemic local anesthetics have a strong antiinflammatory effect, but their application has only been shown to be of clinical significance in **___2___** where they decrease inflammation and pain, and speed recovery when compared to placebo.

Answer 48

1. G protein-coupled 2. visceral surgery

Question 49

O que é a Anestesia Tumescente?

Answer 49

* injecao subcutanea de grandes volumes de AL diluído em combinacao com epinefrina e outros agentes, mais comumente usada por Cir Plásticos em Lipo-succao

Question 50

Quais os pp fatores relacionados ao paciente influenciam a Farmacocinetica dos AL? (3)

Answer 50

* Idade * Status cardiovascular * Funcao hepatica

Question 51

Comparison of the blood concentration of local anesthetics after various routes of administration reveals that the anesthetic drug level is highest after **___1___** blockade, followed in order of decreasing concentration by injection into the caudal epidural space, lumbar epidural space, brachial plexus, and subcutaneous tissue. When a local anesthetic solution is exposed to an area of greater **___2___**, a greater rate and degree of absorption occur.

Answer 51

1. intercostal nerve 2. vascularity

Question 52

Resorption of local anesthetics follows a biphasic pattern, with an initial fast peak reflecting the **___1___** and later a slower second peak corresponding to **___2___**. The addition of epinephrine to local anesthetic solutions slows the **___3___** phase. The net clinical effect is a more profound block, and lower systemic levels

Answer 52

1. fluid phase 2. resorption from the lipid compartment 3. first

Question 53

The primary extraction of Local Anesthetics takes place in the **___1___**, but local anesthetics are also rapidly extracted by **___2___**.

Answer 53

1. liver 2. lung tissue

Question 54

Excretion of the metabolites of amide-type local anesthetics occurs via the **___1___**. Less than 5% of the unchanged drug is excreted via the kidney into urine.

Answer 54

1. kidney

Question 55

Newborn infants have immature hepatic enzyme sys- tems and hence **___1___** elimination of lidocaine, bupi- vacaine, and ropivacaine.

Answer 55

1. prolonged

Question 56

Patient age may influence the physiologic disposition of local anesthetics. The half-life of lidocaine after intravenous administration averaged 80 minutes in human volunteers varying in age from 22 to 26 years, whereas volunteers 61 to 71 years of age demonstrated a significantly **___1___** lidocaine half-life

Answer 56

1. prolonged

Question 57

The dose or blood level of local anesthetic required to produce CNS toxicity is usually **___1___** than that resulting in circulatory collapse.

Answer 57

1. lower

Question 58

Os sintomas iniciais de toxicidade de AL no SNC sao inicialmente:

Answer 58

* Excitatorios. *If a sufficiently large dose or rapid intravenous injection of a local anesthetic is administered, the initial signs of CNS excitation are rapidly followed by a state of generalized CNS depression. Seizure activity ceases, and respiratory depression and ultimately respiratory arrest may occur.*

Question 59

Convulsions caused by an inadvertent intravenous bolus of local anesthetic can generally be terminated by:

Answer 59

* small IV doses of a benzodiazepine, such as midazolam, or by small intravenous doses of propofol.

Question 60

Efeito da PaCO₂ e Acidose na toxicidade por AL (3)

Answer 60

* Hipercapnia aumenta FSC e aumenta o risco de Toxicidade * o pH elevado facilita a conversar da forma basica em Cation, que nao se difunde bem pela membrana neuronal e promove ion-trapping * Hipercapnia e Acidose diminuem a ligacao proteica plasmatica dos AL *The clinical implication of this effect of hypercapnia and acidosis on toxicity deserves emphasis. Seizures produce hypoventilation and a combined respiratory and metabolic acidosis, which further exacerbates the CNS toxicity*

Question 61

Baseado no risco de toxicidade por anestesicos locais, o que sempre deve estar a disposição do anestesiologista que faz bloqueio? (4)

Answer 61

1. monitorizacao 2. tanque de oxígeno 3. via aerea de resgate 4. drogas anticonvulsivantes (mdz, tiopental, ppf)

Question 62

Quais os efeitos dos AL no sistema cardiovascular? (3)

Answer 62

1. efeito direto cardíaco 3. efeito direto vascular 3. efeito indireto por bloqueio simpatico ou parassimpático

Question 63

Quais os efeitos cardiacos diretos dos AL? (4)

Answer 63

* Inotropismo negativo por bloqueio de canais de Na * inibicao do metabolismo de ácidos graxos * interferencia com homeostase do Calcio, diminuindo o influxo e liberacao do RES * Inibicao da cadeia respiratoria da mitocondria

Question 64

Qual o efeito vascular dos AL? (3)

Answer 64

* Doses baixas: vasoconstriccao * Doses altas: vasodilatacao * Cocaina: sempre vasoconstriccao (inibicao da recaptacao de noradrenalina)

Question 65

*These differential effects of lidocaine and bupivacaine have been advanced as explanations of the antiarrhythmic properties of lidocaine versus the arrhythmogenic potential of bupivacaine.* * Quais sao?

Answer 65

Bupivacaine depresses the rapid phase of depolarization (Vmax) in Purkinje fibers and ventricular muscle to a greater extent than lidocaine does. In addition, the rate of recovery from a use-dependent block is slower in bupivacaine-treated papillary muscles than in lidocaine-treated muscles. **This slow rate of recovery results in incomplete restoration of Na+ channel availability between action potentials, particularly at high heart rates.**

Question 66

All local anesthetics, but especially bupivacaine, can cause rapid and profound cardiovascular depression. The cardio- toxicity of bupivacaine appears to differ from that of lido- caine in the following manner: (4)

Answer 66

1. razao Colapso-CV/Tox-SNC é menor para bupi 2. maior frequencia de arritmias ventriculares e FV fatal 3. gestantes mais sensíveis aos efeitos cardiotoxicos 4. Ressuscitacao mais dificil com bupi

Question 67

Pharmacokinetic studies have estimated that Intralipid decreases cardiac bupivacaine concentration by 11% within 3 minutes of administration, and cerebral bupiva- caine content by 18% within 15 minutes. Even though these findings are theoretical, they underline the notion that Intralipid should not be considered an antidote with full antagonistic properties. Quais as outras propriedades do Intralipid? (3)

Answer 67

1. reduz a concentracao de Bupi em orgaos-alvo 2. Melhora metabolismo 3. Efeito benéfico direto em Canais de Ca²⁺ *Intralipid is a valuable contribution to, but not a substitute for, careful and meticulous conduct of regional anesthesia.*

Question 68

Principais diferenças de Bupi x Ropi

Answer 68

1. Bupi é mais potente 2. Bupi é mais cardiotoxica *Ropivacaine is a single (S)-stereoisomer that differs from levobupivacaine in the substitution of a propyl for the butyl group on the piperidine ring.*

Question 69

Quais disturbios HEL-AB potenciam o efeito cronotropico e inotrópico negativo de Lido e Bupi? (3)

Answer 69

* Hipercapnia * Acidose * Hipoxia *Todos exacerbados por convulsos que podem ocorrer com a intoxicação de AL*

Question 70

Paciente com dor lombar, parestesia, dor radicular e hiperestesia apos BSA. Qual o diagnostico mais provavel?

Answer 70

Sintomas neurológicos transitórios

Question 71

Coming back to the nine different subtypes of sodium channels, research efforts have been directed at blocking specific isoforms thought to be of particular relevance for defined pain conditions. The **___1___** subtype, for example, has been linked to somatic pain, and to hereditary syndromes of hyperalgesia or insensitivity to pain

Answer 71

1. Nav1.7