Local Anesthetics

Are nonselective voltage-gated sodium channel blockers
that inhibit conduction of APs in all afferent and efferent neurons to and from the CNS

Precautions

Ester LAs

e.g. Procaine

e.g. Tetracaine

e.g. Benzocaine

Adverse Reactions

Toxicity

Allergic & Hypersensitivity Reactions

Idiosyncratic Reactions

high plasma levels due to overdosing, rapid absorption, slow metabolism, unintentional iv injection

Measuring MRD (maximum recommended dose)

MRD in mg = MRD mg/kg X weight in kg

MRD in mL = MRD mg ÷ mg/mL

Can be primary or secondary

Primary: can be from direct trauma to injection site

Secondary: from a lack of function of a nerve (usually lingual nerve)

Signs and Symptoms:
-edema
-skin peeling
-ischemic necrosis

Signs and Symptoms:
-transient anesthesia or paresthesia (lips, tongue)
May take 2-6 months in worst cases

CNS effects

CVS effects

Pregnancy/Breastfeeding

LAs cause CNS depression after stimulation in high doses or accidental iv injection
(-excitation->restlessness->convulsions->unconsciousness)

LAs are cardiac depressants

No significant effects in normal doses

-fall in BP
-local vasodilation

Bupivicaine can be cardiotoxic and cause ventricular tachycardia

Overdose effects on CVS

-low BP
-depress conduction, excitability, and contractility
-may progress to ventricular arrhythmia and AV block

Sympathetic Reactions

With LAs containing Epinephrine or Levonordefrin

-Healthy adults: MRD = 0.2mg epinephrine, 1.0mg levonordefrin per visit
-ASA III patients: MRD = 0.04mg epinephrine

Most allergic reactions happen with Ester type (from PABA) LAs and with atopic patients

Sodium bisulfite an anti-oxidant in LAs containing vasoconstrictors can cause allergic reactions

Reactions:
-Rash
-angioedema
-asthma
-anaphylaxis

Especially with Prilocaine (systemic) and Benzocaine (topical)

Can cause Methemoglobinemia:
-LA metabolites (orthotolwidine) bind hemoglobin and reduce O2 circulation
-Children and patients with G6PD anemia are most susceptible

Signs and Symptoms:
-cyanosis (nails, lips)
-fatigue, weakness
-nausea
-sedation
-seizures

Pregnancy

Only use Lidocaine and Prilocaine in the 2nd trimester

Never use Mepivacaine, Articaine, or Bupivacaine during pregnancy

Breastfeeding

Bupivacaine can cause toxicity to nursing infants

Drug-Drug Interactions

Not taken with other CNS depressants

Use LAs containing vasoconstrictors with caution if the patient is taking:

Amiodarone

-MOA inhibitors (MOA inhib. will be ineffective)
-TCAs
-ergot type drugs (fungi derived) cause increased BP
-non-selective β-adrenergic receptor blocking agents
-Thyroid hormones (epinephrine effects on CVS)

Inhibits Lidocaine metabolism
(Use Articaine instead)

Structure of LAs

Duration of Action

Determined strength of LA bond to protein (Na+ channel)
Stronger bond = Longer duration of action


Pharmacokinetics

Distribution

Clearance

Absorption

Rate and extent of absorption depends on:
-Vascularity
-LAs physicochemical properties
-Vasoconstrictor presence
-Dose of LA

LAs with greater lipid solubility = greater Vd (degree of tissue uptake)

Amide LAs

Ester LAs

Metabolized in liver by cytochrome P450
-to be more hydrophilic for excretion mainly by kidneys (urine) or some by liver (bile)

e.g. Propoxycaine

Effects of Lidocaine overdose
-dizziness, blurred vision, tinnitus, lethargy, abnormal tongue sensation

Metabolized by tissue and plasma pseudocholinesterases into (PABA) and other metabolites to be excreted by kidneys

Mode of Action

Act on Voltage-gated Na+ channels (integral membrane
proteins) on intracellular side, have reversible & concentration-dependent effect

Onset of Action

consist of 3 structural domains:

  1. Aromatic group
  2. Linker : ester (COO) or amide (NHCO)
  3. Secondary or tertiary amine group

Potency

Topical anesthetics

Exert their effect on free nerve endings near to the skin

Come in form of spray, gel, ointment.

Xylocaine & Benzocaine have short anesthetic effect and give surface anesthesia

Amide LAs

e.g. Lidocaine

e.g. Prilocaine

e.g. Mepivacaine

e.g. Articane

e.g. Bupivacaine

Risk of Methemoglobinemia and paraesthesia following mandibular nerve block

Produce parathesia following mandibular nerve block

Most lipophilic, most potent, longest duration of pulpal anesthesia, longest half life, great degree of tissue uptake Vd and higher risk of cardiotoxic

Determined by the aromatic group which gives the LA lipid solubility

High lipid solubility, lower concentration of LA is required

Amine groups give hydrophilic nature, LAs exist as protonated (RNH+) and neutral (RN + H+)

Only neutral form can cross neuronal membranes, this prevents LAs from working in cases of infection (acidic pH)

Low pH (acidic) = more protonated
Higher pH (basic/alkaline) = more neutral

Factors affecting duration of action:

  1. Protonated LAs: dissociate slower
  2. Dose administered
  3. Addition of a vasoconstrictor (slows absorption)

Example: Bupivacaine less likely to diffuse due to its high protein binding capacity

Degree of tissue uptake (Vd)

Higher Vd = higher elimination half-life = longer to eliminate = high toxicity risk

Example: Bupivacaine has a half-life of 5.5 hours, compared to Lidocaine's 2 hours

Cytochrome P450 can have isoenzymes: CYP34A and CYP1A2

PABA may trigger allergic reactions especially in atopic patients