03b - Local Anesthetics II

ester vs amide local anesthetics

classification of local anesthetics according to their chemical linkages

• ester local anesthetics → readily hydrolyzed in aqueous solution

  • metabolism by plasma pseudocholinesterase

• amide local anesthetics → resistant to hydrolysis

  • greater percentage of drug excreted unchanged in urine

  • metabolism by liver CYP450

pKa and onset of local anesthesia

basic compounds that are poorly soluble in water and unstable on exposure to air

• pKa value ranges from 7.5-10

• drugs with lower pKa possess a more rapid onset of action than those with higher pKa

pH of tissue and LA effectiveness

pH of LA solution and pH of tissue greatly influences nerve block action

• acidification of tissue decreases local anesthetic effectiveness

  • inflammatory process produces acidic products, lowering tissue pH

• LA without epinephrine = 6.5; LA with epinephrine = 3.5

  • LA containing epinephrine are acidified to inhibit oxidation and breakdown by adding sodium metabisulfite to prolong effectiveness of drug

  • lower pH more likely to cause burning sensation and slower onset of anesthesia

buffering / alkalinization of LA

raising pH of LA solution will speed its onset of action, increase clinical effectiveness, and make injection more comfortable

• LA base is unstable and precipitates out of alkalinized solutions

• buffered LAs may use sodium bicarbonate or carbon dioxide immediately before injection for greater comfort and more rapid onset

solubility of LA

lipid solubility is related to its intrinsic potency

• more lipid solubility = more effective conduction blockade at lower concentrations

• can dissolve and interact with nerve membrane more effectively

protein binding of LA

degree of protein binding is responsible for duration of activity

• greater degree of binding will attach more securely to receptor sites for longer duration

• long-acting LA → bupivacaine, etidocaine, ropivicaine, tetracaine

• recovery from nerve blocks is slower than onset because LA remains bound to nerve membrane and slowly releases

vasoactivity

vasoactivity affects anesthetic potency and duration of anesthesia

• LAs with greater vasodilating properties increases perfusion to the site

• injected LA is absorbed into cardiovascular comjpartment more rapidly and is carried away from injection site and away from nerve, providing a shortened duration and decreased potency

duration of anestheia

onset of nerve block is relatively rapid, while recovery is slower because LA is bound to nerve membrane

• longer acting LAs are more firmly bound to membrane and are released more slowly from receptor sites in sodium channels

• removal of drug influenced by vascularity of injectio nsite and presence/absence of vasoactive substance

  • decreased vascularity = increased duration

  • addition of vasopressor = decreased perfusion = increased duration

ester local anesthetic metabolism

ester local anesthetics are hydrolyzed in plasma by pseudocholinesterase

• rate of hydrolysis affects toxicity risk

  • chlorprocaine → most rapidly hydrolyzed = least toxic

  • tetracaine → slowly hydrolyzed = greatest potential toxicity

• procaine undergoes hydrolysis to PABA (excreted in urine) and diethylamine alcohol (undergoes further biotransformation)

  • allergic reactions to PABA, which is a major metabolite of ester LAs

  • atypical form of pseudocholinesterase causes inability to hydrolyze ester LAs, leading to prolongation of higher LA blood levels and increased potential for toxicity

atypical plasma cholinesterase

plasma cholinesterase produced by liver to hydrolyze ester LAs and succinylcholine in blood

• hydrolysis is rapid, quickly terminating drug action and minimizing risk of overdose

• 1/2820 people have atypical form, from inherited autosomal recessive trait

• atypical plasma cholinesterase determined by patient’s response to succinylcholine

  • will have prolonged apneic period

• dibucaine number determined from blood sample to determine atypical plasma cholinesterase

  • normal = 66-86; atypical = as low as 20

amide local anesthetics

metabolized mainly by the liver for lidocaine, mepivacaine, etidocaine, bupivacaine

• liver function and hepatic perfusion influences rate of transformation

  • decreased hepatic flow or poor liver function metabolizes amide LAs more slowly, resulting in higher anesthetic blood levels and increased toxicity risk

  • liver dysfunction (ASA4-5) or heart failure (ASA4-5) represent relative contraindication

• prilocaine → primary metabolism in liver but possibly also in lungs

• articaine → contains ester and amide components and undergoes metabolism in blood and liver

  • shorter half-life due to metabolism in both blood and liver

active metabolites

biotransformation products of LAs can prossess clinical activity if accumulated in blood

• prilocaine → produces orthotuluidine that induces formation of methemoglobinemia

• lidocaine → monoethylglycinexylidide and glycine xylidide responsible for sedative effect

renal excretion

kidneys are primary excretory organs for LAs and its metabolites

• significant renal impairment may be unable to eliminate parent LA compound and metabolites from blood, leading to elevated blood levels and increased toxicity

• renal disease (ASA4-5) represents relative contraindication to LAs

  • includes renal dialysis and chronic glomerulonephreitis or pyelonephritis

systemic actions of LA

most systemic actions of LAs are related to their blood/plasma level in target organ

• higher level = greater clinical action

• LAs absorbed into circulatory system, carrying out to all cells of the body

  • blood level depends on rate of uptake into circulatory system and rate of distribution and biotransformation to remove from blood

CNS effects of LAs

readily cross BBB and cause depression of CNS

• at low therapeutic levels → no clinically significant CNS effects

• at toxic overdose levels → generalized tonic-clonic convulsions may occur

• CNS more susceptible to actions of LA, so symptoms of overdose are CNS in origin and usually excitatory in nature

  • observable signs → slurred speech, shivering, muscular twitching, generalized lightheadedness, dizziness, inability to focus, tinnitus, drowsiness, disorientation

  • symptoms → numbness of tongue, warmed flushed feeling of face, pleasant dreamlike state

• sedation may develop in place of excitatory signs

  • if excitation or sedation observed in first 5-10 min of administration, it should warn clinician of rising blood levels and possible serious reaction

anticonvulsant properties

some LA have anticonvulsant properties at blood levels below those that cause seizures

• procaine, lidocaine, mepivacaine, prilocaine, cocaine

• some used IV to terminate seizures → procaine, mepivacaine, lidocaine

  • lidocaine’s anticonvulsant blood level close to cardiotherapeutic range

• mechanism:

  • epileptic patients possess hyperexcitable cortical neurons

  • LAs depress CNS to raise seizure threshold by decreasing excitability to terminate seizures

cardiovascular effects of LAs

LAs have direct effects on myocardium and peripheral vasculature

• cardiovascular system more resistant than CNS → toxicity happens at higher blood levels

• LAs produce myocardial depression related to LA blood level by decreasing electrical excitability, conduction rate, and force of contraction

• can be used to manage hyperexcitable myocardium that manifests as cardiac dysrhythmias

  • procaine and lidocaine → clinical liability in antidysrhythmic actions

  • procainamide → procaine with amide linkage replacing ester link

  • tocainamide → analog of lidocaine because lidocaine is ineffective after oral administration, but has 40% incidence of adverse effects

lidocaine as antiarrhythmic

lidocaine is both a local anesthetic and antiarrhythmic drug

• anti-dysrhythmic actrivity = 1.8 - 6 mcg/mL

• used primarily in management of premature ventricular contractions and ventricular tachycardia, as well as ACLS for management of cardiac arrest caused by ventricular fibrillation

  • cause decrease in myocardial contractility and decreased cardiac output, leading to circulatory collapse

peripheral vascular effects of LAs

most LAs produce peripheral vasodilation by relaxing vascular smooth muscle

• increased blood flow for faster drug absorption, decreased depth of anesthesia, shorter duration, more bleeding, higher local anesthetic blood flow

  • causes hypotension due to direct depression of myocardium and smooth muscle relaxation in vessel walls

• cocaine → only LA drug that produces vasoconstriction

• ropivacaine causes cutaneous vasoconstriction, whereas its congener bupivacaine produces vasodilation

vasoconstrictors

drugs that constrict blood vessels and control tissue perfusion

• added to LA solutions to oppose inherent vasodilatory actions of LAs

• constrict blood vessels → decrease blood flow to site of administration and decrease bleeding

• slows absorption into cardiovascular system → lower anesthetic blood levels and decrease risk of anesthetic toxicity

• increases duration of action → keeps anesthetic near nerve

sympathomimetic amines

• direct-acting → exert action onto adrenergic receptors

  • epinephrine, norepinephrine, levonordefrin, isoproterenol, dopamine, methoxamine, phenylephrine

• indirect-acting → cause release of NE from adrenergic nerve terminals

  • tyramine, amphetamine, methamphetamine, hydroxyamphetamine

• mixed-acting → both direct and indirect actions

  • metaraminol, ephedrine

dilutions of vasoconstrictors

vasoconstrictor concentration is commonly written as a ratio

• 1:1000 = 1g of solute in 1000mL of solution

• vasoconstrictors in dental LA solutions are much less concentrated

  • to produce 1:10,000 → 1mL of 1:1000 added to 9mL solvent

  • to produce 1:100,000 → 1mL of 1:10,000 to 9mL solvent

epinephrine pharmacology

• proprietary name → adrenalin

• chemical structure → acid salt (highly soluble in water)

• source → synthetic or adrenal medulla

• mode of action → acts on ⍺ and β-adrenergic receptors

  • β effects predominate

• systemic actions:

  • myocardium → stimulates β1 receptors

  • pacemaker cells → stimulates β1 receptors and increases irritability of cells to increase dysrhythmias

  • coronary arteries → dilation to increase coronary artery blood flow

  • BP → systolic increased, diastolic decreased (small dose due to β stimulation) or increased (larger dose due to ⍺ stimulation)

  • vasculature → smaller arterioles and precapillary sphincters

  • hemostasis → vasoconstrictor during surgical procedures via ⍺ receptor stimulation

  • respiratory → potent dilator (β effect) of bronchiole smooth muscle

maximum doses of epinephrine

least concentrated solution that produces effective pain control should be used

• healthy patient → 0.2mg; cardiovascular disease → 0.04mg

• lidocaine available with epi at 1:50,000 and 1:100,000

  • duration of effective pulpal and soft tissue equivalent with all forms

norepinephrine

• also known as → levarterenol

• source → synthetic and natural forms form adrenal medulla

• mode of action → ⍺ receptor (90%); ¼ as potent as epi

• vasculature → vasoconstriction through ⍺ stimulation

  • can lead to soft tissue necrosis

levonordefrin

• also known as → neo-cobefrin

• source → synthetic vasoconstrictor

• mode of action → direct ⍺ stimulation (75%) and some β activity (25%)

  • 15% as potent as a vasopressor as epi

• systemic actions → produces less cardiac and CNS stimulation than epi

• availability → obtained as mepivacaine in 1:20,000 dilution

  • maximum dose → 15% as effective as epi so it is used in higher concentration

  • maximum dose should be 1mg per appointment; 20mL of a 1:20,000 dilution (11 cartridges)

treating patients with LA

determine relative risk presented by patient prior to administering LAs

• LAs are depressants on excitable membranes → CNS, CVS

• LAs undergo biotransformation primarily in liver (amides) or blood (esters)

• small percentage of LAs are excreted in active unmetabolized form in the kidney, so kidney function must be evaluated

psychogenic reactions of LAs

most undesirable effects are produced not by the drug but as a response to act of drug administration

• can be life threatening if not managed promptly

• common reactions → vasodepressor syncope, hyperventilation

  • other reactions include tonic-clonic convulsions, bronchospasm, angina pectoris

tools for patient assessment

medical history, physical examination, dialogue history

• adequate use of tools can prevent up to 90% of threatening medical emergencies in dental practice

• evaluate physical stress and psychological stress, determine treatment modification and need of psychosedation or sedation, determine contraindications

ASA physical status guidelines

• ASA I → normal healthy patient

• ASA II → mild systemic disease

• ASA III → severe systemic disease

• ASA IV → severe systemic disease that is constant threat to life

  • may not be appropriate for routine outpatient dental treatment and may need hospital-based care

• ASA V → moribound patient not expected to survive without patient

• ASA VI → declared brain-dead patient, organ donation context

selecting a LA

rationale approach based on:

1. how long is pain control needed

2. is post-treatment pain control needed

3. is hemostasis needed

4. are there contraindications

considerations for LAs

shorter duration anesthetic should be considered if postoperative anesthesia represents a potential risk

• pediatric patients, individuals with intellectual and developmental disabilities, T1-DM patients

• 3% mepivacaine recommended for use in short procedures

OraVerse / phentolamine mesylate

local anesthesia reversal agent that shortens duration of residual soft tissue anesthesia to minimize risk of self-inflicted injury

• ⍺-adrenergic receptor competitive antagonist

  • antagonizes ⍺1 and ⍺2 receptors

  • stimulates β-adrenergic receptors in heart and lungs

• approved for diagnosis of pheochromocytoma, hypertension in pheochromocytoma, and prevention of tissue necrosis after NE extravasation

• not recommended for children <6 years and <15kg

• recommended dose based on number of cartridges and vasoconstrictor administered

  • administer at same location in equal volumes; up to maximum 2 cartridges

duration of pulpal and soft tissue anesthesia

• 3% mepivacaine → short duration, no epinephrine

• articaine + epinephrine → fast onset, diffuses through bone

  • can cause paresthesia if used for inferior alveolar nerve block

• lidocaine 2% + epinephrine 1:100,000 → common standard

• bupivacaine 0.5% + epinephrine 1:200,000 → longest duration of anesthesia

how many cartridges of 2% lido with epi 1:100,000 can we administer to a 32 pound patient?

32lb / 2.2 = 14.5kg

14.5kg x 4.4 mg/kg (max dose) = 64mg (max total dose)

64mg / 34mg/cartridge = 1.88 cartridges