Medical Pharmacology Chapter 15: Local Anesthetics

Local Anesthetics: Clinical Uses

• Overview

  • Basic Pharmacology of Local Anesthetics

    Attribution: Ferrell S Local Anesthetics Basic Pharmacology https://www.youtube.com/watch?v=kixLNWJ7nIs (11/2015) University of Kentucky Department of Anesthesiology YouTube Channel:  https://www.youtube.com/channel/UC_caxps8p1QaSXho_L6G0Fg

  • Most frequent use: regional anesthesia

  • Less common use:

    •  Prevention and treatment of cardiac arrhythmias

    •  Prevention/management: increased intracranial pressure (ICP)

      • Lidocaine (Xylocaine) (1.5 mg/kg IV): effective as thiopental (Pentothal) in preventing ICP increases associated with tracheal intubation

      • Mechanism: (probable) -- lidocaine (Xylocaine)-mediated decrease in cerebral blood flow (CBF) by increasing cerebral vascular resistance

        •  Reduced CBF leads to reduced cerebral blood volume leads to reduced ICP

      • Advantage of lidocaine (Xylocaine) vs. barbiturates: reduced risk of drug-induced hypotension

      • Lidocaine (Xylocaine) also reduces blood pressure response to direct laryngoscopic tracheal intubation, an effect probably secondary to generalized cardiovascular depression

    •  Analgesia

    •  Treatment of grand mal seizure

• Topical/Surface anesthesia

  • Location: application to mucous membranes

    •  Nose

    •  Mouth

    •  Esophagus

    •  Tracheobronchial tree

    •  Genitourinary tract

  • Commonly used drugs

    • Cocaine (4%-10%)

      •  > 50% of rhinolaryngologic cases (USA)

      •  Unique pharmacological property: produces localized vasoconstriction as well as anesthesia

        •  Localized vasoconstriction:

          1. Less bleeding

          2. Improved surgical field visualization

      •  Cocaine substitution:

        •  Lidocaine (Xylocaine) -oxymetazoline (Afrin) combinations

        •  Tetracaine (pontocaine)-oxymetazoline (Afrin) combinations

    • Tetracaine (pontocaine) (1%-2%)

    • Lidocaine (Xylocaine) (2%-4%)

  • Ineffective agents:

    • Procaine (Novocain) and chloroprocaine (Nesacaine): poor mucous membrane penetration

  • Nebulized lidocaine (Xylocaine) for surface anesthesia

    • Upper and lower respiratory tract prior to bronchoscopy or fiber-optic laryngoscopy

    • Treatment for intractable cough

    • Normal subjects: No effect on airflow resistance (they produce some bronchodilation)

    • Patients with asthma: nebulized lidocaine (Xylocaine) may increase airflow resistance (bronchoconstriction)-- concern if bronchoscopy is intended for this patient group

    • Systemic concentration following nebulized lidocaine (Xylocaine)

      • Following mucosal absorption: systemic concentration may be similar to IV injection

        • Reasons:

          • Large surface area

          • Significant vascularity of tracheobronchial region

  • Skin Surface Application

    • Barrier: keratinized skin layer

      • Higher local anesthetic concentrations required:

        •  5% lidocaine (Xylocaine)-prilocaine (Citanest) cream {2.5% lidocaine (Xylocaine) and 2.5% prilocaine (Citanest)}

          • No local irritation

          • Even absorption

          • No systemic toxicity

      • Combination of local anesthetic: Definition: eutectic mixture of local anesthetics (EMLA)

        • Melting point of combined drug is lower then either lidocaine (Xylocaine) or prilocaine (Citanest) alone.

          • General definition: eutectic--said of a mixture which has the lowest melting point which it is possible to obtain by the combination of the given components. 

    • Application Characteristics

      • 1-2 grams of EMLA cream/10 cm² of skin plus occlusive dressing

      • Duration of application to achieve adequate local anesthesia-- examples:

        • Skin-graft harvesting: two hours

        • Cautery of genital warts: 10 minutes

    • Clinical uses of EMLA applications (pain relief)

      •  Venipuncture

      •  Lumbar puncture

      •  Myringotomy in adults and children

      •  Arterial cannulation

    • Special uses

      •  in combination with nitroglycerin ointment -- makes venous cannulation easier by causing vasodilation

      •  EMLA use in blood sampling: no effect on blood analysis

      •  EMLA use in preventing pain associated with intradermal skin tests:

        • Predisposes to false negatives which results in decreases flare response associated with weakly positive reactions.

    • Factors affecting EMLA analgesia time to onset, duration of action, and efficacy

      •  Skin blood flow

      •  Epidermal/girl thickness

      •  Application duration

      •  Presence of pathology

      •  Blacks: possibly less responsive than whites

    •    Contraindications/Concerns

      • Methemoglobin levels secondary to prilocaine (Citanest) metabolism may be of concern in young children (< three months)

        • If EMLA cream is used while other methemoglobin-inducing drugs are used [e.g. sulfonamides, acetaminophen, phenytoin (Dilantin), nitroglycerin, nitroprusside sodium (Nipride).

      •  EMLA cream not recommended for mucosal application due to faster lidocaine (Xylocaine)/prilocaine (Citanest) absorption

      •  EMLA cream not recommended for application to skin wounds (wound infection risk, increased)

      •  EMLA cream not recommended for patients taking mexiletine (Mexitil, amine lidocaine analog) (in antiarrhythmic drug) since additive/synergistic effects may occur

      •  EMLA cream: contraindicated in patients are allergic to amide local anesthetics

    • Other topical local anesthetic formulations

      • Pramoxine (Tronothane, Prax) applications

        •  Skin or mucous membrane application: pain or leave due to

          1. Dermatoses

          2. Hemorrhoids

          3. Minor burns

        •  Reduce pain associated with sigmoidoscopy

        •  Upper airway anesthesia prior to direct laryngoscopy

        •  Not recommended for:

          • Nasal/tracheal mucosal application (irritation)

      •  Dyclonine (Dyclone, Seroquel 5%-1%), piperocaine, hexylcaine-- applications

        •  Mucous membrane anesthesia for direct laryngoscopy

        •  Dyclonine (Dyclone): upper airway anesthesia for patients allergic to bupivacaine (Marcaine) and procaine (Novocain)

          • Rationale: ketone structure dyclonine (Dyclone) makes cross sensitivity with amide or ester local anesthetics less likely

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181; Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433. 

• Local Infiltration

  • Definition: Extravascular placement of the local anesthetic in the region to be anesthetized

    •  Example: subcutaneous local anesthetic injection in support of intravascular cannula placement

  • Preferred local anesthetics for local infiltration

    •  Most common: lidocaine (Xylocaine)

    •  Other choices: 0.25% Ropivacaine (Naropin) or Bupivacaine (Marcaine) (effective for pain management at inguinal operative location)

  • Duration of action:

    •  Duration extended by 2X using 1:200,000 epinephrine

    •  Caution: Epinephrine-containing local anesthetic solution should not be injected intracutaneously (intradermal) or into tissues supplied by "end-arteries" such as ears, nose, fingers because vasoconstriction may be sufficiently severe to produce tissue ischemia and gangrene.

      • "Vascular ischemia of the toes"

        Heilman J (M.D.) Vascular ischemia of the toes with characteristic cyanosis. http://www.en.wikipedia.org/wiki/File:Ischemia.JPG

• Peripheral Nerve Block

  • Procedure: local anesthetic injection into tissues around individual nerves or nerve plexuses (e.g. brachial plexus)

  • Mechanism:

    •  Local anesthetic diffusion path: nerve outer surface (mantle) to the nerve core [driving force: concentration gradient]

    •  Anesthetized first: mantle fibers (innervating more proximal structures)

    •  Anesthetized last: core fibers (innervating more distal anatomy)

      • Explanation of why anesthesia develops proximately first

      • Recovery in the opposite direction (sensation returns proximally first; lastly the distal anatomy)

  • Mixed peripheral nerves: (motor/sensory)

    • Sequence of onset and recovery (motor anesthesia first or sensory anesthesia first): dependent on anatomical locations within the nerve fiber

  • Rapidity of onset: Dependencies

    • Drug pK dependency: pK (at a given tissue pH) determines the fraction all of local anesthetic in the nonionized formed.

      • Un-ionized form = lipid soluble, active form, capable of penetrating membranes combining with local anesthetic receptors located on the internal membrane surface.

      •  Examples:

        •  Lidocaine (Xylocaine) time to onset = 3minutes

        •  Bupivacaine (Marcaine) time to onset = 15 minutes

          • Rationale: greater lidocaine (Xylocaine) fraction present in the un-ionized (uncharged) active form

      •  Specific examples:

        • 0.5% bupivacaine (Marcaine) or ropivacaine (Naropin): similar onset and duration of brachial plexus block

        • Ropivacaine (Naropin) (subclavian perivascular block): time to onset -- 4 minutes; sensory block duration -- > 13 hours

        • Ropivacaine (Naropin): onset and duration of action similar to bupivacaine (Marcaine)

      •   Not recommended:

        • Tetracaine (pontocaine): slow onset and more likely to cause systemic toxicity; not recommended for peripheral nerve block or for local infiltration

  • Duration of action-dependencies

    • Drug lipid solubility

    • Extent of drug protein binding

    • Dose

    • Prolongation of drug effect:

      • safer with added vasoconstrictor (e.g. epinephrine) than by increasing local anesthetic dose

        • Example: bupivacaine (Marcaine) + epinephrine: peripheral nerve block may last 14 hours (in some reports)

• Intravenous Regional Anesthesia (Bier Block)

  • Procedure:

    • Local anesthetic injection into an extremity isolated by tourniquet

    • Result: rapid anesthesia onset; skeletal muscle relaxation

  • Duration of anesthetic action:

    • Dependent on how long the tourniquet is kept inflated

    • Following tourniquet deflation: rapid recovery as blood dilutes local anesthetic concentration

  • Probable Mechanism:

    • Drug action on nerve endings and nerve trunks

  • Choice of local anesthetics

    •  Ester or amide type IV local anesthetics may be used

    •  Most frequently used amide agents:

      • Lidocaine (Xylocaine)

      • Prilocaine (Citanest)

        • At deflation, no clinically significant methemoglobinemia (3% of hemoglobin as methemoglobin)-- 10% required for cyanosis.

      • Comparing comparable IV regional anesthesia with 50 ml (0.5%) lidocaine (Xylocaine) or prilocaine (Citanest): lower plasma prilocaine (Citanest) concentrations following tourniquet deflation, compared to lidocaine (Xylocaine)

        • Prilocaine (Citanest) may be safer in terms of reduced systemic toxicity risk

    •    Agents not recommended:

      •  Chloroprocaine (Nesacaine) -- High incidence of thrombophlebitis

      •  Bupivacaine (Marcaine) -- More likely than other local anesthetic to cause cardiotoxicity upon tourniquet deflation

      •  Ropivacaine (Naropin)-Might also cause cardiotoxicity upon tourniquet deflation (less likely than with bupivacaine (Marcaine))

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.;

Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

• Epidural Anesthesia

  • Definition

    • Anesthesia caused by local anesthetic solutions injected into epidural or sacral caudal space.

  • Mechanisms:

    •  Direct action on nerve roots and spinal cord following local anesthetic diffusion across the dura.

    •  Diffusion of local anesthetic into paravertebral region through the intervertebral foramina causing paravertebral nerve blocks.

  • Onset of action:15-30 minute delay 

  • Choice of local anesthetics:

    •  Lidocaine (Xylocaine): frequently used; diffuses well for tissues

    •  Bupivacaine (Marcaine) and Ropivacaine (Naropin) (0.5%-0.75%):

      • Prolonged sensory anesthesia

      • Motor anesthesia: less intense and shorter duration with ropivacaine (Naropin); greater tendency for Alpha- delta and C fiber blockade

        • Reduced ropivacaine (Naropin) motor effects may be beneficial for obstetrical patients in labor and for patients experiencing acute/chronic pain

      • Ropivacaine (Naropin)-Reduced systemic toxicity compared to bupivacaine (Marcaine) allows ropivacaine (Naropin) concentrations of up to 1% to be used surgically.

      • Analgesia/anesthesia for labor/cesarean section similar with 0.5% bupivacaine (Marcaine) or ropivacaine (Naropin) [motor blocked duration shorter in parturients receiving ropivacaine (Naropin)]

      • 0.25% ropivacaine (Naropin) and syrup.25% bupivacaine (Marcaine) (intermittent dosing into epidural space): equally effective in managing labor pain

      • Postoperative analgesic: 0.2% ropivacaine (Naropin) (6-10 ml/hr)

      • Local anesthetic plasma concentrations following epidural anesthesia in parturients:

        •  Local anesthetics: traverse the placenta and may affect the fetus for 24-48 hours (not necessarily adversely)

        •  Special considerations:

          • Mepivacaine (Carbocaine): less readily metabolized by the fetus or neonate compared to adult: longer halftimes of elimination

          • Increased lipid solubility and protein binding of bupivacaine (Marcaine) may reduce its access to the fetus.

          • Lidocaine (Xylocaine): (even low doses) leads to  maternal systemic absorption and consequently fetal systemic presence

          • Bupivacaine (Marcaine): not detectable in neonatal plasma (one day following cesarean section using bupivacaine (Marcaine)-spinal anesthesia

• Systemic local anesthetic absorption

  • Lidocaine (Xylocaine) -- peak plasma levels: 3-4 μg/mL following 400 mg injected epidurally

  • Bupivacaine (Marcaine) --peak average plasma level 0.3 μg/mL --(after 30 minutes; 70-100 mg of 0.5% solution with 1:200,000 epinephrine)

    •  Peak plasma level 1 μg/mL-- if epinephrine is not included in the local anesthetic solution

    •  Epinephrine inclusion: general reduction of systemic local anesthetic absorption by 1/3

    •  Consequences of systemic epinephrine absorption (low concentration, beta₂ adrenergic receptor mediated effects notable):

      • Peripheral vasodilation

      • Reduced systemic blood-pressure

      • Increased heart rate; increased myocardial contractility.

• Spinal Anesthesia

  • Definition

    • Anesthesia following local anesthetic injection into lumbar subarachnoid space.

  • Site of action:

    •  Primary: preganglionic fibers leading the spinal cord in the anterior rami

    •  Secondary: superficial spinal cord layers

  • Zones of differential anesthesia (causes)

    1. Local anesthetic concentration gradient effects

    2. Different nerve fiber types have different sensitivities to local anesthetics

  • Anesthesia levels

    • Level of sympathetic nervous system "denervation": extends about two spinal segments cephalad (above) the level sensory anesthesia

    • Level of motor anesthesia extends about two segments below sensory anesthesia

    • Reason: differential sensitivity to local anesthesia

  • Factors affecting local anesthetic dosages:

    1. Patient height (determines subarachnoid spatial volume)

    2. Segmental level of anesthesia required

    3. Duration of anesthesia required

    4. Total local anesthetic dose: more important than concentration or volume effects

  • Local anesthetics used for spinal anesthesia

    • Most commonly used agents: tetracaine (pontocaine), lidocaine (Xylocaine), bupivacaine (Marcaine)

    •  Characteristics of some drugs:

      •  Lidocaine (Xylocaine): may be associated with a higher risk of transient neurological adverse effects compared to bupivacaine (Marcaine)

        • If lidocaine (Xylocaine) used: limit dose to 60 mg

      • Bupivacaine (Marcaine): More effective than tetracaine (pontocaine) in preventing lower-extremity tourniquet pain (orthopedic surgery cases)

      • In parturients: intrathecal mepivacaine (Carbocaine, 2.5 mg)  + 10 ug sufentanil (Sufenta) allow effective labor analgesia while allowing patients to continue to walk.

      • Ropivacaine (Naropin) (3 ml of 0.5% or 0.75%): Sensory anesthesia present; however, motor blockade present in only 50% of patients if 0.5% dosage used.

      • Chloroprocaine (Nesacaine):  Not placed in subarachnoid space due to neurotoxicity risk

    • Factors determining spread of drug following lumbar injection:

      • Specific gravity of the local anesthetic solution

        •  Glucose addition: increased specific gravity above that of CSF (hyperbaric)

        •  Distilled water addition: decreased specific gravity below that of CSF (hypobaric)

    • Duration of action: amides vs. esters

      •  CSF does not contain significant cholinesterase activity -- no enzymatic influence on ester local anesthetic duration:

        • Duration of action of amides and ester-local anesthetics placed in subarachnoid spaces --influenced by the vascular drug absorption rates

      •  Intrathecal tetracaine (pontocaine): significant increase in spinal cord blood flow

        • Preventable/reversible by epinephrine addition, which increases tetracaine (pontocaine)-induced spinal anesthesia, up to 2X.

          • There is less vasodilation with lidocaine (Xylocaine).

      •  Bupivacaine (Marcaine): vasoconstriction

Drawing by Lindsey Parker, (c) University of Kansas Medical Center

• Physiological Effects-- Spinal anesthesia

  •  Consequences of sympathetic blockade:

    •  Arteriolar dilation

    •  No significant effect on systemic BP due to compensatory upper extremity vasoconstriction.

      • No cerebrovascular vasoconstriction

      • Total sympathetic blockade due to spinal anesthesia: associated with a reduction in systemic vascular resistance of < 15%.

        • Rationale: arteriolar smooth muscle does not dilate maximally because of intrinsic tone

    •  Many major cardiovascular response secondary to spinal anesthesia due to:

      •  Effects on venous circulation

      •  Venules: minimal intrinsic tone retention; maximal dilation during spinal anesthesia

      •  Consequences of venous-side dilation:

        • Reduced venous return to heart leads to decreased cardiac output and consequently decreased systemic blood-pressure

        •  Severe systemic hypotension in hypovolemic patients

          •  Treatment:

            • α-adrenergic receptor agonist administration

            • Slightly-head down patient repositioning

    •   Effects on heart rate:

      •  Cardiac slowing (bradycardia) secondary to blockade of preganglionic cardiac accelerator nerves (T1 to T4)

    •  This bradycardia response may be worsened in the presence of reduced preload and as a result, reduce stimulation of atrial stretch receptors (which, when activated, cause cardioacceleration)

    •   High-spinal anesthesia: Effects on ventilation

      • Apnea may occur due to abnormal medullary ventilatory center function, which is secondary to ischemia due to reduced cerebral blood flow.

      • Apnea is unlikely due to phrenic nerve paralysis

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.;Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

• Cocaine Toxicity

  • Mechanism:

    • Excessive sympathetic stimulation

      • Norepinephrine and dopamine reuptake blockade

  • Pharmacokinetics

    • Peak plasma concentrations:

      • 30-40 minutes following intranasal administration

      • 5 minutes following IV/smoke administration

    • Maximal physiological effects: intranasal cocaine (15-40 minutes)

    • Duration of effects is about 60 minutes or longer following peak effect

    • Elimination halftime is 60-90 minutes

    • Metabolism: plasma esterases

  •   Adverse Effects: acute administration

    •  Coronary vasospasm/myocardial ischemia/infarction

    •  Cardiac arrhythmias (including ventricular fibrillation)

    •  Hypertension

    •  Myocardial ischemia may be long lasting, possibly secondary to delayed coronary artery vasospasm

    •  Dose-dependent reduction in uterine blood flow may lead to fetal hypoxemia

    •  Hyperpyrexia/seizures

    •  Topical cocaine + epinephrine or cocaine administration in the presence of myocardium-sensitizing volatile anesthetics, e.g. halothane:

      • Enhanced cocaine-mediated cardiac stimulation

      • Cocaine may be contraindicated in patients with hypertension or coronary vascular disease and in patients receiving agents that enhance catecholamine effects (e.g., MAO inhibitors)

  • Treatment of cocaine toxicity:

    • Nitroglycerin

    • IV diazepam (Valium) for management of cocaine induced seizures

    • Caution: esmolol (Brevibloc) management of cocaine-induced tachycardia may predispose to coronary vasospasm

Primary Reference: Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.; Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.