Pharmacology Of Local Anesthesia
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Pharmacology of local anesthesia and its toxicity By: Dr. Salah Abdel-Fattah Assist. Prof.of Anesthesia KFU
LOCAL ANESTHETICS Local anesthetics are drugs, which reversibly block
generation, propagation and oscillations of electrical impulses in the excitable tissues.
MECHENISM OF ACTION • Block nerve fiber conduction by acting directly on nerve membranes to inhibit sodium ion from crossing the membrane – Nerves cannot depolarize – Conduction of impulses is blocked
Mechanism of Action • Site of action - Inside the membrane • Binding sites within the Na+ channel
Extracellular solution Ion selective pore Voltage sensor
+++ Intracellular Solution
Gating
Local Anesthetic Binding Site H+
LA Hyd ro Path phobic way
LA
+
H+
LA+ LA +++ Voltage sensor
LA+ Hydrophilic Pathway
-70 mV -15 mV
Intracellular Solution
Extracellular solution
LA
MODE OF ACTION NERVE AXON MEMBRANE LAH+ SODIUM CHANNEL
INJECTION
LAH+
LA
LA
SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE
• 1. Diffusion of the base form across the nerve sheath and nerve membrane • 2. Re-equilibration between the base and cationic forms in the axoplasm • 3. Penetration of the cation into and attachment to a receptor site within the sodium channel. • 4. Blockade of the sodium channel
Nerve Fiber and Local Anesthetic Setup Sequence of clinical anesthesia Sympathetic block (vasodilate & skin T0) Loss of pain and temperature sensation Loss of proprioception Loss of touch and pressure sensation Loss of motor function
STRUCTURE OF LOCAL ANESTHETICS R
N R
Aromatic Group Chain
Intermediate
Amine
STRUCTURE OF LOCAL ANESTHETIC HYDR OPHILIC
LIPOPHILIC GROUP
GROUP AMIDE OR ESTER LINK
PHARMACOLOGY • Vary in duration of action, site of metabolism and potency • Two Classes – Esters – Amides
CLASSIFICATION OF LOCAL ANESTHETICS ESTERS
AMIDES
• • • •
• • • • • • • •
Procaine Chlorprocaine Cocaine Tetracaine
Lignocaine Bupivacaine Levo-Bupivacaine Ropivacaine Benzocaine Etidocaine Prilocaine Mepivacaine
Pharmacology - Continued • Esters – Short, moderate or long duration of effect – Metabolized by cholinesterases in blood and skin – Chlorprocaine, cocaine and procaine (short acting) – Tetracaine - long duration of effect
Pharmacology - Continued • Amides – Long duration of effect – Metabolized by liver – Lidocaine, mepivacaine and prilocaine (moderate duration of effect )
PROPERTIES OF LOCAL ANESTHETICS PROPERTIES METABOLISM
ESTERS
AMIDES
Rapid by plasma cholinesterase
Slow, hepatic
Less likely
More likely
Possible - PABA derivatives form
Very rare
STABILITY IN SOLUTION
Breaks down in ampules (heat, sun)
Very stable chemically
ONSET OF ACTION
Slow as general rule
Moderate to fast
Higher (8.5-8.9)
Close to body pH = 7.4 (7.6-8.1)
SYSTEMIC TOXICITY ALLERGIC REACIONS
pKa’s
Common features of Local Anesthetics • Weak bases (pKa > 7.4) [poorly water soluble]
• Packaged as an acidic hydrochloride [pH 4-7]
• In solution- non-ionized lipid soluble (free base) and ionized water soluble (cation) • Lipid soluble form crosses axonal membrane • Water soluble form blocks sodium channel
Important Clinical Properties of Local Anesthetics • ONSET • POTENCY • DURATION OF ACTION
Important Clinical Properties of Local Anesthetics ONSET = pKa • pKa = pH at which 50% of drug is ionized • LA’s < 50% exists in the lipid soluble nonionized form • Only the nonionized form crosses into the nerve cell
Important Clinical Properties of Local Anesthetics Speed of Onset • low pKa = fast onset • Bupivacaine 8.1 Lidocaine 7.7 • ? LA action in septic tissue – acid tissue -> ionized % of LA -> slow entry into membrane -> low concentration of LA for block
Effects of pH on Local Anesthesia Weak Bases ( pka of 8-9) pH
pH
Ionized form
Ionized form
Important Clinical Properties of Local Anesthetics INCREASED DOASGE • Intensity & Duration <=> INCRESED • Increase dose via increased volume or concentration of LA
Important Clinical Properties of Local Anesthetics DURATION OF ACTION Duration <=> protein binding • Bupivacaine 95% • Lidocaine 65% • Procaine 6%
Important Clinical Properties of Local Anesthetics Anesthetic Potency Potency <=> lipid solubility Higher solubility <=> can use a lower concentration and reduce potential for toxicity [LA]
Important Clinical Properties of Local Anesthetics Absorption of local anesthetics • Site of injection: IV > tracheal > intercostal > caudal > epid > brachial plexus > sciatic > SC • Presence of vasoconstrictors • LA agent highly tissue bound are more slowly absorbed (e.g. etidocaine)
Distribution 1-Tissue perfusion: The highly perfused organs (brain, lung, heart, kidney) are responsible for rapid uptake 2-Tissue/Blood partition coefficient: Strong plasma protein binding tends to retain anesthetic in the blood
FACTORS AFFECTING DURATION OF NERVE BLOCK Type of Local anesthetic Concentration Volume Use of additives Type of nerve block
ADDITION OF EPINEPHRINE Concentration 5microgram/ml Identifying intravascular injection Duration of action Peak plasma concentration of by 20% 50%. Quality of motor block.
ADDITION of Sodium Bicarbonate NaHCO3 - increase pH & nonionized base Speeds onset of block 1 mEq NaHCO3 per 10 ml Lido/Mepivacaine 0.1 mEq NaHCO3 per 10 ml Bupivacaine
Important Clinical Properties of Local Anesthetics Metabolism • ESTERS Metabolism via pseudocholinesterase
So pt with abnormal pseudocholinesterase at high risk for toxic side effects • AMIDES Metabolism via hepatic enzymes (hepatic, CHF)
Common Routes of Administration • Topical – Usually ester – Usually ointments or drops • Injection – Intradermal – Spinal – Epidural – Caudal
Clinical use of LA • • • • •
Regional anesthesia and analgesia Intravenous regional anesthesia Blunt tracheal intubation stress response Antiarrhythmic e.g. Lidocaine Topical
COMMONLY USED LOCAL ANESTHETICS • • • •
Lignocaine Bupivacaine Prilocaine Mepivacaine
NEW LOCAL ANESTHETICS • Levo-Bupivacaine • Ropivacaine
Adverse Effects and toxicity • Cardiac Effects – Depress cardiac conduction system – Negative chronotropic effect – Negative ionotropic effect • Central Nervous System – Capable of crossing blood-brain barrier • Nervousness • Excitation • Tremors • Convulsion • Coma and death
Adverse effects and toxicity (Continued) • Respiratory system: - Depress hypoxic drive - Apnea: central or peripheral
Adverse effects and toxicity (Continued) • Vascular Effects – Cocaine produces intense vasoconstriction • Can lead to destruction of tissue by reducing blood supply
– All other local anesthetics • Vasodilation hypotension – High doses may lead to hypotension causing cardiovascular collapse
Adverse Effects - Continued • Topical – Blanching • Difficult to find vein
– Erythema (redness) – Rash and itching in response to histamine release
Treatment of systemic toxicity • Stop injection of LA • Oxygen • Tracheal intubation and control ventilation if necessary • Suppress seizure activity (thiopental or midazolam • Treat ventricular dysrhythmia and CVS support.
MAXIMUM RECOMMENDED DOSE Lignocaine (Infiltration, Epidural) 4mg/Kg body wt. Lignocaine With Adrenaline 7mg/Kg body wt. Bupivacaine Infiltration & Epidural 3mg/kg body wt. Adrenaline as vasoconstrictor 5mcg /ml - 20mcg/ml. Total dose should not exceed over 20ml of 1:200,000 in 10 minutes
LOCAL ANESTHETICS Local anesthetics are drugs, which reversibly block
generation, propagation and oscillations of electrical impulses in the excitable tissues.
MECHENISM OF ACTION • Block nerve fiber conduction by acting directly on nerve membranes to inhibit sodium ion from crossing the membrane – Nerves cannot depolarize – Conduction of impulses is blocked
Mechanism of Action • Site of action - Inside the membrane • Binding sites within the Na+ channel
Extracellular solution Ion selective pore Voltage sensor
+++ Intracellular Solution
Gating
Local Anesthetic Binding Site H+
LA Hyd ro Path phobic way
LA
+
H+
LA+ LA +++ Voltage sensor
LA+ Hydrophilic Pathway
-70 mV -15 mV
Intracellular Solution
Extracellular solution
LA
MODE OF ACTION NERVE AXON MEMBRANE LAH+ SODIUM CHANNEL
INJECTION
LAH+
LA
LA
SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADE
• 1. Diffusion of the base form across the nerve sheath and nerve membrane • 2. Re-equilibration between the base and cationic forms in the axoplasm • 3. Penetration of the cation into and attachment to a receptor site within the sodium channel. • 4. Blockade of the sodium channel
Nerve Fiber and Local Anesthetic Setup Sequence of clinical anesthesia Sympathetic block (vasodilate & skin T0) Loss of pain and temperature sensation Loss of proprioception Loss of touch and pressure sensation Loss of motor function
STRUCTURE OF LOCAL ANESTHETICS R
N R
Aromatic Group Chain
Intermediate
Amine
STRUCTURE OF LOCAL ANESTHETIC HYDR OPHILIC
LIPOPHILIC GROUP
GROUP AMIDE OR ESTER LINK
PHARMACOLOGY • Vary in duration of action, site of metabolism and potency • Two Classes – Esters – Amides
CLASSIFICATION OF LOCAL ANESTHETICS ESTERS
AMIDES
• • • •
• • • • • • • •
Procaine Chlorprocaine Cocaine Tetracaine
Lignocaine Bupivacaine Levo-Bupivacaine Ropivacaine Benzocaine Etidocaine Prilocaine Mepivacaine
Pharmacology - Continued • Esters – Short, moderate or long duration of effect – Metabolized by cholinesterases in blood and skin – Chlorprocaine, cocaine and procaine (short acting) – Tetracaine - long duration of effect
Pharmacology - Continued • Amides – Long duration of effect – Metabolized by liver – Lidocaine, mepivacaine and prilocaine (moderate duration of effect )
PROPERTIES OF LOCAL ANESTHETICS PROPERTIES METABOLISM
ESTERS
AMIDES
Rapid by plasma cholinesterase
Slow, hepatic
Less likely
More likely
Possible - PABA derivatives form
Very rare
STABILITY IN SOLUTION
Breaks down in ampules (heat, sun)
Very stable chemically
ONSET OF ACTION
Slow as general rule
Moderate to fast
Higher (8.5-8.9)
Close to body pH = 7.4 (7.6-8.1)
SYSTEMIC TOXICITY ALLERGIC REACIONS
pKa’s
Common features of Local Anesthetics • Weak bases (pKa > 7.4) [poorly water soluble]
• Packaged as an acidic hydrochloride [pH 4-7]
• In solution- non-ionized lipid soluble (free base) and ionized water soluble (cation) • Lipid soluble form crosses axonal membrane • Water soluble form blocks sodium channel
Important Clinical Properties of Local Anesthetics • ONSET • POTENCY • DURATION OF ACTION
Important Clinical Properties of Local Anesthetics ONSET = pKa • pKa = pH at which 50% of drug is ionized • LA’s < 50% exists in the lipid soluble nonionized form • Only the nonionized form crosses into the nerve cell
Important Clinical Properties of Local Anesthetics Speed of Onset • low pKa = fast onset • Bupivacaine 8.1 Lidocaine 7.7 • ? LA action in septic tissue – acid tissue -> ionized % of LA -> slow entry into membrane -> low concentration of LA for block
Effects of pH on Local Anesthesia Weak Bases ( pka of 8-9) pH
pH
Ionized form
Ionized form
Important Clinical Properties of Local Anesthetics INCREASED DOASGE • Intensity & Duration <=> INCRESED • Increase dose via increased volume or concentration of LA
Important Clinical Properties of Local Anesthetics DURATION OF ACTION Duration <=> protein binding • Bupivacaine 95% • Lidocaine 65% • Procaine 6%
Important Clinical Properties of Local Anesthetics Anesthetic Potency Potency <=> lipid solubility Higher solubility <=> can use a lower concentration and reduce potential for toxicity [LA]
Important Clinical Properties of Local Anesthetics Absorption of local anesthetics • Site of injection: IV > tracheal > intercostal > caudal > epid > brachial plexus > sciatic > SC • Presence of vasoconstrictors • LA agent highly tissue bound are more slowly absorbed (e.g. etidocaine)
Distribution 1-Tissue perfusion: The highly perfused organs (brain, lung, heart, kidney) are responsible for rapid uptake 2-Tissue/Blood partition coefficient: Strong plasma protein binding tends to retain anesthetic in the blood
FACTORS AFFECTING DURATION OF NERVE BLOCK Type of Local anesthetic Concentration Volume Use of additives Type of nerve block
ADDITION OF EPINEPHRINE Concentration 5microgram/ml Identifying intravascular injection Duration of action Peak plasma concentration of by 20% 50%. Quality of motor block.
ADDITION of Sodium Bicarbonate NaHCO3 - increase pH & nonionized base Speeds onset of block 1 mEq NaHCO3 per 10 ml Lido/Mepivacaine 0.1 mEq NaHCO3 per 10 ml Bupivacaine
Important Clinical Properties of Local Anesthetics Metabolism • ESTERS Metabolism via pseudocholinesterase
So pt with abnormal pseudocholinesterase at high risk for toxic side effects • AMIDES Metabolism via hepatic enzymes (hepatic, CHF)
Common Routes of Administration • Topical – Usually ester – Usually ointments or drops • Injection – Intradermal – Spinal – Epidural – Caudal
Clinical use of LA • • • • •
Regional anesthesia and analgesia Intravenous regional anesthesia Blunt tracheal intubation stress response Antiarrhythmic e.g. Lidocaine Topical
COMMONLY USED LOCAL ANESTHETICS • • • •
Lignocaine Bupivacaine Prilocaine Mepivacaine
NEW LOCAL ANESTHETICS • Levo-Bupivacaine • Ropivacaine
Adverse Effects and toxicity • Cardiac Effects – Depress cardiac conduction system – Negative chronotropic effect – Negative ionotropic effect • Central Nervous System – Capable of crossing blood-brain barrier • Nervousness • Excitation • Tremors • Convulsion • Coma and death
Adverse effects and toxicity (Continued) • Respiratory system: - Depress hypoxic drive - Apnea: central or peripheral
Adverse effects and toxicity (Continued) • Vascular Effects – Cocaine produces intense vasoconstriction • Can lead to destruction of tissue by reducing blood supply
– All other local anesthetics • Vasodilation hypotension – High doses may lead to hypotension causing cardiovascular collapse
Adverse Effects - Continued • Topical – Blanching • Difficult to find vein
– Erythema (redness) – Rash and itching in response to histamine release
Treatment of systemic toxicity • Stop injection of LA • Oxygen • Tracheal intubation and control ventilation if necessary • Suppress seizure activity (thiopental or midazolam • Treat ventricular dysrhythmia and CVS support.
MAXIMUM RECOMMENDED DOSE Lignocaine (Infiltration, Epidural) 4mg/Kg body wt. Lignocaine With Adrenaline 7mg/Kg body wt. Bupivacaine Infiltration & Epidural 3mg/kg body wt. Adrenaline as vasoconstrictor 5mcg /ml - 20mcg/ml. Total dose should not exceed over 20ml of 1:200,000 in 10 minutes
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