PharmacologyPharmacology ofof locallocal anesthesiaanesthesia andand itsits toxicitytoxicity
By:By:
DrDr. Salah Abdel-Fattah. Salah Abdel-Fattah
Assist. Prof.of AnesthesiaAssist. Prof.of Anesthesia
KFUKFU
LOCAL ANESTHETICSLOCAL ANESTHETICS
Local anesthetics are drugs, which reversibly block generation, propagation and oscillations of electrical impulses in the excitable tissues.
MECHENISM OF ACTIONMECHENISM 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 ActionMechanism of Action
• Site of action - Inside the membrane
• Binding sites within the Na+ channel
GatingGatingE
xtra
cell
ular
sol
utio
n
Intr
acel
lula
r S
olut
ion
Ion selectivepore
+ + +Voltage sensor
Ext
race
llul
ar s
olut
ion
Intr
acel
lula
r S
olut
ion
LocalLocal AnestheticAnesthetic BindingBinding SiteSite
+ + +Voltage sensor
LA
LA+
H+
LA
HydrophobicPathway
LALA
LA+
H+
-70 mV-15 mV
LA+
HydrophilicPathway
SODIUM CHANNEL
MODEMODE OFOF ACTIONACTION
NERVE AXON MEMBRANE
LA
LA
INJECTION LAH+
LAH+
SEQUENCE OF EVENTS WHICH RESULT SEQUENCE OF EVENTS WHICH RESULT IN CONDUCTION BLOCKADEIN 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
1. Sympathetic block (vasodilate & skin T0)
2. Loss of pain and temperature sensation
3. Loss of proprioception
4. Loss of touch and pressure sensation
5. Loss of motor function
STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICSANESTHETICS
Aromatic Group Intermediate
Chain
R
N R
Amine
STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICANESTHETIC
AMIDE ORESTER LINK
LIPO-PHILIC GROUP
HYDRO-
PHILIC
GROUP
PHARMACOLOGYPHARMACOLOGY
• Vary in duration of action, site of metabolism and potency
• Two Classes– Esters– Amides
CLASSIFICATION OF LOCAL CLASSIFICATION OF LOCAL ANESTHETICSANESTHETICS
ESTERS• Procaine• Chlorprocaine• Cocaine• Tetracaine
AMIDES• Lignocaine• Bupivacaine• Levo-Bupivacaine• Ropivacaine• Benzocaine• Etidocaine• Prilocaine• Mepivacaine
Pharmacology - ContinuedPharmacology - 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 - ContinuedPharmacology - Continued
• Amides– Long duration of effect– Metabolized by liver– Lidocaine, mepivacaine and prilocaine
(moderate duration of effect )
PROPERTIES OF LOCAL PROPERTIES OF LOCAL ANESTHETICSANESTHETICS
PROPERTIES ESTERS AMIDESMETABOLISM Rapid by plasma
cholinesteraseSlow, hepatic
SYSTEMIC TOXICITY Less likely More likely
ALLERGIC REACIONS 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
pKa’s Higher (8.5-8.9) Close to body pH = 7.4 (7.6-8.1)
Common features of Local Common features of Local AnestheticsAnesthetics
• 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
ImportantImportant ClinicalClinical PropertiesProperties ofof LocalLocal AnestheticsAnesthetics
• ONSET• POTENCY• DURATION OF ACTION
Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal 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 Important Clinical Properties of Local AnestheticsLocal Anesthetics
Speed of Onset
• low pKa = fast onset
• Bupivacaine 8.1Lidocaine 7.7
• ? LA action in septic tissue– acid tissue -> ionized % of LA
-> slow entry into membrane -> low concentration of LA for block
Effects of pHEffects of pHon Local Anesthesiaon Local Anesthesia
pH Ionized form
Weak Bases ( pka of 8-9)
pH Ionized form
Important Clinical Properties of Local Important Clinical Properties of Local AnestheticsAnesthetics
INCREASED DOASGE
• Intensity & Duration <=> INCRESED
• Increase dose via increased volume or concentration of LA
Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal Anesthetics
DURATION OF ACTION
Duration <=> protein binding• Bupivacaine 95%• Lidocaine 65%• Procaine 6%
Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal Anesthetics
Anesthetic Potency
Potency <=> lipid solubility
Higher solubility <=> can use a lower concentration and reduce potential for toxicity [LA]
Important Clinical Properties of Local Important Clinical Properties of Local AnestheticsAnesthetics
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)
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
Distribution
FACTORS AFFECTING DURATION FACTORS AFFECTING DURATION OF NERVE BLOCKOF NERVE BLOCK
Type of Local anestheticConcentrationVolumeUse of additives Type of nerve block
ADDITION OF EPINEPHRINEADDITION OF EPINEPHRINE
Concentration 5microgram/ml
Identifying intravascular injection
Duration of action
Peak plasma concentration of by 20% - 50%.
Quality of motor block.
� 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
ADDITION of ADDITION of Sodium BicarbonateSodium Bicarbonate
Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal Anesthetics
Metabolism
• ESTERSMetabolism via pseudocholinesterase
So pt with abnormal pseudocholinesterase at high risk for toxic side effects
• AMIDES Metabolism via hepatic enzymes (hepatic, CHF)
CommonCommonRoutes of AdministrationRoutes of Administration
• Topical– Usually ester– Usually ointments or drops
• Injection– Intradermal– Spinal– Epidural– Caudal
Clinical use of LAClinical use of LA
• Regional anesthesia and analgesia
• Intravenous regional anesthesia
• Blunt tracheal intubation stress response
• Antiarrhythmic e.g. Lidocaine
• Topical
COMMONLY USED LOCAL COMMONLY USED LOCAL ANESTHETICSANESTHETICS
• Lignocaine
• Bupivacaine
• Prilocaine
• Mepivacaine
NEW LOCAL ANESTHETICSNEW LOCAL ANESTHETICS
• Levo-Bupivacaine
• Ropivacaine
Adverse Effects and toxicityAdverse 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 toxicityAdverse effects and toxicity(Continued)(Continued)
• Respiratory system:
- Depress hypoxic drive
- Apnea: central or peripheral
Adverse effects and toxicity Adverse effects and toxicity (Continued)(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 - ContinuedAdverse Effects - Continued
• Topical– Blanching
• Difficult to find vein
– Erythema (redness)– Rash and itching in response to histamine
release
Treatment of systemic toxicityTreatment 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 DOSEMAXIMUM 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
Top Related