pharmacology of local anesthesia
DESCRIPTION
Pharmacology of Local AnesthesiaTRANSCRIPT
![Page 1: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/1.jpg)
PharmacologyPharmacology ofof locallocal anesthesiaanesthesia andand itsits toxicitytoxicity
By:By:
DrDr. Salah Abdel-Fattah. Salah Abdel-Fattah
Assist. Prof.of AnesthesiaAssist. Prof.of Anesthesia
KFUKFU
![Page 2: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/2.jpg)
LOCAL ANESTHETICSLOCAL ANESTHETICS
Local anesthetics are drugs, which reversibly block generation, propagation and oscillations of electrical impulses in the excitable tissues.
![Page 3: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/3.jpg)
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
![Page 4: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/4.jpg)
Mechanism of ActionMechanism of Action
• Site of action - Inside the membrane
• Binding sites within the Na+ channel
![Page 5: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/5.jpg)
![Page 6: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/6.jpg)
![Page 7: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/7.jpg)
![Page 8: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/8.jpg)
GatingGatingE
xtra
cell
ular
sol
utio
n
Intr
acel
lula
r S
olut
ion
Ion selectivepore
+ + +Voltage sensor
![Page 9: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/9.jpg)
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
![Page 10: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/10.jpg)
SODIUM CHANNEL
MODEMODE OFOF ACTIONACTION
NERVE AXON MEMBRANE
LA
LA
INJECTION LAH+
LAH+
![Page 11: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/11.jpg)
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
![Page 12: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/12.jpg)
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
![Page 13: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/13.jpg)
STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICSANESTHETICS
Aromatic Group Intermediate
Chain
R
N R
Amine
![Page 14: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/14.jpg)
STRUCTURE OF LOCAL STRUCTURE OF LOCAL ANESTHETICANESTHETIC
AMIDE ORESTER LINK
LIPO-PHILIC GROUP
HYDRO-
PHILIC
GROUP
![Page 15: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/15.jpg)
PHARMACOLOGYPHARMACOLOGY
• Vary in duration of action, site of metabolism and potency
• Two Classes– Esters– Amides
![Page 16: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/16.jpg)
CLASSIFICATION OF LOCAL CLASSIFICATION OF LOCAL ANESTHETICSANESTHETICS
ESTERS• Procaine• Chlorprocaine• Cocaine• Tetracaine
AMIDES• Lignocaine• Bupivacaine• Levo-Bupivacaine• Ropivacaine• Benzocaine• Etidocaine• Prilocaine• Mepivacaine
![Page 17: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/17.jpg)
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
![Page 18: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/18.jpg)
Pharmacology - ContinuedPharmacology - Continued
• Amides– Long duration of effect– Metabolized by liver– Lidocaine, mepivacaine and prilocaine
(moderate duration of effect )
![Page 19: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/19.jpg)
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)
![Page 20: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/20.jpg)
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
![Page 21: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/21.jpg)
ImportantImportant ClinicalClinical PropertiesProperties ofof LocalLocal AnestheticsAnesthetics
• ONSET• POTENCY• DURATION OF ACTION
![Page 22: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/22.jpg)
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
![Page 23: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/23.jpg)
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
![Page 24: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/24.jpg)
Effects of pHEffects of pHon Local Anesthesiaon Local Anesthesia
pH Ionized form
Weak Bases ( pka of 8-9)
pH Ionized form
![Page 25: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/25.jpg)
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
![Page 26: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/26.jpg)
Important Clinical Properties of Important Clinical Properties of Local AnestheticsLocal Anesthetics
DURATION OF ACTION
Duration <=> protein binding• Bupivacaine 95%• Lidocaine 65%• Procaine 6%
![Page 27: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/27.jpg)
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]
![Page 28: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/28.jpg)
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)
![Page 29: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/29.jpg)
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
![Page 30: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/30.jpg)
FACTORS AFFECTING DURATION FACTORS AFFECTING DURATION OF NERVE BLOCKOF NERVE BLOCK
Type of Local anestheticConcentrationVolumeUse of additives Type of nerve block
![Page 31: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/31.jpg)
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.
![Page 32: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/32.jpg)
� 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
![Page 33: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/33.jpg)
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)
![Page 34: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/34.jpg)
CommonCommonRoutes of AdministrationRoutes of Administration
• Topical– Usually ester– Usually ointments or drops
• Injection– Intradermal– Spinal– Epidural– Caudal
![Page 35: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/35.jpg)
Clinical use of LAClinical use of LA
• Regional anesthesia and analgesia
• Intravenous regional anesthesia
• Blunt tracheal intubation stress response
• Antiarrhythmic e.g. Lidocaine
• Topical
![Page 36: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/36.jpg)
COMMONLY USED LOCAL COMMONLY USED LOCAL ANESTHETICSANESTHETICS
• Lignocaine
• Bupivacaine
• Prilocaine
• Mepivacaine
![Page 37: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/37.jpg)
NEW LOCAL ANESTHETICSNEW LOCAL ANESTHETICS
• Levo-Bupivacaine
• Ropivacaine
![Page 38: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/38.jpg)
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
![Page 39: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/39.jpg)
Adverse effects and toxicityAdverse effects and toxicity(Continued)(Continued)
• Respiratory system:
- Depress hypoxic drive
- Apnea: central or peripheral
![Page 40: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/40.jpg)
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
![Page 41: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/41.jpg)
Adverse Effects - ContinuedAdverse Effects - Continued
• Topical– Blanching
• Difficult to find vein
– Erythema (redness)– Rash and itching in response to histamine
release
![Page 42: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/42.jpg)
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.
![Page 43: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/43.jpg)
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
![Page 44: Pharmacology of Local Anesthesia](https://reader033.vdocuments.mx/reader033/viewer/2022061117/54676075af79596e458b52b7/html5/thumbnails/44.jpg)