Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
EO 003.19 Local Anesthetics PA Course EO 003.19 EO 003.19 Learning Objectives • To understand the mechanism of action of local anesthetics • To understand indications, contraindications, and adverse effects of local anesthetics • To be able to select an appropriate local anesthetic (practical applications will will covered in next lecture) EO 003.19 Local Anesthetics • Work by blocking the generation and propagation of nerve impulses when applied locally in adequate concentrations. – Blocks sodium channels • This block is reversible thus normal function returns to the nerve when the local anesthetic is removed by the blood stream. EO 003.19 EO 003.19 Nerve Impulse Transmission EO 003.19 EO 003.19 Ionized Extracellular solution LA LA H+ H+ LA+ LA+ LA +++ Voltage sensor LA+ Hydrophilic Pathway -70 mV -15 mV Intracellular Solution Local Anesthetics Binding Sites EO 003.19 pKa, pH and Why They Matter • pKa = pH at which ionized and non-ionized base are equally present. LA’s are weak bases with pKa of 8- 9. • Onset of action related to amount of LA present as base form. • As environment becomes more acidic (lower pH/ more H+ ), equilibrium shifts to the cationic form, which does not diffuse readily in to the nerve. EO 003.19 Pharmacologic Actions Order of blockade of nerves depends on • Nerve size (from small to big: C, B, Ad, Ag,Ab,Aa) • Myelination Sequence of nerve loss Loss of pain Temperature Touch Proprioception Skeletal muscle tone EO 003.19 Desirable Properties of Local Anesthetics • Reversiblility • Non-irritating to tissues • Rapid onset of action • Long duration of action (to facilitate procedures) • High therapeutic index • Effective topically and by injection • Ideal physical properties (solubility and stability) EO 003.19 General Anesthetic Structure 2 1 hydrophobic 3 hydrophilic EO 003.19 Classification of Anesthetics esters amides EO 003.19 Esters • Not very stable in solution; easily broken down by sunlight, heat • Metabolized by cholinesterases in blood and skin. Para-aminobenzoic acid (PABA) is a by-product of metabolism • Examples: benzocaine, cocaine, procaine, tetracaine EO 003.19 Amides • Long duration of effect • Cleared from the site of anesthesia by local blood flow, then metabolized by liver to water soluble products which are removed by the kidney • Fairly stable in solution • Examples: articaine, bupivacaine, lidocaine, mepivacaine, prilocaine & ropivacaine. EO 003.19 Allergy to LA’s • Esters may cause allergy due to para- aminobenzoic acid, which is a breakdown product of all these agents. Thus allergy to one ester means allergy to all esters. • Allergy to an amide is very rare. • History of allergy to an ester or another amide does not rule out use of an amide. • Most “allergy” to dental LA is psychogenic (anxiety reaction to dental procedure) EO 003.19 Physicochemical properties Determines potency, onset and duration of action 1. pKa, dissociation constant • Proportion of ionized to non-ionized molecules • Correlates with onset • Equilibrium exists • low pH = more in ionized state & unable to cross membrane • Sodium bicarbonate – pH and non-ionized base = faster onset • Acidic tissues (ie septic) - ionized = slower entry EO 003.19 Physicochemical properties 2. Lipid solubility - Correlates with potency • Higher solubility = more potent, thus can use smaller dose (more molecules penetrate into axioplasm) 3. Protein binding - Correlates with duration of action • Increased binding = longer duration of action EO 003.19 LA and Blood Flow • • • Vasodilation: affects duration of action. At clinically useful concentrations, the LA’s (except cocaine) are vasodilators. Inhibiting blood flow increases duration of the block- done deliberately during IV regional anesthesia, or may be a result of circulatory impairment. Vasoconstrictors added to LA for this effect. EO 003.19 Epinephrine • Most common vasoconstrictor used with • • • • local anesthetics Prolongs duration of anesthesia Increases the intensity of blockade Reduces systemic absorption of LA Reduces surgical bleeding EO 003.19 Epinephrine • Solutions of epinephrine containing 5 mcg/ml (1:200,000) appear to be optimal for the reduction of surgical bleeding and systemic absorption of local anesthetics EO 003.19 Epinephrine Manifestations of systemic epinephrine absorption • Increased heart rate. • Increased cardiac output. • Decreased systemic vascular resistance – confusing, but small vessels in skin, mucosa and viscera are constricted, while vasculature of skeletal muscles relaxes Warning epinephrine is light and heat sensitive. It oxidizes easily: do not use if pinkish or brownish in color or if a precipitate is visible. EO 003.19 Epinephrine Contraindications to the addition of epinephrine • Peripheral nerve blocks in areas that may lack • • • • • • collateral blood flow (penis, digits) Unstable angina Cardiac dysrhythmias Uncontrolled hypertension Treatment with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or sympathomimetics Uteroplacental insufficiency Intravenous (IV) regional anesthesia EO 003.19 Routes of Administration of LA • Topical/surface – Skin, mucous membranes, eye, – ointments, drops, lozenges, gels, creams, sprays – Many OTC • Injection – Infiltration – Regional – Intrarticular – Epidural – Spinal – Intravenous EO 003.19 Systemic absorption • Rate of systemic absorption depends on route fast slow Intravenous Tracheal Intercostals Caudal Paracervical Epidural Brachial plexus Sciatic/femora Subcutaneous EO 003.19 Clinical Uses Topical/Surface • Used to relieve pain and itching of sunburn, insect bites, skin abrasions, hemorrhoids, needle sticks, teething etc. This type of use is not generally recommended, since there is risk of sensitization/ absorption, and other drug or non drug measures are available. • Numb area prior to dental procedures, other diagnostic procedures EO 003.19 Clinical Uses Infiltration (used for superficial surgery) – Removal of moles, warts, sebaceous cysts • Used for IV insertion • Regional block • Intravenous • Epidural • Spinal EO 003.19 Spinal Anesthesia • These products contain NO ANTIMICROBIAL PRESERVATIVE. They are in single-dose vials. • spinal products are hyperbaric due to addition of dextrose. The patient is positioned so that anesthesia is achieved at the appropriate nerve roots EO 003.19 Drug Interactions • With topical or infiltration anesthesia, interactions are • • • • unlikely, since systemic absorption should be very low. Inhalation anesthetics and general anesthetic premeds MAOI’s : increase risk of hypotension Neuromuscular blockers: LA may enhance/ prolong action Cholinesterase inhibitors increase likelihood of toxicity with ester LA’s EO 003.19 Adverse Effects of LA’s • Hypersensitivity – Usually due to preservative or metabolite of ester – Skin rash, contact dermatitis, asthmatic attack, anaphylactic • Musculoskeletal – Local anesthetics are myotoxic when injected directly into skeletal muscle • Respiratory – Lidocaine depresses the hypoxic drive – Apnea can result from phrenic and intercostal nerve paralysis or depression of medullary centre EO 003.19 Central Nervous System Concentration Toxicity Low Circumoral paresthesia, mild relaxation/sedation, generalized analgesia Moderate Euphoria, lightheadedness, dysphoria, slurred speech, drowsiness, sensory changes (blurred, double vision), twitching Moderate to High Disorientation, tremor, unconsciousness, seizures High Coma, respiratory arrest EO 003.19 Vascular & Cardiac Effects of LA’s • Cocaine causes an intense vasoconstriction which can lead to destruction of tissue by reducing blood supply • Other local anesthetics show an initial vasoconstriction, then vasodilation • Higher concentrations decrease cardiac conduction velocity, automaticity, contractility, cardiac output and blood pressure = cardiovascular collapse. Normally, there will be signs of CNS toxicity first; these cardiac effects occur at high plasma concentrations. EO 003.19 Special Populations • Pregnancy: no good studies, but retrospective analyses show no risk to fetus. LA’s do cross the placenta. • Breast feeding: some distribution into breast milk, but appears safe. • Infants: under 9 months, have low plasma protein concentrations, which may enhance effects of bupivicaine. Lidocaine preferred. EO 003.19 Individual Agents… EO 003.19 Bupivacaine (Marcaine®) • Onset of action: intermediate (slower than lidocaine) • Duration of action: long (3 to 10 hours) • Products: available as 0.25% and 0.5% solutions, with and without epinephrine, in various volumes and containers. Multidose vials contain parabens; products with epinephrine also contain Na metabisulfite (antioxidant) EO 003.19 Bupivicaine Dosing (Adult) • Based on healthy, 70 kg young male • Peripheral nerve block: 12.5 to 175 mg (5 to 70 mL of 0.25% soln) • Local infiltration: up to 175 mg (70 mL) of 0.25% solution without epi. • If using epi, max dose = 225 mg. • Total daily doses may go up to 400 mg. EO 003.19 Lidocaine Parenteral Solution (Xylocaine®) • Rapid onset; duration 1 to 3 hours. • Products: • 1% and 2 % parenteral solutions, with and without epi. Note that the multidose vials contain parabens, but are to be discarded 3 days after initial puncture. Use single dose vials and discard remaining solution if possible. Sodium metabisulfite present in the “with” solutions. EO 003.19 Lidocaine Parenteral Solution • Adult dose: • Digits (no epi !): 1 to 5 mL of 1% solution (onset fast, within 2- 5 minutes) • local infiltration: less than 40 mL of 1% solution (onset within 1-2 minutes) • Percutaneous: less than 30 mL of 1% solution EO 003.19 Lidocaine Endotracheal • Gives surface anesthesia for procedures • • • • involving nasal/ respiratory tracts Delivers 10 mg/ spray New canisters must be primed (5 to 10 pumps). Don’t need to re-prime after changing nozzle, just void air. For procedures in oropharynx, 2 to 6 sprays. For intubation, 5 sprays to 40. EO 003.19 Lidocaine 2% Jelly • For surface anesthesia/ lubrication of urethra (ie • • • • during catheterization); proctoscopy, rectoscopy, endoscopy. Not effective on intact skin Endotracheal intubation: about 2 mL applied to end of trach tube Female urethra: 5 to 10 mL Male urethra: about 20 mL for entire surface; 5 to 10 mL for anterior portion EO 003.19 Lidocaine 2% Viscous • For topical anesthesia of mouth and pharynx, surface • • • • • anesthesia with introduction of instruments into digestive/ resp tracts, pain due to esophagitis “pink lady” = mixed with Diovol For mouth and throat: 5 to 10 mL; swish and spit or swallow slowly For esophagitis: 5 to 15 mL, swallowed in a single gulp Max 60 mL in 24 hours Onset within 5 minutes; lasts 20 to 30 minutes EO 003.19 Lidocaine Topical 5% • Comes in 50 mL plastic bottles; spearmint flavoured. • For pain due to inflamed tissue in mouth, or for surface oral anesthesia for dental procedures • 1 to 4 mL applied with a cotton swab EO 003.19 Lidocaine/ Prilocaine Topical EMLA: Eutectic Mixture of Local Anesthetics Intact skin: anesthesia for needle insertion or for superficial surgical procedures. Used, especially in children, to reduce pain of vaccination. OK with MMR, DPTP, Hib, Hep B. Leg Ulcers: cleansing and debridement Genital Mucosa: surface anesthesia for short surgical procedures or infiltration anesthesia EO 003.19 Lidocaine/ Prilocaine Topical • • • • • DO NOT USE FOR: application to mucus membrane except for adult genital mucosa. Application inside the ear due to possibility of ototoxicity Area around the eyes; it irritates the cornea Infants less than 3 months old infants predisposed to methemoglobinemia; this includes those receiving sulfonamides. EO 003.19 EMLA Application • Intact skin: cream applied thickly to area; occlusive dressing applied; or may use patch form. Area is cleaned prior to procedure. After 1 hour, get about 3 mm depth of anesthesia. • Genitalia: cream applied without occlusion; anesthesia occurs in 5- 10 minutes • Leg ulcers: apply up to 10 g; remove after 30 to 60 minutes and clean/ debride. EO 003.19 SUMMARY Choice of Ideal LA for Indication: Quick onset Appropriate duration Lowest toxicity Highest specificity Minimize allergic potential