Adobe Systems Local anesthetics Department of Pharmacology MU Adobe Systems Local anesthetics (LA) ̶cause temporary loss of sensation in a limited area by local reversible inhibition of sensory neurons ̶sensitivity of nerve fibers to LA: vegetative > sensory > motoric nerve fibers ̶in sensory fibers the perception of heat is blocked first, later the perception of pain stimuli, and then also the touch Adobe Systems LA - mechanism of action ̶penetration into sensitive nerve fibers ̶ ̶blockade of voltage-gated sodium channels responsible for fast depolarization along nerves ̶ ̶binding on the inner side of the nerve membrane, and preventing Na+ ions flow other effects: ̶vasodilation (sympathetic nerve fibers blockade) ̶ ̶antiarrhythmic/proarrhythmic effects (influence on Na+ channels in myocardium) Adobe Systems LA - chemical structure ̶amphiphilic substances: - aromatic group is lipophilic - nitrogen group is hydrophilic (ionisable) connected via ester or amide bond (ester-type and amide-type) Adobe Systems LA - chemical structure ̶LA are weak bases ̶ pKa = 8-9, efficacy of LA depends on tissue pH – ratio of ionized/non-ionized form ̶ ̶higher pH = increased efficacy– more molecules are non-ionized = increased penetration to nerve fibers ̶ ̶low pH = less effective, ionized molecules of LA do not penetrate to neurons, e.g. in tissues with inflammation Adobe Systems LA - pharmacokinetics ̶absorption depends on drug concentration on the site of administration, dose, blood perfusion, physical-chemical properties of drug and on the presence of vasoconstrictor agents ̶distribution - in the whole body, amides: strong binding to plasma proteins ̶ ̶metabolisation - plasmatic esterases are involved - fast (ester LA) - hepatic metabolism via CYP- slower (amide LA) ̶ ̶excretion of metabolites - kidneys Adobe Systems Vasoconstrictor agents ̶additives for lowering systemic toxicity ̶ ̶compensation of vasodilation induced by LA ̶ ̶decrease in LA consumption ̶ ̶increased duration of analgesia (delayed diffusion of LA) in acral parts with caution – risk of ischemic necrosis adrenaline, ev. noradrenaline alfa1-agonists (nafazolin) derivatives of vasopressin Adobe Systems LA – routes of administration ̶topical (surface) anesthesia - transdermal penetration of LA in the form of solution, spray, gel, ointment mucosa, cornea, esophagus, respiratory tract, decubitus -frequently used in urology (catheterization) and before other painful instrumental procedures, inhalation of trimecaine before bronchoscopy - EMLA (eutectic mixture of local anesthetics) – mixture of lidocaine and prilocaine for topical use on intact skin. EMLA is frequently used in pediatrics approximately 15-60 minutes before invasive procedure (blood collection, cannulation). Adobe Systems LA – routes of administration ̶infiltration anesthesia subcutaneous, submucosal, intramuscular, intraarticular blocks nerve conduction near their site of administration - low concentrations of both LA and vasoconstrictor agents - often used for minor surgical and dental procedures Adobe Systems ̶conduction anesthesia -peripheral – block of both nerve trunks and individual nerves - -central – always without vasoconstrictor agents! epidural anesthesia – perioperative and obstetric analgesia – it is necessary to stop in advance use of warfarin (+ anticoagulant agents), ASA (+ antiplatelet agents), LMWH, usual amount of LA 16 mL subarachnoideal anesthesia (spinal, lumbal) – intrathecal administration of LA into intervertebral space, usual amount of LA 4 mL LA – routes of administration Adobe Systems https://upload.wikimedia.org/wikipedia/commons/thumb/b/ba/Epidural_blood_patch.svg/250px-Epidural_b lood_patch.svg.png Adobe Systems LA – routes of administration •intravenous regional anesthesia (Bier block) -trimecaine 1%, lidocaine 0,5 % - -toxic LA should not be used (bupivacaine) - -quick onset and inhibition of motor functions - -exsanguination of the limb (elevation + tourniquets), procedures max. up to 2 hrs (risk of ischemia) - -no postoperative analgesia - -bleeding must be stopped carefully Adobe Systems https://dentistryandmedicine.blogspot.cz/2012/05/regional-anesthesia-manualupper.html Adobe Systems Ester type of LA cocaine ̶the first known LA (in use since 1884) ̶ ̶natural compound, isolated from leaves of Erythroxylon coca ̶ ̶central psychostimulant with high risk of addiction ̶ ̶for surface anesthesia Adobe Systems procaine ̶the oldest synthetic LA (1905) ̶slow onset, short duration ̶for infiltration and conduction anesthesia (it penetrates poorly the skin) tetracaine ̶fast onset ̶high systemic toxicity – only for surface anesthesia of oral cavity and throat (combined with chlorhexidine) benzocaine ̶only for topical anesthesia of oral cavity, ear and throat (available in combination with antiseptics) Ester type of LA Adobe Systems LA of ester type are structurally similar to para-aminobenzoic acid → high allergenic potential Ester type of LA Adobe Systems Amide type of LA trimecaine ̶universal, for all types of local anesthesia ̶used also as the class I antiarrhythmic drug lidocaine (syn. xylocaine and lignocaine) ̶universal LA for surface, infiltration and conduction anesthesia ̶class I antiarrhythmic drug ̶ in patents treated with betalytics, Ca2+ channel blockers and in patients with epilepsy doses of trimecaine and lidocaine must be halved Adobe Systems mepivacaine ̶in dentistry, in patients with KI of catecholamines articaine ̶used in dentistry ̶fast onset, long effect bupivacaine ̶all type of local anesthesia ̶treatment of acute pain - continually to epidural space ̶cardiotoxic levobupivacaine ̶lower cardiovascular toxicity and neurotoxicity Amide type of LA Adobe Systems ropivacaine ̶for all types of anesthesia except from subarachnoidal prilocaine ̶surface anesthesia EMLA ̶spinal anesthesia for short surgical procedures cinchocaine (dibucaine) ̶surface (topical) anesthesia ̶highly toxic ̶ Amide type of LA Adobe Systems Allergic reactions are less frequent → LA of amide type are used more frequently than LA of ester type Amide type of LA Adobe Systems LA - according to their efficacy ̶weak procaine (effect lasts approximately 45 minutes), benzocaine ̶ ̶intermediate trimecaine, lidocaine (effect lasts approximately 90 minutes) ̶ ̶strong tetracaine, articaine, bupivacaine (effect lasts approximately 120 minutes-12 hours), levobupivacaine, ropivacaine, mepivacaine Adobe Systems Toxic effects of LA CNS Excitation Inhibition tonic-clonic seizures Areflexia Respiratory failure Coma Cardiovascular system Hypotension Arythmia Bradycardia Alergic symptoms more in esters than in amides, anaphylactic reaction Vasoconstrictor toxicity local hypoxia up to necrosis (acral parts), celkově restlessness, tachycardia, hypertension Methemoglobinaemia because of metabolite (o-toluidine) cumulation Adobe Systems Alergic and anaphylactic reaction to LA symptoms: ̶pruritus ̶urticaria ̶swellings ̶anaphylactic shock- restlessness, anxiety, breathlessness, vomiting ̶Quincke‘s oedema – without inflammation, fast onset in face, affecting lips, face and throat ( suffocation!!) therapy: ̶oxygen and infusion of 5% substituive solution with noradrenaline ̶hydrocortisone i.v. ̶antihistamines ̶in case of respiratory failure, keep free airways, artificial respiratory ventilation Adobe Systems Systemic toxic reaction to LA symptoms: (most often till 15 min from LA administration): ̶restlessness, hand tingling, hot or cold, nausea, vertigo, cold sweat ̶tachypnea ̶tremor, fasciculations, seizures ̶tachycardia, increased blood pressure in the beginning with the subsequent decrease, unconsciousness, bradycardia ̶in the final phase respiratory and cardivascular failure therapy: ̶lay down patient, oxygen in respiratory insufficiency ̶diazepam i.v. in seizures ̶slow adrenaline continually i.v. if there is critical decrease of BP ̶resuscitation in respiratory and cardiac failure Adobe Systems Some of the LA can be also used as antiarrhythmic agents (class 1b). lidocaine trimecaine