Local anesthetics Dr. Cermanova 2015 Minor modification by Dr. Sterba 2015

Local Anesthetics Block sensory transmission from a limited area of the body to the CNS a group of chemically similar agents block the voltage-gated sodium channels of excitable membranes administered locally by topical application or by injection into the target area, the anesthetic effect can be restricted to a localized area, eg, the cornea or an arm !!! effect is terminated by absorption to systemic circulation systemic adverse effects. Many drugs classified in other groups, have significant local anesthetic effects eg, antihistamines and beta-blockers,.

Ion flows and an action potential the action potential is triggered by a brief pulse of electric current depolarization of membrane opening of voltage-gated Na+ channels inactivation of voltage-gated Na+ channels return to the closed conformation even if restimulated, the membrane cannot produce a second action potential until the Na+ channels have returned from the inactivated to the simply closed conformation video: http://www.youtube.com/watch?v=ifD1YG07fB8

Chemistry are esters or amides of simple benzene derivatives weak bases all carry at least one amine function become charged through the gain of a proton (H+). the degree of ionization is a function of the pKa of the drug and the pH of the medium. pKa of most local anesthetics is between 8.0 and 9.0 Because the pH is low as 6.4 in infected tissue, the degree of ionization of the drug will vary - significant effects on the proportion of ionized to nonionized drug.

Cocaine Procaine Lidocaine Articaine Bupivacaine Mepivacaine

Chemistry In the body, they exist as - the uncharged base or as a cation The relative proportions of these two forms is governed by their pKa and the pH of the body fluid according to the Henderson-Hasselbach equation: Cationic form log = pKa - pH Unchanged form Because pKa of most local anesthetics is between 8.0 and 9.0 , the cationic form is though to be the most active form at the receptor site. Cationic form cannot readily leave closed chanels, but the uncharged forms is very important for rapid penetration of biologic membranes.

Metabolism of local anesthetics • Most ester-linked local anesthetics are quickly hydrolyzed by enzymes in blood (plasma choline esterases) • Amide-linked local anesthetics can be widely distributed via the circulation and are hydrolyzed in the liver. • Water-soluble metabolites are excreted in the urine  

Effect of vasoconstriction on local anesthetics Local anesthetics are removed from depot site mainly by absorption into blood. Addition of vasoconstrictor drugs such as epinephrine reduces absorption of local anesthetics, thus prolonging anesthetic effect and reducing systemic toxicity. Epinephrine is included in many local anesthetics Know your patient’s health status!!! May induce palpitation, arrhythmias or chest pain when absorbed in high doses Do no use in very peripheral parts of the body- risk of ischemia

Mechanism of Action LA block voltage-dependent sodium channels and reduce the influx of sodium ions, thereby preventing depolarization of the membrane and blocking conduction of the action potential. LA gain access to their receptors from the cytoplasm or the membrane. the drug molecule must cross the lipid membrane to reach the cytoplasm, the more lipid-soluble (nonionized, uncharged) form reaches effective intracellular concentrations more rapidly than does the ionized form. once inside the axon, the ionized (charged) form of the drug is the more effective blocking entity. Thus, both the nonionized and the ionized forms of the drug play important roles, the first in reaching the receptor site and the second in causing the effect.

Binding of local anesthetic to receptor The affinity of the receptor site within the sodium channel for the LA is a function of the state of the channel The LA receptor is not accessible from the external side of the cell membrane Drugs binds to - open and inactivated channels, therefore for those with higher activity/firing - receptors near the intracellular end of the channel and block the channel in a time – and voltage –dependent fashion Use dependence - rapidly firing fibers are usually blocked before slowly firing fibers.

Factors affecting onset and duration of action of local anesthetics pH of tissue pKa of drug Lipid solubility of drug Concentration of drug Time of diffusion from needle tip to nerve Time of diffusion away from nerve Nerve morphology and length of the nerve affected

Effects Nerves fiber diameter physiologic firing rate Differential sensitivity of various types of nerve fibers to LA – Factors which may influence sensitivity: fiber diameter smaller fibers are blocked more easily than larger ones, myelination - myelinated fibers are blocked more easily than unmyelinated ones, physiologic firing rate Use dependence - activated pain fibers fire rapidly - selectively blocked anatomic location fibers located in the periphery of a thick nerve bundle are blocked sooner than those in the core - exposed earlier to higher concentrations of the anesthetic - sensory.

Nerve morphology and LA action Critical length of the nerve must be blocked to induce LA 2-3 Ranvier nodes in myelinated neurons This often means 8-10 mm of nerve length

Other tissues class I antiarrhythmic agents. Most local anesthetics also have weak blocking effects on skeletal muscle neuromuscular transmission, but these actions have no clinical application The mood elevation induced by cocaine – CNS effect by ↑ dopamine

Susceptibility to block of types of nerve fibers.* Fiber Type Function Diameter (mm) Myelination Conduction Velocity (m/s) Sensitivity to Block Type A Alpha Proprioception, motor 12-20 Heavy 70-120 + Beta Touch, pressure 5-12 30-70 ++ Gamma Muscle spindles 3-6 15-30 Delta Pain, temperature 2-5 12-30 +++ Type B Preganglionic autonomic <3 Light 3-15 ++++ Type C Dorsal root pain 0.4-1.2 None 0.5-2.3 Sympathetic postganglionic 0.3-1.3 0.7-2.3 *Reproducedfrom Katzung BG (editor): Basic & Clinical Pharmacology, 8th ed. McGraw-Hilf, 2001,

Clinical Use Interactions minor surgical procedures spinal anesthesia most commonly spinal anesthesia slow epidural infusion at low concentrations has been used successfully for postoperative analgesia in the same way as epidural opioid infusion. Repeated epidural injection in anesthetic doses may lead to tachyphylaxis. Interactions High concentrations of extracellular K+ may enhance local anesthetic activity, elevated extracellular Ca2+ may antagonize it. K prodluzuje pristup k vazebnemu mistu

Adverse effects: overdose, accidental iv administration – aspirate in ↑ vascular areas typically 1-5 min after inj. circumoral and/or tongue numbness (in the areas which should be locally unaffected) CNS effects: initially manifest as sedation, lightheadedness, slurred speech, sensory disturbances (metallic taste, tinnitus) , restlessness, nystagmus; higher blood levels may result in tremor, muscle twitching, tonic-clonic convulsions. Severe convulsions may be followed by coma with respiratory and cardiovascular depression. Treatment of toxicity: Severe toxicity is best treated symptomatically. Convulsions are often treated with intravenous diazepam or a short-acting barbiturate such as thiopental. Hyperventilation with oxygen is helpful. Occasionally, a neuromuscular blocking drug may be used to control violent convulsive activity. The cardiovascular toxicity of bupivacaine overdose is difficult to treat and has caused fatalities in healthy young adults.

Adverse and toxic effects: Cardiovascular effects Vasodilators Block of sympathetic innervation and direct smooth muscle effects With the exception of cocaine. Cardiotoxic effects high concentrations and pts with cardiac disease may induce cardiodepressant effects - bradycardia and even cardiac arrest Or reentry ventricular tachycardia with palpitation Bupivacaine - most toxic Cocaine is primarily not cardiodepressant - stimulates the heart, but may induce chest pain

Adverse and toxic effects: treatment oxygenation with mask treatment of convulsions – diazepam i.v. or thiopental in hypotension due to the vasodilation – noradrenaline i.v. in cardiac arrest – adrenalin lipid emulsion injections (commercially available preparation) as rescue therapy/atnidote in severe intoxications

Other toxic effects Prilocaine Allergic reactions Methemoglobinemia - by cumulating metabolite (toluidine-like) – hemoglobin oxidation Cave! Children, pts with IHD, respiration insufficiency, gravidity Treatment: oxygenation, methylen blue (reduction of hemoglobin) Allergic reactions now rare (<1%), particularly in amides (no cross-reactivity within the group) more often in ester subclass – PABA metabolites are responsible, cross-reactivity within the class! Treatment of anaphylactic shock – adrenaline, corticoids, oxygen.. Local neurotoxic action In high concentrations of LA histological damage and permanent impairment of function.

Classification of local anesthetics Duration of action: short acting (< 60 min) procaine medium acting (60-120 min): lidocaine, articaine mepivacaine, prilocaine, trimecaine, long acting(> 120 min): bupivacaine, tetracaine, etidocaine, ropivacaine Chemical structure esters: procaine, tetracaine, benzocaine amides: lidocaine, trimecaine, articaine, mepivacaine, prilocaine, bupivacaine, ropivacaine,,, etidocaine

The attack of nerve may be at the level of: Spinal cord: By injection of local drug in sub -arachnoid space in CSF, this must be bellow L 2 Epidural: The drug is injected outside dura [no puncture] to block the nerve roots at its exit from spinal cord. Nerve plexus: Cervical, brachial, lumbosacral Peripheral nerve: Radial, ulnar, median, sciatic, femoral, popletial, facial, mandibular. Injection into tissues, skin, subcutaneous.

Spinal anesthesia Anatomy Epidural anesthesia

Schematic diagram of the typical sites of injection of local anesthetics in and around the spinal canal. When local anesthetics are injected extradurally, it is referred to as an epidural block. A caudal block is a specific type of epidural block in which a needle is inserted into the caudal canal via the sacral hiatus. Injections around peripheral nerves are known as perineural blocks (eg, paravertebral block). Finally, injection into cerebrospinal fluid in the subarachnoid (intrathecal) space is referred to as a spinal block.

Cocaine block norepinephrine reuptake at sympathetic neuroeffector junctions vasoconstricting actions When used as a drug of abuse cocaine's cardiovascular toxicity includes severe hypertension with cerebral hemorrhage, cardiac arrhythmias, and myocardial infarction. Current clinical use of cocaine is largely restricted to topical anesthesia for ear, nose, and throat procedures, where its intense vasoconstriction can serve to reduce bleeding.

FUTURE DEVELOPMENTS Sustained-Release Formulations recently, efforts have focused on drug delivery systems that can slowly release anesthetic, Less Toxic Agents; More Selective Agents