Local Anesthetics

1. Local Anesthetics S. HabibianDehkordi D.V.M, Ph.D, Postdoctral Research Assistant in Neuropharmacology, Postdoctral Research Associate in Neuroscience

2. Local Anesthetics • Used at multiple sites throughout the body: • Epidural • Spinal • Peripheral nerve blocks • IV (Bier Block) • Skin sites locally

3. Lidocaine Bupivacaine Etidocaine Mepivacaine Prilocaine Ropivacaine Amides and Esters • Chloroprocaine (Nesacaine) • Cocaine (crack) • Procaine • Tetracaine (Pontocaine)

4. Mechanism of Action • Local anesthetics work in general by binding to sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing. • The Cell membrane consists of ion pumps, most notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular.

5. General Structure • A lipophilic group…usually a benzene ring • A Hydrophilic group…usually a tertiary amine • These are connected by an intermediate chain that includes an ester or amide linkage • LAs are weak bases

6. Lipid solubility • Most lipid soluble: • Tetracaine • Bupivicaine • Ropivacaine • Etidocaine • Increased lipid solubility also equals greater potency and longer duration of action. • Why? • Because it has less of a chance of being cleared by blood flow • Decreased lipid solubility means a faster onset of action. • What else effects onset of action???

7. pKa • Local anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset. • The charged cation form more avidly binds to the Na+ channel receptors inside the cell membrane. • pKa > 7.4 more cations, pKa < 7.4 more anions

8. AMIDES • Bupivacaine, Etidocaine and Ropivacaine- very high potency and lipid solubility, very long duration and protein binding also. • Lidocaine, Prilocaine and Mepivacaine- have intermediate potency and lipid solubility and intermediate duration of action and protein binding.

9. ESTERS • Chloroprocaine and Procaine- have low potency and lipid solubility and also low duration and protein binding. • Cocaine- has intermediate potency and solubility and intermediate duration and protein binding • Tetracaine- has high potency and lipid solubility along with a long duration of action and high protein binding

10. Plasma protein binding • What protein are LAs bound??? • Mostly a1-acid glycoprotein • To a lesser degree albumin

11. Absorption • Mucous membranes easily absorb LA • Skin is a different story… • It requires a high water conc. for penetration and a high lipid concentration for analgesia • Which LAs can we use for this? • EMLA cream- 5% lidocaine and 5% prilocaine in an oil-water emulsion • An occlusive dressing placed for 1 hour will penetrate 3-5mm and last about 1-2 hours. • Typically 1-2 grams of drug per 10cm2 of skin

12. Rate of systemic absorption • Intravenous > tracheal > intercostal > caudal > paracervical > epidural> brachial plexus > sciatic > subcutaneous • Any vasoconstrictor present?? • High tissue binding also decreases the rate of absorption

13. Metabolism • Amides… • N-dealkylation and hydroxylation • P-450 enzymes, liver, slower process than esterase activity • Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacaine • Prilocaine has a metabolite…. • o-toluidine • This causes methemoglobin to form (Benzocaine can also cause methemoglobin to form) • Treated with methylene blue 1-2mg/kg over 5 minutes • Reduces methemoglobin Fe3+ to hemoglobin Fe2+

14. Metabolism • Esters… • Pseudocholinesterase • Procaine and benzocaine are metabolized to… • PABA (p-aminobenzoic acid) allergy risk • Tetracaine intrathecal has it’s action terminated by… • No esterase activity intrathecally therefore absorption into bloodstream terminates it’s action

15. Clinical Uses • Esters • Benzocaine- Topical, duration of 30 minutes to 1 hour • Chloroprocaine- Epidural, infiltration and peripheral nerve block, max dose 12mg/kg, duration 30minutes to 1 hour • Cocaine- Topical, 3mg/kg max., 30 minutes to one hour • Tetracaine- Spinal, topical, 3mg/kg max., 1.5-6 hours duration

16. Clinical Uses • Bupivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg max., 1.5-8 hours duration • Lidocaine- Epidural, spinal, infiltration, peripheral nerve block, intravenous regional, topical, 4.5mg/kg or 7mg/kg with epi, 0.75-2 hours duration • Mepivacaine- Epidural, infiltration, peripheral nerve block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours • Prilocaine- Peripheral nerve block (dental), 8mg/kg, 30 minutes to 1 hour duration • Ropivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg, 1.5-8 hours duration

17. Systemic Toxicity • Blockage of voltaged-gated Na channel affects action potential propagation throughout the body…therefore the potential is present for systemic toxicity. • Mixtures of LA have additive affects • i.e. a 50% toxic dose of lidocaine and a 50% toxic dose of bupivicaine have 100% the toxic affect of either drug

18. Systemic Toxicity • Neurological • Symptoms include cicumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness. • Muscle twitching heralds the onset of tonic-clonic seizures with respiratory arrest to follow.

19. Local anesthetic toxicity • Seizure treatment: • Thiopental 1-2mg/kg abruptly terminates seizure activity • Benzos and hyperventilation…decrease CBF and therefore drug exposure. These raise the threshold of local anesthetic-induced seizures • Chloroprocaine injected intrathecally can cause prolonged neurotoxicity. This is likely due to a preservative no longer used with this agent. (Sodium bisulfate)

20. Local anesthetic toxicity • Repeated doses of 5% lidocaine and .5% tetracaine may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics. • Pooling of drug around the cauda equina resulted in permanent neurological damage • Animal studies suggest that neuro damage is: Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic

21. Local anesthetic toxicity • Transient Neurological Symptoms • This is associated with dysethesia, burning pain and aching in lower ext, buttocks. • Follows spinal anesthesia with variety of agents (lido), attributed to radicular irritation and resolves in 1 week usually • Risk factors include • Lidocaine intrathecally • Lithotomy position • Obesity • Outpatient status

22. Local anesthestic toxicity • Respiratory center may be depressed (medullary)…postretrobulbar apnea syndrome • Lidocaine depresses hypoxic respiratory drive (PaO2) • Direct paralysis of phrenic or intercostal nerves

23. LA cardio toxicity • All LA’s depress spontaneous Phase IV depolarization and reduce the duration of the refractory period • Myocardial contractility and conduction velocity are depressed at higher concentrations • All LA’s except cocaine cause smooth muscle relaxation and therefore vasodilation (art) whick can lead to brady, heart block and hypotension…cardiac arrest.

24. LA cardio toxicity • Major cardiovascular toxicity usually results from 3 times the blood concentration of LA that causes seizures. • Therefore cardiac collapse is usually the presenting sign under GA. • R isomer of bupivacaine avidly blocks cardiac sodium channels and dissociates very slowly. Making resuscitation prolonged and difficult.

25. LA cardio toxicity • Levo-bupivacaine (S isomer) is no longer avaliable in the US but had a cardiovascular profile similar to ropivacaine. • Ropivacaine has a larger therapeutic index and it is 70% less likely to cause severe cardiac dsyrhythmias than bupivacaine • Also ropviacaine has greater CNS tolerance • The improved safety profile is due to a lower lipid solubility

26. LA toxicity treatment • Supportive care: intubation, vasopressors, appropriate defibrillation, fluids, stop injection of LA, anything else…. • Intralipid…Bolus 1cc/kg of 20% intralipid, 0.25cc/kg/min of 20% intralipid for 10 minutes • Bolus can be repeated every 5 minutes up to a maximum of 8cc/kg of 20% intralipid • Cardiac support should be continued as ACLS dictates • Epi and vasopresin should likely both be used in the resusitation efforts (animal model data from A & A)

27. True Allergic Reactions to LA’s • Very uncommon • Esters more likely because of p-aminobenzoic acid (allergen) • Methylparaben preservative present in amides is also a known allergen

28. Local Anesthetic Musculoskeletal • Cause myonecrosis when injected directly into the muscle • When steroid or epi added the myonecrosis is worsened • Regeneration usually takes 3-4 weeks • Ropivacaine produces less sereve muscle injury than bupivacaine

29. Drug Interactions • Chloroprocaineepidurally may interfere with the analgesic effects of intrathecal morphine • Opioids and a2 agonists potentiate LA’s • Propranolol and cimetidine decrease hepatic blood flow and decrease lidocaine clearance • Pseudocholinesterase inhibitors decrease Ester LA metabolism • Dibucaine (amide LA) inhibits pseudocholinesterase • Sux and ester LA need pseudochol. for metabolism therefore adminstering both may potentiate their activity • LA potentiate nondepolarizing muscle relaxant blockade

30. Other agents with LA properties • Meperidine • TCAs (amitriptyline) • Volatile anesthetics • Ketamine • Tetrodotoxin (blocks Na channels from the outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA.

31. Thanks for your attentions Questions