Pharmacology II Local Anesthetics Lecture Notes PDF

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 26 Local Anesthetics Background (a) noicicption = pain awarness (b) nerve ending receptors in peripheral tissues transmit impulse to CNS through primary afferent fibers and relayed by seco...

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 26 Local Anesthetics Background (a) noicicption = pain awarness (b) nerve ending receptors in peripheral tissues transmit impulse to CNS through primary afferent fibers and relayed by secondary afferent fibers to the brain (c) drugs can block pain perception in the periphery or in the CNS (d) drugs can block pain through inhibition of sodium channels in neurons in the spinal cord (e) local anesthetics block sodium channels in axons (f) cocaine was first local anesthetic introduced by Koller in 1884 as a topical ophthalmic anesthetic Basic Pharmacology of Local Anesthetics Chemistry (a) lipophilic group (aromatic ring) connected by an intermediate chain via an ester or amide to a ionizable group (tertiary amine) (b) ester linage drugs have shorter duration of action (c) pKa of most is between 8.0 – 9.0 (d) at physiological pH 7.4 most are charged and cationic (water soluble, not lipid soluble) (e) problem, charged form is most active at receptor but can not cross membranes to get to the receptor (f) infected sites have low pH (from bacterial growth), drugs are less effective because low pH promotes ionized form which is poorly lipid soluble (can not cross membranes) (g) Table 26-1 pg 485 for the structures of local anesthetics Pharmacokinetics Absorption (a) absorption from site of injection is controlled by (1) dosage (2) site of injection (3) drug-tissue binding (4) local tissue blood flow (5) use of vasoconstrictors (epinephrine) (6) physiochemical properties of the drug itself (b) vasoconstrictors (epinephrine) co-administered will reduce blood flow and prolong actions of the local anesthetic  2 (c) epinephrine, clonidine and dexmedetomidine are agonists at alpha 2 receptors in the spinal cord, when co-administered with local anesthetics they prolong the actions by blocking the release of Substance P which reduces sensory neuron firing Distribution (a) amides widely distributed (b) esters too rapidly biotransformed with very short half life Biotransformation (a) ester converted in the plasma by esterase enzymes (b) amides converted in the liver (takes longer compared to plasma bio- transformation) (c) procaine and chloroprociane half lives < 1 min (esters) (d) lidocaine (amide) takes 1.6 hours to be fully eliminated but this can increase to 6 hours with liver disease Pharmacodynamics Mechanism of Action (a) block voltage gated sodium channels (b) during action potential, (1) sodium channel opens, sodium flows in, (2) neuron depolarizes to + 40 mV (3) sodium channel closes (4) potassium channel opens (5) potassium flows out (6) neuron repolarizes (7) sodium channel returns to resting state (c) other ways to disrupt sodium channels (1) toxins block sodium channels (tetradotoxin) (2) these toxins bind to receptor and block flow of sodium (d) local anesthetic blockade of sodium channels is voltage and time- dependent SAR Studies (a) structure activity relationships (SAR) (b) potency correlated positively with lipid solubility Size and Degree of Myelination of Target Neurons (a) Size and degree of myelination contribute to the actions of local anesthetics (1) drugs preferentially block small fibers (2) small fibers transmit over shorter distance (3) for myelinated fibers 2-3 successive nodes of Ranvier  3 must be blocked to stop conduction impulse (4) preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission (b) Effect of Firing Frequency (1) drug blockade is more marked in high firing neurons (2) sensory (pain) fibers have high firing rates (c) Effect of Fiber Position in he Nerve Bundle (1) fibers located circumferentially are first exposed to local anesthetic (2) proximal sensory fibers are located in the outer portion of the nerve trunk Clinical Pharmacology (a) usual routes of administration (1) topical (nasal mucosa, wound [incision site] margins) (2) injection into vicinity of peripheral nerve endings (peri- neural infiltration) (3) injection into major nerve trunks (blocks) (4) injection into the epidural or subarachnoid spaces surrounding the spinal cord (b) Bier Bock used iv for regional block in lower and upper extremities (c) duration of action for these drugs in Table 26-2 pg 487 (d) vasoconstrictors (epinephrine) increases the duration of action by decreasing the blood flow at the site of injection (e) speed onset of action with sodium bicarbonate to the injection solution (1) this shifts the pH and converts more of the drug to the lipid- soluble (unionized) form (f) repeated injections of local anesthetics can induce tachyphylaxis (g) effects of pH on drug actions (1) injection drugs are in pH 4-6 (acidic) buffer to improve stability (2) after injection the drug is converted by body fluids to pH 7.4 (3) repeated injection depletes the buffering capacity of the tissues (4) tachyphylaxis results (h) cocaine used for ENT procedures because of excellent absorption from topical application and potent vasoconstrictor effects Toxicity (a) systemic effects following absorption of the local anesthetic for the site of administration (injection) (b) direct neurotoxicity from the local effects of these drugs when high  4 concentrations are administered in close proximity to the spinal cord and other major nerve trunks. (c) elevated blood levels can induce a variety of toxic actions CNS Toxicity (a) inadvertent intravascular administration induces local anesthetic toxicity (1) circumoral and tongue numbness (2) metallic taste (3) nystagmus and muscular twitiching (4) tonic-clonic convulsions (5) generalized CNS depression follows seizure activity (b) midazolam raises seizure threshold and prevents seizure activity from larger doses Neurotoxicity (a) pooling of excess drug in the cauda equina leads to toxicity not related to excess sodium channel blocking that results in neuropathic symptoms Cardiovascular (a) excess local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction (b) cocaine is an exception, it blocks NE uptake and cause blood pressure increase (vasoconstriction) Allergic Reactions (a) ester type local anesthetics are biotransformed to p-aminobenzoic acid (PABA) derivatives, responsible for allergic reactions (b) amide local anesthetics not biotransformed to PABA, allergic reactions extremely rare Required Drugs are in Bold including those in the above text. Amides (count the number of “i” letters) lidocaine lidocaine + hydrocortisone (patch) bupivacaine prilocaine mepivacaine  5 ropivacaine levobupivacaine articaine (often used in dentistry) dibucaine (old time local) Esters chloroprocaine cocaine (local) procaine tetracaine benzocaine Intralipid: Intralipid® (parenteral lipid emulsion with an interesting clinical usage) Intralipid = intravenous lipid emulsion for overdose See “Lipid Resuscitation” on the top of pg 494 in Katzung. Ionization of the local anesthetics: “adding bicarbonate to a local anesthtic-a strategy sonetimes used in clinical practice-will raise the effective concentration of the nonionized [lipid soluble] form and thus shorten the onset time of a regional blokc [acts faster]” Katzung pg 479. Here are a few interesting points to think about and learn. (1) A bottle of lidocaine pH 6.5 this is the pH where the drug is most stable no one wants a drug that has a shelf life of 2 days, most want a year or more. when injected, human intersitial tissue fluids raise the pH of the injected drug to human pH 7.45 this is the pH where the drug will work the best but, the second injection if needed, you need more time to finish the suturing, the second injection will not work well because the buffering capacity of the tissue fluise were “mostly” depleted by the first injection try to work fast but safely. (2) A vial of lidocine mixed with epinephrine pH 4.5  6 epinephrine will vasoconstrict and keep the anesthetic at the site of injection longer, that’s good but, look at the pH 4.5 which the tissue fluids have to buffer up to pH 7.45, good luck so, add some sodium bicarbonate, and bring the pH up to pH 7.45, this does thebuffering work for the patient again the pH and shelf life stability, add the sodium bicarbonate just before use no problem the FDA product insert will tell you how much sodium bicarbonate to add, to a volume of x ml. (3) This is what we have have with the vials BEFORE pH adjustment and injection. Only lipid soluble drugs can easily pass across membranes. To find the sodium receptor the liodocaine drug must cross lipid membranes vial pH # molecules of drug # molecules of drug unionized ionized lipid soluble water soluble 4.5 1 10 000 7.4 1 4 (4) A infected clinical site will have an acidic pH (no buffering capacity) because bacteria produce lactic acid. Do not inject anesthetic into an infected site unless required. (5) The cause of pain from an injected drug (im or sc) is complex and poorly understood. Acidic drugs are more painful when injected im or sc compared to neutral drugs (pH 7.4). Some physicians will bubble CO2 gas into a vial of lidocaine. This may help reduce the pain of injection because one or more of the following reasons or some other reason I am not aware of. (a) CO2 may change the charge on lidocaine and make it more lipid soluble and work faster. (b) CO2 may “ion trap” lidociane within the nerve bundle or neuron which will improve the anesthetic action of the drug. (c) CO2 itself has an anesthtic effect on tissues.  7 Amides (count the number of “i” letters) lidocaine lidocaine + hydrocortisone (patch) bupivacaine prilocaine mepivacaine ropivacaine levobupivacaine articaine dibucaine (local) Esters chloroprocaine cocaine (local) procaine tetracaine benzocaine proparacaine (ophthalmic) Misc Intralipid® (parenteral lipid emulsion)