Local Anesthetics LA

1. Local Anesthetics LA Prepared by : Dr Alia Alshanawani College of Medicine, KSU.

2. LA: Reversibly block impulse conduction along nerve axons & other excitable membrane that utilize Na+ channels for Action Potential generation. Uses: block pain sensation (nociception) from specific area of ! body. Cocaine was ! 1st LA isolated from Coca plant as an ophthalmic anesthetic; Its chronic use: psychological dependence (addiction).

3. Followed by procaine & then Lidocaine (Lid) which is ! most widely used LA. What characteristics of LAs make them ideal agents for anesthesia? As ropivacaine 1- Rapid/ faster onset, 2- Long Duration of Action, 3- Reversible & selective blockade of sensory nerves without motor blockade, 4- Minimal local tissue irritation & no systemic toxicities (cardiac & CNS).

4. Weak base & available as salts to increase solubility & stability. Consist of lipophilic gp (aromatic ring): memb penetration ++ intermediate chain via an ester or amide to ionizable gp: for channel blockade . Chemistry of LA

8. •Absorption of injected LA, esp systemic: depends on: 1- dosage, 2- site of inj, (VASCULARITY): IV > tracheal > intercostals > paracervical > epidural > brachial plexus > sciatic > SC 3- drug-tissue binding, 4- local blood flow, 5- use of Vasoconstrictors (epinephrine/ phenylephrine) & 6- ! physiochemical property of ! drug. Absorption in highly vascular area (trachea, intercostal) is > poor perfused tissues (dermis & SC fat).

9. Epinephrine/ VC: Slow ! removal & reduce systemic absorption of LA from inj site by decreasing blood flow (upto 30%) & cause higher local tissue conc. of ! drug & prolong conduction blockade. + reduce CNS & systemic tox. Used with short/ intermediate duration of action: (procaine, Lid & mepivacaine). VCs are < effective in prolonging anesthetic action of more lipid-soluble, long-acting drugs (bupivacaine & ropivacaine) which are highly tissue-bound.

10. Distribution ! Amide LAs are widely distributed after IV bolus inj. Initial rapid phase into highly perfused organs (brain, kidney, liver & heart), then a slower phase to moderately perfused organs (Muscle, GIT).

11. Acidification of urine: ionization & excretion of LA Ester-type hydrolyzed rapidly in ! blood (by pseudo-choline-sterase) to inactive metabolites; short plasma t1/2 (< 1 min). ! amide linkage is hydrolyzed by liver cytochrome P450 with different rates order (prilocaine (fastest) > Lid > bupivacaine (slowest). All ester & amide LAs converted to more water-soluble metabolites & excreted in urine. Metabolism & Excretion

12. Toxicity from amide-type LA occur in hepatic D. Ex: elimination t1/2 of Lid increase from 1.6 hr in normal pat to > 6 hr in liver disease pat. amide LA also affected by enz inhibitors. Reduced hepatic bld flow: decrease their elimination.

13. Block ! Initiation & propagation of action potential (AP) by preventing voltage-gated Na+ channels. Activity is PH-dependent, increased at alkaline PH. Its penetration to Na+ channels is very poor at acid PH. Inflamed tissues (acidic): resistance to LA. Elevated extracellular Ca2+ antagonizes ! action of LA by Ca2+ which increase ! surface potential on ! membrane. MOA

14. Smaller & more lipophilic LA: ! Faster rate of interaction with Na+ channels. Potency is +vely correlated with lipid solubility. Lid, procaine, & mepivacaine are > water-soluble than tetracaine, bupivacaine, & ropivacaine that are > potent & have longer DOA. Long acting (bupivacaine ) also bind more extensively to plasma proteins & can be displaced by other protein-bound drugs. Structure- Activity Characteristics of LA:

15. Other actions of LA on nerves: 1- Loss of sensation from site of painful stimuli 2- Motor paralysis during surgery; desirable; but also limit ! ability of patient to cooperate in obstetric delivery. Disadvantages In Spinal anesthesia, motor paralysis: impair respiratory activity & AN blockade: hypotension & urinary retention (catheterization).

16. 1- Effect on fiber diameter: LA block conduction in small-diameter nerve fibers > readily than in large fibers. (bec electrical impulse is shorter) Pain sensation is blocked > readily than other sensory modalities. Motor axons (large diameter), are relatively resistance. LAs block conduction in ! following order: smallmyelinated (pain impulses), non- myelinated (C-fibers), large myelinated axons.

17. 2- Effect on firing frequency Blockade by LA is > at higher frequencies of depolarization. Sensory (esp pain) fibers have High firing rate & long AP duration. while Motor fibers fire at a slower rate & have shorter AP duration.

18. Properties of LAs

20. Surface/topical anesthesia Local infiltration Peripheral nerve block Bier block (IV regional anesthesia) Epidural anesthesia Spinal anesthesia (subarachnoid) Methods of administration: Six Placement Sites

21. Epidural Spinal

23. Effective analgesia in specific regions of ! body. Route of administration: 1- Topical/ surface application (nasal mucosa, wound margins) 2-Inj in ! vicinity of peripheral nerve endings (infiltration) & major nerve trunks (blocks) 3- Inj into ! epidural or subarachnoid spaces surrounding ! spinal cord. 4- IV regional anesthesia (Bier block) for surgery < 60 min in limbs. Clinical pharm

24. Short: proc- & chloropro- caine Intermediate: Lid, mepiva- & prilo- caine Long-acting: tetra-, bupiva-, & ropiva- caine. duration can be prolonged by increasing ! Dose/ adding VC agent. Duration of Action

25. To increase onset of LA: + Na-bicarbonate to LA sol; LA become > lipid soluble. Repeated inj of LA: tachyphylaxis (extracellular acidosis) Pregnancy increase LA tox. Topical LA: eye, ENT & for cosmetic surgery. Properties: 1- rapid penetration across ! skin/ mucosa & 2- low tendency to diffuse away from ! site of application. Cocaine bec of excellent penetration & local VC used for (ENT) procedures. Has irritating effect so NOT used in ophthalmic procedure. Other topical: Lid + VC, tetracaine, dibucaine, benzocaine, & dyclonine.

26. OTHER USES: LAs have membrane-stabilizing effects; Both IV Lid & po (mexiletine, tocainide) used to Tr patients with neuropathic pain syndrome: (uncontrolled, rapid, sensory fiber firing). Systemic LA: as adjuncts to TCA (amitriptyline) & anticonvulsant (carbamazepine). Systemic toxicity: CNS & CV system.

27. A- CNS: 1- All LAs at low conc: sleepiness, light headiness, visual & auditory disturbances & restlessness. Early symp: tongue numbness + metallic taste. Rare, but High plasma conc.: nystagmus & muscular twitching, then tonic-clonic convulsions. Followed by generalized CNS depression (apnea). Toxicity

28. Convulsions: excessive LA level in ! bld. If large dose of LA is required: Rx pre-medication with BDZs prophylaxis. 2- For cocaine: widely abuse drug, severe CV toxicity; HTN, arrhythmia, & myocardial Failure. B- Neurotox: direct neuronal tox. With excessive high conc. Chloroprocaine & Lid are > neurotoxic than others in spinal anes.,: transient irritation (neuropathic symptoms).

29. C- CVS: direct effect on ! hrt & smooth muscle & indirect effect on ! ANS. Depress strength of cardiac contraction, ECG changes & cause arteriolar dilatation;; hypotension. Bupivacaine is > cardiotoxic than other long-acting LA. Ropivaciane: CV & CNS tox, but < than Bupivacaine. Cocaine blocks Norepinephrine uptake: VC & HTN + cardiac arrhythmia & ischemia.

30. D- Hematologic effects: Large dose of prilocaine: accumulation of Oxidizing Agent (o- toluidine) that convert Hg to metHg.;; cyanosis & chocolate-colored. Not recommended in infants. (Benzocaine can also cause metHg). Rx: IV methylene blue/ ascorbic acid. E- Allergic rxs: (Not with amides) Ester-type LAs are metabolized to P-ABA derivatives; allergic rxs.