1. 1 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.nociception  Cocaine was ! 1 st LA isolated from Coca plant as an ophthalmic anesthetic; Its chronic use: psychological dependence (addiction). 2

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). 3

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. 4

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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). 8

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. 9

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). 10

11.  Acidification of urine: ionization & excretion of LA  Ester-type hydrolyzed rapidly in ! blood (by pseudo- choline-sterase) to inactive metabolites; short plasma t 1/2 (< 1 min).  ! amide linkage is hydrolyzed by liver cytochrome P 450 with different rates order (prilocaine (fastest) > Lid > bupivacaine (slowest).  All ester & amide LAs converted to more water-soluble metabolites & excreted in urine. 11

12.  Toxicity from amide-type LA occur in hepatic D. Ex: elimination t 1/2 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. 12

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 Ca 2+ antagonizes ! action of LA by Ca 2+ which increase ! surface potential on ! membrane. 13

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. 14 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). 15

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: small myelinated ( pain impulses), non- myelinated (C-fibers), large myelinated axons. 16

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. 17

18. DrugOnset Dura -tion Plas -ma t 1/2 SENotesCoc- Medi um M 1 hr CV & CNS, due to block of amine uptake Rarely used, only as spray for URT Pro-MShort < 1hr CNS: restlessness, shivering, anxiety CVS: B.cardia, VD & decrease COP No longer used 18

19. LidRapidM 2 hr As procaine but < tendency to CNS Widely used + IV in ventricular arrhythmia. Mepivacaine is similar Ametho c- (tetrac V. Slow Long 1 hr As Lid spinal & corneal anesthesia. Bupivac - SlowLong 2 hr As Lid but > CVS Widely used (long DOA). Ropivacine is similar, with less cardioTox. Priloc-MM 2 hr No VD MetHgemi a Widely used, not for obstetric (neonatal metHgemia. 19

20.  Surface/topical anesthesia  Local infiltration  Peripheral nerve block  Bier block (IV regional anesthesia)  Epidural anesthesia  Spinal anesthesia (subarachnoid) 20

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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. 23

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. 24

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. 25

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. 26

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). 27

28.  Convulsions: excessive LA level in ! bld. If large dose of LA is required: R x 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). 28

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. 29

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. 30