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).
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 onset, 2- Long Duration of Action, 3- Reversible & selective blockade of sensory nerves without motor blockade, 4- Minimal local tissue irritation & no systemic toxicities.
Chemistry of LA • 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 .
•Absorption 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 bld flow, 5- use of Vasoconstrictors (epinephrine/ phenylephrine) & 6- ! physiochemical property of ! drug. Absorption in highly vascular area is > poor perfused tissue.
Epinephrine/ VC: Slow ! removal & reduce systemic absorption of LA from inj site by decreasing bld flow & 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.
Distribution ! Amide LAs are widely distributed after IV bolus inj. Initial rapid phase into highly perfused organs, then a slower phase to moderately perfused organs.
Metabolism & Excretion • Acidification of urine: ionization & excretion of LA • Ester-type hydrolyzed rapidly in ! bld (by pseudo-choline-sterase) to inactive metabolite; short plasma t1/2 (< 1 min). • ! amide linkage is hydrolyzed by liver cyto P450 with diff rate (prilocaine (fastest) > Lid > mepivacaine > ropivacaine > bupivacaine (slowest). • All converted to water-soluble metabolites & excreted in urine.
Toxicity from amide-type LA occur in hepatic D. Ex: elimination t1/2 of Lid 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.
MOA • Block ! Initiation & propagation of AP by preventing voltage-gated Na+ channels. • Activity is PH-dependent, increased at alkaline PH. Its penetration to Na+ chs is very poor at acid PH. Inflamed tissues (acidic): resis to LA. • Elevated extracellular Ca2+ antagonizes ! action of LA by Ca2+ w increase! surface potential on ! membrane.
Structure- Activity Characteristics of LA: • Smaller & more lipophilic LA: ! Faster rate of interaction with Na+ chs. • Potency is +vely correlated with lipid solubility. Lid, procaine, & mepivacaine are > water-soluble than tetracaine, bupivacaine, & ropivacaine that are more potent & have longer DOA. • Long acting (bupivacaine ) also bind more extensively to plasma proteins & can be displaced by other drugs.
Other actions on nerves: 1- Loss of sensation from site of painful stimuli 2- Motor paralysis during surgery Disadvantages • In Spinal anesthesia, motor paralysis: impair respiratory activity & AN blockade: hypotension & urinary retention (catheterization).
1- Effect on fiber diameter: LA block conduction in small-diameter nerve fibers > readily than in large fibers. • Pain sensation is blocked > readily than other sensory modalities. • Motor axons (large diameter), are relatively resistance. • LAs block conduction in ! following order: small myelinated (nociceptive impulses), non- myelinated (C-fibers), large myelinated axons.
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.
Classification: Six Placement Sites • Surface/topical anesthesia • Local infiltration • Peripheral nerve block • Bier block (IV regional anesthesia) • Epidural anesthesia • Spinal anesthesia (subarachnoid)
Clinical pharm 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.
Local Infiltration: Extravascular placement of ! LA in ! region to be anesthetized • Peripheral Nerve Block: LA inj into tissues around individual nerves or nerve plexuses (e.g. brachial plexus).
DOA • Short: proc- & chloropro- caine • Intermediate: Lid, mepiva- & prilo- caine • Long-acting: tetra-, bupiva-, & ropiva- caine. • DOA can be prolonged by increasing ! Dose/ adding VC agent.
To increase onset of LA: + Na-bicarbonate to LA sol. • 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, pramoxine, dibucaine, benzocaine, & dyclonine.
OTHER USES: • LAs have membrane-stabilizing effects; Both IV Lid & po (mexiletine, tocainide) used to Tr pat with neuropathic pain syndrome: (uncontrolled, rapid, sensory fiber firing). • Systemic LA: as adjuncts to TCA (amitriptyline) & anticonvulsant (carbamazepine) combination. • Systemic toxicity: CNS & CV system.
Toxicity 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).
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).
C- CVS: direct effect on ! hrt & smooth muscle & indirect effect on ! ANS. • Depress strength of cardiac contraction, ECG changes & cause arteriolar dilatation;; hypotension. • Cocaine blocks Norepinephrine uptake: VC & HTN + cardiac arrhythmia & ischemia. • Bupivacaine is > cardiotoxic than other long-acting LA. • Ropivaciane: CV & CNS tox, but < than Bupivacaine.
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 e amides) Ester-type LAs are metabolized to P-ABA derivatives; allergic rxs.