1. Local Anesthetics LA

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 onset,
2- Long Duration of Action,
3- Reversible & selective blockade of sensory nerves without motor blockade,
4- Minimal local tissue irritation & no systemic toxicities.

4. 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 .

8. • 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.

9. 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.

10. ! Amide LAs are widely distributed after IV bolus inj.
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.

11. 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.

12. Toxicity from amide-type LA occur in hepatic D
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.

13. 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.

14. Potency is +vely correlated with lipid solubility.
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.

15. 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).

16. 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.

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 SE Notes Drug Onset Duration Plasma t1/2 Coc- M 1 hr
CV & CNS
Rarely used, only as spray for URT
Pro-
Short
< 1hr
CNS: restlessness, shivering, anxiety
CVS: B.cardia & decrease COP
No longer used

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

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

21. Epidural
Spinal

23. 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.

24. 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).

25. 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.

26. 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.

27. 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. 

28. 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).

29. Convulsions: excessive LA level in. bld
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).

30. 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.

31. 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.