Title: Local Anesthetics
1Local 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.
4Chemistry 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 .
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8- Absorption esp systemic depends on
- 1- dosage,
- 2- site of inj, (VASCULARITY) IV gt tracheal gt
intercostals gt paracervical gt epidural gt brachial
plexus gt sciatic gt 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 gt 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 lt 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,
- then a slower phase to moderately perfused organs.
11Metabolism 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 (lt 1 min). - ! amide linkage is hydrolyzed by liver cyto P450
with diff rate (prilocaine (fastest) gt Lid gt
mepivacaine gt ropivacaine gt bupivacaine
(slowest). - All converted to water-soluble metabolites
excreted in urine.
12- Toxicity from amide-type LA occur in hepatic D.
Ex elimination
t1/2 of Lid from 1.6 hr in normal pat to gt 6 hr
in liver disease pat. - amide LA also affected by enz inhibitors.
- Reduced hepatic bld flow decrease their
elimination.
13MOA
- 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. -
14Structure- 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 gt
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 gt readily than in large fibers. - Pain sensation is blocked gt 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 gt 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.
18Properties of LAs
Drug Onset Duration Plasma t1/2 SE Notes
Coc- M M 1 hr CV CNS Rarely used, only as spray for URT
Pro- M Short lt 1hr CNS restlessness, shivering, anxiety CVS B.cardia decrease COP No longer used
19Lid Rapid M 2 hr As procaine but lt 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 Long 2 hr As Lid but gt CVS Widely used (long DOA). Ropivacine is similar, with less cardioTox.
Priloc- M M 2 hr No VD MetHgemia Widely used, not for obstetric (neonatal metHgemia.
20Classification Six Placement Sites
- Surface/topical anesthesia
- Local infiltration
- Peripheral nerve block
- Bier block (IV regional anesthesia)
- Epidural anesthesia
- Spinal anesthesia (subarachnoid)
21Epidural
Spinal
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23Clinical 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 lt 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).
25DOA
- 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.
28Toxicity
- 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. 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 gt 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 gt cardiotoxic than other
long-acting LA. - Ropivaciane CV CNS tox, but lt 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.