Pharm: Local anesthetics Flashcards
Local anesthetic definition
An agent that reversibly prevents transmission of nerve impulse in the region to which it is applied, without affecting consciousness.
Accomplished by disruption of afferent nerve conduction by inhibition of nerve impulse generation in the neuron and its propogation
Structure of local anesthetics
- Hydrophilic and hydrophobic domains separated by an intermediate ester or amide linkage
Local anesthetics - acids or bases?
Weak bases d/t quaternary amine group
What 2 forms do LAs exist in in the body?
Uncharged base and charged cation
Cation is hydrophilic, uncharged form is lipophilic and can cross membranes
pKa
The pH at which 50% of the molecule is in ionized form and 50% is in non-ionized form
The higher the difference between pKa and pH of body fluid, the more drug will exist in ionized form and therefore unable to penetrate membranes n shit
What does potency of LA depend on
lipid solubility
What does onset of action depend on
pKa and lipid solubility
What does duration of action depend on
Protein binding
What does absorption depend on
- Site of injection (vascularity)
- Dose of LA
- Drug’s intrinsic properties (protein binding - more binding, less absorption)
- Addition of epinephrine (vasoconstriction –> less uptake)
Peak blood levels at various sites following injection
IV>tracheal>intercostal>caudal>lumbar epidural>brachial plexus>sciatic>SQ
Distribution
- Depends on organ uptake or vascularity of injection site
- Two-compartment model: initial alpha phase of rapid distribution in blood and highly perfused organs, exponential decline followed by slow beta phase reflecting distribution into less perfused organs (linear decline)
Metabolism and excretion
Differs between amides and esters
Esters: hydrolyzed by enzyme in plasma, pseudocholinesterase or butrylcholinesterase: rapid hydrolysis to water soluble metabolites –> short 1/2life
Amides: transformed by hepatic carboxyl esterases and CYP450 enzymes, metabolites dependent on renal clearance
Mechanism of LAs
- REVERSIBLY BIND to intracellular portion of sodium channel and inactivate it –> threshold for excitation increases, impulse conduction slows, rate of rise of AP amplitude decreases, ability to generate AP is diminished as more and more Na channels blocked
- if Na current blocked over critical length of nerve (2-3 nodes of Ranvier in myelinated nerve), propagation no longer possible
- Effects more marked in ACTIVATED state Na channels than resting state or inactivated state
- Recovery from drug block is 10-1000x slower in inhibited channels in ACTIVE state than inactivated
Differential block
The action of local anesthetic is not limited to only sensory nerves, but the nerve fibers differ in their susceptibility to local anesthetics
- Smaller and myelinated nerves get blocked earlier
- Active fibers blocker more than inactive
- Nerve fibers proximal to side of LA injection blocked earlier than distal fibers
What determines systemic toxicity?
- Dose of drug administered
- Rate of absorption of drug
- Site injected, its vascularity, use of vasoconstrictors
- Biotransformation and elimination of drug from circulation
What type of LA is safest w/ respect to systemic toxicity?
Short-acting esters d/t their clearance by pseudocholinesterase
How do LA cause CNS toxicity?
- They readily cross BBB creating dose dependent effects
- High risk for high potency agents like bupivacaine and ropivacaine
- They cause depression of cortical inhibitory pathways, allowing unopposed excitatory neuronal pathways (seizures) followed by generalized CNS depression
Early signs of CNS toxicity
Circumoral numbness, dizziness, tinnitus, blurred vision, restlessness/agitation/seizures followed by CNS depression (respiratory arrest, unconsciousness
Factors increasing potential for CNS toxicity
Intrinsic factors: low protein binding, decreased clearance such as liver failure or pseudocholinesterase deficiency
Extrinsic factors: Metabolic or respiratory acidosis
Wtf do we do if CNS tox occurs?!?!
It’s CRITICAL to prevent hypoxemia and acidosis b/c acidosis worsens the toxicity
We must intubate and mechanically ventilate
Cardiovascular toxicity
- Requires much higher doses than for CNS tox, correlates w/ potency
- Cardiac Na channel blockade is the cause –> results in depression of myocardial contractility and reduced refractory period
- All LA (except cocaine and ropivacaine at certain doses) are vasodilators –> cardiovascular collapse
Tx of cardiovascular tox
ACLS algorithm, rapid intralipid infusion
Cauda Equina Syndrome from LA
Reported w/ continuous spinal catheters infusing lidocaine in order to permit repetitive dosing to facilitate adequate anesthesia and maintenance of block for extended periods
Mechanism not related to Na channel blockade, but rather to myriad of deleterious effects including conduction failure, membrane damage, cytoskeletal disruption, accumulation of intracellular Ca, disruption of axonal transport and apoptosis
Transient Neurological Syndrome (TNS) from LA
Transient pain or dysesthesia linked to use of lidocaine for spinal anesthesia
Now a/w neurologic deficits like cauda equina syndrome, but pain can be quite severe
Not related to dose of lidocaine used
- Increased risk w/ certain positions during surgery such as lithotomy
- Increased risk with ambulatory anesthesia
- Also found w/ Procaine and Mepivacaine, but not Bupivacaine or Chlorprocaine
Allergic reaction to LA
- High incidence w/ esters d/t PABA metabolites, a known allergen
- Amides have no such metabolites. Methylparaben may be a preservative used in some amide preperations of amide LAs which metabolizes to PABA
- No cross rxn between the two groups
- THEREFORE preservative free amides should be used in patients w/ known hypersensitivity to esters
