Pharm U3 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 propagation
describe the typical structure of a local anesthetic
hydrophilic (tertiary amine) and hydrophobic (aromatic) domains separated by an intermediate ester or amide linkage
how are local anesthetics stored?
weak bases stored as salts to increase stability
how do local anesthetics exist in the body?
2 forms - uncharged base (lipophilic form) and charged cation (hydrophilic form)
how are the proportions of the two forms of local anesthetics governed?
by pKa and pH
at what pKa will the drug exist as ionized form and NOT be able to penetrate membranes and be slower for onset?
higher difference between pKa and pH of body fluid
potency
correlates lipid solubility
onset of action
depends on pKa and lipid solubility
duration of action
depends on protein binding
absorption depends on what?
site of injection, dose, drug intrinsic properties (protein binding - less absorption if highly protein bound), addition of epinephrine (vasoconstriction - less blood flow and uptake)
what is the two compartment model of distribution?
initial alpha phase of rapid distribution in blood and highly perfused organs with exponential decline - slow beta phase with distribution into less perfused organs with linear decline
metabolism and excretion based on what
differs between amides and esters
esters hydrolyzed by what?
hydrolyzed by an enzyme in plasma (pseudocholinesterase or butrylcholinesterase) cases rapid hydrolysis to water soluble metabolites therefore have very short half lives
amides transformed by what?
hepatic carboxyl esterases and CYP-450 enzymes (so liver disease such as cirrhosis slows metabolism and may lead to toxicity)
local anesthetic mechanism of action
bind reversibly to the intracellular portion of sodium channel and inactivate the channel = threshold for excitation increases, impulse conduction slows, the rate of rise of action potential amplitude decreases and then the ability to generate an action potential is completely abolished
what is the critical length to block the sodium current?
in myelinated nerves critical length is 2-3 nodes of Ranvier
when is the nerve fiber most easily blocked?
when sodium channel is in the activated state than resting or inactivated state
which nerves are blocked first
smaller, myelinated, active fibers blocked first
which factors determine toxicity
dose, rate of absorption, site injected, its vascularity, vasoconstrictors, biotransformation and elimination of the drug
CNS toxicity - high risk drugs - what makes them high risk?
bupivacaine and ropivacaine - high potency agents
CNS toxicity mechanism
anesthetics cause depression of cortical inhibitory pathways allowing unopposed excitatory neuronal pathways (seizure activity) which is followed by generalized CNS depression
early signs of CNS toxicity
numbness, dizziness, tinnitus, blurred vision, CNS excitation (restlessness, agitation, seizures)
later signs of CNS toxicity
CNS depression - respiratory arrest and unconsciousness
factors increasing potential for CNS toxicity
intrinsic: low protein binding (malnourished states, liver disease) and extrinsic: metabolic or respiratory acidosis
