Ph- Local Anesthesia Flashcards
What are the 3 chemical categories of local anesthetics?
What drugs belong to each category?
- Esters
- cocaine - Amides
- lidocaine
- mepivacaine
- bupivacaine
- prilocaine
- ropivacaine - Vasoconstrictors
- epinephrine
What is the goal of local anesthetics?
Are they reversible or irreversible?
What is the mechanism by which they operate?
Local anesthetics are used to REVERSIBLY suppress pain sensation by inhibiting nerve conduction in the vicinity of their application.
They act by inhibiting the activity of voltage-gated Na+ channels
Local anesthesia is defined as the loss of ____________ without the loss of _______________.
Loss of sensation in a body part without loss of consciousness or CNS control over vital functions
What is the common overall chemical structure that local anesthetics share?
- hydrophobic group [aromatic]
- ester or amide linkage
- hydrophilic, ionizable group [ 2 or 3 amino group]
With local anesthetics, what is the hydrophobicity proportional to?
Hydrophobicity is proportional to the potency and duration of action of the drug.
The more hydrophobic a drugs:
- more delivery and association to target sites/channel proteins [Faster acting]
- slower rate of metabolic processing by plasma enzymes or liver enzymes [longer acting]
What does the chemical linkage between the hydrophobic aromatic ring and the hydrophilic amino group of local anesthetics determine?
Duration of action:
- Esters = hydrolyzed by plasma esterases so they have a short duration of action
- Amides = survive the plasma and are degraded in the liver, so they have a longer t1/2
*if concerned of side effects due to circulatory distribution of local anesthetic, use an ester
What is the only local anesthetic agent with nerve impulse blockage AND vasoconstriction?
What are the side effects?
Cocaine
- catecholamine uptake block leads to:
1. toxic side effects
2. CNS mood altering properties
3. cardiovascular side effects
What is the most widely used local anesthetic?
Describe the speed, potency, and length of effect.
Lidocaine
- fast speed of action
- more potent than procaine
- longer-lasting than procaine [moderate duration]
What 2 amide local anesthetics are to be avoided in obstetrics?
- Mepivacaine- toxic to neonates
2. Prilocaine- causes methemoglobinemia which is enhanced in neonates
What amide local anesthetics has greater cardiac toxicity than lidocaine? If this is a concern, which drugs should be used instead?
bupivacaine
*if cardiotoxicity is a concern, use ropivacaine instead
How are local anesthetics delivered?
What influence does absorption and distribution through the circulatory system have?
They are delivered locally by direct injection or application at the desired site.
Absorption/distribution through the circulatory system is:
- NOT important for determining onset of anesthetic activity
- CRUCIAL for determining rate of recovery and potential toxicity
What 4 factors determine the systemic distribution of local anesthetics?
- dosage
- vascularity at the site of administration
- strength of binding to tissue
- presence of vasoconstricting substances
Epinephrine is less effective at increasing the duration of action of _________________, because __________________________.
Which amide drugs are least likely to need epinephrine?
vasoconstrictors are less effective at increasing the duration of action of more lipophilic and inherently longer acting substances because they interact more strongly with the tissue and are less susceptible to spread through local blood flow anyway
The long acting amides are bupivacaine and ropivacaine
Describe the 2 main actions of cocaine.
- anesthetic activity by blocking Na channels
2. vasoconstrictive activity by inhibiting catecholamine uptake and consequently potentiating a-adrenergic signaling
Local anesthetics have an ionizable 2 and 3 amino group that allows the local anesthetic to exist in one of two forms. What are they?
What is the pka of most local anesthetics?
What form is likely to predominate at physiological pH?
- neutral, deprotonated amine [weak base]
- protonated, charged cation [weak acid]
pka is 8-9
Since physiologic pH is near 7, most of the time the drug exists as a protonated cation
What is the rationale for the general amphiphilic chemical structure of local anesthetics?
- cationic form of the anesthetic is primarily responsible for blockade of Na channel
- to cross the hydrophobic plasma membrane to reach the site of action, they must be in neutral form
Charged amine group provides the electrostatic block of ion conduction through the voltage-gated Na channel, and the hydrophobic aromatic group facilitates partitioning into the hydrophobic plasma membrane of target tissue
Why are anesthetics less effective in inflamed areas ?
inflammation creates a more acidic so more local anesthetics are in the cationic, protonated state. This means less is able to cross the membrane, lowering their cellular concentration
How are local anesthetics eliminated from the body?
- Esters are rapidly broken down in the plasma by esterases w/ a half life of less than a minute. They are excreted renally.
- Amide-linked drugs travel through the circulation to the liver where they are modified by N-dealkylation and then hydrolyzed by liver microsomal enzymes
When Na channels are blocked, what are the 4 effects on the action potential?
- greater threshold for generation
- reduced rate of depolarization
- prolonged AP
- reduction in max depolarization
Describe the structure of the voltage-gated Na channel.
What is the target of local anesthetics?
3 subunits- A, B1, B2
A = 4 subunits each consisting of 6 membrane-spanning helices
4 domains form a ring at the cell membrane with a single aqueous pore where Na flows through the middle
Between the 5th and 6th transmembrane helix, there is a pore formed. TTX and STX block the outer pore region, anesthetics block the inner pore region
Most local anesthetics block the pore near the intracellular mouth at the sixth transmembrane helix of the fourth domain
What are the 3 main reasons natural toxins like tetrodotoxin, saxitoxin and dinoflagellates are not used in anesthesia despite their ability to block the external Na channel pore?
- not use-dependent [would block all nerves, not just those that are overfiring]
- binding is relatively non-reversible
- large-scale production is not possible
What does it mean that anesthetics are “use-dependent”?
Which drugs are less use dependent?
The degree of inhibition is directly related to the frequency of nerve stimulation
Cytoplasmic anesthetics are charged and bind open or inactive states.
Lipophilic drugs are less use-dependent because they bind to open, closed AND inactive