Local Anesthetics Overview Flashcards
What do local anesthetics produce?
a class of drugs that produce transient, reversible loss of sensory, motor, and autonomic function when exposed to neural tissue, specifically central and peripheral nerve pathways
LA uses: what type of block is produced?
central or peripheral nerves (for anesthesia and/or analgesia)
LA uses: what is the MOA of local anesthetic nerve blocks?
(regional anesthesia): target specific nerve regions of the body for reversible loss of sensation (spinal, epidural, caudal, major nerve blocks)
What are some alternative uses for LA?
- Topical application to skin/mucous membranes
- Infiltration into the tissue
- IV infusions (lidocaine) for cardiac dysrhythmias
What is the origin of local anesthetics?
Erythroxylon coca, leaves of the cocoa shrub
Who was the first to use a version of local anesthetics?
Native Peruvians would chew an alkali abstract of these leaves for its stimulant and euphoric effects
What is Erythroxylon coca an ancestor to?
modern day cocaine
What is the history of LA in 1860?
Albert Niemann, a chemist, the first to isolated cocaine
What is the history of LA in 1884?
Karl Koller introduced cocaine as an ophthalmologic anesthetic
What is true about early use of cocaine?
- Widely used despite strong addictive properties (1884)
- Only available local anesthetic for 30 years
What is the history of LA in 1905?
Albert Einhorn synthesized procaine, an ester, which replaced cocaine as the only available local anesthetic for the next 50 years
What is the history of LA in 1943?
Nils Lofgren synthesized lidocaine, an amide, considered to be the standard to which all other local anesthetics are compared
Define epineurium.
the external connective-tissue sheath of a nerve trunk
Define perineurium,
the sheath of connective tissue surrounding a bundle (fascicle) of nerve fibers within a nerve.
Define endoneurium.
the delicate connective tissue network holding together the individual fibers of a nerve trunk.
What are the major type of nerve fibers layers?
epineurium, perineurium and endoneurium
What is unique about nerve tissues?
that it possesses membrane bound, voltage gated sodium and potassium channels
What do nerve tissues produce?
membrane depolarization following chemical, mechanical, or electrical stimuli
What do neurons maintain?
a resting membrane potential by active transport and passive diffusion of ions, particularly Na+ and K+
What is the Na/K pump?
pump (via active transport) modulates the transport of 3 Na+ ions that move extracellularly for every 2 K+ ions that move intracellularly
What does the cell membrane create?
creates a concentration gradient that preferentially favors the extracellular diffusion of K+ and the intracellular diffusion of Na+
What controls ion influx and efflux?
Membrane bound voltage gates
What is true about the membrane bound voltage gates?
assume a conformational change, allowing sodium and potassium to move across a cell membrane
What does the cell membrane consist of?
of a lipid bilayer, lipophilic, hydrophobic
What is the cell membrane impermeable to?
to charged ions, only uncharged forms can get through
What is the alpha subunit?
Nerve cell membrane contains special Na+ channels with a large conducting pore known
What is the site that local anesthetics target? (2)
- The alpha subunit is the site of ion conduction and is the binding site of local anesthetics
- There are also smaller adjacent beta subunits
What are the three functional states of sodium channel?
- Activated-open
- Resting-closed
- Inactivated-closed
What type of sodium channels to LA preferentially bind to?
activated-open or inactivated-closed states, but not to the resting-closed state
What do LA do at the sodium channel?
local anesthetics prevent the channel from opening and prevent action potential propagation
What is true about all LAs but benzocaine?
are tertiary amines and when injected will exist in BOTH unionized (lipid soluble) and ionized (water soluble) forms according to their particular pKa value
What is the diffusion of the LA look like?
The uncharged, lipid-soluble (unionized portion) of the local anesthetic must first diffuse through the neuron cell membrane and then gain access to the interior of the neuron sodium channel and bind to their receptor inside the sodium channel
What happens once the LA is inside the neuron?
a new equilibrium forms between ionized & unionized fractions and the ionized fraction binds to the receptor on the inside of the sodium channel
What is the MOA of LA?
block action potential generation within nerves by binding to and inactivating the sodium channels within nerve tissue
LA: Bind to sodium channels to receptors ________ the channel
within
What does LA binding prevent?
influx of Na+ & slows rate of depolarization of nerve action potential so that threshold potential is not reached
LA: Does NOT _________
alter membrane resting potential
What produces the myelin sheath?
produced by the Schwann cell
What is the myelin sheath?
wraps around each axon
Lipid-rich substance that insulates nerves- ⬆️ nerve conduction
Where do myelinated nerves extend?
discontinuously from the roots of the spinal cord to near the entry of the target organ
What are the nodes of raniver?
”myelin sheath gaps” that facilitate rapid conduction of nerve impulses (saltatory conduction)
What moves freely at the nodes?
drugs and ions pass freely
What is the typical molecular structure of LA?
Aromatic ring> hydropcarbon bond (Ester or amide) and tertiary amine.
What is the lipophilic part of the LA molecular part?
Aromatic Ring: Enhances diffusion across membrane
What classifies the LA?
Hydrocarbon bond (Ester or amide)
What is Hydrophillic part o the LA?
On/off switch: whether molecule exists as a quaternary water soluble form or tertiary lipid soluble form (pKa/pH)
What is the onset of LA related to?
pKa (pKa = speed of onset)
What is true about LA near physiologic pH?
have the most rapid onset of action
What is potency related to?
Lipid solubility
What effects the duration of action? (3)
- Protein binding
- Lipid solubility
- Vasodilation
What is true about the pH of LA?
weak BASES (so are opioids) with pKa values somewhat above physiologic pH
What is true about pKa of LA?
Exist in ionized (charged) and unionized (uncharged) fractions
What is the henderson-hasselbalch equation?
The percentage of ionized to unionized form is dependent on pKa
What is true when the pKa and pH are equal?
When the pKa of a drug = pH, 50:50 ionized to unionized
Which forms crosses the lipid bilayer?
UNIONIZED
What form binds to the Na+ channels?
IONIZED
What happens to a weak base (BH+ = B = H+) in an acidic environment?
shift to left to more ionized form
What happens to a weak base (BH+ = B = H+) in an basic environment?
shift to right to more Unionized form (what crosses cell membrane)
_______ added to some to speed onset of weak bases
Bicarb
What happens to a weak Acid (AH = A- + H+) in an basic environment?
shift to right to more ionized form
What happens to a weak Acid (AH = A- + H+) in an acid environment?
shift to left to more unionized form
What happens to Lidocaine when injected into physiological pH?
pKa = 7.74, when injected into plasma where physiologic pH = 7.4
65% ionized/35% remains unionized
What happens to tetracaine when injected into physiological pH?
pKa = 8.6, when injected into plasma where physiologic pH = 7.4
95% ionized/5% remains unionized
What is true about pKa of chloroprocaine?
has high pKa but also rapid onset of action d/t high concentration used in clinical practice
Review slide LA pKa.
Slide 25-26
What happens to an LA injected into an infected acidic environment?
more ionized- does not work as well
Know chart of differential blockade.
Slide 28
What does differential blockade result from?
Size of nerve fiber, myelination and location within nerve bundle
What is myelination?
(presence & amount)
Must cover several nodes of Ranvier to block conduction
What is the onset of blockade progression?
Autonomic→ superficial pain→ touch→ temperature→ motor function→ proprioception
What are additional sites of actions for LA?
- LA also block voltage-dependent K+ ion channels
- Calcium ion currents (L-type) may also be blocked by local anesthetics
- may also act on G-protein-coupled receptors (modulate intracellular Ca++)
What are the components of LA blockade of voltage-dependent K+ ion channels?
- Low affinity for the K+ channels
- Blockade may explain the broadening of the action potential in the presence of local anesthetics
What are the components of calcium ion currents (L-type) may also be blocked by local anesthetics?
Structural similarity between voltage-dependent calcium ion channels and Na+ ion channels
What is minimum effective concentration of LA?
necessary to produce conduction blockade of nerve impulses
What is minimum effective concentration analogous with?
the minimum alveolar concentration (MAC) for inhaled anesthetics: guide use and dosing
What influences minimum effective concentration?
Nerve fiber diameter
What effect do large nerve fibers have on minimum effective concentration?
Larger nerve fibers require higher concentrations of local anesthetics for production of conduction blockade
What decreases minimum effective concentration?
Increased tissue pH or high frequency nerve stimulation
What is true about each locals anesthetics minimum effective concentration?
- Each local anesthetic has a unique Cm
- Reflects differing potencies of each drug
What is the minimum effective concentration of motor fibers?
approximately twice that of sensory fibers
What is true about sensory anesthesia?
may not always accompany skeletal muscle paralysis
What is true about the total dose for an subarachoid versus epidural anesthesia?
Less local anesthetic is needed for subarachnoid anesthesia than for epidural anesthesia
What is true about why less local anesthetic needed in the subarachnoid?
Reflects greater access of local anesthetics to unprotected nerves in the subarachnoid space
What is tissue blood flow properties of LA?
vasodilators to varying degrees (except cocaine & ropivacaine)
What is the topical MOA of cocaine?
its vasoconstrictive properties as it prevents NE reuptake
What is the difference between lidocaine and mepivacaine?
Lidocaine has enhanced vasodilator activity when compared to mepivacaine – results in greater systemic absorption and shorter duration of action of lidocaine
What the impact of increased blood flow on absorption and duration?
⬆️ flow to site = ⬆️ absorption (also ⬆️ risk of toxicity)= ⬇️ duration
What are the order of highest peak plasma concentration?
The highest peak plasma concentration of local anesthetic occurs when injected into:
Intercostal>caudal>epidural>brachial plexus>sciatic femoral
What determines the ultimate plasma concentration of LA?
determined by the rate of tissue distribution and the rate of clearance of the drug
What influences absorption of LA from site of injection to systemic circulation? (4)
- Site of injection
- Dosage
- Use of epinephrine
- Pharmacologic characteristics of the drug
What effect does lipid solubility have on the LA?
Important in redistribution of LA to highly perfused tissues (brain, heart, kidneys) and is primary determinant of local anesthetic potency
What does increased lipid solubility correlate with?
with increased protein binding, increased potency, longer duration of action, and higher tendency for severe cardiac toxicity and lower concentration of these drugs are required for the production of blockade than if nonlipid soluble LAs are used
What influences distribution and excretion?
Protein binding of local anesthetics
What does lipid solubility parallel?
of the local anesthetic and is inversely related the plasma concentration of the drug
How is LA eliminated from the plasma?
by metabolism & excretion
What are other factors influencing LA absorption and plasma concentration?
patient factors: age, cardiovascular status, hepatic function
What determines duration of action of LA? (2)
determined by protein binding and lipid solubility
What prolongs the conduction blockade?
High affinity for protein & lipids
What do LAs primarily bind to?
α-1 acid glycoprotein
What impact do the lungs have on LA?
Lungs are capable of extracting local anesthetics such as lidocaine, bupivacaine, and prilocaine from the circulation
What is the first pass pulmonary extraction of Bupivacaine?
dose dependent
What impact does propranolol have on bupivacine?
Propranolol impairs bupivacaine extraction by the lungs (common receptor site)
What impact does propranolol have on clearance on lidocaine and bupivacaine?
Propranolol decreases plasma clearance of lidocaine and bupivacaine, reflecting propranolol-induced decreases in hepatic blood flow or inhibition of hepatic metabolism
What can occur in pregnant women with LAs?
There may be clinically significant transplacental transfer of local anesthetic between mother and fetus
What influences the degree and rate of diffusion of LAs across the placenta?
=Plasma protein binding influences the rate and degree of diffusion of local anesthetic across the placenta
Prilocaine > Lidocaine > Bupivacaine
How can ion trapping occur in the fetus? Which medication is this most associated with?
Acidosis in the fetus (occurring with prolonged labor) can result in accumulation of local anesthetic molecules in the fetus (ion trapping)- major concern with bupivacaine for its ⬆️ cardiotoxic effects
What is the properties of LAs?
LAs are basic drugs with both water soluble & lipid soluble properties
Factors that raise pH of their environment ______ their lipid solubility
increase (base + base = unionized)
Factors that lower pH of their environment ________ their water solubility
increase (base + acid = ionized)
What is ion trapping?
Changes to pH which result in altered proportions of lipid & water soluble fractions of the LA drug
What limits an LAs renal excretions?
Poor water solubility of local anesthetics limits its renal excretion of unchanged drug to less than 5%
What is the exception to the poor excretion by LAs?
Exception is cocaine, of which (10-12% of unchanged drug in urine)
What is the clearance and elimination related to for amide LA?
Clearance values and elimination half-times for amide LA represent mainly hepatic metabolism
What is the clearance and elimination related to for ester LA?
Ester LA shortened elimination ½-time due to rapid hydrolysis in plasma & liver
What do metabolism of ester LA produce?
produce water soluble metabolites as para-aminobenzoic acid (PABA)- more readily excreted in the urine
What are the ester LA?
Procaine
Chloroprocaine
Tetracaine
Cocaine
Benzocaine
What are the amides LA?
Lidocaine
Mepivacaine
Prilocaine
Bupivacaine
Ropivacaine
Articaine
Review differences of ester and amide.
What determines the choice of LA for peripheral nerve blockade?
determined by desired speed of onset, block intensity, and duration of anesthesia and analgesia
Review ester and amide characteristics.
Review ester and amide characteristics.
