Local Anesthetics Flashcards
What is the definition of a local anesthetic?
Local inhibitors of PNS without loss of consciousness or vital functions, inhibiting sensory transmission to brain and/or motor impulse transmission to muscles
Are local anesthetics analgesics?
No, they are not specific inhibitors of the pain pathway (i.e. opioid analgesics). They just nonspecifically inhibit the conduction of aciton potentials
What are the three components of the structure of a local anesthetic?
- Aromatic ring
- Intermediate linkage (ester or amide)
- Terminal amine (can gain proton and become stuck in a compartment)
What form of the local anesthetic (LA) is active and how does it work? That is, what is the mechanism of action?
Only the protonated form -> binds to the LA binding site on the OPEN sodium channel and stabilizes the inactive state of the channel
Extends refractory period by delaying return to closed / resting conformation (occurs in a progression from increased threshold to total action potential abolishment)
What is meant by critical length?
If sodium current is blocked over a “critical length” of the nerve, action potential propagation will no longer be possible, you will have effective anesthesia
What lipid solubility profile for a LA is most clinically effective and why?
Moderate hydrophobicity
Too low - hydrophilic molecules cannot cross to interior of membrane
Too high - hydrophobic molecules will get stuck in the membrane and not want to enter the cellular cytoplasm
What does the pKa of the given local anesthetic determine? What is their relative pKa range
The time of onset. All are basic overall, with pkas between 8-9
Low pKa = LA is relatively acidic, will exist in deprotonated and uncharged form -> rapid crossing of membrane and rapid onset
High pKa = LA is relatively basic, will exist in protonated form which is charged -> slow crossing of membrane and slower onset
What is the general structure of the voltage-gated sodium channel?
Has four transmembrane domains, with an intracellular site for binding local anesthetic
What is the primary factor which determines duration of action of local anesthetics?
Protein binding -> how well they bind the receptor
Since receptor binding site is hydrophobic, more lipophilic = higher binding = increased duration of action
What are the characteristics of a very rapid-onset, long-lasting LA?
Moderately lipophilic, low pKa
How are LAs typically prepared, and what should be done when administering them clinically?
Typically prepared as a low pH salt, which increases their solubility / stability by keeping them charged.
Add sodium bicarbonate with injection -> makes the pH more basic, deprotonating the LA and giving it a quick onset of action
When are topical local anesthetics used and are they safe?
Typically for short-term pain relief of mucous membranes
Can be unsafe and cause irregular heartbeats, respiratory depression, and death with prolonged and toxic effects (absorbed into circulation through skin)
What is infiltration vs regional anesthesia and which one is most commonly done?
Infiltration - Injection of LA without considering course of nerve, for minor, superficial surgery
Regional anesthesia - injection of LA around specific nerves that provide sensation to area of body being operated
What are three examples of regional anesthesia procedures?
- Spinal anesthesia - injection into lumbar cistern for lower abdominal, pelvic, rectal, or orthopedic surgery
- Epidural anesthesia - Injection into epidural space -> for childbirth / labor
- Nerve block - injection around nerve truck for site distal to surgery -> i.e. brachial plexus for hand surgery
What are some uses of nerve blocks?
- Therapeutic - treat pain
- Diagnostic - to determine source of pain
- Prognostic - to see if blocking the nerve surgically would provide pain relief
- Pre-emptive - to prevent pain from a procedure
What is a Bier’s block and it’s limitation?
Intravenous regional anesthesia
IV injection of a LA in patient wearing a tourniquet to prevent blood flow. Easy to do. Can be done for any surgical procedure on an extremity
Limitation = discomfort from wearing tourniquet
What are the types of A and C fibers and what information do they carry? How do they relate with respect to diameter / myelination?
A = heavily myelinated, in order of descending diameter
A-alpha - unconscious proprioception, motor
A-beta - DC-ML = fine touch, pressure
A-gamma - intrafusal spindle information
A-delta - ALS - acute pain, temperature
C= unmyelinated, small diameter
C - ALS - slow, aching and burning
For a local anesthetic, is it easier to block a myelinated or unmyelinated nerve, and a small or large nerve?
Myelinated nerve -> only needs to block 3 consecutive nodes of Ranvier to block saltatory conduction
small diameter nerve -> electrical field travels farther on sections of larger nerve, and the nodes will be much farther apart (need a wider area of anesthetic to cover)
What properties of the nerve fiber with respect to firing rate and location in nerve bundle make it more susceptible to LA? What does this explain with respect to motor / sensory
Hiring firing rate = faster block (more sodium channels vulnerable)
More peripheral = faster block. Explains why motor fibers tend to be blocked before sensory fibers within a fascicle
What is often done to prevent toxicity of LA? When is this not indicated?
Reduce blood flow to the area of injection and reduction in systemic circulation by injection with epinephrine
Not indicated for areas with limited collateral circulation, like distal extremities and penis -> can cause gangrene and hypoxic tissue damage
How are ester LA’s metabolized?
Via pseudocholinesterase enzymes in the plasma, very rapidly, with metabolites excreted in urine
When will ester LA metabolism be slowed or inactive?
- Pseudocholinesterase deficiency
- Esters administered into CSF -> need vascular absorption before inactivation
- Pregnancy / parturition decreases activity -> longer recovery
How are amide LA’s metabolized
Via CYP450’s in liver
When should amide LA dosage be decreased?
Newborns -> immature hepatic enzymes, contraindicated
Elderly -> reduced hepatic blood flow
What are the toxic effects of LA in the CNS and what is done prophylactically?
CNS stimulation by depressing cortical inhibition pathways
-> dizziness, tremors, metallic taste, confusion, respiratory depression
Premedicate with benzodiazepines
What are the cardiovascular effects of LA’s?
By blocking SANS conduction, they result in decreased cardiac output and arteriolar vasodilation (except cocaine) -> hypotension
What class of LA’s is most likely to cause an allergic reaction and why?
Esters -> derivatives of p-aminobenzoic acid (PABA)
List the clinically important ester LA’s?
Drugs not containing “i” before the caine
- Cocaine
- Procaine
- Benzocaine
- Tetracaine
List the clinically important amide LA’s?
Drugs containg ‘i’ before the caine
- Lidocaine
- Bupivacaine
- Ropivacaine
What is the primary clinical use and adverse effects of cocaine?
Mucous membrane -> topical agent for numbing and vasoconstriction (sympathetomimetic effect). Can be used to decrease post-op bleeding
Adverse effects - hyper-sympathetic effects cardiac + addiction
What is the primary clinical use of procaine and its adverse effects?
Used IV for nerve block, infiltration, and dental procedures
Adverse effects - none - but short half-life and derivative of PABA can reduce effectiveness of sulfonamides
What is the primary clinical use of benzocaine and its adverse effects?
Only used TOPICALLY -> low pKa gives rapid onset. Used in creams / ointments
Adverse effects - methemoglobinemia possible
What is done to treat methemoglobinemia?
Give IV methylene blue
What is the primary clinical use of tetracaine and its primary adverse effect?
Used for high potency and long action in spinal anesthesia. Also for topical anesthesia of trachea, larynx, and esophagus
Adverse effect -> slowly metabolized, can cause systemic toxicity
What is the relative onset and clinical uses of lidocaine?
Rapid onset (low pKa)
Used topically, or for all clinical procedures.
Also used to treat ventricular arrythmias
Why would bupivacaine or ropivacaine be used over lidocaine?
Produce a much longer duration of action
What are the clinical uses of ropivacaine?
Long-term, potent blockade needed in epidural, infiltration, nerve block, and spinal
What extra activity does ropivacaine have that’s kinda juicy?
Vasoconstriction - does not need to be given with epinephrine
Do bupivacaine and ropivacaine preferentially block the motor system or sensory system? Why is this relevant?
Blocks the sensory system first - good for labor (epidural to facilitate birth of da bb)
Why is ropivacaine preferred over bupivacaine?
Bupivacaine is cardiotoxic
