4 Local Anesthetics Flashcards
Choice of local anesthetic is based on …
Duration of action
Topical LAs are used to anesthetize…
Skin, eye, throat, mucus membranes
Injection of LA into CSF in lumbar region
Spinal anesthesia
Blocks sympathetic fibers in the subarachnoid space
Injection into the epidural space
Epidural anesthesia
Injection into tissue
Infiltration anesthesia
Advantage of infiltration anesthesia
Anesthesia w/o disrupting normal body function
Disadvantage of infiltration anesthesia
Requires large amounts of drug
Intravenous region anesthesia is also known as…
Bier’s block
Local anesthetics are classified as either…
“Esters” or “amides”
A lipophilic group connected to a hydrophilic group by either an ester or amide bond
The both have different physiological properties
Esters have ______ duration of action and _______ systemic toxicity
Shorter
Increased
Differences in ______ can also affect potency and clinical properties
Stereochemistry
Local anesthetics are typically administered as _____ to increase stability and solubility
Salts
How are local anesthetics transported across the cell membranes
They are weak bases (pKa = 7.5-9) and at physiologic pH they are predominantly IONIZED (LAH+)
Binding site is on inner membrane
Need to be in NON-IONIZED (LA+ H+) form to cross membrane
Once inside, become IONIZED to bind to Na+ channel
Neutral LA can also pass through the membrane via the HYDROPHOBIC PATHWAY
In general, the closer a LA’s pKa is to physiological pH…
The higher the concentration of the drug in the non-ionized form
Membrane transport increases, thus a faster onset of action
Ex: Lidocaine (pKa 7.8) has faster onset than bupivacaine (pKa 8.1)
What is the exception to the rule about pKa and membrane transport?
BENZOCAINE has a pKa of 3.5
It is ALWAYS in the non-ionized form
It’s used for TOPICAL application ONLY
_________ decreases membrane transport of LAs due to increased acidification
Inflammation (infection)
________ makes the pH more basic and may increase non-ionized drug concentrations and thus, the degree of LA transport
Bicarbonate
What is the MOA for local anesthetics?
Block Na+ channels and inhibit neuronal firing**
Complete block results from the drug binding to more and more Na+ channels - increases the threshold for excitation and impulse conduction slows
As more channels are blocked the rate of the action potential declines and complete block is achieved
Extent of neuronal block is ______ and ______ dependent
Voltage (potential) and time (firing)
Local anesthetics have high affinity for channels in ________ and ________ states and low affinity for channels in ________ state
High affinity = activated (open) and inactivated states
Low affinity = resting (closed) state
Basically, the block is more effective in rapidly firing axons than in resting axons
____________ LAs have a faster rate of integration with the Na+ channels
Smaller and more lipophilic
Long-acting LAs also bind more extensively to _______
Proteins
___________ increases the membrane potential (hyperpolarizes), so more channels are in the resting state and the block is diminished
Elevated Ca2+
________ depolarizers the membrane, so more channels are in the inactivated state and the block is enhanced
Elevated K+
LAs may target a variety of other proteins (potentially affecting their MOA)
Ion channels (K+ and Ca2+)
Enzymes (adenylate cyclase)
Receptors (NMDA, 5HT3, neurokinin-1)
Potency of an LA is correlated to _______ and ________, and is measured relative to ________.
Lipid solubility and duration of action
Procaine
Increased lipid solubility results in …
Increased time at site of action, and hence, increased duration of action
Cocaine and Mepivacaine are _____ as potent as Procaine
2x (medium duration of action)
Lidocaine is ______ as potent as Procaine
4x (Medium duration of action)
Tetracaine, Bupivacaine, and Ropivacaine are ____ as potent as Procaine
16x (long duration of action)
What are the important pharmacokinetic points for LAs?
They exert their effect at the site of application
Pharmacokinetics is important for elimination and potential adverse effects (CNS, cardiac)
Rapidly diffuse away from the site of application
Duration of action is dependent on time at site of action
Toxic effects (CNS, cardiac) are dependent on half-life
Systemic absorption of LAs is affected by…
Dosage Site of injection (vascular area vs fat) Drug-tissue binding Chemical properties of the drug Local blood flow Vasoconstriction agents (ie Epinephrine)
Why is epi frequently coadministered with local anesthetics?
Decreases diffusion of drug
Prolongs duration of action
Decreases systemic absorption
Decreases risk of systemic toxicity
How are amides metabolized?
In the liver by the CYP450s
Toxicity is more likely in patients with HEPATIC DISEASE or reduced hepatic blood flow
How are esters metabolized?
Rapidly metabolized by butyrylcholinesterases in the plasma
Mutations can affect metabolism of ester LAs
How are LAs excreted?
Metabolites excreted through the renal system
In a differential block, the block is …
Not limited to intended site
It blocks noxious stimuli but also blocks motor nerves
May lead to motor paralysis, respiratory impairment, and hypotension
Different degrees of sensory and motor nerve block (ie bupivacaine vs etidocaine)
How does anatomic arrangement affect anesthetic action?
Effect hits proximal fibers and proceeds to more distal fibers within a nerve bundle
How does the intrinsic susceptibility of nerve fibers to blocks affect anesthetic action?
Diameter, degree of myelination and conduction velocity
Smaller diameter fibers are more sensitive than large
Myelinated fibers are less sensitive than unmyelinated of same diameter
The faster the conduction velocity, the less sensitive the fiber
CV side effects of LAs
(Due to inhibition of Na+ and Ca2+ channels)
Arrhythmias, vasodilation, hypotension
BUPIVACAINE - increased binding to cardiac Na+ channels —> slower dissociative times
COCAINE - increased sympathetic tone
What may decrease the cardiac toxicity of LAs?
IV lipid administration (“lipid sink”)
CNS side effects of LAs
Depression of cortical inhibitory pathways
Sedation, visual/auditory disturbances, circumoral numbness, nystagmus, muscle twitching, convulsions, death
Are allergic reactions to LAs a thing?
They are RARE with AMIDES
p-aminobenzoic acid (PABA) is a metabolite of ESTERS that may cause hypersensitivity
Possible blood related side effects of LAs
Prilocaine metabolite may produce methemoglobinemia
What are the possible PNS side effects of LAs?
Prolonged sensory and motor deficit following high doses
What are some localized toxicities that can result from LA administration?
Neural injury - neurotoxic effects produced by high concentrations or if inadvertently injected intrathecally
Transient neurological symptoms (TNS) - transient pain, dysethesia linked to use of lidocaine for spinal anesthesia
If someone develops a hypersensitivity reaction to an LA, it is likely…
An ester, not an amide
If a patient develops methemoglobinemia following LA administration, it was likely…
Prilocaine
If a patient develops transient neurological symptoms (transient pain, dysesthesia) following LA administration, it was likely…
Lidocaine used for spinal anesthesia
What was the first synthetic local anesthetic to be developed?
Procaine (Novocain)
It’s an ester-type drug, developed in late 1800s
Short duration of action
Metabolic product is para-aminobenzoic acid (PABA) which can cause allergic reactions and inhibit sulfonamide action
How is procaine (Novocain) used today?
For infiltration anesthesia and diagnostic nerve blocks (ie in colonoscopy)
Lacks topical activity, but has minimal systemic toxicity and no local irritation
Ester-type drug with slow onset but long duration of action, that is approx. 16x more potent and more toxic than procaine
Tetracaine (Pontocaine)
Severe toxicity with high volume peripheral blocks
How is tetracaine (pontocaine) used?
Preferred for ophthalmological use (retrobulbar)
Spinal anesthesia - combined with 10% dextrose to increase the specific gravity (solution is more dense than CSF - hyperbaric)
Ester-type drug that is very lipophilic and always in non-ionized form at physiologic pH
Benzocaine (Americaine)
Used topically only to treat sunburn, minor burns, and pruritis in OTC preps
Why is benzocaine only used topically?
B/c it’s readily transported through membrane due to low pKa
What is the FDA safety warning for benzocaine?
Risk of methemoglobinemia with prolonged use
Cocaine is an ________ drug used for _______
Ester-type
Topical anesthesia of mucous membranes typically around the upper respiratory tract
Can also reduce bleeding in dental procedures
MOA for cocaine
Inhibits Na+ channels secondary to its effect on increasing the DA in the CNS and periphery
Adverse effects of cocaine as an LA
CNS and CV side effects
Use with caution in addicts or with other drugs that increase catecholamines
What is the prototype amide drug?
Lidocaine
Lidocaine is ______ absorbed and has a _______ duration of action
Rapidly absorbed (rapid onset)
Intermediate duration
Has greater potency and longer duration of action than procaine
What are the uses for Lidocaine?
Moderate topical activity and minimal local irritation
Wide range of applications
Preferred for infiltration blocks and epidural anesthesia
NOT preferred for spinal blocks b/c of risk of TNS
Can also be used as an antiarrhythmic agent
Amide-type LA with intermediate duration and highest rate of clearance of the amides
Prilocaine (Citanest)
Most important side effect of Prilocaine?
Methemoglobinemia - due to metabolites
Excessive methemoglobin in the blood (chocolate color) —> SOB, fatigue, dizziness, dysrhythmias, seizures, coma death
Do not use in patients with methemoglobinemia
A patient comes to the ED with SOB, fatigue, and dizziness. Their EKG shows some minor dysrhythmias. You’re awesome at history taking and discover they had a dental procedure done earlier today. What’s going on and how will you treat it?
They have methemoglobinemia from prilocaine
Give em methlylene blue to reverse it
Prilocaine use is largely limited to…
Dentistry
Amide-type drug with long duration of action used primarily for post-op pain control
Bupivacaine (Marcaine)
How is Bupivacaine used?
Post-op pain control
Spinal anesthesia, infiltration blocks and epidural anesthesia
Preferred as epidural during labor and childbirth
What is the preferred LA for epidurals during childbirth and why?
Bupivacaine
B/c more potent sensory block than motor block (so it reduces pain w/o paralysis so you can push that baby out)
Bupivacaine has greater _______ than other amides
Cardiotoxicity
Higher degree of lipophilic its, so it diffuses away from cardiac channels more slowly
S-enantiomer of bupivacaine that’s also a long-acting amide
Ropivacaine
Less lipid soluble and cleared more rapidly than bupivacaine, so less likely to produce adverse events and less cardiotoxic
BUT it’s metabolized by CYP3A4, so possible drug interactions
How is Ropivacaine used?
For peripheral and epidural blocks (but bupivacaine still preferred for L&D b/c of the differential block)
Vaso-constricting effects at clinical doses (so don’t have to add epi)
Which LA is the only one that doesn’t need to be coadministered with epi?
Ropivacaine, b/c it’s the only vasoconstrictor
Amide-type drug similar to bupivacaine but with intermediate duration of action
Mepivacaine (Carbocaine)
Preferred for peripheral nerve blocks but not used topically or in L&D
Amide-type drug with long duration but INVERSE differential block
Etidocaine (Duranest)
May cause motor block before or without sensory block
So it paralyzes you but you still feel pain 😳🗡😳🗡😳
Amide-type LA that also has an additional ester group which subjects it to metabolism by plasma esterases
Articaine (Septocaine)
Because of the metabolism, it has a decreased half-life and decreased potential for systemic toxicity
How is articaine used?
Widespread use in dental medicine due to its large therapeutic window and low potential for systemic toxicity
Allows for the injection of more drug later into the procedure
Adverse effects of articaine
Rare, but may include the development of persistent paresthesias (3x more likely with articaine than other LAs)
Amide-type drug used as a spinal anesthetic outside the US but topical only in US
Dibucaine (Nupercainal)
Why do we even bother learning about dibucaine (nupercainal)?
Dibucaine number test, used as a measure of butyrylcholinesterase activity (to see if a patient can metabolize ester anesthetics due to mutations or deficiencies)
Number 80 or below is considered deficient
How are centrally acting muscle relaxants used?
For the relief of spastic muscle disorders, including the abnormal function of bowel and bladder
An increase in tonic stretch reflexes and flexor muscle spasms, together with muscle weakness
Spasticity
Associated with cerebral palsy, MS, and stroke
Difficult to treat without worsening muscle weakness
What are the centrally acting spasmolytic agents?
Baclofen
Cyclobenzaprine
Diazepam
Tizanidine
What are the direct acting spasmolytic agents?
Dantrolene
Botulinum Toxin (BoTox)
What are the target proteins for spasmolytic agents?
GABA-a
GABA-b
Alpha-2
Ca2+ channels
How does Diazepam (Valium) work as a spasmolytic?
Acts on the GABA-a receptor to facilitate GABA-mediated presynaptic inhibition in the spinal cord
Different alpha subtypes of the GABA receptor mediate different responses. Diazepam affects all the subtypes, so a dose sufficient to act as muscle relaxant produces heavy sedation
How is Diazepam (Valium) used?
For local muscle trauma and as an adjunct in chronic spasticity
BUT a dose sufficient to act as muscle relaxant produces heavy sedation.
Why is Diazepam (Valium) may not the greatest for muscle relaxation?
Affects all subtypes of GABA, so a dose sufficient to act as muscle relaxant also produces heavy sedation
What is the MOA for Baclofen (Lioresal)?
Agonist at GABA-b receptors
Stimulation opens K+ channels —> hyperpolarization and presynaptic inhibition of Ca2+ influx
Inhibits AC and cAMP formation and decreases release of excitatory transmitters in brain/spinal cord
How is baclofen (Lioresal) administered?
Orally
T1/2 = 3-4 hours
Side effects of Baclofen (Lioresal)?
Drowsiness
Weakness
Increased seizure activity
Respiratory depression may occur with intrathecal administration
MOA for Tizanidine (Zanaflex)
Alpha-2 receptor agonist
Produces both pre- and post-synaptic inhibition of spinal cord synaptic activity to decrease muscle spasticity
Inhibits pain transmission in dorsal horn while limiting muscle weakness
How is Tizanidine (Zanaflex) used?
Chronic and acute muscle spasms
Inhibits pain transmission in dorsal horn with limited muscle weakness
Side effects of Tizanidine (Zanaflex)
Sedation
Some hypotension
Dry mouth
Weakness
Falls in elderly
Hepatotoxicity
MOA for Dantrolene (Dantrium)
Inhibits Ca2+ release from the SR by blocking the ryanodine receptor 1 (RyR1) channel
Interferes with excitation-contraction coupling of actin and myosin in skeletal muscle fibers
Minimal effects on cardiac or smooth muscle b/c Ca2+ release is mediated by different receptor (RyR2)
How is Dantrolene (Dantrium) used?
To treat neuroleptic malignant syndrome and malignant hyperthermia
MOA for Botulinum Toxin (BoTox)
Inhibits ACh release from nerve at neuromuscular junction
Small amounts injected locally to control muscle spasms following stroke or neurological injury
Effects persist for weeks to months
Large amount scan be very toxic - spread of toxin to unwanted areas may be problematic
