Local Anesthetics Flashcards
Chemistry of Local Anesthetics
Most local anesthetics can be classified as either ester linked or amide linked; all local anesthetics share similar properties.
-All LAs have three structural domains: an AROMATIC GROUP, AND AMINE GROUP, AND AN ESTER OR AMIDE LINKAGE connecting these 2 groups.
-The structure of the aromatic group influences the hydrophobicity of the drug, the nature of the amine group influences the rate of onset and potency of the drug, and the structure of the amide or ester group influences the duration of action and side effects of the drug.
-The target site for these drugs is he cytoplasmic side of the voltage-gated sodium channel.
Molecules with low hydrophobicity (more water-loving) are largely restricted to the polar aqueous extracellular environment.
Molecules with increased hydrophobicity; permeability through the cell membrane also increases.
At a certain hydrophobicity, this relationship reverses; leads to decreased permeability-they partition into the membrane and remind there (essentially trapped).
LA binding site on the sodium channel
-Contains hydrophobic residues: more hydrophobis drugs bind more tightly to the target, which increases the potency of the drug.
-Practical need for the drug to diffuse across several membranes to target; LAs with moderate hydrophobicity are the clinically most effective.
-Excessively hydrophobic drugs have limited solubility in the aqueous environment around a nerve.
-Molecules that do dissolve remain in the first membrane.
AMINE GROUP
-The amine group can exist in either 2 forms:
1. protonated (positive charge): conjugate acid
2. deprotonated (neutral) form: conjugate base.
LAs are weak bases: pKa range from 8-10.
At te physiologic pH of 7.4, both the protonated form and neutral form exist in solution.
As the drug pKa increases, there is a greater fraction of molecules in the protonated form.
-Neutral forms cross membranes more easily than positive forms; positive forms bind with higher affinity to the target binding site.
-The target site is located in the voltage-gated sodium channel, it is accessible from the intracellular entrance of the channel.
-Moderate hydrophobicity (weak base) of neutral form can cross the membrane, once the drug is inside the cell, it rapidly gains a proton and bind to the sodium channel.
-Major path by which protons reach the drug molecules: through the channels pore to the extracellular environment.
-As the extracellular pH becomes more acidic (lowers), there is a higher chance of that the drug will become protonated at the binding site.
Mechanism of action of LAs
Anatomic Considerations
-Peripheral nerve is composed of a collection of different types of nerve fibers surrounded by 3 connective membranes (sheaths); the epineurium, the perineurium, and the endoneurium (made up of connective tissue and cellular membranes).
-LA molecules must pass through all 3 of these sheaths before they can reach the neuronal membranes.
-THE MAJOR BARRIER TO LA PENETRATION INTO THE NERVE IS THE PERINEURIUM: an epithelium-like tissue that uncles axons into separate fascicles.
LAs EFFECT…
-Nocireceptors and afferent, efferent, somatic and autonomic nerves: all of these fibers may be contained in a peripheral nerve, conduction in all fibers may be blocked by LAs.
In more proximal regions of the body…
-Shoulder and thigh, innervated by axons traveling superficially in a peripheral nerve.
In more distal regions of the body…
-Hands and feet; innervated by axons traveling closer to the core of the nerve
THEREFORE, proximal areas are numbed BEFORE DISTAL AREAS.
-Different fibers within a peripheral nerve; also blocked at different times.
General order in which functional defecits occur due to differential blockade: first pain, second pain, temperature, touch, proprioception (pressure, position, stretch), and FINALLY skeletal muscle tone and voluntary tension.
The ability to block sensory impulses without motor effects varies.
Lidocaine
Difficult to block Adelta-fibers without also blocking Agamma-motor fibers.
AMIDE LINKED LA
MOST COMMONLY USED LA.
Moderate hydrophobicity: enhanced hydrophobity relative to procaine; this slows its rate of hydrolysis.
Relatively low pKa: a large fraction is in neutral form at physiologic pH: results in RAPID DIFFUSION OF DRUG THROUGH MEMBRANES.
Lidocaine’s duration of action is based on two factors:
1. its moderate hydrophobicity keeps the drug near the area of entry.
2. its amide linkage prevents drug degradation by esterases.
-Vasoconstrictive effects of co-administered epinephrine; extends lidocaine duration of action significantly.
Uses: infiltration, peripheral nerve block, epidural, spinal, and topical.
-Used as a class 1 anti arrhythmic by blocking sodium channels in cardiac myocytes.
Metabolism in the liver:
-N-dealkylated by p450 enzymes; subsequently undergoes hydrolysis and hydroxylation.
Metabolites of lidocaine only have weak anesthetic activity.
TOXIC EFFECTS ARE MAINLY IN THE CNS AND HEART!
-drowsiness, tinnitus (ringing in ears), twitching and seizures.
-CNS depression and cardiotoxicity occur at high plasma levels.
Mechanism: inhibit voltage-gated sodium channels in excitable cell membranes.
Clinical applications in infiltration anesthesia, peripheral nerve block, epidural, spinal, and topical anesthesia, class 1 anti arrhythmic (suppresses abnormal rhythms of the heart).
Side effects: CNS excitation
Contraindications: Hypersensitivty to amide linked LAs.
Lidocaine has a rapid onset of action, a medium duration of action (1-2 hours), and is moderately potent, due to its moderate hydrophobicity allowing channel binding.
Lidocaine may require concurrent administration of epinephrine to prolong its duration of action.
Infiltration anesthesia.
Commonly used topical LA.
Lidocaine is the most widely used injected anesthetic (used in dental practice); rapid rate of onset, long duration of action, extremely low incidence of allergic reaction.
Bupivacaine
AMIDE-LINKED LA
Long duration of action
Highly hydrophobic and highly potent.
Uses: spinal, epidural, and peripheral nerve block and in infiltration; used widely for labor and post-operative anesthesia (low concentrations, provides 2-3 hours of pain relief WITHOUT MOTOR BLOCKADE).
Metabolized in the liver: N-dealkylation by p450 enzymes.
-Toxicities: cardiotoxicity at higher concentrations (not used as commonly for labor and post-operative anesthesia); blocks cardiac myocyte sodium channels during systole, very slow to dissociate during diastole and can trigger arrhythmias.
-Racemic mixture of R-enantiomers and S-enantiomers
-S-enantiomer (levobupivacaine) is reported safer and less cardiotoxic than bupivacaine; similar in safety to the structurally homologous ropivacaine.
You CAN achieve sensory block without significant motor block.
Diluted epidural bupivacaine is frequently used during labor (epidurally); relieves pain while allowing ambulation; more effect on nociception than on locomotor activity.
Clinical applications in infiltration, regional, epidural, and spinal anesthesia, sympathetic nerve block.
Side effects: same as lidocaine (CNS excitation) and additionally, cardiotoxicity at higher concentrations.
Contraindications: local infection at the prepared site of spinal anesthesia, use in spinal anesthesia in the presence of septicemia, severe hemorrhage, shock, or arrhythmias such has complete heart block.
Bupivacaine is highly hydrophobic, high potency, long duration of action.
The cardiotoxicity at higher concentrations limits its use.
The R-enantiomer and S-enantiomer have different affinities for the sodium channel and therefore different cardiovascular effects; the S-enantiomer is levobupivacaine.
Infiltration anesthesia
Injected anesthetic used in dental practice.
More potent, longer-acting than lidocaine or mepivacaine.
Used for lengthy dental procedures and for postoperative pain.
Useful central nerve blockade as an epidural during labor.
At low concentrations, bupivacaine provides adequate pain relief WITHOUT significant motor block.
Cardiotoxicity reported at high concentrations; dilute solutions used in obstetrics are rarely toxic.
Ropivacaine and levobupivacaine may be safer.
Levobupivacaine
S-enantiomer of bupivacaine
It has the same clinical applications as bupivacaine infiltration, regional, epidural, and spinal anesthesia, sympathetic nerve block).
Side effects: compared to bupivacaine, levobupivacaine causes less vasodilation and has a longer duration of action.
Contraindications: same as bupivacaine (local infection at the prepared site of spinal anesthesia, use in spinal anesthesia in the presence of septicemia, severe hemorrhage, shock, or arrhythmias such has complete heart block).
Highly hydrophobic, high potency, long duration of action.
The cardiotoxicity at higher concentrations limits its use.
Compared to bupivacaine, levobupivacaine is less potent.
Voltage-gated sodium channel
-LA prevent impulse transmission by blocking individual sodium channels in neuronal membranes.
Three main conformational states:
Open, inactivated, resting.
-Going from the resting to the open state: the channel moves through several transient “closed” conformations.
-At the resting neuronal membrane potential of -60 to -70 mV, the channels are in equilibrium; majority are in the resting state and a minority are inactivated.
-During an action potential, resting channel move through the closed conformations and finally open briefly to allow sodium ions to enter the cell; sodium influx results in depolarization of the membrane.
-Just after the channels have opened, the channel changes to the inactivated state spontaneously, and this stops the influx of sodium and the membrane repolarizes; the inactivated state returns slowly to the resting state: THIS TIME NEEDED FOR TRANSITION THE INACTIVATED TO THE RESTING STATE=refractory period; no new AP can be generated during this period.
Modulated receptor hypothesis
The different comformational states of the sodium channel (resting, various closed, open, and inactivated) bind LAs with different affinities.
-LAs HAVE HIGHER AFFINITY FOR CLOSED, OPEN AND INACTIVATED THAN RESTING STATE.
Molecular mechanism of channel inhibition: physical occlusion of the pore; restriction of activation of the channel.
Dissociation rate of LA: various among the different LAs.
Slower than the normal recovery phase in the presence of LAs; LAs extend the refractory period by about 50-100 fold.
Tonic and phasic inhibition
The degree of inhibition of sodium current by LA depends on the frequency of impulses in the nerve.
When there is a long interval between action potentials and, the level of inhibition of each impulse is the same, and the inhibition is said to be TONIC.
When the interval between action potentials is short, the level of inhibition increases with each successive impulse, and the inhibition is said to be PHASIC, or use-dependent.
-Tonic inhibition: time between APs is long compared to LA dissociation time.
-Phasic (use-dependent) inhibition: Time between APs is short compared to LA dissociation time; more and more channels are blocked with each action potential (level on inhibition increases).
Clinical importance
-Tissue injury or trauma causes nocireceptors to fire at high rates (PAIN).
-A LA will block nocireceptors in a PHASIC MANNER; inhibits pain signals more than other sensory or motor impulses.
-Sensory or motor impulses are blocked tonically.
Other receptors for local anesthetics
LAs interact with other channels:
-potassium channels and calcium channels
-ligand gated channels (nicotine acetylcholine receptors)
-transient receptor potential (trp) channels.
LAs interact with receptors:
-several G protein-coupled receptors (muscarinic cholinergic receptors, beta-adrenergic receptors, and receptors for substance P).
-LAs uncouple some G proteins from their cell surface receptors.
-Clinical importance in most cases.
-Sodium channel affinity is high and dominates.
Clinical situations:
-spinal anesthesia; direct inhibition of receptors (substance P NK1, bradykinin B2, glutamate AMPA and NMDA receptors).
Systemic Absorption of LAs
After administration by injection or topical application, LAs DIFFUSE TO THEIR SITES OF ACTION!!!
-Taken up by the local tissues
-Then removed from the site of administration by the systemic circulation.
Factors determining systemic toxicity:
-The amount of LA that enters the systemic circulation.
-Potency of the LA
Factors that influence the rate and extent of systemic absorption:
-Properties of the injected solution such has its viscosity.
-Vascularity of the injection site: greater absorption from densely perfused tissue, greater absorption with multiple administrations.
-Drug concentration
-Addition of a vasoconstrictor
Epinephrine: often administered with a sort-acting or medium-acting LA; reduces blood flow to the area of injection and causes vascular smooth muscles to contract, which slows the rate of removal of the LA.
Increases the concentration of anesthetic around the nerve; enhances the DURATION OF ACTIONG of the LA.
Decreases the maximal concentration in the systemic circulation: decreases the LAs SYSTEMIC TOXICITY.
Vasoconstriction can also lead to tissue hypoxia and damage; vasoconstrictors are not used with LAs in the extremities.
Distribution of Local Anesthetics
LAs diverted into the systemic circulation travel in the venous system to the capillary bed of the lung.
As the first capillary bed reached by the drug, the lung “cushions” the impact of the drug on the brain and other organs.
The lung also plays a role in metabolizing amide-linked LAs.
LAs in the circulation bind to two major plasma proteins: ALPHA-1 ACID GLYCOPROTEIN AND ALBUMIN.
LAs can also bind to erythrocytes.
Binding to plasma proteins decreases as pH decreases; this suggests that the neutral form of LAs binds these proteins with higher affinity.
LAs also bind tissue at the site of injection and other sites; the more hydrophobic the agent, the greater the tissue binding.
Volume of distribution (Vd): the amount of drug that distributes to the tissues from the circulation.
-Less hydrophobic LA: procaine: higher plasma concentration and therefore a smaller Vd.
-More hydrophobic LA: bupivacaine: lower plasma concentration and therefore a larger Vd.
LAs with a larger Vd are eliminated more slowly (in the tissues and not the plasma to get filtered by the glomerulus in the kidney).
Metabolism and Excretion of Local Anesthetics
-Ester-linked LAs: metabolizes by tissue and plasma esterases, the process is fast (minutes) and metabolites are excreted via the KIDNEY.
-Amide-linked LAs: metabolized in the liver by p450 enzymes: aromatic hydroxylation, N-dealkylation, and amide hydrolysis.
The metabolites are then returned to the circulation and excreted by the kidney.
Alterations in liver perfusion or enzyme velocity change metabolism! Amide-linekd LAs can lead to toxicity in cirrhosis patients (liver is not working to metabolize drug).
SOME metabolism can occur extrahepatically in the lung and kidney.
Administration of Local Anesthetics
The method of administration of the local anesthetics can determine both the THERAPEUTIC EFFECT and the EXTENT OF SYSTEMIC TOXICITY.
- Topical anesthesia
- Infiltration Anesthesia
- Peripheral nerve blockade
- Central nerve blockade
- IV regional anesthesia
Topical Anesthesia
Short-term pain relief when applied to the mucous membranes or skin.
-The drug must cross the EPIDERMAL LAYER: stratum corneum (outermost layer of epidermis) is a major obstacle; reaches the endings of Adelta-fibers and C-fibers in the dermis.
-After crossing the epidermis, the LAs are absorbed rapidly into the circulation, which increases the risk of systemic toxicity.
TAC: a mixture of tetracaine, adrenaline (epinephrine) and cocaine; this is sometimes used before suturing small cuts. There is a concern about cocaine toxicity or addiction.
Alternatives such as EMLA are now used.
Infiltration Anesthesia
-Infiltration Anesthesia is used to numb an area of skin (or mucosal surface) via an injection.
Injected intradermally or subcutaneously, often at several neighboring sites near the area to be anesthetized.
Infiltration anesthesia produces numbness much faster than topical anesthesia; agent does not have to cross an epidermis.
Injection can be painful; the solution is usually acidic to keep the drug in an ionized, soluble form; addition of sodium bicarbonate can reduce injection pain.
-Local anesthetics most commonly used for infiltration anesthesia: lidocaine, procaine, bupivacaine.
Use in dentistry
-Often BOTH an injected and a topical anesthetic agent are used; injected agent blocks the sensation of pain during the procedure (either as local infiltrations or as field or nerve blocks); topical agent allows for painless needle penetration.
-Benzocaine and lidocaine are commonly used topical anesthetics; insoluble in water and poorly absorbed into the circulation, which decreases the likelihood of systemic toxicity!!
-Numerous injected anesthetics are used in dental practice: lidocaine, mepivacaine, bupivacaine.
