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Pharmacology: Local Anesthetics
Terms in this set (31)
What is the chemical structure of most local anesthetics?
Most consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine).
Do amide or ester local anesthetics have a shorter duration of action?
Since ester links (as in procaine) are more prone to hydrolysis than amide links,
esters usually have a shorter duration of action
Why are many local anesthetics sold as hydrochloride salts?
They are weak bases marketed as water-soluble salts (hydrochlorides) because the
hydrochloride salts are mildly acidic, which increases the stability of the local anesthetic
esters and any accompanying vasoconstrictor substance.
How does pH and charge play into the effectiveness of local anesthetics? Why do infected tissues respond poorly to local anesthetics?
Most local anesthetics have a pK of 8-9, so
the largest fraction at physiologic pH will be the cationic form
. The cationic form is the most active form at the receptor site, but the uncharged form is required for rapid penetration of the cell membranes (the anesthetic receptor is not accessible from the external side of the cell membrane). Ergo, local anesthetics are much less effective in infected tissues because
these tissues have a low extracellular pH, so that a very low fraction of nonionized local anesthetics is available for diffusion into the cell.
Why are local anesthetics often administered with a vasoconstrictor like epinephrine?
The duration of action of a local anesthetics is proportional to the time during which it is in contact with nerve.
Epinephrine reduces systemic absorption of local anesthetics from the depot site by decreasing blood flow in these areas
, which is important for drugs with short durations of action. It also
prevents the toxic effects of systemic absorption
Which factors affect the systemic absorption of local anesthetics?
• Site of injection
• Drug-tissue binding
• Presence of vasoconstrictors
• Physicochemical properties of the drug
How does vascularization affect the absorption of a local anesthetic?
Application of a local anesthetic to a highly vascular area (tracheal mucosa) results in more rapid absorption and thus higher blood levels than if it had been injected into a poorly perfused area (tendon, dermis or subcutaneous fat).
Why is epinephrine used in spinal anesthesia?
directly enhances and prolongs
acting on α2-adrenoceptors, which inhibit release of substance P and reduce sensory neuron firing.
Recognition of this fact has led to the use of
the α2 agonists clonidine and dexmedetomidine to augment local anesthetic effect
t* in the subarachnoid space and on peripheral nerves.
What happens if an adjuvant vasoconstrictor given with a local anesthetic reaches systemic circulation?
There may be delayed wound healing, tissue edema, or necrosis after local anesthesia due to
increased oxygen consumption of the tissue
(via sympathomimetic amines); this, together with vasoconstriction, leads to
hypoxia and local tissue damage
Why don't you use vasoconstrictors with local anesthetics in hand or foot surgery?
The use of local anesthetics containing vasoconstrictors during surgery of the digits, hands or feet resulting in prolonged constriction of major arteries in the presence of limited collateral circulation could produce irreversible hypoxic damage, tissue necrosis and gangrene.
How are ester-linked local anesthetics metabolized?
Ester-linked local anesthetics are metabolized by tissue and plasma esterases (pseudocholinesterases). This process is fast and the resulting metabolites are excreted by the kidney.
How are amide-linked local anesthetics metabolized?
The amide-linked local anesthetics are in general degraded by liver cytochrome P450 enzymes. The three major routes of hepatic metabolism are aromatic hydroxylation, N-dealkylation and amide hydrolysis. Metabolites are excreted by the kidney.
What is the mechanism of action of local anesthetics?
block voltage-gated sodium channels by binding the receptors near the intracellular end of the channel
and blocking the channel.
What happens when increasing amounts of local anesthetic block voltage-gated sodium channels?
Progressively increasing concentrations of a local anesthetic
increase the threshold for excitation; impulse conduction slows, the rate of rise of the action potential declines, the action potential amplitude decreases, and finally the ability to generate an action potential is abolished
. These effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve propagation across the blocked area is no longer possible.
Do local anesthetics have a higher affinity for active or resting axons?
Local anesthetics have a
higher affinity for active axons
; channels in the rested state, which predominate at more negative membrane potentials, have a lower affinity for local anesthetics than activated (open) and inactivated channels.
How does size and charge affect local anesthetics?
The smaller and more lipophilic the molecule, the faster the rate of interaction with the sodium channel receptor. Potency is also positively correlated with lipophilicity (as long as the agent retains sufficient hydrophilicity to diffuse to the site of action.)
Which local anesthetics have longer durations of action? Why?
Tetracaine, bupivacaine and ropivacaine are more lipophilic
than lidocaine, procaine and mepivacaine, making them more potent and with longer durations of action. These long-acting local anesthetics also bind more extensively to proteins.
Name the ester-linked local anesthetics.
Name the amide-linked local anesthetics.
Which nerve fibers are affected first by local anesthetics?
Lightly myelinated B fibers (preganglionic autonomic), small unmyelinated C fibers (mediating pain sensations), and small myelinated Aδ fibers (mediating pain and temperature sensations)
are blocked before larger myelinated Aγ, Aβ and Aα fibers (carrying postural, touch, pressure and motor information). Thus,
pain fibers are blocked first; other sensations disappear next; and motor function is blocked last.
How do local anesthetics affect cardiac cells?
Some are useful antiarrhythmic agents at concentrations lower than those required to produce nerve block. Others (bupivacaine and ropivacaine) can cause lethal arrhythmias in high concentrations.
What are the adverse effects of local anesthetics on the CNS?
• Restlessness/tremor proceeding to clonic convulsions
• Central stimulation is followed by CNS depression
• Respiratory failure leads to death
• Depression of cortical inhibitory pathways
How can convulsions caused by local anesthetics be prevented?
They may be prevented by
administering the smallest dose required for adequate anesthesia
. When large doses must be given, premedication with a benzodiazepines, like diazepam, provides significant prophylaxis against seizures.
How do local anesthetics cause peripheral neurotoxicity?
When applied at excessively high concentrations, all local anesthetics can be toxic to nerve tissue. The mechanism of neurotoxicity is unknown, but it does not result from excessive sodium channel blockade.
How do local anesthetics affect the cardiovascular system?
block sodium channels and thus depress cardiac pacemaker activity, excitability and conduction
. At very high concentrations, they may also block Ca2+ channels. They also depress the strength of cardiac contraction and
cause arteriolar dilation, leading to hypotension
. Cardiovascular collapse/death usually occur only after large doses, but it can happen with small amounts of bupivacaine used for infiltration anesthesia.
Which local anesthetic is more cardiotoxic than others?
is more cardiotoxic than other local anesthetics.
How does cocaine differ from other local anesthetics in its effects on the cardiovascular system?
The blockade of norepinephrine uptake results in vasoconstriction and hypertension, and possibly cardiac arrhythmias. The vasoconstriction produced by cocaine can lead to ischemia and in chronic abusers to ulceration of the mucous membrane and even damage to the nasal septum.
How does prilocaine administration affect hemoglobin?
of prilocaine lead to
accumulation of o-toluidine, an oxidizing agent capable of converting hemoglobin to methemoglobin
. Sufficient methemoglobin will cause cyanosis and chocolate-colored blood. Such levels of methemoglobinemia may cause
decompensation in patients with cardiac or pulmonary disease
and require immediate treatment. Reducing agents such as
methylene blue may be given IV to convert methemoglobin to hemoglobin
Why are some people allergic to ester-linked local anesthetics?
The ester type local anesthetics are
metabolized to paraaminobenzoic acid (PABA) derivatives
. These metabolites are responsible for allergic reactions in a small percentage of the population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to agents of the amide group are extremely rare.
How are the adverse effects of local anesthetics managed?
Supportive treatment of the cardiovascular system includes IV fluids and, when appropriate, vasopressors (myocardium-stimulating, like ephedrine). Convulsions may be controlled with oxygen and by IV diazepam or ultrashort-acting barbiturates, or succinylcholine. If hypotension occurs, use vasoconstrictors given IM or IV. Treat allergic reactions to anesthetics according to severity. Use diphenhydramine for mild cutaneous reactions, and use SC epinephrine for more serious reactions.
Why is procaine contraindicated with sulfonamide use?
Procaine is hydrolyzed in vivo to produce PABA, which inhibits the action of sulfonamides
. Thus, large doses should not be administered to patients taking sulfonamide drugs.
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