Slides 1 Flashcards
What do local anesthetics do?
They reversibly block impulse conduction along nerve axons that utilize sodium channels as the
primary means of action potential generation.
What are local anesthetics used for?
1) To block pain sensation from specific areas of the body.
2) To block sympathetic vasoconstrictor impulses to specific areas of the body.
At least three nociceptors
are recognized:
1) Acid
2) Injury
3) Heat
What does a nerve ending have?
Opioid receptors
What do opioid receptors do?
Inhibit action potential generation
What does the axon have?
Na+ and K+ channels
What do Na+ and K+ channels do?
Propagate action potentials
Synaptic transmission involves:
The release of substance P, a neuropeptide (NP), and glutamate and activation of their receptors on the secondary neuron.
What modulates the transmission process?
Alpha2 adrenoceptors and opioid receptors
What are the ionotropic glutamate receptors?
1) α-amino-3-hydroxy-5-methylisoxazole-4-
proprionic acid (AMPA) receptors
2) Kainic acid (KA) receptors
3) N-methyl-D-aspartate (NMDA) receptors
Where are AMPA receptors found?
In all neurons
What are AMPA receptors permeable to?
Na+ and K+, but NOT to Ca+2
Where are KA receptors found?
1) Hippocampus
2) Cerebellum
3) Spinal cord
What are KA receptors permeable to?
Na+ and K+, and some to Ca+2
Where are NMDA receptors found?
In all neurons
What are NMDA receptors permeable to?
Na+, K+, and Ca+2
Peptides often coexist with ___ in the same neuron.
A conventional nonpeptide transmitter
Substance P is contained in and released from:
Small unmyelinated primary sensory neurons in the spinal cord and brain stem.
What does substance P do?
Causes a slow EPSP in target neurons = transmit noxious stimuli.
Substance P is also released with:
Glutamate
What is the first local anesthetic introduced into clinical practice for ophthalmic use, in 1884?
Cocaine
What is the chronic use of cocaine associated with?
Psychological dependence (addiction).
What was synthesized to improve upon the clinical properties of cocaine in 1905, and became the dominant local anesthetic for about 50 years?
Procaine
What anesthetic was discovered in 1943 that is now the most widely used local anesthetic?
Lidocaine
What is the chemical makeup for most local anesthetics?
A lipophilic group (aromatic) connected to an ionizable group (tertiary amine) via an ester or amide linkage.
Local anesthetics are:
a) Strong acids
b) Strong bases
c) Weak acids
d) Weak bases
d) Weak bases
Local anesthetics exist in the body as:
Either uncharged bases or cations.
Which is the most active form: Uncharged bases or cations? Why?
The cationic form, because it can’t exit from the closed channels
Why do local anesthetics also exist in an uncharged form?
Because it’s important for rapid penetration of biologic membranes, since the receptor is not accessible from the external side of the cell membrane.
Local anesthetics are less effective when:
Injected into infected tissue, because low pH cause ionization of the drug.
What does low pH do to local anesthetics?
Causes ionization of the drug.
Esters have a shorter duration of action than amides, because:
They are more prone to hydrolysis
What are the classifications of local anesthetics?
1) Amides
2) Esters
What are some examples of amide local anesthetics?
1) Lidocaine (Lignocaine)
2) Bupivicaine
3) Ropivacaine
4) Mepivacaine
5) Levobupivicaine
6) Prilocaine
What are some examples of ester local anesthetics?
1) Cocaine
2) Procaine
3) Tetracaine
4) Benzocaine
What is the local anesthetics’ primary mechanism of action?
Blockade of voltage-gated sodium channels.
How do local anesthetics carry out their mechanism of action?
Local anesthetics bind to receptors near the intracellular end of the sodium channel and block the channel in a time and voltage dependent fashion.
What happens when progressively increasing concentrations of
a local anesthetic are applied to a nerve fiber?
1) The threshold for excitation increases
2) Impulse conduction slows
3) The rate of rise of the action potential declines
4) The action potential amplitude decreases
5) The ability to generate an action potential is completely abolished.
On what basis do nerve fibers differ significantly in their susceptibility to block by local anesthetics?
On the basis of differences in size and degree of myelination.
Which fibers are blocked first by local anesthetics?
The smaller B and C fibers.
Which fibers are blocked last by local anesthetics?
Motor fibers
What are the side effects of local anesthetics?
1) Motor paralysis =
a) Limits cooperation during obstetric delivery
b) Impairs respiratory activity
2) Autonomic nerve block = hypotension and urinary retention (from bladder function interference)
3) Some (bupivacaine and ropivacaine) cause lethal arrhythmias in high concentrations.
Which local anesthetic has an antiarrhythmic effect on the heart at concentrations lower than those needed to
produce nerve block?
Lidocaine
What is the half life of ester-based local anesthetics?
<1 minute
Absorption of the local anesthetic to the
systemic circulation from the site of application depends on many factors such as:
Local blood
flow
Application to a highly vascular area results in
__(low/high) blood levels of the local anesthetic.
High
What do vasoconstrictor substances (like epinephrine) do?
Reduce the systemic absorption of the local
anesthetic from the injection site
How do vasoconstrictors reduce systemic absorption of the local anesthetic from the injection site?
By decreasing
blood flow, and prolonging its local effect (systemic toxic effects of local anesthetic is also reduced)
What does epinephrine do when used in spinal anesthesia?
Stimulates α2 adrenoceptors = inhibits
release of substance P (neurokinin-1) and
reduce sensory neuron firing = enhances and
prolongs local anesthesia
Which 2 α2-agonists
have been used to augment local anesthetic effect in the subarachnoid space and peripheral nerves?
1) Clonidine
2) Dexmedetomidine
