Test 3: Local Anesthetics Basic Overview Flashcards
All currently available local anesthetics consist of a ______ phenyl ring and a ____ or ______ amine. (Blue box!)
All currently available local anesthetics consist of a lipophilic phenyl (benzene) ring and a tertiary or quaternary amine.
Describe the chemical structure of a local anesthetic.
A benzene ring (Lipophilic) on one side is bonded to a tertiary/quaternary amine (Hydrophilic) on the other side.
-The bond between the benzene ring and the carbon (Amine) group determines whether the drug is an amide or an ester.
What are the 3 characteristic segments in the chemical structure of a local anesthetic?
1) Intermediate ester or amide carbon group
2) Unsaturated aromatic ring/Benzene ring
-Lipophilicity
3) An amine end (tertiary or quaternary)
-Hydrophilicity
-Able to ionize at physiologic pH
Which LA is an example of a Racemic Mixture?
Bupivicaine
Which LA is an example of a pure enantomer?
Levobupivicaine
Which type of LA is metabolized via hydrolysis by plasma/tissue cholinesterase?
Esters
-Occurs throughout the body
-Rapid
-Exception: Cocaine
How is Cocaine metabolized?
In the Liver
Which type of LA is metabolized in the Liver by the CYP450 system?
Amides
-Significant blood level may develop with rapid absorption because it has to have a transport mechanism to get to blood from Liver. Hangs out in blood until then. Rapid absorption of a lot of it will decrease the enzymes, and lead to higher levels.
Which type of LA is more likely to have allergic reactions?
Esters > Amides due to PABA.
-Allergy to one ester is allergy to all.
What is PABA?
para-aminobenzoic acid
The reason why Esters have allergy potential.
If you have an allergy to one amide, can you switch them to another amide?
Yes.
Can’t do this for esters though.
Which type of LA has a shorter duration of action?
Esters
-Shorter due to rapid metabolism
-Tetracaine is the longest acting ester
Why are amides longer acting?
-Longer acting because they are more lipophilic & protein bound
-Require transport to the liver for metabolism
What is the class, onset, and DOA of Chloroprocaine?
-Ester
-Fast
-30-60 min
Comes in a higher concentration, so faster onset.
What is the class, onset, and DOA of Lidocaine?
-Amide
-Fast
-90-120 min
What is the class, onset, and DOA of Bupivicaine?
-Amide
-Slow
-180-600 min
What is the class, onset, and DOA of Ropivicaine?
-Amide
-Slow
-180-600
What is Pka?
The pH at which 50% of a drug is in the charged (or ionized) and water-soluble form, whereas the remaining half is uncharged (or nonionized) and lipid soluble.
-LAs are weak bases
What happens to weak bases at a pH significantly less than its pKa?
They become mostly ionized.
-Therefore drugs that have a higher pKa (relative to pH 7.4) are ionized to a greater extent at body pH than those with a lower pKa.
Decreased pKa = ____ time to onset of action.
Decreased pKa = decreased time to onset of action (faster onset).
-In general, the closer the pKa is to pH 7.4, the more rapid the onset.
-Exception: Chloroprocaine
Because their ionization is less, local anesthetics with lower pK a (7.6–7.8), such as lidocaine, mepivacaine, and prilocaine, tend to have a more rapid onset of action than drugs with a greater pK a (8.1–8.6), such as bupivacaine, tetracaine, and procaine.
Why does Chloroprocaine have a rapid onset of action?
-pKa is 9.1
But, using 3% concentration gives a rapid onset of action.
A base in an alkaline environment is ______, ____ soluble, and _____ diffusable across the bilipid membrane. (Blue Box!)
A base in an alkaline environment is non-ionized, lipid soluble and easily diffusable across the bilipid membrane.
Why are Local Anesthetics stored as acidic solutions?
-Longer shelf life.
-When we put them into body, now dropping it in a more basic environment, driving it towards the non-ionized form.
Manufacturers acidify local anesthetic solutions to increase solubility and stability (the free base is more susceptible to photodegradation and aldehyde formation), which results in a longer shelf life.
Local anesthetics provide _____, as long as they are in the site of deposition. (Blue box!)
Local anesthetics provide analgesia, as long as they are in the site of deposition.
LAs are primarily what kind of amines?
Tertiary - can cross BBB.
What is the target site of action for a LA?
The Voltage gated Na Channel
-Binding site is inside the cell (pore channel). Binds to ionized form
-Channel has to be open or inactive for binding to occur.
What are factors that potency is dependent on?
-pH and pKa
-Potency is related to lipid solubility.
How does onset differ between SAB and epidurals?
-SAB: no nerve sheaths, direct access to nerves, fast onset
-Epidural: requires 10xs more dose to produce dense block
How does protein binding affect DOA of LAs?
Increased Protein binding = Increased DOA
How does vascular uptake effect the DOA of LAs?
-LA provide analgesia as long as they are in the site of deposition
-Vasoconstriction slows the rate of uptake (keeping it at site of action).
-Lido + Epi (or neosynephrine)
-Not really necessary with long acting LA’s b/c the DOA of the Bupiv can outlast that of Epi.
Describe what happens when a Local Anesthetic is injected into the tissues.
1) Inject a weak base LA into the tissues. (tissues are typically a more acidic environment)
2) Protonates depending on pH & pKa (some becomes ionized form)
3) Non-ionized form crosses the lipid membrane
4) Intracellular pH is decreased and the LA equilibrates again (becomes ionized once inside the cell)
5) Ionized LA antagonizes the Voltage Gated Na+ Channel (attaches to the binding site)
___ layers of connective tissue are barriers to local anesthetics. (Blue Box!)
3 layers of connective tissue are barriers to local anesthetics.
-Endoneurium
-Perineurium
-Epineurium
What is an axon?
An extension of a centrally located neuron.
-Functional unit of peripheral nerves
What is the axolemma?
Cell membrane like structure.
-Bilipid Layer
-Proteins and ion channels
-Axoplasm – intracellular contents
What are Schwann Cells?
Cells that support and insulate each neuron
-Small non-myelinated nerves, Schwann cells cover several axons
-Larger myelinated nerves, Schwann cells cover only one axon and produce several concentric layers of myelin.
What is the myelin sheath?
-Allows for faster conduction of impulses
-Myelinated nerves are larger & more difficult to block than unmyelinated nerves
What are the Nodes of Ranvier?
Segments of nerve between Schwann cells that do not contain myelin.
-Contain the Voltage Gated Sodium Channels - LA site of action
-Saltatory Conduction – AP’s jump from node to node
-Have to act on 3 nodes to block conduction.
What are fascicles?
A bundle of axons in a peripheral nerve.
What is the Endoneurium?
Delicate connective tissue composed of longitudinally arranged collagen around the myelin sheath of each myelinated nerve fiber
-Surrounds and embeds the axons in the fasiculi.
What is the Perineurium?
-Layers of flattened overlapping collagenous cells
-Binds a group of axons together to form a fascicle
What is the Epineurium?
Areolar connective tissue that functionally holds the fasciles together to form the peripheral nerves.
