Test 3: Local Anesthetics Basic Overview

Question 1

All currently available local anesthetics consist of a ______ phenyl ring and a ____ or ______ amine. (Blue box!)

Answer 1

All currently available local anesthetics consist of a lipophilic phenyl (benzene) ring and a tertiary or quaternary amine.

Question 2

Describe the chemical structure of a local anesthetic.

Answer 2

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.

Question 3

What are the 3 characteristic segments in the chemical structure of a local anesthetic?

Answer 3

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

Question 4

Which LA is an example of a Racemic Mixture?

Answer 4

Bupivicaine

Question 5

Which LA is an example of a pure enantomer?

Answer 5

Levobupivicaine

Question 6

Which type of LA is metabolized via hydrolysis by plasma/tissue cholinesterase?

Answer 6

Esters
-Occurs throughout the body
-Rapid
-Exception: Cocaine

Question 7

How is Cocaine metabolized?

Answer 7

In the Liver

Question 8

Which type of LA is metabolized in the Liver by the CYP450 system?

Answer 8

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.

Question 9

Which type of LA is more likely to have allergic reactions?

Answer 9

Esters > Amides due to PABA.
-Allergy to one ester is allergy to all.

Question 10

What is PABA?

Answer 10

para-aminobenzoic acid

The reason why Esters have allergy potential.

Question 11

If you have an allergy to one amide, can you switch them to another amide?

Answer 11

Yes.

Can’t do this for esters though.

Question 12

Which type of LA has a shorter duration of action?

Answer 12

Esters
-Shorter due to rapid metabolism
-Tetracaine is the longest acting ester

Question 13

Why are amides longer acting?

Answer 13

-Longer acting because they are more lipophilic & protein bound
-Require transport to the liver for metabolism

Question 14

What is the class, onset, and DOA of Chloroprocaine?

Answer 14

-Ester
-Fast
-30-60 min

Comes in a higher concentration, so faster onset.

Question 15

What is the class, onset, and DOA of Lidocaine?

Answer 15

-Amide
-Fast
-90-120 min

Question 16

What is the class, onset, and DOA of Bupivicaine?

Answer 16

-Amide
-Slow
-180-600 min

Question 17

What is the class, onset, and DOA of Ropivicaine?

Answer 17

-Amide
-Slow
-180-600

Question 18

What is Pka?

Answer 18

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

Question 19

What happens to weak bases at a pH significantly less than its pKa?

Answer 19

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.

Question 20

Decreased pKa = ____ time to onset of action.

Answer 20

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.

Question 21

Why does Chloroprocaine have a rapid onset of action?

Answer 21

-pKa is 9.1
But, using 3% concentration gives a rapid onset of action.

Question 22

A base in an alkaline environment is ______, ____ soluble, and _____ diffusable across the bilipid membrane. (Blue Box!)

Answer 22

A base in an alkaline environment is non-ionized, lipid soluble and easily diffusable across the bilipid membrane.

Question 23

Why are Local Anesthetics stored as acidic solutions?

Answer 23

-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.

Question 24

Local anesthetics provide _____, as long as they are in the site of deposition. (Blue box!)

Answer 24

Local anesthetics provide analgesia, as long as they are in the site of deposition.

Question 25

LAs are primarily what kind of amines?

Answer 25

Tertiary - can cross BBB.

Question 26

What is the target site of action for a LA?

Answer 26

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.

Question 27

What are factors that potency is dependent on?

Answer 27

-pH and pKa
-Potency is related to lipid solubility.

Question 28

How does onset differ between SAB and epidurals?

Answer 28

-SAB: no nerve sheaths, direct access to nerves, fast onset
-Epidural: requires 10xs more dose to produce dense block

Question 29

How does protein binding affect DOA of LAs?

Answer 29

Increased Protein binding = Increased DOA

Question 30

How does vascular uptake effect the DOA of LAs?

Answer 30

-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.

Question 31

Describe what happens when a Local Anesthetic is injected into the tissues.

Answer 31

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)

Question 32

___ layers of connective tissue are barriers to local anesthetics. (Blue Box!)

Answer 32

3 layers of connective tissue are barriers to local anesthetics.
-Endoneurium
-Perineurium
-Epineurium

Question 33

What is an axon?

Answer 33

An extension of a centrally located neuron.
-Functional unit of peripheral nerves

Question 34

What is the axolemma?

Answer 34

Cell membrane like structure.
-Bilipid Layer
-Proteins and ion channels
-Axoplasm – intracellular contents

Question 35

What are Schwann Cells?

Answer 35

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.

Question 36

What is the myelin sheath?

Answer 36

-Allows for faster conduction of impulses
-Myelinated nerves are larger & more difficult to block than unmyelinated nerves

Question 37

What are the Nodes of Ranvier?

Answer 37

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.

Question 38

What are fascicles?

Answer 38

A bundle of axons in a peripheral nerve.

Question 39

What is the Endoneurium?

Answer 39

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.

Question 40

What is the Perineurium?

Answer 40

-Layers of flattened overlapping collagenous cells
-Binds a group of axons together to form a fascicle

Question 41

What is the Epineurium?

Answer 41

Areolar connective tissue that functionally holds the fasciles together to form the peripheral nerves.