Test 3: Local Anesthetics Basic Overview (pt 2) Flashcards

1
Q

Ions pass through pore channels in the ______. _____ channels are the most significant. (Blue Box!)

A

Ions pass through pore channels in the axolemma. Na+ Channels are the most significant.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is Resting Membrane Potential?

A

The voltage difference across a membrane.
-An ionic imbalance between ECF and ICF (axoplasm) that causes an AP.
-Maintained by Na/K ATPase
-Axolemma is permeable to K efflux (pushing K out to maintain negative charge intracellularly)
-Axolemma is impermeable to Na

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the normal resting membrane potential for a neuron in microvolts?

A

-70 to - 90 mV.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the process of an action potential being created.

A

-Stimulation causes sudden influx of Na+, hit threshold, and depolarization occurs.
-K+ channels open rapidly
-Membrane potential rises to +20 mV
-Na channels close at the peak, but K+ channels stay open, and K exits the cell down its concentration gradient.
-Na/K ATPase actively removes intracellular Na (3 Na leave the cell for each 2 K that enter)
-K+ passively diffuses back into the cell to restore RMP.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Local anesthetics preferentially bind to both the ____ and ___________ states of the Voltage Gate Na Channel. (Blue Box!)

A

LA’s preferentially bind to both the OPEN & INACTIVATED states of the Nav.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

When does the Resting (Closed) State occur?

A

When the membrane is at its resting membrane potential.
-Channel is closed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the Open (active) state?

A

Action potential leads to the opening of the resting channel to allow passage of Na+ into the cell.
-Reversal of membrane potential until threshold is reached
-Conformational change in the proteins that compose the channel occurs, and it opens.
-LA can bind to the pore channel from the intracellular side in this state.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the Inactive State?

A

The inactivation gate closes the channel pore from the intracellular side, and the channel inactivates.
-Marked by the return of V-G Na Channels to an impermeable state, preventing the initiation of an AP.
-Lasts until the restoration of RMP
-LAs can still work in this state.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where do Local Anesthetics bind?

A

LA’s bind reversibly to receptors within or adjacent to the internal opening of the NaV.
-Intracellular receptors have an inc affinity for ionized form of LA.
-Once the LA enters the lipid bilayer, intracellular pH is more acidic, so the LA is driven towards its ionized form. Which is good, because that is what can bind to the receptor.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the 2 pathways to the binding site?

A

-Hydrophilic: Through the pore interior. (If the pore happens to be open, it can go down and through the channel itself).
-Hydrophobic: Through the lipid membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the actions of the LA after it binds to the receptor?

A

-Stabilizes the inactivated state of the channel, preventing further activation
-Can also bind inside the pore and prevent ion flux (“Open State Block”).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why are Local Anesthetics called “Use Dependent”?

A

-LA’s work faster as the Nav is repetitively depolarized
-Greater # of Nav are in the inactivated & open state
-Inc opportunity for LA binding = accumulation of LA bound Nav

Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials. Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Local anesthetics also effect GPCRs, causing what effects?

A

-Affects intracellular Ca signaling pathways
-Inflammatory modulating actions result from interruptions in these pathways.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Local Anesthetics also suppress Polymorphonuclear Leukocyte priming, which does what?

A

-An additional inflammatory modulating action of LAs.
-Prevents overactive inflammatory responses without impairing host defenses or suppressing normal inflammation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the two stages of Polymorphonuclear leukocyte priming?

A

PMNL are activated via a two stage process (granulocyte type WBC):
-Priming – first encounter with a stimulus
-Full active – second encounter with a stimulus.
LAs suppress this to prevent overactive inflammatory responses.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How does Ca++ channel binding result in significantly less potent LA effects?

A

Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How does K+ channel binding effect LAs?

A

From Katzung:
Increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

List the components of a differential block in order of first onset of blockade to last.

A

-Autonomic Function
-Pain
-Touch
-Temperature
-Motor Function
-Proprioception

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

List the components of a differential block in order of first to recover -> last to recover.

A

-Proprioception
-Motor function
-Temperature
-Touch
-Pain
-Autonomic Function.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What factors can affect block onset?

A

-Dose of the drug (Depth of the blockade)
-Multi-layered membrane around the nerves
-pKa of the drug
-pH of the tissues
-Generally: myelinated fibers are blocked before non-myelinated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Why are myelinated fibers blocked before non-myelinated?

A

Myelin increases the diffusion barrier BUT only need to block the nodes of ranvier versus the entire length of the nerve.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What factors influence nerve sensitivity to Local Anesthetics?

A

-Diameter: the larger the nerve, the longer the onset
-Myelination: the greater the myelination, the greater the diffusion barrier to LAs.

23
Q

What are the A-Alpha Fibers?

A

-Largest and most heavily myelinated fibers.
-Fastest conduction velocity of ALL fibers
-Proprioception and motor
-Blocked last.

24
Q

What are the A-Beta Fibers?

A

-Second fastest conduction behind A-Alpha (speed is equal to A-Gamma)
-Motor
-Blocked intermediately

25
Q

What are the A-Gamma Fibers?

A

-Responsible for reflexes
-Motor
-Blocked intermediately

26
Q

What are the A-Delta Fibers?

A

-Have the slowest conduction velocity of all A–fibers
-Responsible for Temperature
-Blocked intermediately

27
Q

What are the B-Fibers?

A

-Similar in size to A-Delta
-Slower conduction velocity and less myelination than A-fibers
-Blocked early (First)

28
Q

What are the C-Fibers?

A

-Smallest of all fibers
-Slowest conduction speed
-Pain and Autonomics
-Blocked early

29
Q

Why is potency correlated with lipid solubility?

A

The axolemma and myelin sheath are made primarily of lipids
-Inc lipid solubility = can pass through these membranes easily.
-Inc lipid solubility correlates with inc protein binding, inc potency, longer DOA, and a higher risk of severe toxicity. Lower concentrations are required for blockade.

30
Q

Describe the properties of Larger LA molecules?

A

-More lipophilic. Relatively water insoluble.
-Highly protein bound (increases DOA)
-Less easily absorbed systemically
-Binds to Na+ Channels with a higher affinity than lower soluble agents
-Inc incidence for CV toxicity
-Higher potency = lower dose (compared to less lipid soluble LAs).

31
Q

Diffusion through the axolemma is dependent on what?

A

-Chemical structure (tertiary vs quaternary)
-Lipid solubility
-State of ionization (pKa and pH): most important factor. More ionized = slower diffusion.

32
Q

What determines the Duration of Action (DOA)?

A

-Protein binding: more protein bound = longer DOA
-Lipid solubility: will stay in the area longer
-Having a large chemical radically bound to the amine end is what increases protein binding, increasing the DOA.

33
Q

How does increased protein binding effect the duration of action?

A

-With increased protein binding, there is increased affinity for the receptor site on the VG Na channel.
-LA should work longer.
-Alpha1-Acid Glycoprotein (AAG) or Albumin will increase the duration of the drug (prefer AAG > Albumin).

34
Q

What factors affect absorption of the LA?

A

-Site of injection
-Dose
-pKa
-Adjuncts: Vasoconstrictors (Epi ↓ systemic absorption), α2 Adrenergic Agonists, Opioids, Ketamine.

More lipid soluble agents are absorbed slower (longer DOA).

35
Q

After Intravenous, which routes have the Greatest -> Least rate of absorption? (Blue Box!)

A

-Interpleural
-Intercostal
-Caudal
-Epidural
-Brachial Plexus
-Femoral/Subarachnoid
-Sciatic
-Subcutaneous

36
Q

Plasma concentration is directly proportional to the _____.

A

Plasma concentration is directly proportional to the the dose (total mg).
-Not the concentration or speed of injectate
-LAs are sequestered in lipophilic tissues (especially more potent ones)
-Direct vasoconstriction of vascular smooth muscle due to agent helps keep it at site of action. Seen with Potent lipophilic agents @ low doses (Ropivicaine, Lidocaine).

37
Q

Do we want Local Anesthetic to be absorbed?

A

No.
-When a local is absorbed from the site of action into the plasma concentration, the clinical analgesic effect starts to deteriorate.
-The faster the absorption, the shorter the duration of action.
-The faster the absorption, the increase risk for toxicity.

38
Q

How does vascularity of the area affect absorption?

A

-The more vascular the area – the faster the absorption.
-The higher the plasma concentration in a shorter amount of time.

39
Q

What do local anesthetics do to vascular smooth muscle?

A

-All local anesthetics except cocaine and in some doses and sites of administration ropivacaine and lidocaine produce relaxation of vascular smooth muscle.
-The resultant vasodilation increases blood flow to the tissue in which the drug is deposited.
-This results in an increase in the drug’s absorption, which limits its duration of action and increases the probability of toxic effects.

40
Q

Why does Cocaine not cause vasodilation?

A

-It blocks the reuptake of Norepi
-Used only topically

41
Q

Why does Ropivicaine and Lidocaine not cause vasodilation?

A

-Have IV vasoconstrictive properties.
-These are the only parenterally administered LAs with mild vasoconstrictive properties.

42
Q

Describe the Distribution of LAs.

A

-Drug gets absorbed into the intravascular space.

Distributed via 2 compartment model:
-Rapid Phase: to highly perfused tissues such as brain, heart, and lungs first. Equilibrium occurs quickly.
-Slow Phase: LA leaves the highly perfused tissue and is deposited in tissue with less perfusion. (ex: Muscle group). Over time, Muscle tissue receives the greatest amount of LA from redistribution.

43
Q

______ or _____ plasma cholinesterase can significantly prolong the half-life of ester LAs. (Blue Box!)

A

Saturated or Inhibited plasma cholinesterase can significantly prolong the half-life of ester LAs.

44
Q

How are Ester LAs metabolized?

A

Via hydrolysis by plasma esterases (in the plasma, RBCs, and the liver)
-Rapid rate of clearance reduces the risk of toxicity.
-1/2 life is related to metabolism. If enzymes are absorbed or used up, won’t be able to break down the drug and could lead to increased toxicity. Won’t affect the DOA at the site of action.

45
Q

How is Cocaine metabolized?

A

-Exception to Esters
-Metabolized in the Liver by Carboxylesterase.

46
Q

Why are Esters more likely to cause allergy?

A

-Contains PABA (metabolite).
-If you’re allergic to one, you’re allergic to all esters.

47
Q

What is the metabolism of Amide LAs?

A

-Undergo biotransformation in the Liver by CYP450.
-Metabolites are excreted in the kidneys (5% are excreted unchanged).

48
Q

Why are patients with renal dysfunction at risk for toxicity with Amide LAs?

A

-Metabolites are excreted in the kidneys (5% unchanged)
-Renal dysfunction = not clearing metabolites.
-At risk for LA toxicity.

49
Q

What is the effect of Hepatic Dysfunction on Amide LAs?

A

-Clinically, hepatic dysfunction does not necessitate a reduction of dose for a single injection nerve block.
-Doses of amides used in continuous infusions or repeat blocks should be reduced 10% to 50%.

50
Q

Saturated, inhibited, or genetically atypical plasma cholinesterase can significantly _____ the plasma HALF-LIFE (not DOA) or ester local anesthetics.

A

Saturated, inhibited, or genetically atypical plasma cholinesterase can significantly prolong the plasma half-life of ester local anesthetics. This would have little effect on duration of the ester agent because absorption away from the site of injection would occur as usual; however, this effect could theoretically increase the potential for systemic toxicity.

51
Q

What determines the rate of elimination of amide local anesthetics?

A

-Hepatic clearance is a function of the hepatic extraction ratio and hepatic blood flow and is the primary factor that determines the rate of elimination of amide local anesthetics.
-The hepatic extraction ratio is dependent on the ratio of free to protein-bound drug and represents the activity level specific to the liver for removing a drug from plasma.
-This ratio indicates the percentage of drug removed with each pass through the liver.
-The clearance of drugs that have higher hepatic extraction ratios depends on adequate hepatic blood flow.
-Hepatic enzyme activity is important when drugs with lower hepatic extraction ratios such as bupivacaine are used.

52
Q

What are pathological conditions that influence hepatic function and may prolong the elimination 1/2 life of LAs?

A

-Upper abdominal surgery
-Laparoscopic surgery
-INH agents
-Hypovolemia
-CHF

May cause a reduction in Hepatic Blood Flow, delaying the metabolism of Amide LAs.

53
Q

Which Amide LA is not metabolized by CYP450?

A

Articaine:
-Inactivated by plasma carboxylesterase.

54
Q

What is different about LAs in pregnant patients?

A

-Inc spread of depth of spinal & epidural anesthesia.
-Decreased thoracolumbar CSF (increases spread of LA)
-Increased neural susceptibility to local anesthetics
-Gravid uterus results in dilated epidural veins (narrowing epidural and SAB space, reducing dose requirement)
-Hormonal changes: Inc progesterone leads to increased sensitivity to LAs. (occurs during 1st trimester before uterus gets big enough to dilate the veins).