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Pharm 2 Flashcards

1
Q

Describe the components of the neuron and their function:

see photo in pharm2: LA

A
  • Dendrites: receives and processes signal
  • Soma: integrates signal and cellular machinery
  • Axon hillock
  • Axon: sends signal
  • Node of ranvier
  • myelin
  • presynaptic terminal: releases neurotransmitters
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2
Q

What is conduction velocity, and how is it affected by myelination and axon diameter?

A

A measure of how fast an axon transmits the action potential.
CV is increased by:
-myelination: the action potential skips along the nodes of ranvier (saltatory conduction)
-Large fiber diameter

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3
Q 
A-alpha Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Heavy myelination

Function: skeletal muscle (motor), proprioception

diameter: 12-20um
speed: +++++

Block onset: 4th

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4
Q 
A-beta Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Heavy myelination

Function: Touch, pressure

diameter: 5-12um
speed: ++++

Block onset: 4th

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5
Q 
A-gamma Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Medium myelination

Function: skeletal muscle (tone)

Diameter: 3-6um

Velocity: +++

Block onset: 3rd

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6
Q 
A-delta Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Medium myelination

function: Fast pain, temperature, touch

Diameter: 2-5um

Velocity: +++

block onset: 3rd

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7
Q 
B Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Light myelination

function: Preganglionic ANS fibers

Diameter: 3um

Velocity: ++

Block onset: 1st

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8
Q 
C sympathetic Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Not myelinated

Function: post-ganglionic ANS fibers

Diameter: 0.3-1.3um

Velocity: +

Block onset: 2nd

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9
Q 
C dorsal root Fibers:
Myelination?
Function?
Diameter (um)?
Velocity?
Block onset?
A

Not myelinated

Function: slow pain, temperature, touch

Diameter: 0.4-1.2um

Velocity: +

Block onset: 2nd

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10
Q

Discuss differential blockade using epidural bupivacaine as an example:

A

Differential blockade is the idea that some fiber types are blocked sooner (easier) than others.

Epidural bupivacaine serves as an excellent example of this:

  • at lower concentrations, epidural bupivacaine provides analgesia while sparing motor function.
  • as the concentration is increased, it anesthetizes more resistant nerve types, such as those that control motor function and proprioception.
  • this is the basis for a ‘walking’ epidural with a low concentration of bupivacaine.
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11
Q

What concept is analogous to ED50 for a local anesthetics?

A

Minimum affect concentration (Cm) is the concentration of local anesthetic that is required to block conduction.

  • fibers that are more easily blocked have a lower Cm.
  • fibers that are more resistant to blockade have a higher Cm.
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12
Q

Rank the nerve fiber types according to their sensitivity to local anesthetics in vivo (most to least sensitive).

A

B fibers > C fibers > small diameter A fibers (gamma and delta) > large diameter A fibers (alpha and beta)

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13
Q

What are the 3 possible configurations of the voltage-gated sodium channels? (see photo in Pharm 2: LA)

A

Resting: the channel is closed and able to be opened if the neuron depolarizes.

Active: the channel is open, and sodium is moving along its concentration gradient into the neuron.

Inactive: the channel is closed and unable to be opened (it is refractory)

*The voltage near the channel determines the state of the channel.

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14
Q

How and when do local anesthetics bind to the voltage-gated sodium channels?

A

The guarded receptor hypothesis states that local anesthetics can only bind to sodium channels in their active (open) and inactive (closed refractory) states. Local anesthetics do NOT bind to sodium channels in their resting state.

Local anesthetics are more likely to bind to axons that are conducting action potentials and less likely to bind to those that are not conducting action potentials. This is called a use-dependent or phasic blockade.

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15
Q

What is an action potential, and how does it depolarize a nerve?

A

A temporary change in transmembrane potential followed by a return to transmembrane potential.

In order for a neuron to depolarize, sodium must enter the cell (this makes the inside more positive).
Once threshold potential is achieved, the cell depolarizes and propagates an action potential.
Depolarization is an all or nothing phenomenon; the cell either depolarizes or it does not.
The action potential only travels in one direction. This is because the sodium channels in upstream portions of the neuron are in the closed/inactive state.

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16
Q

What happens when a nerve repolarizes?

A

If depolarization is the accumulation of positive charges (sodium) inside the neuron, then repolarization is the removal of positive charges from the inside of the cell. This is accomplished by removing potassium.

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17
Q

How do you local anesthetics affect neuronal depolarization? (see photo in Pharm2: LA)

A

Local anesthetics bind to the alpha–subunit on the inside of the sodium channel when it is either in the active or inactive state.

  • when a critical number of sodium channels are blocked, there aren’t enough open channels for Na+ to enter the cell in sufficient quantity.
  • The cell can’t depolarize and the action potential can’t be propagated. whatever modality that nerve services (pain, movement, etc) is blocked.

LA do NOT affect resting membrane potential or threshold potential.

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18
Q

Discuss the role of ionization with respect to local anesthetics. (see photo in Pharm2: LA)

A

LA are weak bases with PKa values higher than 7.4, we can predict that >50% of the LA will exist as the ionized, conjugate acid after injection.

The non-ionized fraction that diffuses into the nerve. Once inside the neuron, the law of mass action promotes re-equilibration of charged and uncharged species. The charged species binds to the alpha-subunit on the interior of the voltage-gated Na+ channel.

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19
Q

Other ways of saying “ionized fraction”

A

“conjugate acid”
“protonated species”
“cation”

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20
Q

What are the 3 building blocks of LA molecules?

How does each one affect the PK/PD profile of the molecule? (see photo in Pharm2: LA)

A

Benzene ring:
lipophilic
permits diffusion through lipid bilayers

Intermediate chain:
Class- ester or amide
metabolism
allergic potential

Tertiary amine:
Hydrophilic
accepts proton
makes molecule a weak base

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21
Q

How can you use the drug name to determine if it is an Ester or Amide? give examples:

A 
Esters: NO "i" before suffix -caine.
Benzocaine
Cocaine
Chloroprocaine
Procaine
Tetracaine
Amides: "i" before suffix -caine
Articaine
bupivacaine
dibucaine
etidocaine
levobupivacaine
lidocaine
mepivacaine
ropivacaine
22
Q

How are ester LA metabolized?

A

pseudocholinesterase

23
Q

How are amide LA metabolized?

A

hepatic carboxylesterase/P450

24
Q

Which LA participates in both metabolic pathways of Ester and amides?

A

Cocaine is an ester but is metabolized by pseudocholinesterase and the liver.

25
Q

Discuss LA allergy and cross sensitivity:

A

True allergy is rare. More common with Esters.
Ester LAs are derivatives of para-aminobenzoic acid (PABA) which is an immunogenic molecule capable of causing allergic reaction. This is reason for cross sensitivity.

Amide LA allergy is incredibly rare. Some multi-does vials contain methylparaben as preservative which is similar to PABA.

If pt has true allergy to ester, all other testers should be avoided. It is safe to select an amide that doesn’t contain methylparaben. Pt with amide allergy can safely receive an ester.

26
Q

What determines LA onset of action? Which drug disobeys this role and why?

A

pKa determines onset.

  • If pKa is closer to pH, onset is faster.
  • If pKa is further from pH, onset is slower.

Chloroprocaine disobeys this rule:

  • it has high pKa, which suggests slow onset.
  • at same time, chloroprocaine is not very potent, so we have to give it in a higher concentration (usually 3%)
  • giving more molecules crease a mass effect that explains why chloroprocaine has rapid onset of action even with high pKa.
27
Q

What determines LA potency?

A

Lipid solubility.
More lipid soluble a LA, the easier it is for the molecule to traverse the neuronal membrane.
B/c more drug enters the neuron, there will be more of it available to bind to the alpha-subunit of voltage-gated sodium channels.

An intrinsic vasodilation effect is a secondary determinant of potency.
Vasodilation increases uptake into systemic circulation, and this reduces the amount of LA available to anesthetize the nerve.

28
Q

What factors determine LA duration of action?

A

Protein binding.
After LA injection, some molecules penetrate the epineurium, some diffuse away into the systemic circulation, and some bind to tissue proteins. Molecules that bind to proteins serve as a reservoir that extends duration of action.

ProteinLA+ Protein + (LA+) LA + (H+)

Lipid solubility and intrinsic vasodilating activity are secondary determinants of duration of action.

  • higher degree of lipid solubility also correlates with longer duration.
  • drug with intrinsic vasodilation activity will increase its rate of vascular uptake and shorten its duration of action.
29
Q

Discuss the intrinsic vasodilation effects of LA. Which LA has the opposite effect?

A

Absorption into bloodstream begins the preocess of delivering drug to its site of action. LA are different: They are given directly to site of action. Absorption into circulation removes them from site of action and contributes to termination of effect.

  • Most LA cause some degree of vasodilation. Those w/ greater degree of intrinsic vasodilation effects (lidocaine) undergo faster rate of vascular uptake, preventing some of the administered dose from accessing nerve.
  • Addition of vasoconstrictor can prolong duration of action, seen when used with LAs that produce the greatest amount of vasodilation.

*cocaine is unique. It always causes vasoconstriction, b/c it inhibits NE reuptake in sympathetic nerve endings in vascular smooth muscle.

30
Q

Rank the amide LA according to pKa:

pKa//ionization % at 7.4//protein binding %

A 
Bupivacaine 8.1//83//96
Levobupivacaine 8.1//83//98
Ropivacaine 8.1//83//94
Lidocaine7.9//76//65
Prilocaine 7.9//76//55
Mepivacaine 7.6//61//78

*as pKa gets further from physiologic pH, the degree of ionization increases.

31
Q

Rank the ester LA according to pKa:

pKa//ionization % at 7.4//protein binding %

A

Procaine 8.9//97//6
Chloroprocaine 8.7//95//0
Tetracaine 8.5//93//76

32
Q

5 factors that govern the uptake and plasma concentration of LA:

A
  • Site of injection
  • Tissue blood flow
  • physiochemical properties of LA
  • metabolim
  • addition of vasoconstrictor
33
Q

Rank injection sites to the corresponding plasma concentrations of LA:
(Most vascular and highest plasma concentration to least vascular and lowest plasma concentration)

A 
Intrapleural 
Intercostal
caudal
Epidural 
Brachial plexus 
Femoral
sciatic
subcutaneous
34
Q

What is the maximum dose for each AMIDE LA?

weight based and max total dose

A 
Levobupivacaine 2mg/kg (150mg)
Bupivacaine 2.5 mg/kg (175mg)
Bupiv w/ epi 3mg/kg (200mg)
Lido 4.5mg/kg (300mg)
Ropi 3mg/kg (200mg)
Mepivacaine 7mg/kg (400mg)
Lido w/ epi 7mg/kg (500mg)
Prilocaine 8mg/kg (if <70kg--> 500mg; if >70kg--> 600mg)
35
Q

What is the maximum dose for each ester LA (weight based and max dose)?

A

Procaine 7mg/kg (350-600mg)
Chloroprocaine 11mg/kg (800mg)
Chloroprocaine w/ epi 14mg/kg (1000mg)

36
Q

What is the most common sign of LA systemic toxicity?

A

Seizures.

Bupivacaine is the exception- cardiac arrest can occur before seizure.

37
Q

List the effects of lidocaine toxicity according to plasma concentration:

A

1-5 mcg/ml = analgesia

5-10 mcg/ml= Tinnitus Numbness of lips and tongue
Skeletal muscle twitching
Restlessness
Vertigo
Blurred vision
Hypotension
Myocardial depression

10-15mcg/mL= seizures
Loss of consciousness

15-25mcg/mL= coma
Respiratory arrest

> 25mcg/mL= Cardiovascular collapse

38
Q

What conditions increase the risk of CNS toxicity from LAST?

A

Hypercarbia: increases cerebral blood flow –> increases drug delivery to brain. Decreases protein binding–> increases free fraction available to enter brain.

Hyperkalemia: raises resting membrane potential, making neurons more likely to depolarize.

Metabolic acidosis: decreases the convulsion threshold and favors ion trapping inside the brain.

*If you were thinking that acidosis should increase the fraction of conjugate acid and decrease the amount of uncharged base that is available to pass through the blood brain barrier, then you were right! Unfortunately, this alone is not enough to decrease the risk of CNS toxicity.

39
Q

Why is the risk of cardiac morbidity higher with bupivacaine than wit lidocaine?

A

2 features determine the extent of cardio toxicity of any local anesthetic:

  • Affinity for the voltage-gated sodium channel in the active and inactive state.
  • Rate of dissociation from the receptor during diastole.

Compared to lido, Bupi has greater affinity for voltage-gated Na+ channel and a slower rate of dissociation from this receptor during diastole. The result is more Bupi remains at receptor for longer. This explains why cardiac morbidity is higher and why resuscitation is so difficult with Bupi.

40
Q

LA in order of difficulty of cardiac resuscitation :

A

Bupivacaine > Levobupivacaine > Ropivacaine > Lidocaine

41
Q

Discuss the modifications to ACLS treatment protocol when applied to LAST:

A

Epinephrine can hinder resuscitation from LAST, and it also reduces the effectiveness of lipid emulsion therapy. If epinephrine is used, it should be given in doses of < 1 mcg/kg.

Amiodarone is the agent of choice for ventricular arrhythmias.

Avoid vasopressin, lidocaine, and procainamide.

42
Q

How does lipid emulsion work for the treatment of LAST:

A

Lipid emulsion acts as a lipid sink: an intravascular reservoir that sequesters local anesthetic and reduces plasma concentration of local anesthetic.

43
Q

Treatment for LAST:

A
  • Bolus 20% 1.5mL/kg (lean body mass) over 1 minute
  • Infusion 0.25 mL/kg/min.
  • If symptoms are slow to resolve, repeat bolus up to 2 more times and increase infusion rate to 0.5mL/kg/min.
  • Continue infusion for 10min after achieving hemodynamic stability
  • Maximum recommended dose is 10mL/kg in the first 30min.
44
Q

90kg patient undergoing liposuction. Surgeon uses tumescent lidocaine 0.1% and asks you to calculate max dose. How much lido can the patient receive? (in mL)

A

Max dose of lidocaine for tumescent anesthesia is 55mk/kg.
90kg x 55mg/kg = 4950mg
0.1% =1mg/mL.
Patient can receive 4950mL.

45
Q

In addition to local anesthetic toxicity, what are other complications of a large volume of tumescent anesthesia?

A

Pulmonary edema d/t volume overload.
If patient experiences CV collapse, 1st calculate the max dose of lidocaine received. If dose is w/I acceptable range consider other complications, such as volume overload and pulmonary embolism.

General anesthesia is recommended if > 2-3L of tumescent solution is injected.

46
Q

Name 2 LAs that are most likely to produce a leftward shift of oxyhemoglobin dissociation curve.
why does this happen?

A

Prilocaine and benzocaine can cause methemoglobinemia.

  • O2 binding sites on heme contain an iron molecule in its ferrous form (Fe++)
  • Oxidation of iron into ferric form (Fe+++) creates methemoglobin.
  • Methemoglobin impairs O2 binding and unbinding from the Hgb molecules, shifting the Oxyhemoglobin dissociation curve left. (creates physiologic anemia).
47
Q

What drugs are capable of causing methemoglobinemia?

A

LA:

  1. Benzocaine
  2. Cetacaine (contains benzocaine)
  3. Priolocaine
  4. EMLA (prilocaine + lidocaine)
Other drugs: 
Nitroprusside
Nitroglycerine
Sulfonamides
Phenytoin
48
Q

What are s/s of methemoglobinemia?

A 
Hypoxia
Cyanosis* (slate-grey pseduocyanosis) 
Chocolate colored blood
Tachycardia
Tachypnea
Mental status change
Coma or death

*Cyanosis in the presence of normal PaO2 is highly suggestive of methemoglobinemia.

49
Q

Tx for methemoglobinemia?

A

Methylene blue 1-2mg/kg over 5 minutes (MAX 7-8mg/kg)

Methylene blue is metabolized by methemoglobin reductase to form leucomethylene blue. This metabolite functions as an electron donor and reduces methemoglobin (Fe+++ back to hemoglobin (Fe++).

50
Q

What are the constituents of EMLA cream?

A

5% EMLA cream is 50/50 combination of 2.5% lidocaine and 2.5% prilocaine.

51
Q

How does prilocaine cause methemoglobin and who is at risk?

A

Prilocaine metabolizes to o-toluidine, which oxidizes hemoglobin to methemoglobin.
Infants and small children are more likely to become toxic.

52
Q

What is the max dose for EMLA cream?

age and weight//max dose//max area of application

A

0-3months or < 5 kg//1g//10cmsq

3-12month and > 5kg//2g//20cmsq

1-6yrs and >10kg//10g//100cmsq

7-12yr and >20kg//20g//200cmsq

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