Lecture 16 (Exam 4) - Local Anesthetics Pt. 1 Flashcards
1
Q
Procaine
- Amide or Ester?
- Metabolite?
- How is this excreted?
- Why do we like this drug a lot?
A
- Ester (only 1 “i”)
- PABA (ParaAminoBenzoic Acid)
- Excreted via urine - UNCHANGED!
- Ester hydrolysis metabolism = fast! & it is very short acting 😁
Slide 34
2
Q
What LA is shorter acting than Procaine?
It is ____x as fast.
How must it be metabolized?
A
Chloroprocaine!
3.5x faster!
Metabolized by Plasma Cholinesterases, too!
*Castillo put a Podcast (not tested) on BB
Slide 34
3
Q
🤰 Does pregnancy ↓ or ↑ plasma cholinesterase?
By what %?
A
Decrease by 40%.
- pay mind to your drugs metabolized this way.
Slide 34
4
Q
Tetracaine
Do we use this a lot?
What is the order of metabolism (fastest to slowest) for these LA: tetracaine, chloroprocaine, procaine.
A
No!
Chloroprocaine > procaine > tetracaine
Slide 34
5
Q
With dose-dependant effects of Lidocaine intravascularly, what plasma concentration (dose) do we give to have an analgesic effect?
A
1-5 mcg/ml
(slide 7)
6
Q
With dose-dependant effects of Lidocaine intravascularly, what plasma concentration (dose) causes the effects of:
Circum-oral numbness
Tinnitus
Skeletal muscle twitching
Systemic hypotension
Myocardial depression
A
5-10mcg/ml
(slide 7)
7
Q
Which LA is the only weak acid?
What’s the pKa?
A
Benzocaine, pKa 3.5
*we usually spray this in anesthesia- but Orajel is the 🐐 when you have a canker sore.
Slide 35
8
Q
With dose-dependant effects of Lidocaine intravascularly, what plasma concentration (dose) causes the effects of:
Seizures
Unconsciousness
A
10-15mcg/ml
(slide 7)
9
Q
List some of the reasons we would use Benzocaine.
What is the onset?
DOA?
Dose?
A
Intubation w/ reactive airway disease, Endoscopy, TEE (transesophageal echocardiography), bronchoscopy
Onset: RAPID 💨
DOA: 30-60 mins
Dose: One 1 sec spray (20%) = 200 - 300 mg
Slide 35
10
Q
With dose-dependant effects of Lidocaine intravascularly, what plasma concentration (dose) causes the effects of:
Apnea
Coma
A
15-25mcg/ml
(slide 7)
11
Q
You suck at intubating bc you are a baby SRNA so you decide to spray extra doses of Benzocaine.
Is this okay?
A
No - you can cause Methemoglobinemia and your pt will become a Smurf. (might die)
Slide 35
12
Q
With dose-dependant effects of Lidocaine intravascularly, what plasma concentration (dose) causes the effects of Cardiovascular depression (RIP)
A
> 25mcg/ml
(slide 7)
13
Q
With LA, what is the molecular structure made of? (3 parts)
A
- Lipophilic portion (first)
- hydrocarbon chain (middle)
- hydrophilic portion (end)
(slide 8)
14
Q
The bond between which 2 parts of the LA molecular structure classifies it as either an Ester or Amide?
A
- Lipophilic portion (first)
- hydrocarbon chain (middle)
(slide 8)
15
Q
For LA molecular structure and its 3 parts, what are the names and associations to the Aromatic Benzene Ring?
A
- Lipophilic portion (first) - Aromatic Part
- hydrocarbon chain (middle)- Intermediate chain
- hydrophilic portion (end) - Amino group
(slide 9)
16
Q
A
Please for the love of Schmidt you better know how to convert pounds to Kg’s…
Answer: 436.5 mg
*remember MAX dose of Methylene Blue is 8 mg/kg
Slide 36
17
Q
How can we differentiate between an ester vs amide when looking at drug names?
A
amides have 2 i’s in its name
esters have 1 i in its name
(slide 9)
18
Q
In regards to the aromatic benzene ring, What 2 parts differentiates the linkage between being an amide vs ester LA?
A
The aromatic part and intermediate chain
(slide 9)
19
Q
For the composition of LA, what’s its:
pH:
Are they acids or bases?
A
pH: 6 (HCl salt)
WEAK BASE
(slide 10)
20
Q
What 2 drugs if given with our LA can change its structure/composition?
A
Epinephrine
Sodium Bisulfite
(slide 10)
21
Q
Which ester drug, Procaine or Tetracaine is more potent?
A
Tetracaine
(slide 11)
22
Q
Which Amide has the highest protein binding%?
And what does this mean for how it will react in our body?
A
Levobupivavaine= >97%
The greater the protein binding = stays in the body longer (longer DOA)
(slide 11)
23
Q
Any alteration in chemical structure leads to changes in ___________
A
Potency
Slide 11
24
Q
Bupivacaine is 3-4x more potent than Mepivacaine. How does this affect the duration of action for Bupivacaine vs. Mepivacaine?
A
Bupivacaine has a longer duration of action because it is more potent than Mepivacaine
Slide 11
25
Drugs that have a pK value closer to body Ph have ____________ onset of action.
Faster
Slide 12
26
Which three drugs discussed in class have a pK value closely resembling normal body pH?
Lidocaine - 7.9
Prilocaine - 7.9
Mepivacaine - 7.6
Slide 12
27
What is the primary determinant of a local anesthetic's potency?
Lipid solubility
Slide 13
28
What is used to upload higher amounts of LA into molecules and have consistent release of LA in the tissues?
Liposomes
Slide 14
29
Liposomes lead to ____________ duration of action and ___________ toxicity due to its timed release of local anesthetics.
Prolonged duration
Decreased toxicity
Slide 14
30
Local anesthetics inhibit passage into nerve membranes by binding to what type of channel?
Voltage Gated Sodium Channels
Slide 15
31
Local anesthetics need to be what form to go inside the cell and block the sodium channel?
Non-Ionized
Slide 15
32
**Cocaine**
1. Ester or Amide?
2. Metabolism?
3. What populations is metabolism ⬇️ ?
1. Ester
2. Metabolized by the plasma & liver cholinesterases (the book says cocaine is one of the only LA that is SIGNIFICANTLY metabolized in the liver)
3. Parturients (laboring mothers), neonates, Elderly, severe hepatic disease
Slide 37
33
**Cocaine**
Peak: ?
Duration: ?
Elimination: ?
What are you cautions with cocaine? (besides addiction)
Peak: 30-45 mins
Duration: 60 mins AFTER peak
Eliminations: Urine (24 - 36hrs)
Cautions: coronary vasospasm, ventricular dysrhythmias, HTN, tachycardia, CAD ❤️
34
Bupivacaine:
__% Protein Bound
____ arterial concentration
95% protein bound
0.32 arterial concentration
(slide 29)
35
Lidocaine:
__% protein bound
____ arterial concentration
70% protein bound
0.73 arterial concentration
(slide 29)
36
Prilocaine:
__% protein bound
____ arterial concentration
55% protein bound
0.85 arterial concentration
(slide 29)
37
If for any reason your pt goes into cardiac arrest 2/2 amide/ester systemic overdose, for the love of God do NOT stop compressions until the _____ ________ is given. Cuz he once heard of a 4 hour code happen until this was given and that pt lived and was d/c 2 weeks later.
Lipid Emulsion
(clinical pearls)
38
Ester Metabolism:
Occurs via _________ by ______________ enzyme in the plasma.
This enzyme is produced where?
Occurs via HYDROLYSIS by CHOLINESTERASE enzyme in the plasma.
Produced in the liver
(slide 26)
39
What's the metabolite of Ester metabolism?
What's the acronym for this metabolite?
T/F: This metabolite produces no allergic reaction.
Para-aminobenzoic acid
PABA
False: PABA causes "allergies"
(slide 26)
40
Which LAs have First-pass Pulmonary Extraction?
Which of those 3 is dose-dependent?
Lidocaine, bupivacaine, and and prilocaine
Bupivacaine is dose-dependent
(slide 27)
41
Renal Elimination and Clearance of LAs:
High or Poor water solubility?
Unchanged drug in urine = __%
Which ester is an exception? (unchanged drug in urine of 10-12%)
Is PABA metabolized or excreted via urine?
Poor water solubility
Unchanged drug in urine = 5%
Cocaine is the exception = 10-12% in urine
PABA is excreted unchanged via urine
(slide 27)
42
Pregnant pts have _____ levels of ______ _______________.
This means that we must give Esters _____________.
Pregnant pts have LOWER levels of PLASMA CHOLINESTERASES.
This means we must give Esters INCREMENTALLY.
Castillo says that the use of Esters with pregnant pts is a "Risk and Benefit decision" but then goes on to says he regularly give Esters as a "tincture"
(slide 28)
43
T/F: Amides pose significant transplacental transfer.
This is because of ___ ________.
Protein binding of Esters is dependent on ____ and degree of _________.
False: ESTERS pose significant transplacental transfer.
ion trapping
rate and degree of diffusion
(slide 28)
44
Remember this graph off slide 28
45
By blocking/inhibiting Na+ passage in nerve membranes what are 3 results?
Slowed rate of depolarization
mV does not reach threshold
No action potential
(Slide 16)
46
What are 3 factors affecting blockade of LA's?
1.) Lipid solubility or nonionized form (Chemistry, PKA, Etc.)
2.) Repetitively stimulated nerve (more stimulating = harder to block)
3.) Diameter of the nerve (larger nerve = more anesthetic needed)
(Slide 17)
47
What are 3 other sites of action targets of LA's?
1.) Potassium channels
2.) Calcium ion channels
3.) GPCR's (ligand gated)
(Slide17)
48
Is there cross-sensitivity between an ester allergy and an amide allergy?
Nope
(clinical pearl)
49
Class Question:
What component of the local anesthetic is required for a conduction block?
A.) Non-ionized form
B.) ionized form
C.) Both non-ionized and ionized forms
D.) None of the above
A.) Non ionized form
(minute 48 from lecture)
50
T/F: In general, the more lipid soluble the local anesthetic is, the greater its potency.
True
(class slide question)
51
How many Nodes of Ranvier need to be blocked for an effective nerve block?
At least 2, preferably 3 (1cm)
(slide 18)
52
Which LA property is most important when it comes to the duration of action? (Castillo actually answers this question in a Most important to Least important.)
A. Protein Binding
B. Lipid Solubility
C. Metabolism
D. Clearance
Most important: Lipid Solubility ("area of distribution")
then Clearance,
Then Protein Binding
Lastly, Metabolism
(class slide question)
53
What value for LA's equates to MAC for Volatiles?
Also labeled as?
Minimum Effective Concentration (MEC)
Cm's (minimum concentration?)
(Slide 18)
54
Larger or smaller fibers need higher concentrations of LA's
Larger
(Slide 18)
55
How much bigger is the diameter of a motor nerve compared to a sensory nerve?
2x
(slide 18)
56
What are the fastest nerve fibers?
What is special about these mentioned in lecture?
Preganglionic B fibers
Involved in the SNS and can cause changes in HR and BP
(slide 19)
57
The pH of the environment past the placenta (towards baby) is more ______ than the maternal environment.
This = _____ ion-trapping of LAs (weak _____)
acidic
MORE ion trapping of LAs (weak base)
(Castillo on slide 28)
58
How does pregnancy effect LA's?
Increased sensitivity
May need less block!!!!
(Fuck what Castillo said in his lecture.)
(slide 19)
59
What regulates the pH between the amniotic sac and maternal circulation?
What can happen to a fetus if LAs are given that reach a systemic level?
If we want to optimize pH to avoid ion trapping that leads to LA ________, we can give ___________.
Placenta
fetal ion trapping --> LA toxicity --> **fetal acidosis/acidemia**
LA toxicity, Bicarb****
(Castillo context for slide 28)
60
What are the last fibers that tend to be effected by LA block?
Unmyelinated C fibers
(Motor is blocked last: A alpha fibers)
(Slide 19)
61
What effects do the preganglionic B fibers have?
Control of SNS (HR, BP). These are the fastest fibers.
(slide 19)
62
What effects do myelinated A and unmyelinated C fibers have?
Pain, Temperature, proprioception, motor
(slide 19)
63
If the pKa is closest to the physiologic pH what is the effect?
more rapid onset of action
(slide 20)
64
What is the effect of a high intrinsic vasodilator activity of a LA?
Decreased potency and duration of action.
The higher vasoconstriction the more the drug will remain localized and have a longer effect.
(slide 20)
65
You have a weak base with pKa value above physiologic pH.
How much of it is in lipid soluble nonionized form?
50%
(Slide 20)
66
Lidocaine
1. Where is it metabolized?
2. What is its metabolite?
3. Is it an anti-dysrhythmic?
4. Dose without EPI? With EPI?
5. Considerations for pregnant moms? 🤰🏽
Lidocaine (Amide)
1. Metabolism: Oxidative dealkylation in liver, then hydrolysis.
2. Metabolite: Xylidide
*Hepatic disease will affect metabolism and elimination
3. It is an Anti-dysrhythmic
4. Maximum infiltration dose: 300 mgs plain (No EPI) & 500 mgs /c EPI (Higher dose because it gets cleared and metabolized slower)
5. Prolonged clearance with Pregnancy Induced Hypertension (PIH) (Body is breaking down more proteins, there are more protein fragments in the blood that it can bind to)
(Slide 30)
67
Prilocaine
1. What is the metabolite?
2. Dose?
3. Signs and symptoms of Prilocaine toxicity?
4. Treatment?
Prilocaine (Amide)
1. Metabolite: Orthotoluidine
*Converts Hemoglobin to Methemoglobin
**⚠️Methemoglobinemia causes cyanosis d/t decreased 02 carrying capacity⚠️***
2. Dose > 600 mgs
3. S/Sx: Cyanosis d/t decreased 02 carrying capacity
4. TX: Methylene Blue
*1 to 2 mgs/kg IV over 5 mins
*Total dose not to exceed 7 to 8 mg/kg
(Slide 31)
68
Mepivacaine
1. It is similar to Lidocaine, except?
2. It is OB approved?
Mepivacaine (Amide)
1. Similar to Lidocaine, except with:
*Longer duration of action
*Lacks vasodilator activity
2. It is not OB approved. Prolonged elimination in fetus & newborn; no OB
(Slide 32)
69
Bupivacaine
1. Where is it metabolized?
2. Is it protein bound?
Bupivacaine (Amide)
1. Metabolism (Liver primarily): aromatic hydroxylation, N-dealkylation, amide hydrolysis, and conjugation
2. Protein (95%) binding site: α1-Acid glycoprotein (Can bind to albumin too.)
(Slide 32)
70
Ropivacaine
1. How is it metabolized?
2. What are the considerations with its metabolites?
3. Is it protein bound?
Ropivacaine (Amide)
1. Metabolism: Hepatic cytochrome P450 enzymes
2. Metabolites: can accumulate with uremic patients
Lesser system toxicity than Bupivacaine
3. It is protein bound: α1-acid glycoprotein
(Slide 33)
71
Dibucaine
1. Where is it metabolized?
2. What is the MOA?
3. What is it used for?
Dibucaine (Amide)
1. Metabolism: Liver
2. MOA: inhibits the activity of normal butyrylcholinesterase (plasma cholinesterase) by more than 70%
3. Used to diagnose sensitivity to Succinylcholine.
* Dibucaine of 80 = normal, Succinylcholine metabolism will not be impaired!
* Dibucaine of 20 = Succinylcholine will be prolonged!
(Slide 33)
72
The first local anesthetic in all of history was??
COCAINE BITCHES!
(Slide 2)
73
Most local anesthetics cause local vasodilation, except for ____ which causes local vasoconstriction.
again, COCAINE BITCHES!!!
(Slide 2)
74
The first ESTER local anesthetic??
Procaine - 1905
(Slide 2)
75
The first AMIDE local anesthetic and also our gold standard for local anesthetics?
Lidocaine!
(Slide 2)
76
Typical uses for local anesthetics?
1. Treat arrhythmias.
2. Analgesia for acute and chronic pain.
3. In anesthesia local anesthetics are used to block autonomic nervous system, sensory anesthesia, and skeletal muscle paralysis.
(Slide 3)
77
In which class of antiarrhythmics will you find local anesthetics?
Class I - Sodium channel blockers. Local anesthetics like lidocaine fall under this class.
As a refresher, the other classes of antiarrhythmics are Class II - Beta blockers, Class III - Potassium channel blockers, Class IV - Calcium channel blockers.
(Slide 3)
78
What is added to local anesthetics to help them vasoconstrict?
Epinephrine!
(Slide 5)
79
Not sure if it will be tested…but MAGA dosing for lidocaine?
1 - 2 mg/kg initial IV bolus, followed by 1 - 2 mg/kg/hr gtt. Terminate in 12 - 72 hrs.
(Slide 6)
80
What are some pharmacokinetic factors that influence LA absorption?
1. Site of injection
2. Dosage --> more dosage covers more nodes of Ranvier --> less conduction
3. Use of Epinephrine
4. Pharmacologic characteristics of the drug
Slide 21
81
Important to memorize the chart. It gives the blood concentration of LA depending on the site of injection.
Slide 21
82
Why is an epidural injection of LA have a shorter duration of action than an injection at the Sciatic level?
Because of the availability of the epidural veins.
Slide 21
83
What concentration of epinephrine do we usually use with LA and why?
Usually 1:200,000 equivalent to 5 mcg/ml of epi that we mix with LA to prolong the duration of action. This limits the systemic absorption of LA by 1/3.
slide 21
84
Pharmacologic characteristics of the LA depends on:
1. Rate of distribution
2. Rate of clearance
Slide 22
85
What does the rate of tissue distribution depend on?
Lipid Solubility
(Lipid solubility is primary determinant of potency--> memorize it!! and stay away from intravascular, go straight to the cut/tip of finger ☝️)
Slide 22
86
What does the rate of clearance (clearance out of the site of injury) of LA depend on?
1. Cardiac Output → ↓ CO and ↓ clearance, so give less.
2. Protein binding → specific to an intravascular component
(LA once gets out of the site of injury, its cleared and will not have any affect at the site of injury. Now LA moves to intravascular space and protein binding of the LA affects its metabolism and clearance from our body. So, LA might be cleared from the site of injury but may not be cleared from the body due to its protein binding capability. )
Slide 23
87
True or false:
The % LA bound to protein is inversely proportional to the % bound to the plasma.
True.
(The higher % of LA bound to protein, lower unbound LA in plasma.)
Slide 23
88
Least protein bound LA will have fastest metabolism and clearance. T/F
True
Slide 24
(Procaine protein bind is 6%- least and has a high metabolism and high clearance)
89
Why is it important to know the protein binding, metabolism and clearance of LA?
Because we re-dose and prevent LA toxicity.
Slide 24
90
Highest protein binding LA are:
Bupivacaine →95%, Levobupivacaine →>97%, and Ropivacaine →94%
Slide 24
91
How are amides metabolized?
Via microsomal enzymes (CYP450) in the liver
Slide 25
92
Name amides that have most rapid, intermediate, and slowest metabolism.
Most rapid → Prilocaine 55% (lowest protein binding capacity)
Intermediate → Lidocaine 70% and mepivacaine77%
Slowest → Etidocaine, Bupivacaine, and Ropivacaine (highest protein binding capacity)
Slide 25
