SS25 Local Anesthetics I (Exam 4) Flashcards
(126 cards)
1
Q
First local anesthetic (LA)
A
- Cocaine
2
Q
Is Cocaine an Ester or Amide?
A
ESTER
3
Q
What was cocaine first used for and what was the effect?
A
- Ophthalmology (1884)
- Local vasoconstriction: shrink nasal mucosa
4
Q
First synthetic ESTER developed in 1905
A
PROCAINE
5
Q
First synthetic AMIDE developed in 1943
A
LIDOCAINE
- Became gold standard for all other LAs
6
Q
What drug class is associated with each Antiarryhthmic class:
- Class I
- Class II
- Class III
- Class IV
- Miscellaneous
Hint: 1 class per group
A
- Class I: Na-channel blockers
- Class II: βeta blockers
- Class III: K-channel blockers
- Class IV: Calcium-channel (CaC) blockers
- Miscellaneous: Adenosine, Electrolyte supplements, digitalis compunds (Cardiac glycosides)
7
Q
What are the uses for LAs?
A
- Treat dysrhythmias
- Analgesia: Acute and Chronic pain
- Anesthesia: ANS Blockade, Sensory Anesthesia, Skeletal Muscle Paralysis
8
Q
LIDOCAINE: Antiarrhythmic Drug Class
A
Class I: Sodium-channel Blockers
9
Q
What is the intra-op infusion dose of lidocaine (multi-modal)?
A
1 mg/kg over an hour
10
Q
Lidocaine: Bolus dose and infusion dose
A
- Bolus: 1 to 2 mg/kg IV over 2 - 4 min
- Infusion: 1 to 2 mg/kg/hr
11
Q
When should the Lidocaine infusion be terminated?
- Which organ systems need to be monitored closely?
A
- Terminate within 12 - 72 hours
- Cardiac, Hepatic, Renal dysfunction
12
Q
Dose-dependent effects of plasma Lidocaine concentration @ 1 - 5 mcg/ml:
A
Analgesia
13
Q
Dose-dependent effects of plasma Lidocaine concentration @ 5 - 10 mcg/ml:
A
- Circum-oral numbness
- Tinnitus
- Skeletal muscle twitching
- Systemic hypotension
- Myocardial depression
14
Q
Dose-dependent effects of plasma Lidocaine concentration @ 10 - 15 mcg/ml:
A
- Seizures
- Unconsciousness
15
Q
Dose-dependent effects of plasma Lidocaine concentration @ 15 - 25 mcg/ml :
A
- Apnea
- Coma
16
Q
Dose-dependent effects of plasma Lidocaine concentration @ >25 mcg/ml :
A
- Cardiovascular Depression
17
Q
What is the molecular structure of LAs?
A
- Lipophilic Portion (Aromatic ring)
- Hydrocarbon Chain (intermediate chain bridging the lipophillic &. hydrophillic portions)
- Hydrophilic (Tertiary Amino Group)
18
Q
What structural component of a LA determines if it is an ester or an amide?
- Significance?
A
- Bond between the lipophilic (aromatic) portion and the hydrocarbon chain will determine if LA is an ester or an amide
- The classification effects clearance and metabolism
Side note: All esters have (1) i & all amides have (2) i’s
19
Q
What type of local anesthetic would you anticipate from the figure below?
A
Ester due to the ester bond between the aromatic and the intermediate chain
20
Q
What type of local anesthetic would you anticipate from the figure below?
A
Amide due to the amide bond between the aromatic and the intermediate chain
Side note: All esters have (1) i & all amides have (2) i’s
21
Q
Bonus: Name these LA drugs based on molecular structure.
A
- Top: Procaine
- Bottom: Lidocaine
22
Q
Majority of LA have a pH of ______ and are Weak ________.
A
- pH of 6 (HCl salts)
- Weak BASES
Side note: drug name + suffix chemical name = base;
prefix chemical name + drug name = acid
23
Q
LA composition:
A
- pH of 6
- Epinephrine (local level)
- Sodium Bisulfite - Increases Epinephrine solubilty and prevents precipitate formation from Epinephrine
24
Q
Bonus: Which amide LA are chiral drugs?
A
- Mepivacaine, Bupivacaine, Ropivacaine
- All 3 contain assymetrical carbon atom
25
Increased potency generally correlates to increased __________.
**Lipid solubility**
26
Per lecture, at a pH of ________: (*table trend*)
-**If ESTER, ↑ non-ionization % = ↑ potency**
-**If AMIDE, ↓ non-ionization % = ↑ potency**
- pH of 7.4
- Amides with higher potency have higher lipid solubility & lower non-ionization fraction
27
**Most potent LA**?
- Class?
- Potency value?
- Lipid solubility?
- Protein binding?
- **Tetracaine** = Ester
- Potency = **16** b/c has **highest lipid solubility** (**80**)
- **PB: 76 %**
28
Order esters from **least to most** potent. Include values.
1. Procaine -1
2. Chloroprocaine - 4
3. Tetracaine - 16
## Footnote
**Hint: Factor of 4*
29
Order **amides** from **least to most** potent. Include values.
- Least:
-Lidocaine = Prilocaine = Mepivacaine - 1
- Most:
-Bupivacaine = Levobupivacaine =Ropivacaine - 4
## Footnote
**Hint: Factor of 4**
30
Which **3 Amides LA** will exhibit the **highest degree of protein binding**? Place in order from **least to most.**
- **What trends are associated with these 3 amides ?**
1. Ropivacaine - 94 %
2. Bupivacaine - 95 %
3. Levobupivacaine - ( > 97 %)
**↑protein binding = ↑ potency, ↓ single dose, slower onset, ↑ duration, ↑ pk**
## Footnote
**Most potent Amides have highest protein bindings**
31
Which **Amide** LA has **lowest degree of protein binding**?
- Lipid solubility?
- What effect does it have on Vd?
- **Prilocaine** - **55 %**
- Vd = **191 L (highest Vd among all other LA)** d/t very low lipid solubility (**0.9**) and protein binding
32
- Only ester LA with rapid onset?
- Only amide LA with rapid onset?
- Ester: Chloroprocaine
- Amide: Lidocaine
33
What are the pk values for the following Ester LA?
- Procaine
- Chloroprocaine
- Tetracaine
- Procaine **8.9**
- Chloroprocaine **8.7**
- Tetracaine **8.5**
34
What are the pk values for the following Amides LA?
- Lidocaine
- Prilocaine
- Mepivacaine
- Bupivacaine
- Levobupivacaine
- Ropivacaine
- Lidocaine **7.9**
- Prilocaine **7.9**
- Mepivacaine ***7.6***
- Bupivacaine **8.1**
- Levobupivacaine **8.1**
- Ropivacaine **8.1**
35
Which **Amide** has the **greatest degree of lipid solubility**?
- Compare potency and duration of action to Lidocaine? (*Greater or less)*
- Bupivacaine (**28**)
- Greater potency & longer duration of action > Lidocaine
36
Nonionized % @ pH of 7.4:
- Procaine
- Chloroprocaine
- Tetracaine
- Procaine = 3 %
- Chloroprocaine = 5 %
- Tetracaine = 7 %
37
Nonionized % @ pH of 7.4:
- Lidocaine
- Prilocaine
- Mepivacaine
- Bupivacaine
- Levobupivacaine
- Ropivacaine
- Lidocaine 25 %
- Prilocaine 24 %
- Mepivacaine 39 %
- Bupivacaine **17 %**
- Levobupivacaine **17 %**
- Ropivacaine - **17 %**
38
**Procaine**:
- **duration of action:**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- **45 - 60 min**
- **500 mg**
- 9 min
- PB: **6 %**
- Vd 65 L
- **Lipid solubility 0.6**
## Footnote
**Highest Vd & Lowest lipid solubility among Esters**
39
**Chloroprocaine**
- **duration of action:**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- 30 - 45 mins (**most rapid overall**)
- max dose: **600 mg**
- 7 min **(Fastest**)
- n/a
- 35 L (**lowest ester Vd**)
- n/a
40
**Tetracaine**:
- **duration of action**
- **max single dose for infiltration**
- Elimination half-time
- **protein binding %**
- Vd
- **Lipid solubility**
- 60 - 180 min (**longest ester**)
- 100 mg **T**opical
- n/a
- **76%**
- n/a
- **80**
41
duration of action of Amide LA:
- Lidocaine
- Prilocaine
- Mepivacaine
- Bupivacaine
- Levobupivacaine
- Ropivacaine
- Lidocaine: **60 - 120 mins**
- Prilocaine: **60 - 120 mins**
- Mepivacaine: *90 -180 mins*
- Bupivacaine: **240 - 480 mins**
- Levobupivacaine: **240 - 480 mins**
- Ropivacaine: **240 - 480 mins**
42
**Lidocaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- Clearance
- **300 mg** (**500 mg w/ Epi**)
- 96 min
- **70 %**
- 91 L
- **2.9**
- 0.95 L/min
## Footnote
**Lidocaine & Prilocaine: SAME potency, duration, pK, & elimination half time**
43
**Prilocaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- **600 mg** (**highest max**)
- 96 min
- **55 %**
- 191 L (**highest Vd**)
- **0.9**
44
**Mepivacaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- Clearance
- **400 mg** (**500 mg w/ Epi**)
- 114 min
- **77 %**
- 84 L
- **1**
- 9.78 L/min (**highest**)
45
**Bupivacaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **Lipid solubility**
- Clearance
- **175 mg** (**225 mg w/ Epi**)
- 210 min (**longest**)
- **95 %**
- 73 L
- **28**
- 0.47 L/min
46
**Levobupovacaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **175 mg** (**225 mg w/ Epi**)
- 156 min
- **> 97%**
- 55 L (**lowest amide Vd**)
47
**Ropivacaine**
- **max single dose for infiltration:**
- Elimination half-time:
- **protein binding %**
- Vd
- **200 mg**
- 108 mins
- **94 %**
- 59 L
48
Table to Review
49
Table to review
50
How do liposomes & LA interact?
- What is the result?
- Liposomes unload a higher amount of LA into molecule & have **consistent, controlled release** of LA into tissues
- Prolonged duration (extended release: ER) & decreased toxicity
51
Which LAs are being linked to Liposomes? (3)
- Lidocaine: gold standard
- Tetracaine: Most potent LA
- Bupivacaine: > potentcy Lidocaine
## Footnote
Most potent amide and ester & the gold standard
52
The FDA released this LA that contains liposomes.
- What is the duration of action?
- **Exparel** (Bupivacaine ER)
- Duration **up to 96hrs**
53
LA: **MOA**?
- Binds to **inner, inactivated closed gate of V-G Na+ channels**
- Block/inhibit Na+ passage in nerve membranes → slows rate of depolrization → unable to reach threshold → no action potential
54
LA must be ___________ and ____________ to go through the cell membrane and block the Na+ gated channel from within the cell
- non-ionized, lipid-soluble
55
What two factors will cause a LA to not work anymore?
- Becoming water-soluble and ionized.
56
What (3) factors affect the degree of LA blockades?
- Lipid solubility or non-ionized form
- Repetitively stimulated nerve (↑ sensitivity)
- Diameter of the nerve (↑ diameter = ↑ LA need)
57
What happens when you expose LA (a weak base) to an acidic environment?
- LA **becomes ionized**
- When LA becomes ionized, it will not cross cell membrane to block Na+ gated channels
58
What component of the LA is required for the conduction block?
Non-ionized form
59
What other receptors can be targeted by LA besides V-G Sodium channels?
* Potassium channels
* Calcium Ion Channels
* G protein-coupled receptors (GCPRs)
60
Minimum Effective Concentration (**MEC or Cm**) (LAs) = _________ (Volatile Agents)
Minimum Alveolar Concentration (MAC)
61
Larger fibers need _____ concentrations of LAs.
higher
62
The diameter of motor nerve is how many times larger than the diameter of the sensory nerve?
2x
63
How many nodes of Ranvier need to be blocked to equate to 1 cm?
- What type of LA administration might require more?
- In terms of a general incision, **3 Nodes of Ranvier** to prevent the conduction (at least 2)
- Peripheral Nerve Block (PNB) requires introducing LA around entire nerve or set
64
Which fibers do LAs block?
- **Preganglionic B fibers** (SNS) = fastest
- **Myelinated A** = Medium
- **Myelinated B-fibers** = faster
- **Myelinated A-δ** & **Unmyelinated C-fibers** = small
- Alters pain, temperature, touch/pressure, proprioception, & motor
65
If a LA were given intravascularly, which fibers would be affected the fastest?
What signs and symptoms would you see?
- **Pre-ganglionic B fibers (SNS)**
- Hypotension and bradycardia
66
T/F: Pregnancy increases sensitivity to LA making it hard to block.
- True
67
What nerve types are typically affected last when administering LA through the epidural/spinal?
What sensations are the last to be affected?
- Myelinated A-δ and unmyelinated C-fibers
- Proprioception and Motor
68
Place in order the fibers that are affected first to last when administering a local anesthetic.
1. Preganglionic B fibers
2. Myelinated B fibers
3. Myelinated A fibers/ Myelinated A-δ fibers
3. Unmyelinated C fibers
69
pKa values closer to physiologic pH result in a _____ rapid onset
more
70
Because the pKA of LA's are above physiologic pH, only about ______% of the drug is in lipid-soluble nonionized form.
50%
71
If a LA has vasodilator activity, what happens to its potency?
What happens to the duration of action?
- Vasodilatory activity **decreases potency** of LA && **shortens duration**
72
Because Lidocaine is a potent vasodilator, it will have ________ systemic absorption.
- greater
- so Lidocaine is less potent of a LA than bupivancaine
73
Because Lidocaine has vasodilator activity, there is (greater/less) _______ systemic absorption. Resulting in a (shorter/longer) ________ duration of action at the site of injection.
- greater
- shorter
74
(4) Factors that influence the absorption of LA.
* Dosage
* Site of injection
* Use of Epinephrine: usually give 5 mcg/mL to counteract vasodilation of LA → prolongs/enhances the
* Pharmacologic characteristics of the drug
75
List the uptake of Local Anesthetics Based on Regional Anesthesia Technique from **highest to lowest blood concentration**.
1. IV
2. Tracheal- highly vascularized
3. Caudal
4. Paracervical
5. Epidural
6. Brachial
7. Sciatic
8. Subcutaneous
## Footnote
MEMORIZE
76
Which pharmalogic characteristic of LAs is the primary determinant of potency that directly affects tissue distrubution?
- **Lipid solubilty** by rate of distribtution
77
The rate of clearance is dependent on what two factors?
- **Cardiac output** (Chronic HTN = lower CO b/c it's pushing against a higher SVR = low CL)
- **Protein binding %**
78
What is the relationship b/w protein binding and clearance?
- **PB % is inversely related to % plasma concentration**
## Footnote
**Per Dr. Castillo↑ Protein binding = ↑ clearance from primary site of action **
79
Where are Amide local anesthetics metabolized?
Liver via microsomal enzymes (CYP 450)
80
T/F: Amides and Esters metabolize at the same rate.
- **FALSE**
- **Amides** metabolize slower than Esters b/c their metabolism is through the **liver**
- **Esters** metabolism is via hydrolysis by cholinesterase enzymes in **plasma**
81
Why is it important to know the metabolizing rate of LA?
- Re-dosing of LA
82
Which amide LA will metabolize the fastest?
**Prilocaine** d/t ↓ PB (55%)
## Footnote
Correlates with PB%: **LOW PB = RAPID Metabolism**
83
Which Amides exhibit intermediate metabolism?
- Lidocaine
- Mepivacaine
84
Which Amides exhibit the slowest metabolism?
- Etidocaine
- Bupivacaine
- Ropivacaine
- Levobupivacaine
85
Again, how are Esters metabolized?
- Hydrolyzed by cholinesterases in plasma
86
Which ester is the exception to plasmaesterase and is metabolized mainly by the liver?
Cocaine
87
What is the metabolite of Ester LAs?
- What is the significance of this metabolite?
- **Para-aminobenzoic acid** (PABA)
- Common cause of Allergic reaction
88
Is there cross-sensitivity between an amide allergy to an ester allergy?
No
89
What are the most common LAs that have first-pass pulmonary extraction?
- **Pulmonary extraction** = LAs are in the lungs and **inactive** which includes:
- Lidocaine
- Bupivacaine (**dose-dependent**)
- Prilocaine
90
Recap: What's First-Pass Pulmonary Extraction?
- Lung acts as a reservoir for LA.
- Disconjugates, hydrolyzes, and/or metabolizes into inactive form so when drug leaves lung it is not effective.
91
- The poor water solubility of local anesthetics usually limits renal excretion of unchanged drug to less than ______%
- The exception is ______, of which 10% to 12% of unchanged drug can be recovered in urine.
- Water-soluble metabolites of local anesthetics, such as _______ resulting from metabolism of ester local anesthetics, are readily excreted in _______.
- The poor water solubility of local anesthetics usually limits renal excretion of unchanged drug to less than **5%**
- The exception is **cocaine**, of which 10% to 12% of unchanged drug can be recovered in urine.
- Water-soluble metabolites of local anesthetics, such as **PABA** resulting from metabolism of ester local anesthetics, are readily excreted in **urine**.
## Footnote
Here we are talking about renal elimination and Clearance **from body**
92
T/F: The more lipid soluble the LA is, the greater the potency.
**True**
## Footnote
MUST UNDERSTAND THIS!
93
**Which local anesthetic property is most important regarding the POTENCY**
**Lipid Solubility** (most important)
94
**Which factor is most important for affecting Duration of Action?**
Protein Binding **OR** Clearance
1. **Protein binding** = MOST IMPORTANT
2. Clearance **from primary site** of action (ie: tooth anesthetic)
95
Lets make sure we understand:
- High lipid solubility = _______?
- **↑lipid soubility = ↑potentcy**
96
T/F: High Protein binding % = Low duration of action.
- FALSE
-**↑Protein binding % = ↑ duration of action**
97
What class of LA should be used on a expecting mother if necessary?
- Ester
98
How will pregnancy affect
plasma cholinesterase levels?
- Lower levels of plasma cholinesterase are seen in pregnancy
- Mainly **Amides LA transfer over to acidic fetal enviro. via transplacental transfer** → **Acid causes LA to convert to ionized form** → **severe fetal acidosis and ion trapping**
- can lead to profound fetal bradycardia, coma/death
- So Esters > Amides
99
If there is ion trapping in the placenta, what can be given to adjust the pH?
Sodium Bicarb
100
**Protein binding = rate and degree of ___________**
**Diffusion**
101
The ↑ protein binding %, the _____ arterial concentration.
- lower
102
**Bupivacaine**
Protein Bound:
Arterial Concentration:
**Bupivacaine**
Protein Bound: 95%
Arterial Concentration: 0.32
103
**Lidocaine**
Protein Bound :
Arterial Concentration:
**Lidocaine**
Protein Bound: 70%
Arterial Concentration: 0.73
104
**Prilocaine**
Protein Bound:
Arterial Concentration:
**Prilocaine**
Protein Bound: 55%
Arterial Concentration: 0.85
105
How is Lidocaine metabolized?
- What is the major metabolite of lidocaine?
- Oxidative Dealkylation in liver, then Hydrolysis
- Metabolite: **Xylidide**
## Footnote
Liver dx will affect metabolism & elimination
106
What is Lidocaine's max infiltration dose?
- 300 mg solo/plain
- 500 mg with Epinephrine (prolongs duration of action)
107
Lidocaine will have prolonged clearance with ______ (complication).
**Pregnancy Induced Hypertension** (decreased CO)
108
What is prilocaine's primary metabolite?
What is the issue with this metabolite?
Metabolite: **Orthotoluidine**
The metabolite converts Hemoglobin to Methemoglobin → Methemoglobinemia
109
What is the result of Methemoglobinemia?
- Fe3+ (Ferric iron) is not capable of carrying O2 → **decreased O2-carying capacity** = Cyanosis
110
What is the max dose of prilocaine?
600 mg
111
What is the treatment for Methemoglobinemia secondary to Prilocaine overdose?
- **Methylene Blue**
- **1 to 2 mg/kg IV over 5 mins** (initial dose)
- **Total dose not to exceed 7 - 8 mg/kg**
112
Mepivacaine is similar to Lidocaine except:
* **Longer duration of action**
* **Lacks vasodilator activity**
* Longer elimination in fetus; **contraindicated in OB**
113
What plasma protein does Bupivacaine bind to?
- 95% bound to **α1-Acid glycoprotein**
114
Bupivacaine: Metabolism
- Aromatic hydroxylation
- N-Dealkyklation
- Amide Hydrolysis
- Conjugation via liver
## Footnote
**CAAN**
115
Ropivacaine:
- Metabolism:
- Metabolite:
- Protein Binding:
- Metabolism: Hepatic CYP450
- Metabolites: Can accumulate with uremic patients (lesser system toxicity than Bupivacaine)
- Protein Binding: 94% bound to **α1-Acid glycoprotein**
116
Dibucaine
Metabolism:
MOA:
Metabolism: Liver
MOA: **Inhibits the activity of normal butyrylcholinesterase (plasma cholinesterase) by more than 70%**
117
Procaine: Metabolite
- clinical significance?
- PABA
- Excreted unchanged in urine
118
Order following LA in order of metabilism rate (high to low).
- Procaine
- Chloroprocaine
- Tetracaine
- What process is used for metabolism?
1. **Chloroprocaine** = 3.5x faster
2. Procaine
3. Tetracaine (**slowest**
- These are all metabolized via **Hydrolysis** (Pregnancy decreases plasma cholinesterase by 40%)
## Footnote
**CPT**
119
What is Benzocaine used for?
Topical anesthesia of mucous membranes:
- ETI
- Endoscopy
- TEE
- Bronch
120
Benzocaine:
- dose
- onset
- duration
- Brief **1 second** spray (20%) = **200 to 300 mg**
- onset: rapid
- duration: **30 - 60 mins**
121
Overdose of Benzocaine can lead to ________.
**Methemoglobinemia**
122
What is the **max dose** of Methylene Blue on a 65 y/o, 120 lb, male patient? in mg.
~ 432 mg or 436.4 mg total
123
What makes Benzocaine unique?
- **Weak acid** instead of a weak base, like most LA.
**pKa = 3.5**
124
Cocaine:
- Peak:
- Duration:
- Elimination:
- Peak: 30-45 mins
- Duration: 60 mins
- Elimination: Urine (24 - 36 hrs)
125
Cocaine adverse effects:
- CARDIAC
- Causes **Coronary vasospasm, ventricular dysrhythmias, HTN, tachycardia, and CAD**
126
Cocaine:
- Metabolism:
- Who should receive decreased amounts of cocaine?
- Metabolized by liver cholinesterase > plasma cholinesterase
- Decrease cocaine use in Parturients (women in labor), Neonates, Elderly, and Severe Hepatic disease
