Lecture 16 (Exam 4 Local Anesthetics Part I) Flashcards
What was the first local anesthetic?
Cocaine
Cocaine is an ester.
What was cocaine first used for and what was the effect?
Ophthalmology (1884)
Local vasoconstriction: shrink nasal mucosa.
What was the first synthetic ester developed in 1905?
Procaine
What was the first synthetic amide developed in 1943?
Lidocaine
Gold Standard
What the uses Local Anesthetics (LAs)?
- Treat dysrhythmias
- Analgesia: Acute and chronic pain
- Anesthesia- ANS Blockade, Sensory Anesthesia, Skeletal Muscle Paralysis
with progressive concentrations of LAs, transmission of autonomic, somatic sensory and somatic motor impulses are interrupted (produces ANS blockade, sensory anesthesia and skeletal muscle paralysis in area innerveted by affected nerve)
What antiarrhythmic Drug Class is lidocaine in?
Class I: Sodium Channel Blockers
MAGA: What is the intra-op infusion dose of lidocaine?
1-2 mg/kg over an hour (terminated 12-72 hours)
1-2 mg/kg initial bolus over 2-4 minutes
What is the IV dose of Lidocaine?
When should lidocaine be terminated?
- 1 to 2 mg/kg IV (initial bolus) over 2 - 4 min.
- 1 to 2 mg/kg/hour (drip)
- terminated 12 - 72 hours
What are considerations of lidocaine?
Careful monitoring: cardiac, hepatic, renal dysfunction
Dose Dependent Effects of Lidocaine if plasma lidocaine concentration is 1-5 mcg/ml.
Analgesia
Dose Dependent Effects of Lidocaine if plasma lidocaine concentration is 5-10 mcg/ml.
- Circum-oral numbness
- Tinnitus
- Skeletal muscle twitching
- Systemic hypotension
- Myocardial depression
Dose Dependent Effects of Lidocaine if plasma lidocaine concentration is 10-15 mcg/ml.
- Seizures
- Unconsciousness
Dose Dependent Effects of Lidocaine if plasma lidocaine concentration is 15-25 mcg/ml.
- Apnea
- Coma
Dose Dependent Effects of Lidocaine if plasma lidocaine concentration is >25 mcg/ml.
- Cardiovascular Depression
Describe the components that make up the molecular structure of lidocaine.
Lipophilic Portion (Aromatic Section)
Hydrocarbon Chain
Hydrophilic (Amino Group)
Bond between the lipophilic portion and the hydrocarbon chain will determine if LA is an ester or an amide.
Composition of LA will have a pH of _____ and are weak _______. ?
pH of 6; weak bases
A majority of LA are weak bases
Procaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration (mg):
pK:
Protein Binding (%):
Procaine
Classification: Ester
Potency: 1
Onset: Slow
Duration after infiltration (min): 45-60
Max single dose for infiltration (mg): 500
pK: 8.9
Protein Binding (%): 6
Chloroprocaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
pK:
Chloroprocaine
Classification: Ester
Potency: 4
Onset: Rapid
Duration after infiltration (min): 30-45
Max single dose for infiltration (mg): 600
pK: 8.7
Tetracaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
pK:
Protein Binding (%):
Tetracaine
Classification: Ester
Potency: 16
Onset: Slow
Duration after infiltration (min): 60-180
Max single dose for infiltration (mg): 100 (topical)
pK: 8.5
Protein Binding (%): 76
Lidocaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
Toxic Plasma Concentration (mcg/mL)
pK:
Protein Binding (%):
Lidocaine
Classification: Amide
Potency: 1
Onset: Rapid
Duration after infiltration (min): 60-120
Max single dose for infiltration (mg): 300
Toxic Plasma Concentration (mcg/mL): >5
pK: 7.9
Protein Binding (%): 70
Prilocaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
Toxic Plasma Concentration (mcg/mL)
pK:
Protein Binding (%):
Prilocaine
Classification: Amide
Potency: 1
Onset: Slow
Duration after infiltration (min): 60-120
Max single dose for infiltration (mg): 400
Toxic Plasma Concentration (mcg/mL): >5
pK: 7.9
Protein Binding (%): 55
Mepivacaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
Toxic Plasma Concentration (mcg/mL)
pK:
Protein Binding (%):
Mepivacaine
Classification: Amide
Potency: 1
Onset: Slow
Duration after infiltration (min): 90-180
Max single dose for infiltration (mg): 300
Toxic Plasma Concentration (mcg/mL): >5
pK: 7.6
Protein Binding (%): 77
Bupivacaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
Toxic Plasma Concentration (mcg/mL)
pK:
Protein Binding (%):
Bupivacaine
Classification: Amide
Potency: 4
Onset: Slow
Duration after infiltration (min): 240-480
Max single dose for infiltration (mg): 175
Toxic Plasma Concentration (mcg/mL): >3
pK: 8.1
Protein Binding (%): 95
Levobupivacaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
pK:
Protein Binding (%):
Levobupivacaine
Classification: Amide
Potency: 4
Onset: Slow
Duration after infiltration (min): 240-480
Max single dose for infiltration: 175
pK: 8.1
Protein Binding (%): >97
Ropivacaine
Classification:
Potency:
Onset:
Duration after infiltration (min):
Max single dose for infiltration:
Toxic Plasma Concentration (mcg/mL)
pK:
Protein Binding (%):
Ropivacaine
Classification: Amide
Potency: 4
Onset: Slow
Duration after infiltration (min): 240-480
Max single dose for infiltration (mg): 200
Toxic Plasma Concentration (mcg/mL): >4
pK: 8.1
Protein Binding (%): 94
Which LA will have a potency of 16?
Tetracaine
Which LA will have a potency of 4?
Chloroprocaine
Bupivacaine
Levobupivacaine
Ropivacaine
Which LA will have rapid onset?
Chloroprocaine
Lidocaine
Which 3 LA will have the highest protein binding?
Levobupivacaine (>97%)
Bupivacaine (95%)
Ropivacaine (94%)
Lipid solubility correlates to _______ of the drug.
Which LA has the highest local solubility?
potency
Tetracaine
What are Liposomes used for?
- Used to upload a higher amount of LA into a molecule & have a consistent release of LA in the tissues.
- Prolonged duration of action & decreased toxicity
FDA released what LA drug that contains liposomes and can last up to 96 hours.
Bupivacaine
MOA of Local Anesthetics
- Binds to voltage-gated Na+ channels
- Block/inhibit Na+ passage in nerve membranes
LA must be non-ionized and lipid-soluble to go through the cell membrane and black the Na+ gated channel from within the cell.
Factors blocking blockade slide.
- Lipid solubility or non-ionized form
- Repetitively stimulated nerve (↑ sensitivity)
- Diameter of the nerve (↑ diameter, ↑ LA)
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.
Site of action targets of LA besides sodium channels.
- Potassium channels
- Calcium Ion Channels
- G protein-coupled receptors
Minimum Effective Concentration or Cm (LAs) = _________ (Volatile Agents)
MAC
What component of the local anesthetic is required for the conduction block?
Non-ionized form (equates with lipid solubility)
Larger fibers need _____ concentrations of LAs.
higher
The diameter of the motor nerve is how many times larger than the diameter of the sensory nerve.
Twice as large in diameter
How many nodes of Ranvier need to be blocked to equate to 1 cm of local anesthesia?
At least 2, preferably 3 Nodes of Ranvier to prevent the conduction (Minimum Effect Concentration)
If 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
What fibers are blocked if the patient can’t tell if they are being poked by a sharp needle?
- Myelinated A and B fibers
What is typically affected last when administering LA through the epidural/spinal?
What fibers are the last to be affected?
- Proprioception and Motor
- Myelinated A-δ and unmyelinated C-fibers
Which patient population will have increased sensitivity and be harder to block?
Pregnancy
Pharmacokinetics of LA
If pKa is close to physiological pH, how does this affect the onset of action?
Faster onset
When administering LA, only ______% of the drug is in lipid-soluble nonionized form.
50%
If a LA has good vasodilator activity, what happens to its potency?
What happens to the duration of action?
LA is less potent
↓ Duration of action
Because Lidocaine has vasodilator activity, there is (greater/less) _______ systemic absorption. Resulting in a (shorter/longer) ________ duration of action.
greater
shorter
Factors that influence the absorption of LA.
- Site of injection
- Dosage
- Epinephrine will prolong the duration of action (limit systemic absorption of LA by one-third).
- Pharmacologic characteristics of the drug
List the uptake of Local Anesthetics Based on Regional Anesthesia Technique from highest blood concentration to lowest blood conc.
________is the primary determinant of potency
Lipid solubility
The rate of clearance is dependent on what two factors?
- Cardiac output
- Protein binding: % bound is inversely related to % plasma. (40% albumin-bound means 60% will float freely in plasma.)
Which LA will metabolize the fastest?
esters:
chloroprocaine> procaine
Procaine d/t the smallest % of protein binding.
amides:
prilocaine (least protein bound)
Which LA will metabolize the slowest?
Levopuivacaine d/t the highest % of protein binding.
Why is it important to know the metabolizing rate of LA.
Re-dosing of LA
Metabolism of Amides.
Location of Metabolism:
Rapid:
Intermediate:
Slow:
Metabolism of Amides.
Location of Metabolism: Microsomal enzyme (Liver)
Rapid: Prilocaine
Intermediate: Lidocaine, Mepivacaine
Slow: Etidocaine, Bupivacaine, Popivacaine
Metabolism of Esterase
Hydrolyzed by hydrocholinesterases in plasma, except cocaine which is metabolized by the liver.
What is the metabolite of esters?
What is the significance of this metabolite?
ParaAminoBenzoic acid (PABA)
Allergies
Is there cross-sensitivity between an amide allergy to an ester allergy?
No
Which one has a slower metabolism
Amides are slower at metabolism.
What are the most common LAs that have first-pass pulmonary extraction?
- Lidocaine
- Bupivacaine (dose dependent)
- Prilocaine
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 urine.
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.
In general, the more lipid soluble the local anesthetic is, the greater the potency. T/F
True
Which local anesthetic property is most important regarding the duration of action?
Lipid Solubility (most important)
Pharmacokinetics: Pregnancy
Plasma cholinesterases levels
Lower levels of plasma cholinesterases
Caution with LA that are esters, bigger impact with normal doses
Ester LAs are still given to pregnant women because the effects of the amide LAs are detrimental to the fetus.
What classification of LAs is more likely to cause ion trapping?
Amides
Ion trapping will lead to LA toxicity in the placenta.
What is ion trapping?
The pH in the fetal environment is more acidic than in maternal circulation.
If there is ion trapping in the placenta, what can be given to adjust the pH?
Sodium Bicarb
Bupivacaine
Protein Bound:
Arterial Concentration:
Bupivacaine
Protein Bound: 95%
Arterial Concentration: 0.32
Lidocaine
Protein Bound :
Arterial Concentration:
Lidocaine
Protein Bound: 70%
Arterial Concentration: 0.73
Prilocaine
Protein Bound
Arterial Concentration
Prilocaine
Protein Bound: 55%
Arterial Concentration: 0.85
Lidocaine Metabolism
Metabolism:
Metabolite:
What will affect metabolism and elimination:
Metabolism: Oxidative dealkylation (liver), hydrolysis
Metabolite: Xylidide
What will affect metabolism and elimination: Hepatic disease
What is Lidocaine max infiltration dose?
Maximum infiltration dose:
300 mg plain
500 mg with EPI (Rate of distribution is slower with epinephrine, so we can give more lidocaine.)
Lidocaine will have prolonged clearance with ______
Pregnancy Induced Hypertension
Prilocaine metabolite.
What is the issue with this metabolite?
Metabolite: Orthotoluidine
The metabolite converts Hemoglobin to Methemoglobin, resulting in Methemoglobinemia.
What is the result of Methemoglobinemia?
Fe3+ (ferric iron) is not capable of carrying O2
dose of prilocaine that we see metabolite
600 mgs
Signs and sx of Methemoglobinemia
Tx:
S/Sx: Cyanosis d/t decreased 02 carrying capacity
Methylene Blue
1 to 2 mg/kg IV over 5 mins (initial dose)
Total dose not to exceed 7 to 8 mg/kg (over 24 hours)
Mepivacaine is similar to Lidocaine except:
- Longer duration of action
- Lacks vasodilator activity
- Prolonged elimination in fetus & newborn
- No Mepivacaine in OB patients
Bupivacaine
Metabolism:
Protein Binding:
Bupivacaine
Metabolism: aromatic hydroxylation, N-dealkylation, amide hydrolysis, and conjugation
Protein Binding: 95% bound to α1-Acid glycoprotein
Ropivacaine
Metabolism:
Metabolite:
Protein Binding
Ropivacaine
Metabolism: Hepatic cytochrome P450 enzymes
Metabolites: Can accumulate with uremic patients
Lesser system toxicity than Bupivacaine
Protein Binding: α1-acid glycoprotein
Dibucaine
Metabolism:
MOA:
Dibucaine
Metabolism: Liver
MOA: inhibits the activity of normal butyrylcholinesterase (plasma cholinesterase) by more than 70%
Procaine
Metabolite:
Procaine
Metabolite: PABA (ester anesthetic), excreted unchanged in the urine
Chloroprocaine
Metabolism:
Pregnancy decreases plasma cholinesterase by ____%
Choloroprocaine
Plasma cholinesterase (3.5x faster than procaine)
40%
Tetracaine metabolism is slower than ______
Procaine
Which LA will have the highest rate of metabolism?
Procaine
Chloroprocaine
Tetracaine
Chloroprocaine (highest level of metabolism) > procaine > tetracaine (slowest)
Benzocaine use:
Uses: Topical anesthesia of mucous membranes:
Tracheal intubation, Endoscopy, Transesophageal echocardiography (TEE), Bronchoscopy
Benzocaine
Onset:
Duration:
Dose: Brief spray (20%) =
Overdose of Benzocaine can lead to ________.
Benzocaine - WEAK ACID
Onset: Rapid
Duration: 30 to 60 minutes
Dose: Brief spray (20%) = 200 to 300 mgs
OD of Benzocaine can lead to Methemoglobinemia
What makes Benzocaine unique?
Weak acid instead of a weak base, like most LA.
pKa = 3.5
How is cocaine metabolized?
Who should receive decreased amounts of cocaine?
Metabolized by plasma and liver cholinesterase
Decrease cocaine use in parturients, neonates, the elderly, and severe hepatic disease
Cocaine
Peak:
Duration:
Elimination:
Cocaine
Peak: 30 to 45 mins
Duration: 60 minutes after peak
Elimination: Urine (24 to 36 hours)
Adverse side effects of cocaine.
Caution is a stimulant; use it with caution.
Cocaine can cause coronary vasospasm, ventricular dysrhythmias, HTN, tachycardia, and CAD.
