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Pharmacology > Local Anesthetic Pharmacology > Flashcards

Local Anesthetic Pharmacology Flashcards

1
Q

3 ways that local anesthetics work are

A

Autonomic blockade

Somatic sensory blockade

Somatic motor blockade

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2
Q

Local ane sites of administration are?

A
  1. infiltrated around nerve
  2. applied to skin and mucous membranes
  3. Injected into subarachnoid and pleural space
  4. Injected into blood vessels..(Exsanguinated)
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3
Q

Membrane ion conc

A

Extracellular…sodium high/K low
Intracellular …potassium high/sodium low.

Ion Channels guarded by a gating mechanism- opens or closes depending on changing physiologic conditions

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4
Q

How is The Velocity an impulse travels proportional to the diameter of fibre

A

Directly proportional to fiber diameter.

the larger the diameter, the higher the conduction velocity

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5
Q

3 types of fibre are

A

A, B and C fibers

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6
Q

Explain A fibres

A 
A fibers   (myelinated) 1 to 22 microns Subdivided into: α β γ δ in order of decreasing size.
alpha fibers are the fastest
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7
Q

Explain B fibres

A

B fibers (myelinated) 1 to 3 micrometers

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8
Q

Explain C fibres

A 
C fibers (unmyelinated fibers) 0.1 to 2.5  micrometers
slowest
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9
Q

PNS fibres comprise of ?

A

A-alpha fibers: motor & proprioception .
A-beta fibers: motor, touch, pressure
A- gamma fibers: motor/muscle tone (muscle spindle)
A-delta fibers: pain, temperature,touch

B-fibers: PREganglionic autonomic

C- fibers: dull pain, temperature, touch, POSTganglionic autonomic– NO MYELIN

the lower the size,the slower the conduction,the easiest to block

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10
Q

Characteristics of the fibers include

Fast and Slow pathways

A

Myelinated A-delta fibers (slowest of the A fibers)

Unmyelinated C fibers (much slower)

XXX Large fibers have the highest conduction velocity and the lowest threshold for excitability

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11
Q

How is the sensitivity of a PN to local Anesthesia related to size

A

The sensitivity of a peripheral nerve to LA is inversely related to size. That is why you see autonomic blockade first, sensory second and motor last

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12
Q

Fyi

A

In a laboratory…larger fibers A delta and gamma are actually more sensitive to local anesthetics than the C fibers which are unmyelinated and small

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13
Q

Factors that affect blockade in different nerve s

A 
anatomic issues (larger nerves found deeper in nerve bundles – harder for the LA to reach)
variable activity in different nerves (pain fibers fire at higher frequency)….i.e. frequency dependent blockade
variable ion channel mechanisms

Motor nerves have larger spaces between their nodes
Autonomic more on the outside…
C fibres are on outside …so easier to block
A alpha needs more to get to it.
Faster or more firing may also increase rate of block
Frequency dependent blockade
Outer…mantle..
Check temp in comparative extremities. Like the toes…if one is colder..pls reposition or pull back catheter…remember autonomic blocked first.

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14
Q

How location affects the spread of local anesthetic

A

Outer surface of a peripheral nerve is known as the mantle (usually more proximal structures)

Inner surface known as core (these fibers usually serve more distal structures)

THE SEQUENCE OF ONSET AND RECOVERY FROM A LOCAL ANESTHETIC BLOCK IN A MIXED PERIPHERAL NERVE RELIES HEAVILY ON WHERE IT IS LOCATED

This factor is much more important than the inherent sensitivity of the nerve fiber to local anesthetics

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15
Q

What is the Clinical sequence of anesthesia:

A

1st- sympathetic block (vasodilatation, warm skin)
2nd – Loss pain and temperature sensation
3rd – Loss of proprioception
4th - Loss of touch and pressure
5th – Motor blockade

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16
Q

Mode of action nerve blockade

A

Voltage gated sodium channels in the inactivated-closed state serve as receptors for local anesthetic molecules

Local anesthetics bind at specific sites on the internal H gate of the channel & physically obstruct the external openings of the channels.

Local anesthetics prevent passage of sodium ions through these channels by binding and stabilizing them in the inactivated-closed conformational state

This blocks impulse conduction during the depolarization phase of the action potential.
prevent from reaching threshold.

can be compared to Inverse agonist.

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17
Q

myelination

A

Myelinated Nerve Fiber:
A Schwann-cell wraps itself around the axon several times, enveloping the axon in a myelin sheath…lipid insulating barrier
Unmyelinated Nerve Fiber:
A single Schwann cell surrounds several axons

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18
Q

Effects of Myelination on a nerve fibre

A 
Decreasing resistance …
increasing capacitance
Difficult to assess at the myelin…
Works at the node.
Block 3 nodes to block a nerve
Nerve fiber bigger….spaces get far apart.
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19
Q

Compare conduction btwn myelinated fibre and unmyelinated fibre

A

propagation of impulse is similar.

Unmyelinated fibers: impulses travel along the length of the fiber in a continuous fashion

Myelinated fibers, conduction is “saltatory”so fast (50X) that it appears as if impulses leap from one node of Ranvier (no myelin) to the next

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20
Q

How Does Frequency of cycling affect the rate of blockade

A

LA s easily access nerve cell Na channels in the “activated-open” state
LA’s easily bind to the receptor in the “inactivated-closed” state
The more frequently the nerve is in this state, (i.e. cycled through an action potential) the more rapidly blockade occurs

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21
Q

since Resting nerve is less sensitive to block than a repetitively stimulated nerve.What will determine the accessibility for block

A

Lipid solubility determines (i.e. it has to diffuse through the axonal membrane instead of through the Na channel to reach its target)

The higher the lipid solubility,the faster the block

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22
Q

How does the distance between nodes of ranvier and the size of a fibre affect the sensitivity of a fibre to a block.How can this be mitigated

A

Distance between Nodes of Ranvier in myelinated fibers contributes to differential nerve block

The internodal distance increases with fiber diameter

An impulse can make it through two blocked nodes but not a third
Blockade of three nodes (1cm) eliminates conduction along a myelinated nerve fiber (A fibers)

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23
Q

Explain differential block

A

Bupivacaine was the first local anesthetic shown to produce a beneficial differential block: Sensory block with incomplete motor block

Pain conducting fibers (A delta, C fibers) blocked
A alpha, beta, & gamma fibers not completely blocked
Patients feel pressure but not pain with surgical stimulation

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24
Q

Name the 2 main classifications of LA

and how the structure is arranged

A

Local anesthetics are classified chemically as aminoamides or aminoesters

The typical molecule consists of a lipophilic head (an aromatic ring), an intermediate chain containing either an amide (NH) or an ester (COO-)
and a hydrophilic tail (a tertiary amine).

BINDS better if it has a charge.

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25
Analyze the difference in metabolism between Aminoamides and Aminoesters
Ester linkage: readily hydrolyzed by non-specific esterases in the plasma and tissues (mostly liver) Faster hydrolysis Cocaine exception…decreases norepi reuptake,,more Norepi in the SA node,hence tarchycardia Cocaine decreases bleeding 2/2 to being great vasoconstrictor…monitor cardiac numbers for MI Amide linkage: metabolized in the liver…slower …higher risk of toxicity
26
What is the variability in potency and DOA between Lipid soluble anesthetics and water soluble anesthetics per molecular structure.
Highly Lipid soluble anesthetics are more potent and have a longer duration of action than water soluble anesthetics.
27
Factors that affect toxicity and potentcy in the molecular structure.
Increase in the length of the intermediate chain (increase number of carbon atoms) increases potency and toxicity and alters metabolism rate and DOA Potency and toxicity also increased with the length of the terminal groups located on the tertiary amine (tail) and aromatic ring Enantiomers of a chiral drug may vary in terms of the pharmacokinetics, pharmacodynamics, and toxicity. Ex. Bupivacaine (racemic) VS L-Bupivacaine(levo enantiomer)
28
FYI for block guide(CM)
Minimum Blocking Concentration Nerve fiber diameter influence Motor nerve higher Cm than sensory Tissue pH,,acidic(infected tissue not good) Onset level becomes very high Frequency of nerve stimulation…faster block Potency of particular LA…more potent..need less molecules
29
With LA,what are the drug delivery systems that we have
``` Offer sustained release properties Prolonged DOA((about 4days) Theoretical decreased toxicity Liposomes Exparel: Bupivacaine extended release liposome injection FDA approved Do not mix or inject any other local anesthetic at the same site Dose: depends on surgical site Max dose: 266mg or 20 ml Cyclodextrins Biopolymers ```
30
LA systemic absorption depends on
Physiochemical characteristics PKA/PH/Lipid solubilty physiologic conditions at site of deposit: TissuepH,Pco2,temp,Patient characteristics volume of solution or vehicle used concentration of anesthetic Peripheral.....use lower conc/higher volume for elderly give lower doses. Albumin conc is down in preg women so less protein binding..more available so reduce the dose. watch for systemic absorption risk
31
The order of absorption by type of block
``` Intravenous Tracheal Intercostal Caudal Paracervical Epidural Brachial Plexus Subarachnoid Subcutaneous ``` The more vascular the region, the higher the risk of toxicity( intercostal)
32
Ionization action of LA
Unionized form diffuses across the nerve sheath and membrane to reach the site of action Once inside the nerve membrane the ionized and non-ionized forms re-equilibrate Ionized form binds a receptor inside the Na channel = blockade pKa = pH at which a drug exists 50% ionized form 50% unionized form
33
Ionization concepts
The ionized form is favored when: 1.Acidic drug in relatively basic environment 2.Basic drug in relatively acidic environment The non-ionized form is favored when: 1. Acidic drug in relatively acidic environment 2. Basic drug in a relatively basic environment All local anesthetics: weak bases with pka values 7.5-9
34
Why are local anesthetics packaged in acidic formulations
They are packaged in acidic formulations and often to preserve epinephrine and bring down the PH – don’t let this fool you they are basic upon injection
35
All local anesthetics: weak bases with pka values 7.5-9
to improve solubility and stability in the vial.
36
What factors determine the proportion of drug in the non-ionized state
PH of the LA solution | PKA of the drug.
37
How does the rate and amount of absorption vary with PH
In areas of high/normal pH values, the rate and amount of absorption is higher; conversely, at lower pH, the rate and amount of absorption are lower
38
What are the ways to influence the ph/pka relationship to speed onset of LA
Adding Bicarb increases the onset, enhances block depth, and increases the spread of the block Infected tissue alterations..its acidic..block higher up..does not work Ion trapping in pregnancy…weak base can cause ion traping..bupi is highly protein bound…this keeps it from crossing in great amount . Temperature: decreasing temperature decrease or slows down absorption and onset. reduces drug absorption across the nerve membrane
39
Potency of LA depends on?
Lipid solubility
40
Duration of Action depends on?
Protein binding Capacity
41
The following factors help with longer duration of action
Tissue Blood Flow..higher flow is better will help move LA Addition of Vasoconstrictors..this will decrease uptake…prolong duration of action…reduce toxicity Lipid solubility…stays more in local tissue that is more lipid Protein Binding…higher protein bound increases duration of action Intrinsic vasodilator activity Lidocaine VS mepivacaine…… .no lidocaine for gangrenous limb Lidocaine is a lil vasodilatory Long uptake also supports longer DOA also may depend on metabolism propranolol and fentanyl may have buffer action. since other drugs are uptake by the lungs
42
Benefits of injecting vasoconstrictor with Local anesthetic
1. Inhibition of systemic absorption of LA 2. Prolongation of the LA effect 3. Detection of intravascular injection with Epi added..
43
What determines the concentration of Local Anesthetic in the blood.
Tissue blood flow.
44
Metabolism of Ester
Primarily hydrolyzed by pseudocholinesterase enzymes in plasma (and to lesser extent - the liver) (<5% excreted unchanged in the urine) Metabolite = para-aminobenzoic acid (PABA) *Exceptional ester is cocaine which is significantly metabolized in the liver and 10-12% excreted unchanged in the urine This is a fast process
45
Metabolism of LA-Amides
Liver Microsomal Enzymes More complex and slower process than metabolism of Esters- Aromatic hydroxylation, N-dealkylation and amide hydrolysis What does that mean for the possibility of systemic toxicity and cumulative effects?? Process Higher possibility of Toxicity....
46
What determines onset of LA
Ph and Pka
47
Know the Max doses of ANesthesia
pls see max dose
48
Local Anesthetic toxicity effects on CNS
Circumoral/tongue numbness, tinnitus, vision changes, dizziness, slurred speech, restlessness Muscle twitching especially in face and then extremities indicates imminent onset of seizures Seizure followed by CNS depression, apnea, HyPOtension What do you do if the patient seizes?? Transient neurologic symptoms (TNS) or Transient radicular irritation – neuro-inflammatory process causes pain in the lower back, buttocks, posterior thighs 6-36 hours after full recovery from SAB – lasts about a week Cauda equina syndrome diffuse lumbosacral injury, numbness in LE, loss of bowel and bladder control, paraplegia Lidocaine 5%, Tetracaine, and Chloroprocaine have been implicated Anterior Spinal Artery Syndrome LE paralysis with +/- sensory deficit Unknown cause, vasoconstrictors?, PVD, advanced age increase the risk
49
cocaine Toxicity
Cocaine -restlessness, tremors, seizures and euphoria Cocaine overdose manifests as massive sympathetic outflow, coronary vasospasm, MI, dysrhythmias including V-fib
50
Local anesthetic toxicity cardiovascular effects
CVS more resistant to toxic effects than CNS! Hypotension (SNS depression), myocardial depression, and AV conduction block Reduced SVR and C.O, widened PRi and QRS, arrhythmias including ventricular tachycardia, possible CV collapse
51
What physiologic situations increases the risk of toxicity per CV effects
Pregnancy, hypoxia, pH abnormalities and CV modulating drugs increase the risk
52
What drug is the most Cv toxic drug
Bupivacaine most CV toxic – cardiac arrest may occur at lower levels of toxic doses (inadvertent IV injection, etc.)
53
LA toxicity treatment of CV collapse
Resuscitation often fails….. Prevention ideal Incremental fractionated dosing Aspirate before every injection (false negative possible) Watch ECG for early signs Basic CPR immediately See figure 10-12 in text American Society of Regional Anesthesia and Pain Medicine Guidelines Modified ACLS (limit medications to epinephrine 10-100ug, amiodarone) Intralipid 20% 1.5 ml/kg rapid bolus immediately; follow with infusion 0.25 ml/kg/min X 10 minutes CPB
54
For Allergic reactions what are the main culprits?
Esters implicated more than Amides (PABA?) | Preservative Reaction? (Methylparaben)
55
whats the effect of Pseudocholinesterase inhibitors on Esters
Pseudocholinesterase inhibitors may prolong the duration of ester anesthetics
56
Whats the effect of CImetidine and Propranol on hepatic blood flow
Cimetidine and propranolol decrease hepatic blood flow  decrease clearance of amide local anesthetics and cocaine
57
FYI
Analgesia promoted by opioids, clonidine, and epinephrine added to LA
58
Selection criteria for choosing LA agents
``` Type of surgery Spreadability Duration of action potency Onset of action Risk of toxicity Site of metabolism ```
59
These drugs can potentiate LA
opioids, clonidine, and epinephrine added to LA
60
Uses of Lidocaine
Cough Suppression Attenuate ICP elevation during laryngoscopy Attenuate BP elevation during laryngoscopy Attenuate reflex bronchospasm that may occur with airway instrumentation Suppression of ventricular dysrhythmias
61
Cocaine uses and side effects
The unique ester Blocks norepinephrine & dopamine reuptake Unique side effect profile CNS: euphoria CV: stimulation, sympathomimetic Different metabolism; liver and plasma esterases Currently still used in ENT surgery
62
Procaine uses and side effects
``` Ester prototype Used in spinal anesthesia prior to development of lidocaine Not currently a favorite Pka 8.9 = 97% ionized slow onset Short DOA Hypersensitivity Higher nausea incidence Higher incidence of CNS side effects Metabolite interferes with the efficacy of sulfonamide antibiotics ```
63
Tetracaine uses and side effects
Primarily used in spinal and corneal anesthesia Long DOA for an ester (especially w/epi added can be up to 6hrs!) Not popular for epidural or PNB Slow onset Profound motor block Toxicity risk w/lg. doses (long DOA) High incidence of TNS
64
Chloroprocaine uses and side effects
Popular in OB epidural anesthesia Ultra Rapid serum hydrolysis greatly reduces toxicity risk to mother and fetus Epidural and PNB when short duration desired Spinal being reinvestigated but still considered “off -label” use Reports of Neurologic injury possibly related to preservative (data inconclusive)
65
Lidocaine uses and side effects
Very popular Topical (4%), regional IV (0.25-0.5%), PNB (1-2%), spinal (1.5-5%) and epidural use (1.5-2%) Rapid onset; intermediate duration 2 active metabolites monoethylglycinexylidide – 80% activity & xylidide 10% activity Spinal use… especially continuous spinal use controversial Linked to cauda equina syndrome
66
Mepivacaine uses and side effects
Structurally similar to bupivacaine Clinically similar to lidocaine Rapid onset Less vasodilation = longer DOA (nice to consider when vasoconstrictor contraindicated) Serum E1/2t ~ 2hrs Slightly more CNS toxicity compared with lidocaine Not effective topically
67
Prilocaine uses and side effects
Rapid metabolism leads to less CNS toxicity than lidocaine Toxic metabolite ortho-toluidine Avoid in OB Doses greater than 600mg = conversion of hgb to methemoglobin Methemoglobinemia also possible with benzocaine, topical lidocaine preparations Give methylene blue 1-2 mg/kg IV over 5 minutes
68
Etidocaine uses and side effects
Used for infiltration/PNB (0.5-1%), and epidural anesthesia (1-1.5%) Highly lipid soluble, long acting with rapid onset (pka = 7.7)
69
Bupivacaine uses and side effects
Longer DOA and longer onset compared w/lidocaine Popular for differential nerve block (sensory>motor) Great choice post-op pain, labor epidural Used spinal (0.5-0.75%), epidural ( 0.0625- 0.5%), peripheral nerve block (0.25-0.5%) Highly protein bound to alpha-1 glycoprotein Side effect pro: very low incidence of neuro complications with spinal Side effect con: very cardio toxic (use 0.5% or lower conc. for epidural, PNB) + Serum E1/2t is 3.5 hours
70
Ropivacaine uses and side effects
S(-) or levo enantiomer of homolog of bupivacaine with a propyl tail on piperidine ring Also good for differential blockade Less cardiotoxic More vasoconstriction 2 active metabolites; shorter serum e1/2t (~ 2hrs) compared with bupivacaine More expensive… use when larger doses needed
71
Levobupivacaine
S(-) enantiomer bupivacaine Less cardiotoxic Serum E1/2t = 2.6hrs More expensive… again reserve for cases where larger local anesthetic doses required
72
Dosing main points
Concentration, Volume, and Total Dose Administered Peripheral nerve block Volume dictated by type of block Choose concentration based on limitations of max dose balanced with density of blockade desired Epidural Volume dictated to what level of block desired 1.25-1.6ml/per segment desired Choose concentration based on density of block desired (i.e. labor VS surgical epidural) Spinal These doses you just have to know

Pharmacology (9 decks)

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