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201 Cards in this Set

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What are local anesthetics?
Drugs that reversibly inhibit the conduction of electrical impulse along nerve fibers
The degree of inhibition is influenced by:
Anatomy of the nerve being blocked;
Tissue conditions;
Physicochemical properties of the local anesthetic agent.
Desirable Properties of LAs
Short Onset
Moderate duration of action
Quick recovery
Non-irritating to tissues
Low systemic toxicity (high therapeutic index)
What is the therapeutic index
Dose producing undesired effects divided by the lowest dose producing desired effect (reflects margin of safety).
High Therapeutic Index =
Low Systemic Toxicity & therefore High Safety Margin
How does diffusion of LA occur?
The axons on the outside of the bundle are exposed the LA earliest and also to the highest concentration. As the drug diffuses into the bundle, the concentration decline due to absorption by the axons and fibrous tissue. If sufficient LA is available, the central axons will be block after those on the outside are blocked. If the peak concentration of anesthetic attained at the center of the nerve bundle insufficient for complete blockade, only a decrement in net conduction may occur. To achieve a state of dense anesthesia the concentration throughout the bundle must be at or above the MIC of the agent. In addition, the length of axon bathed by this concentration must be adequate to achieve blockade. This makes regional anesthesia somewhat unpredictable and helps explain partial sensory blockades.
How are neurons generally arranged?
In bundles
How does the diffusion of most LA occur in the neuron?
Initially from mantle to core & then thru progression in their onset ill decay.
Describe the progression of the onset of most LA in neurons?
The axons on the outside of the bundle are exposed to the LA earliest and in the highest concentration. As the drug diffuses into the bundle, the concentration decline due to absorption by the axons and fibrous tissue. If sufficient LA is available, the central axons will be block after those on the outside are blocked. If the peak concentration of anesthetic attained at the center of the nerve bundle insufficient for complete blockade, only a decrement in net conduction may occur.
How do we achieve a state of dense anesthesia?
The concentration throughout the bundle must be at or above the MIC of the agent. In addition, the length of axon bathed by this concentration must be adequate to achieve blockade.
What makes regional anesthesia somewhat unpredictable? This help to explain partial sensory blockades.
The fact that the density of the anesthesia is dependent on the the concentration of the agent & the length of the axon that is bathed in the agent.
What is the size and function of B fibers
0.25 mcirons
Preganglionic autonomic activities
What is the size and function of C fibers
0.5microns
They communicate Temperature & Dull Pain
What is the size and function of A delta fibers
0.5microns
They communicate Temperature & Dull Pain
What is the size and function of A-gamma fibers
0.75 microns
They are found in Muscle Spindle & help to control Muscle Tone
What is the size and function of A-beta fibers?
0.75 micron
Light pressure & touch
What is the size and function of A-alpha fibers?
1.0 micron
Somatic motor & proprioception
True/false
C-fibers are Unmyelinated?
True
A minimal length of myelinated fibers must be exposed to LA to block conduction of impulses.
How many successive nodes must be exposed to adequate concentrations of LA for block to be predicted?
At least three.
If only one node is blocked, impulse can bypass
How are neurons myelinated?
Myelinated neurons are wrapped in Schwann cells which are invested in a coating of myelin, a good insulator.
How does myelination affect neurons' conductivity?
The coating would completely stop impulse conduction if it were not for gaps in the insulation known as nodes of Ranvier.
How is transmission affected along nodes of ranvier?
These gaps focus the electrical current of depolarization of the membrane and force the wave of depolarization to jump from node to subsequent node.
How does the effect of jumping from node to node speed the conduction of nerve impulses?.
Rather than spreading slowly down the membrane (slower process), the impulse jumps from node to node (thus jumping over the myelinated portions), a process known as saltatory conduction.
True/false?
Smaller nerve fibers are more vulnerable to blockade in lower concentrations of local anesthetics.
True.
As concentrations are increased, larger nerve fibers are blocked.
In what order are these nerve fibers affected by anesthesia, starting with the those affected first?
C, B, A-gamma, A-delta, A-beta, A-alpha
B > C,A-delta > A-gamma, A-beta > A-alpha
Smaller ones are blocked before larger ones. Their sizes are respectively - 0.25, 0.5, 0.5, 0.75, 0.75, 1.0
Where are spindle fibers found?
Within the fleshy portions of muscles, embedded in extrafusal muscle fibers
What occurs during neuroaxial anesthesia blockade (list in order of occurence)?
First autonomic block - decrease in blood pressure.
Inability to differentiate temperature.
Inability to feel sharp pain (needle prick).
Loss of proprioception - no idea where their limbs are.
May have sensory loss but still have intact motor – patient may move their limbs in the OR.
What is the MIC
MINIMUM INHIBITORY CONCENTRATION which is the minimum concentration of local anesthetic necessary to produce conduction blockade of nerve impulses.
What does the MIC of each drug represent?
The potency.
Each local anesthetic has a unique Cm.
MIC is measured in Cm. What influences Cm?
Nerve fiber diameter - larger fibers requiring ↑ concentrations to produce conduction blockade.
Cm of motor fibers are 2X that of sensory.
How does anesthesia affect AP?
They block Na channels --> decreased AP.
As the concentration of local anesthetic in the solution increases, the number of functioning sodium channels decreases as they are progressively blocked.
At what point during the disruption of AP is MIC achieved?
With fewer sodium channels able to respond to the action potential (b/c of anesthesia), less sodium moves into the cell and the amplitude of the action potential decreases. When a critical level of blockade is reached, the depolarization is inadequate to cause neighboring sodium channels to open. The concentration of local anesthetic at this point is called the minimum inhibitory concentration (MIC).
How does pH affect MIC?
An increased tissue pH can decrease the Cm (hence an increased MIC)
MIC is independent of axon thickness in myelinated axons & unmyelinated neurons at the steady state. Why then are thinner axons blocked before thicker ones?
Since steady-state conditions are rarely seen in clinical practice, thinner axons may be blocked before thicker axons, giving rise to the belief that thinner axons are blocked at lower anesthetic concentrations.
The MIC of local anesthetics is similar in many ways to the minimal alveolar concentration (MAC) of inhaled anesthetics; how is the concept useful clinically?
It is not
What factors limit our ability to estimate the concentration of local anesthetic at the axon?
LAs injected into the body are subject to absorption, dilution, and metabolism, and neurons are enveloped in tissue, muscle, and blood vessels.
How is the knowledge of the MIC of LAs useful?
They provide a standard for comparison of the potencies of different local anesthetic agents.
MOA of LAs?
Local anesthetics produce their effect by blocking sodium (Na+) channels inside the neuronal membrane.
This blockage prevents an increase in sodium permeability during an action potential, resulting in negation of electrical conduction. 
Sodium Channel must be in the activated-open or inactivated-closed to be blocked.
(Local anesthetics work by preventing membrane depolarization).
The resting membrane potential of most nerve cell is
-60 to -90 mV
At RMP, the cell nerve cell is more permeable to _________
K+ ions
How are waves of depolarization propagated along the length of the axon?
When the nerve is active, Na+ channels in the membrane are triggered to open and the Na+ permeability increases so the membrane potential becomes less negative. If the membrane potential increases enough, additional Na+ channels open, and wave of depolarization is propagated along the length of the axon.
At RMP (-90mV), what is the postion of the activation & inactivation gates
The activation (on the outside) is closed & the inactivation (on the inside) is opened. Na is not allowed in.
At mV of -90 to +35 what are the positions of the activation/inactivation gates?
Both are open, Na is entering the cell
When the Na channel of the nerve cell is in anactivated state, what is happening with the Na ion & the activation/incativation gate?
The activation gate is opened but the inactivation gate is closed so Na is not able to enter the cell.
What state does the equilibrium of local anesthetic binding and dissociation favor?
LA Favors binding the channel when it is in either the open or the inactive state.
(When the channel is in the resting state, the equilibrium favors dissociation).
A nerve impulse is carried along an individual neuron as a sequence of three events.
What occurs in the first sequence?
First, the impulse is received by the neuron as a signal from outside the cell. In most cases, this signal is the arrival of a chemical neurotransmitter from a neighboring neuron across a synapse. However, sensory neurons can respond to other chemicals or to energy (e.g., light, heat, or pressure).
A nerve impulse is carried along an individual neuron as a sequence of three events.
What occurs in the second sequence?
Where the nerve enters the spinal cord, the impulse is converted to the release of a neurotransmitter.
What two facts are essential in understanding the transmembrane potential?
The first is that the value of the potential depends on both the concentration of the individual ion and the permeability of the membrane to the ion & the second is that the concentration differential at the membrane surface determines the transmembrane potential.
What happens if the permeability of the membrane changes?
The potential changes, even if there is no change in ion concentration.
What does ion concentration, membrane permeability & membrane concentration differential influence?
The ability of the transmembrane potential to change rapidly with only a small movement of ions.
The action potential and nerve conduction are both "all or none phenomena. Explain
If for any reason the degree of depolarization fails to raise the membrane potential to the point where the sodium channels open, the nerve impulse will stop. If enough sodium channels open to bring the transmembrane potential to the "threshold" value of approximately -50 m V, the impulse will be conducted.
LA produce their action by blocking Na+ channels. There are four major MOA, what are they?
1. Displacing Ca++ the from axolemma (Ca controls Na permeability in the axolemma).
(2) Altering surface membrane charge --> hyperpolerization or influencing the process of repolarizatiom.
(3)Because LA are lipohilic they can dissolve into the axolemma --> conformational changes -->closure of Na channels.
(4) Blocks propogation of AP by binding reversibly to specific receptors in the internal opening of the Na channel.
LAs are are weak bases, how do weak bases behave in aqueous solution?
They do not readily dissociate into charged ions (a significant fraction of the molecules are in the uncharged or unionized state when in solution ).
What are the two forms of anesthetics?
Free base form (B)= lipophilic unionized fraction;
Cationic form (BH+)= hydrophilic ionized fraction
BH+ <=> B + H+
The relative proportions of charged and uncharged LA molecules is a function of the dissociation constant of the drug & the environmental pH. This constant can be expressed as:
pKa=pH – log[base]/[conjugate acid] - the Henderson-Hasselbach equation
Since pKa is a constant, the ratio of ionized to unionized local anesthetic is determined solely by the pH of the solution, and when the pH equals the pKa, what is the ratio of base to cation
1:1
When the pH equals the pKa, the concentration of base is equal to the concentration of cation.
What does pKa define?
pKa defines the pH at which the amount of ionized and unionized drug fraction is equal.
How does physiologic pH affect the onset of LA?
Local anesthetics with a pKa closer to physiologic pH (7.4) will have a quicker onset related to an increased unionized drug fraction. 
How does the local pH of the area the LA is injected in determine how much of the drug crosses the lipid bilayer of the nerve?
The local pH determines the % ionized and unionized drug form.
The unionized form crosses the lipid bilayer of the nerve.
After the LA crosses the lipid bilayer, what is the sequence of events that follows?
Once inside, charged ionized form binds to intracellular receptor site (Na+ channel)-->
Decrease Na+ permeability;
Decrease Rate of depolarization (slope);
Failure to achieve threshold potential;
Propagated AP does not develop;
Conduction is block
How does the cell develop an electrical potential (transmembrane potential) across the membrane?
The cell membrane consists of a double layer of long-chain fatty acids, arranged with the hydrophilic carboxylic acid group on the outside, facing the aqueous environment both inside and outside the cell. The center of the membrane consists of the long hydrocarbon "tails" of the fatty acids and is highly hydrophobic. This hydrophobic core of the membrane is essentially impermeable to charged molecules and acts as a good insulator. These properties allow the cell to develop an electrical potential (transmembrane potential) across the membrane. This potential arises from the difference in intracellular and extracellular concentration of various ions and is essential to the function of all excitable membranes.
Free Base Form (B) =
Unionized Lipophilic (Uncharged Form)
** Determines onset of action
Cationic Form (BH+) =
Ionized = Charged Form
** Determines block duration
What is the rule regarding acidic drugs in acidic pH?
Acid drugs become more NON ionized in acidic pH
What is the rule regarding basic drugs in basic pH?
Basic drugs become more NON ionized in basic pH (alkaline pH)
Basic drug in acidic environment becomes:
More ionized
Acidic drug in basic environment becomes:
More ionized
Hydrophilic molecules are:
Ionized molecules (charged)
Hydrophilic molecules dissolve in water
Lipophilic molecules are:
Non-ionized molecules (non charged)
Lipophilic molecules penetrate membranes
Which one passes thru the cell membrane?
Ionized/nonionized?
Nonionized
What are the 3 things that help to determine whether a drug is MAJORITY in lipophilic or hydrophilic form?
Whether the drug is an acid drug or a base drug;
The pKa of the drug (pH at which number of ionized = number of nonionized molecules);
pH into which the drug is going to be placed.
When given the Acid/Base nature of the drug,
Drug’s pKa &
Environmental pH drug is put into.
What can you do with this information?
Be able to predict whether majority of drug is in the ionized form or non-ionized form;
Be able to state whether majority of drug is in the hydrophilic form or lipophilic form;
Be able to predict whether it can be absorbed across membrane (PO) or dissolved in water (SQ, IM).
What was the first LA
Cocaine (1884) for ophthalmology surgery.
It was later injected to interrupt nerve impulse conduction in local anesthesia
First synthetic LA
The ester derivative, procaine (1905)
This LA was was synthesized as an amide LA in 1943. It produces more rapid, more intense & longer lasting conduction blockade than procaine. Unlike procaine it is effective topically & is a highly effacacious cardiac antidisrrhythmic drug. For these reasons, it is the standard to which other anesthetics are compared.
Lidocaine
What fibers are peripheral nerve fibers comprised of?
Myelinated A & B and unmyelinated C fibers
What are the pain conducting nerve fibers?
Myelinated A-delta & unmyelinated C fibers
Which nerve fiber is most readily blocked by LA?
Preganglionic B fibers
Hoe does acidosis as in tissue infection affect LA?
A LA is a weak bases and at physiological pH (7.4), < 50% of it is nonionized (available).
Acidosis increases the ionized fraction of the drug --> possibly poor quality blockade.
__________ (Ionized/Nonionized) drug molecules are generally _______ lipid soluble.
Un-ionized drug molecules generally are lipid soluble. (They can traverse the lipid component of cell membranes).
True/false?
The nonionized fraction of a drug is more readily absorbed from the GI tract, reabsorbed from renal tubules, and subject to hepatic metabolism.
True
(Because they are absorbed thru the lipid component of cell membranes)
What is the pKa of tetracaine?
What happens when it is placed in an acidic environment?
8.5
It is a weak base.
In an acidic enviroment, less than 50% is unionized.
What is the pKa of lidocaine?
What happens when it is placed in an acidic environment?
7.9
It is a weak base.
In an acidic enviroment, less than 50% is unionized.
The pKa of lidocaine is 7.9 (50% of the drug ionized & 50% unionized)
At the following pH's what percentage of lidocaine is ionized/unionized?
7.6. 7.4, 7.2
7.6 - 33/67
7.4 - 25/75
7.2 - 17/83
How does sodium bicarb affect LA?
The addition of sodium bicarbonate to local anesthetic solutions appears to speed the onset of action.
Explain why NaBicarb speed the onset of LAs?
Alkalization increases the % of unionized drug available to cross the nerve membrane, thus speeding onset of action.
What is the commonly used dosing of NaBicarb to LAs?
1 mEq Bicarbonate to 10 cc of local anesthetic (except bupivacaine).
Bupivacaine precipitates at pH > 6.8 in solution so only 0.1 meq/cc or none is used.
What blocks is the technique of alkinization (adding Bicarb) LAs used with?
Brachial plexus and epidural blocks.
In what condition would alkinization be ineffective?
Infected tissue (it is acidic).
List the basic properties of LAs?
Weakly basic tertiary amines;
Poorly water soluble;
Prepared as water-soluble HCL salts that are strongly acidic (pH < 6).
Epinephrine is unstable in an alkaline pH.When epi is added to LA (an alkaline) how is it kept stable?
Commercially prepared local anesthetics containing epinephrine often have sodium bisulfite added to lower pH to 4.
In solution, how do LAs exist?
In equilibrium as ionized and nonionized forms.
True/false?
Nonionized (lipid-soluble) base crosses axonal membranes.
True
True/false?
Ionized (water-soluble) cation is responsible neural blockade.
True
The core structure of all local anesthetics consists of three major components, what are they?
Lipophilic group --> Usually a benzene ring;
Hydrophilic group --> Usually a quaternary amine;
Intermediate chain --> Contains an ester or amide group.
Local anesthetics consist of three major chemical moieties, list them.
Lipophilic aromatic ring.
Hydrophilic tertiary amine.
Ester or amide linkage.
Whis the pKa for Chloroprocaine (Nesacaine)?
9.0
(It is an ester)
Whis the pKa for Cocaine?
8.7 (it is an ester)
What is the pKa for Procaine?
8.9
(it is an ester)
What is the pKa of Tetracaine
8.2
(it is an ester)
What is the pKa of Americaine
None
(Americaine is an ester)
What is the pKa of Bupivacaine (Marcaine)?
8.1
(it is an amide)
What is the pKa of Dibucaine (Nupercaine)?
8.8
(it is an amide)
What is the pKa of Etidocaine (Duranest)?
7.7
(it is an amide)
wHAT IS THE PkA OF Lidocaine (Xylocaine)?
7.8
(it is an amide0
What is the pKa OF Mepivacaine (Carbocaine)?
7.6
(IT IS AN AMIDE)
What is the pKa of Prilocaine (Citanest)?
7.8
(it is an amide)
What is the pKa of Ropivacaine (Naropin)?
8.1(it is an amide)
Changes in the amine ring or chemical structure of LA result in marked alterations, what are these alterations?
Lipid/aqueous solubility, potency, and protein binding.
LAs are classified into two major groups. What are these groups and what is the basis for these classifications?
Amino esters and amino amides.
Classification is based on the linkage between the lipophilic and hydrophilic components: the major differences between the esters and amides are metabolism (pseudocholinesterase vs liver) and allergic potential (ester greater than amide).
How are ester LAs metabolized?
By pseudocholinesterase (plasma cholinesterase)and partially by red cell esterases.
Metabolism of ester LAs
With the exception of Cocaine, they are mostly metabolized by cholinesterases & secondarily by the liver. Some of the LA is excreted unchanged in the urine.
In what pt population is pseudocholinesterase decreased?
In neonates and in pregnancy (atypical pseudocholinesterase).
Duration of action of ester LAs is then prolonged.
What does the Ester hydrolysis results in?
Formation of para-amino benzoic acid (PABA), which have allergic potential.
Procaine, tetracaine & chloroprocaine
Of these three esters, which is hydrolyzed the fastest?
Chloroprocaine is hydrolyzed four times faster than procaine, and procaine is hydrolyzed four times faster than tetracaine.
How are Amide Local Anesthetics metabolized?
By amidases (hepatocytes) and microsomal enzymes in the liver.
What can prolongs the duration of action of amides?
Liver disease
Amide local anesthetics are metabolized by the liver. What are the 3 main routes of biotransformation that have been identified?
Aromatic hydroxylation, N-dealkyl-ation, and amide hydrolysis.
What is the the order of clearance of these LAs going from slowest to fastest - lidocaine, mepivacaine, bupivacaine,prilocaine, etidocaine?
Bupivacaine < mepivacaine < lidocaine <etidocaine < prilocaine (Big Mama Loves Eating Pork)
How does severe cirrhosis affect lidocaine's Vd, T1/2 and clearance?
The half-life and volume of distribution are increased, while clearance is decreased because of decreased enzyme activity and shunting.
Amides may be manufactured with PABA (methylparaben) added as a preservative. Why is this information important?
PABA has allergic potential, it should be avoided in patients who have an “allergy” to LAs.
(**Amide local anesthetics are not broken down to PABA).
What does the following characteristics of LA determine?
Lipid Solubility, Protein Binding, pKa &Intrinsic Vasodilator Activity
Lipid solubility - potency
Protein binding - duration of action;
pKa - onset;
Intrinsic vasodilator - duration of action & affects potency also
The rapid onset of procaine and 2-chloropropine blockade [pKa = 9] is due to?
A high solution concentration and thus a greater diffusion gradient.
After LAs are injected, how much of it is metabolized at the site and how much of it is excreted?
The local anesthetic drugs are absorbed after injection of the local anesthetic at the site of administration. Only small amounts are excreted unchanged in the urine, and very little metabolism occurs at the site of injection.
What fraction of the LA penetrate the brain?
The nonionized or free base liophilic fraction.
Local anesthetics that are _______(highly/poorly) protein bound have a shorter duration
LAs that are poorly protein bound have a shorter duration & vice versa.
Less protein bound = less ionized = quicker onset = quicker off
What does the strength of the bond with the site determine?
The length of its effect.
The stronger the bond, the harder it will be for local blood flow to wash it away to get metabolized or redistributed.
Drugs exist in the blood in two forms, what are they?
Either dissolved in plasma or bound to proteins. The two main plasma proteins that bind with drugs are albumin and a-l-acid glycoprotein (AAG), although globulins, lipoproteins, and erythrocytes may bind drugs as well.
How does protein binding affect drug distribution and action?
Generally only the free portion traverses cell membranes and reaches its site of action.
By limiting drug excursion into the tissues, extensive protein binding results in a small calculated Vd.
How does the protein binding influences clearance of drug?
It is the unbound fraction that is available for metabolism and clearance by the liver and kidney.
As a general rule, albumin is the major protein that binds acid drug, whereas glycoprotein binds many basic drugs, including many narcotics, propranolol, verapamil, quinidine, and amide LAs. Certain drugs can bind to both proteins. Give two examples of these?
Fentanyl & sufentanil
How does the degree of protein binding correlate to lipid solubility?
Higher lipid solubility = higher degree of protein binding
How does Acid-base disturbances affect drug binding?
A base drug in acidic environment become more ionized and vice versa.
(Plasma concentrations of the drug in question & available sites for binding also affect drug binding).
Explain:
pKa = Speed of onset
The free base, lipid soluble, unionized fraction is what penetrates the nerve.
The drug’s pKa determines the unionized drug fraction available.
The amount of unionized drug determines onset time.
The closer the drug’s pKa is to physiologic pH, the quicker the onset.
Total dose =
Volume X concentration
Absoption is a function of --?
Dosage; Site of injection;
Addition of vasoconstrictor;
Specific characteristics of drug used (Lipid solubility,
Protein binding, pKa, intrinsic vasodilator properties).
The rate of systemic absorption is proportionate to ---?
The vascularity of the site of injection.
The higher the vascularity, the quicker the absorption.
**Blood > Intratracheal > Intercostal > Caudal > Epidural > Brachial Plexus > Sciatic > Subarachnoid > Subcutaneous
B- I- C- E- P-S &
Intratracheal before intercostal anatomically,
sciatic before subarachnoid before subcutaneous alphabethically
What does adding a vasoconstrictor into a mixture with a local anesthetic does?
Decreases absorption of the local anesthetic into the blood. (Eg Epinephrine or less commonly, Neosynephrine).
Vasoconstrictors = Decreased Absorption = Decreased Systemic Toxicity =
Increased Duration of Action
True/false?
Re-distribution half - time (T1/2 alpha) is very quick related to equilibration with vessel-rich tissue.
True
True/false?
Local anesthetics rapidly distribute throughout total body water after they reach the bloodstream.
True
In single-shot techniques, the local anesthetic begins to dissipate into the surrounding nonneural tissue as soon as it is injected. What speeds the removal of drug from the site of action?
Uptake and redistribution by blood.
Nerve blocks normally decay in reverse order of their onset. Explain
Even as the drug begins to diffuse from the outer axons into the surrounding tissue, it may still be diffusing into the central axons. As the drug diffuses out of the core of the nerve, it moves into the outer layers, maintaining the local anesthetic concentration in those axons. Thus, nerve blocks normally decay in reverse order of their onset such that the central axons recover first.
Some drugs have first pass ecxtraction by the lungs. Name them. Which one's extraction is dose dependent.
Lidocaine
Bupivacaine (dose dependent – saturates quickly)
Prilocaine
Extraction by the lungs limits the concentration of drug that reaches the CNS & CV.
Highly protein bound LAs cross to a lesser degree than less protein bound LAs. Which one of these would have a higher amt cross over? Bupivacaine vs lidocaine.
Lidocaine > Bupivacaine
Ester LA are not available to cross the placenta, because?
Of their rapid hydrolysis.
When LA is used in delivery, if labor is prolonged, how does this affect the fetus?
Prolonged labor can result in
fetal acidosis 2° to ion trapping (accumulation of LA).
What is ion trapping?
When a pH gradient exists across a membrane, the concentration of total drug may be quite different on each side. The un-ionized fraction traverses the membrane freely and equilibrates. But the ionized form, which cannot cross the membrane, is trapped on the side with a pH that favors ionization. As in LA crossing the placenta (***Fetal pH is much lower than maternal).
True/false?
Renal disease usually does not have a significant effect on metabolism of local anesthetics.
True
How are LAs excreted?
LAs are largely eliminated by metabolic conversion to more polar compounds and removed by the kidney.
All local anesthetics EXCEPT _____ and ________, possess the ability to cause vasodilatation in the area they are injected, increasing blood flow to that area.
As a result, LA increase their own absorption into the central circulation.
Cocaine & Ropivacaine (these cause vasoconstriction).
What are isobaric LAs?
Isobaric LAs stays where they are placed.
They have the same density or specific gravity as CSF.
The SG of NS is (1.003-1.008).
How does the vasodilatory effect of LAs affect potency & duration?
There is less drug available at the receptor site to elicit an effect.
Increased intrinsic vasodilator properties = decreased potency and duration.
**Intrinsic Vasodilator Activity is negatively correlated to potency and Duration of Action**
What are hypobaric LAs?
Hypobaric LAsare that that above site of placement.
They have a density or specific gravity that is less than CSF.
SG of sterile water is <1.003
Sterile water added to LAs make them hypobaric.
What are Hyperbaric LAs?
Hyperbaric LAs
– Sink down
- LA has a density or specific gravity that is greater than CSF (>1.008)
to make a LA hyperbaric, add D5W
Which LA is very popular for use in obstetrics related to its quick onset and duration of action and also the high concentration that can be safely administered?
2-Chloroprocaine (Nesacaine):
Quickest onset and shortest duration of action of all LAs;
Possesses the highest pKa of all LAs, but the shortest duration of action.
The low systemic toxicity of this agent allows the use of high concentrations (3%). Increased dose = more rapid onset.
 
Manufactured as a lyophilized powder that requires dilution, as well as a hyperbaric solution premixed with dextrose.
Commonly used in a hypobaric spinal mixture for perineal cases.
Longest duration of action of all spinal agents.
Which LA is this?
Tetracaine (Pontocaine)
Higher margin of safety compared to Bupivacaine.
Takes three times more of this drug to cause CV collapse than it does to cause convulsions.
If injected intra-arterial, it is safer than Bupivacaine (due to its high CV/CNS toxicity ratio).
Only LA agent given intravenously on a routine basis in the O.R. to blunt the adrenergic response to intubation, and minimize burning on injection from Propofol.
Which LA is this?
Lidocaine
Small therapeutic window;
Can cause cardiotoxicity (toxicity often results in refractory cardiac arrest);
Concentrations > 0.5% are not recommended.
What LA is this?
Bupivacaine (Marcaine) 
Similar to Bupivacaine (S-stereoisomer plus has a propyl instead of a butyl) in onset, duration of action, and relative potency but less cardiotoxic.
Causes vasoconstriction.
Causes less motor block but has equipotent sensory block to bupivacaine.
Popular in obstetric anesthesia as pain is controlled and motor function is spared.
What LA is this?
Ropivacaine (Naropin)
Can cause methemoglobinemia in a dose-dependent fashion;
Accumulation of metabolite (ortho-toluidine) which is capable of converting hemoglobin to methemoglobin
(patient appears cyanotic, blood is chocolate-colored);
Spontaneous recovery occurs in 2-3 hours from discontinuation.
Acute treatment = Methylene blue 1-2 mg/kg IV
Which LA is this?
Prilocaine 
What is the maximum dose of of lidocaine used in LA (with/without Epi)?
w/o Epi = 7mg/kg
with Epi = 5mg/kg
What is the primary clinical use of bupivacaine?
Infiltration, Neuroaxial Blocks, Peripheral Nerve Blocks
What is the primary clinical use of ropivacaine?
Epidural, Peripheral Nerve Blocks
What is the primary clinical use of chlorprocaine?
Epidural Blocks, Nerve Blocks
What is the primary clinical use of mepivacaine?
Axillary, Peripheral Nerve Blocks
What is the primary clinical use of tetracaine?
Spinal & Axilllary Blocks
What is the primary clinical use of benzocaine
Topical anesthetic spray
What is the primary clinical use of cocaine?
Topical liquid anesthetic
Allergies are rare with amides. When a pt say that he/she is allergic to LA, what does he/she most often mean?
Metabolism of ester LA yields para-aminobenzoic acid (PABA) which is a known allergen. This is often what the pt is referring to.
What is Methylparaben?
A preservative in LA that is also metabolized to PABA and may cause allergic reactions.
What is the benefit of adding Epinephrine to LA?
Maximum dose increased.
Duration prolonged.
Slower absorption into the central circulation decreases toxicity.
LA toxicity primarily involves which systems?
Central Nervous System (CNS)
Cardiovascular System (CV)
Most episodes of local anesthetic toxicity result from?
High blood levels of local anesthetic caused either from accidental intravascular injection or increased uptake from perivascular areas, such as epidural space or axillary sheath.
Prevention and treatment of local anesthetic toxicity is dependent on..?
The injection of an appropriate volume and concentration of LA; knowledge of the pharmacologic properties of these drugs, and increased vigilance for the early detection of toxic reactions.
The site of injection, choice of drug, dose of anesthetic, addition of vasoconstrictors, and metabolism determine blood levels of local anesthetic.
With a high degree of tissue binding(etidocaine and bupivacaine)and a large volume of distribution (prilocaine) how will these characteristics affect the plasma level of the LA?
The plasma level will be lowered - binding & redistribution decrease drug level in circulation.
What is the relationship between total dose of local anesthetic and plasma concentration?
It is linear.
What is the actual effect of the addition (to LA)of vasoconstrictive agents like epinephrine or phenylephrine?
They vasoconstrict the vessels --> slower washout time of the LA --> increased duration of action of the LA. The action of these vasoactive drugs is dependent on the sensitivity of the vasculature at the injection site and also the vasoconstrictive or dilating properties of the specific LA themselves.
Because little metabolism of local anesthetics occurs at the site of injection, what must happen in order for the LA to be metabolized?
Absorption and delivery to the site of metabolism (for amides, the liver; for esters, the plasma) is necessary.
S/S Systemic LA Toxicity
Initial symptoms involve excitation of the CNS, as inhibitory pathways in the limbic system and cortex are depressed.
Later symptoms involve depression of the CNS, as both inhibitory and excitatory pathways are blocked.
If there is rapid absorption & inadvertent rapid intravenous injection, what may happen?
May result in CNS toxicity.
LA readily cross the Blood Brain Barrier (BBB) and can produce excitation and depression.
True/false?
CNS toxicity is proportional to LA potency.
True.
The more potent the more CNS toxicity.)
(Longer-acting drugs tend to be more toxic).
How does hypercarbia affect drug toxicity?
Convulsive threshold is decreased by 50% in the presence of hypercarbia. Increase in PaCO2 increases cerebral blood flow and decreases pH resulting in decreased protein binding…more free drug available.
LAs cause a dose-dependent depression in myocardial contractility and they also exhibit vasodilating properties. Which two LAS are exceptions?
Cocaine & ropivicaine. They have vasoconstricting properties.
What is Cauda Equina Syndrome?
Cauda equina syndrome is a serious condition caused by compression of the nerves in the lower portion of the spinal canal. Cauda equina syndrome is considered a surgical emergency because if left untreated it can lead to permanent loss of bowel and bladder control and paralysis of the legs.
High concentrations of LA may cause neural toxicity. Which 2 LAs have been implicated?
Both 3% chloroprocaine and 5% xylocaine
What are recommendations to prevent cauda enquina syndrome when using lidocaine?
Do not used 5% Lidocaine through a continuous spinal catheter.
Use 5% Lidocaine cautiously for procedures involving the high lithotomy position, where perfusion of the cauda equina may be compromised and the nerves may be more vulnerable.
Recommended to dilute the dose administered with equal volumes of CSF prior to injection
What are the stages of LA toxicity?
CNS Excitation
CV Excitation
CNS Depression
CV Depression
Death
What are the classic early CNS symptoms of LA toxicity?
Circumoral Numbness - Earliest Sign;
Metallic Taste;
Lightheadedness;
Dizziness;
Blurred Vision;
Tinnitus.
What are the later CNS symptoms of LA toxicity?
Disorientation
Shivering
Muscle Twitching
Tonic/Clonic Seizures
Unconsciousness
Apnea
What are early CV s/s of LA toxicity?
Tachycardia
Hypertension (related to the CNS excitatory effects).
What are late CV s/s of LA toxicity?
Bradycardia
Hypotension
Dysrhythmias
Asystole
- Direct depression of cardiac and vascular smooth muscle
- Decrease in myocardial electrical activity, conduction rate, and force of contractions.
Signs of LA toxicty in order of occurence
Disorientation
Metallic taste
Tingling in the mouth & tongue
Tinnitus & auditory hallucination
Muscular spasms
Seizures
Coma
Resp arrest
Cardiac arrest
Death
Treatment of LA Toxicity:
STOP injection.
Call for help!
Apply 100% oxygen.
Have patient hyperventilate.
Administer Midazolam or Thiopental.
Prepare for the next stage.
Ventilate and Intubate
Administer vasopressors
CPR
How can you raise the seizure threshold?
Oxygen raises the seizure threshold.
Hypocarbia raises the seizure threshold.
Decrease CBF --> decrease delivery of LA
Barbiturates and benzodiazepines are readily available, and also raise the seizure threshold.
****But, if you decrease CBF you will decrease the ability of getting rid of the LA in the brain....
Prevention is best, what can you do to prevent an OD?
Select the correct dose and concentration of LA.
Use a test dose and incremental injections with frequent aspirations.
Monitor patients closely.
Use benzodiazepines to raise the seizure threshold…on everybody.
Use epinephrine as an intravascular marker.
Listen to your gut!
LA exist in two molecular forms; as charged cation (AH+) or as a neutral free-base molecule (A). Equilibrium between the two is determined by:
pH = pKa + log (A/AH+)
Henderson-Hasselbach equation
Expressed for convenience as: pKa = pH – log[base]/cation. Where pKa is equal to pH at which an individual drug will have equal parts protonated (cation, ionized) and deprotonated (neutral, nonionized); 50/50.
pKa of most LA is between 7.5 and 9.0, therefore cations outnumber base in normal tissue pH (7.4).
LAs are weak bases(hydrochloric salts) that are poorly soluble in water, with a pH < ____
6
Both forms of LA (ionized & nonionized) are important in conduction blockade. Explain.
Free base (nonionized) diffuses more easily through the bilipid nerve membrane, however the Cation (ionized) form binds to the receptor sites; blocking the Na+ channel, suppressing the action potential.
____ (Nonionized/ionized) form diffuse through cell membrane;
________ (Nonionized/Ionized) form blocks receptors;
Hydrophilic = _____ (nonionized/ionized) molecules;
Lipophilic = ______ (ionized/nonionized)
Nonionized form diffuse through cell membrane
Ionized form blocks receptors
Hydrophilic = ionized molecules;
Lipophilic = nonionized molecules.
Duration of action is generally correlated to lipid solubility. Explain.
Highly lipid soluble LAs have a longer duration of action b/c they are less likely to be cleared away by blood flow.
The CNS is the site of premonitory signs of OD in awake pts. What are these signs?
Circumoral numbness, tongue paresthesia & dizziness. Sensory complaints may include tinnitus & blurred vision.