Nurs614 Exam 2 Local Anesthetics

Front 1

What are local anesthetics?

Back 1

Drugs that reversibly inhibit the conduction of electrical impulse along nerve fibers

Front 2

The degree of inhibition is influenced by:

Back 2

Anatomy of the nerve being blocked;
Tissue conditions;
Physicochemical properties of the local anesthetic agent.

Front 3

Desirable Properties of LAs

Back 3

Short Onset
Moderate duration of action
Quick recovery
Non-irritating to tissues
Low systemic toxicity (high therapeutic index)

Front 4

What is the therapeutic index

Back 4

Dose producing undesired effects divided by the lowest dose producing desired effect (reflects margin of safety).

Front 5

High Therapeutic Index =

Back 5

Low Systemic Toxicity & therefore High Safety Margin

Front 6

How does diffusion of LA occur?

Back 6

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.

Front 7

How are neurons generally arranged?

Back 7

In bundles

Front 8

How does the diffusion of most LA occur in the neuron?

Back 8

Initially from mantle to core & then thru progression in their onset ill decay.

Front 9

Describe the progression of the onset of most LA in neurons?

Back 9

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.

Front 10

How do we achieve a state of dense anesthesia?

Back 10

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.

Front 11

What makes regional anesthesia somewhat unpredictable? This help to explain partial sensory blockades.

Back 11

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.

Front 12

What is the size and function of B fibers

Back 12

0.25 mcirons
Preganglionic autonomic activities

Front 13

What is the size and function of C fibers

Back 13

0.5microns
They communicate Temperature & Dull Pain

Front 14

What is the size and function of A delta fibers

Back 14

0.5microns
They communicate Temperature & Dull Pain

Front 15

What is the size and function of A-gamma fibers

Back 15

0.75 microns
They are found in Muscle Spindle & help to control Muscle Tone

Front 16

What is the size and function of A-beta fibers?

Back 16

0.75 micron
Light pressure & touch

Front 17

What is the size and function of A-alpha fibers?

Back 17

1.0 micron
Somatic motor & proprioception

Front 18

True/false
C-fibers are Unmyelinated?

Back 18

True

Front 19

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?

Back 19

At least three.
If only one node is blocked, impulse can bypass

Front 20

How are neurons myelinated?

Back 20

Myelinated neurons are wrapped in Schwann cells which are invested in a coating of myelin, a good insulator.

Front 21

How does myelination affect neurons' conductivity?

Back 21

The coating would completely stop impulse conduction if it were not for gaps in the insulation known as nodes of Ranvier.

Front 22

How is transmission affected along nodes of ranvier?

Back 22

These gaps focus the electrical current of depolarization of the membrane and force the wave of depolarization to jump from node to subsequent node.

Front 23

How does the effect of jumping from node to node speed the conduction of nerve impulses?.

Back 23

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.

Front 24

True/false?
Smaller nerve fibers are more vulnerable to blockade in lower concentrations of local anesthetics.

Back 24

True.
As concentrations are increased, larger nerve fibers are blocked.

Front 25

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

Back 25

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

Front 26

Where are spindle fibers found?

Back 26

Within the fleshy portions of muscles, embedded in extrafusal muscle fibers

Front 27

What occurs during neuroaxial anesthesia blockade (list in order of occurence)?

Back 27

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.

Front 28

What is the MIC

Back 28

MINIMUM INHIBITORY CONCENTRATION which is the minimum concentration of local anesthetic necessary to produce conduction blockade of nerve impulses.

Front 29

What does the MIC of each drug represent?

Back 29

The potency.
Each local anesthetic has a unique Cm.

Front 30

MIC is measured in Cm. What influences Cm?

Back 30

Nerve fiber diameter - larger fibers requiring ↑ concentrations to produce conduction blockade.
Cm of motor fibers are 2X that of sensory.

Front 31

How does anesthesia affect AP?

Back 31

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.

Front 32

At what point during the disruption of AP is MIC achieved?

Back 32

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).

Front 33

How does pH affect MIC?

Back 33

An increased tissue pH can decrease the Cm (hence an increased MIC)

Front 34

MIC is independent of axon thickness in myelinated axons & unmyelinated neurons at the steady state. Why then are thinner axons blocked before thicker ones?

Back 34

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.

Front 35

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?

Back 35

It is not

Front 36

What factors limit our ability to estimate the concentration of local anesthetic at the axon?

Back 36

LAs injected into the body are subject to absorption, dilution, and metabolism, and neurons are enveloped in tissue, muscle, and blood vessels.

Front 37

How is the knowledge of the MIC of LAs useful?

Back 37

They provide a standard for comparison of the potencies of different local anesthetic agents.

Front 38

MOA of LAs?

Back 38

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).

Front 39

The resting membrane potential of most nerve cell is

Back 39

-60 to -90 mV

Front 40

At RMP, the cell nerve cell is more permeable to _________

Back 40

K+ ions

Front 41

How are waves of depolarization propagated along the length of the axon?

Back 41

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.

Front 42

At RMP (-90mV), what is the postion of the activation & inactivation gates

Back 42

The activation (on the outside) is closed & the inactivation (on the inside) is opened. Na is not allowed in.

Front 43

At mV of -90 to +35 what are the positions of the activation/inactivation gates?

Back 43

Both are open, Na is entering the cell

Front 44

When the Na channel of the nerve cell is in anactivated state, what is happening with the Na ion & the activation/incativation gate?

Back 44

The activation gate is opened but the inactivation gate is closed so Na is not able to enter the cell.

Front 45

What state does the equilibrium of local anesthetic binding and dissociation favor?

Back 45

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).

Front 46

A nerve impulse is carried along an individual neuron as a sequence of three events.
What occurs in the first sequence?

Back 46

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).

Front 47

A nerve impulse is carried along an individual neuron as a sequence of three events.
What occurs in the second sequence?

Back 47

Where the nerve enters the spinal cord, the impulse is converted to the release of a neurotransmitter.

Front 48

What two facts are essential in understanding the transmembrane potential?

Back 48

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.

Front 49

What happens if the permeability of the membrane changes?

Back 49

The potential changes, even if there is no change in ion concentration.

Front 50

What does ion concentration, membrane permeability & membrane concentration differential influence?

Back 50

The ability of the transmembrane potential to change rapidly with only a small movement of ions.

Front 51

The action potential and nerve conduction are both "all or none phenomena. Explain

Back 51

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.

Front 52

LA produce their action by blocking Na+ channels. There are four major MOA, what are they?

Back 52

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.

Front 53

LAs are are weak bases, how do weak bases behave in aqueous solution?

Back 53

They do not readily dissociate into charged ions (a significant fraction of the molecules are in the uncharged or unionized state when in solution ).

Front 54

What are the two forms of anesthetics?

Back 54

Free base form (B)= lipophilic unionized fraction;
Cationic form (BH+)= hydrophilic ionized fraction
BH+ <=> B + H+

Front 55

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:

Back 55

pKa=pH – log[base]/[conjugate acid] - the Henderson-Hasselbach equation

Front 56

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

Back 56

1:1
When the pH equals the pKa, the concentration of base is equal to the concentration of cation.

Front 57

What does pKa define?

Back 57

pKa defines the pH at which the amount of ionized and unionized drug fraction is equal.

Front 58

How does physiologic pH affect the onset of LA?

Back 58

Local anesthetics with a pKa closer to physiologic pH (7.4) will have a quicker onset related to an increased unionized drug fraction. 

Front 59

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?

Back 59

The local pH determines the % ionized and unionized drug form.
The unionized form crosses the lipid bilayer of the nerve.

Front 60

After the LA crosses the lipid bilayer, what is the sequence of events that follows?

Back 60

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

Front 61

How does the cell develop an electrical potential (transmembrane potential) across the membrane?

Back 61

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.

Front 62

Free Base Form (B) =

Back 62

Unionized Lipophilic (Uncharged Form)
** Determines onset of action

Front 63

Cationic Form (BH+) =

Back 63

Ionized = Charged Form
** Determines block duration

Front 64

What is the rule regarding acidic drugs in acidic pH?

Back 64

Acid drugs become more NON ionized in acidic pH

Front 65

What is the rule regarding basic drugs in basic pH?

Back 65

Basic drugs become more NON ionized in basic pH (alkaline pH)

Front 66

Basic drug in acidic environment becomes:

Back 66

More ionized

Front 67

Acidic drug in basic environment becomes:

Back 67

More ionized

Front 68

Hydrophilic molecules are:

Back 68

Ionized molecules (charged)
Hydrophilic molecules dissolve in water

Front 69

Lipophilic molecules are:

Back 69

Non-ionized molecules (non charged)
Lipophilic molecules penetrate membranes

Front 70

Which one passes thru the cell membrane?
Ionized/nonionized?

Back 70

Nonionized

Front 71

What are the 3 things that help to determine whether a drug is MAJORITY in lipophilic or hydrophilic form?

Back 71

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.

Front 72

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?

Back 72

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).

Front 73

What was the first LA

Back 73

Cocaine (1884) for ophthalmology surgery.
It was later injected to interrupt nerve impulse conduction in local anesthesia

Front 74

First synthetic LA

Back 74

The ester derivative, procaine (1905)

Front 75

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.

Back 75

Lidocaine

Front 76

What fibers are peripheral nerve fibers comprised of?

Back 76

Myelinated A & B and unmyelinated C fibers

Front 77

What are the pain conducting nerve fibers?

Back 77

Myelinated A-delta & unmyelinated C fibers

Front 78

Which nerve fiber is most readily blocked by LA?

Back 78

Preganglionic B fibers

Front 79

Hoe does acidosis as in tissue infection affect LA?

Back 79

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.

Front 80

__________ (Ionized/Nonionized) drug molecules are generally _______ lipid soluble.

Back 80

Un-ionized drug molecules generally are lipid soluble. (They can traverse the lipid component of cell membranes).

Front 81

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.

Back 81

True
(Because they are absorbed thru the lipid component of cell membranes)

Front 82

What is the pKa of tetracaine?
What happens when it is placed in an acidic environment?

Back 82

8.5
It is a weak base.
In an acidic enviroment, less than 50% is unionized.

Front 83

What is the pKa of lidocaine?
What happens when it is placed in an acidic environment?

Back 83

7.9
It is a weak base.
In an acidic enviroment, less than 50% is unionized.

Front 84

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

Back 84

7.6 - 33/67
7.4 - 25/75
7.2 - 17/83

Front 85

How does sodium bicarb affect LA?

Back 85

The addition of sodium bicarbonate to local anesthetic solutions appears to speed the onset of action.

Front 86

Explain why NaBicarb speed the onset of LAs?

Back 86

Alkalization increases the % of unionized drug available to cross the nerve membrane, thus speeding onset of action.

Front 87

What is the commonly used dosing of NaBicarb to LAs?

Back 87

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.

Front 88

What blocks is the technique of alkinization (adding Bicarb) LAs used with?

Back 88

Brachial plexus and epidural blocks.

Front 89

In what condition would alkinization be ineffective?

Back 89

Infected tissue (it is acidic).

Front 90

List the basic properties of LAs?

Back 90

Weakly basic tertiary amines;
Poorly water soluble;
Prepared as water-soluble HCL salts that are strongly acidic (pH < 6).

Front 91

Epinephrine is unstable in an alkaline pH.When epi is added to LA (an alkaline) how is it kept stable?

Back 91

Commercially prepared local anesthetics containing epinephrine often have sodium bisulfite added to lower pH to 4.

Front 92

In solution, how do LAs exist?

Back 92

In equilibrium as ionized and nonionized forms.

Front 93

True/false?
Nonionized (lipid-soluble) base crosses axonal membranes.

Back 93

True

Front 94

True/false?
Ionized (water-soluble) cation is responsible neural blockade.

Back 94

True

Front 95

The core structure of all local anesthetics consists of three major components, what are they?

Back 95

Lipophilic group --> Usually a benzene ring;
Hydrophilic group --> Usually a quaternary amine;
Intermediate chain --> Contains an ester or amide group.

Front 96

Local anesthetics consist of three major chemical moieties, list them.

Back 96

Lipophilic aromatic ring.
Hydrophilic tertiary amine.
Ester or amide linkage.

Front 97

Whis the pKa for Chloroprocaine (Nesacaine)?

Back 97

9.0
(It is an ester)

Front 98

Whis the pKa for Cocaine?

Back 98

8.7 (it is an ester)

Front 99

What is the pKa for Procaine?

Back 99

8.9
(it is an ester)

Front 100

What is the pKa of Tetracaine

Back 100

8.2
(it is an ester)

Front 101

What is the pKa of Americaine

Back 101

None
(Americaine is an ester)

Front 102

What is the pKa of Bupivacaine (Marcaine)?

Back 102

8.1
(it is an amide)

Front 103

What is the pKa of Dibucaine (Nupercaine)?

Back 103

8.8
(it is an amide)

Front 104

What is the pKa of Etidocaine (Duranest)?

Back 104

7.7
(it is an amide)

Front 105

wHAT IS THE PkA OF Lidocaine (Xylocaine)?

Back 105

7.8
(it is an amide0

Front 106

What is the pKa OF Mepivacaine (Carbocaine)?

Back 106

7.6
(IT IS AN AMIDE)

Front 107

What is the pKa of Prilocaine (Citanest)?

Back 107

7.8
(it is an amide)

Front 108

What is the pKa of Ropivacaine (Naropin)?

Back 108

8.1(it is an amide)

Front 109

Changes in the amine ring or chemical structure of LA result in marked alterations, what are these alterations?

Back 109

Lipid/aqueous solubility, potency, and protein binding.

Front 110

LAs are classified into two major groups. What are these groups and what is the basis for these classifications?

Back 110

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).

Front 111

How are ester LAs metabolized?

Back 111

By pseudocholinesterase (plasma cholinesterase)and partially by red cell esterases.

Front 112

Metabolism of ester LAs

Back 112

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.

Front 113

In what pt population is pseudocholinesterase decreased?

Back 113

In neonates and in pregnancy (atypical pseudocholinesterase).
Duration of action of ester LAs is then prolonged.

Front 114

What does the Ester hydrolysis results in?

Back 114

Formation of para-amino benzoic acid (PABA), which have allergic potential.

Front 115

Procaine, tetracaine & chloroprocaine
Of these three esters, which is hydrolyzed the fastest?

Back 115

Chloroprocaine is hydrolyzed four times faster than procaine, and procaine is hydrolyzed four times faster than tetracaine.

Front 116

How are Amide Local Anesthetics metabolized?

Back 116

By amidases (hepatocytes) and microsomal enzymes in the liver.

Front 117

What can prolongs the duration of action of amides?

Back 117

Liver disease

Front 118

Amide local anesthetics are metabolized by the liver. What are the 3 main routes of biotransformation that have been identified?

Back 118

Aromatic hydroxylation, N-dealkyl-ation, and amide hydrolysis.

Front 119

What is the the order of clearance of these LAs going from slowest to fastest - lidocaine, mepivacaine, bupivacaine,prilocaine, etidocaine?

Back 119

Bupivacaine < mepivacaine < lidocaine <etidocaine < prilocaine (Big Mama Loves Eating Pork)

Front 120

How does severe cirrhosis affect lidocaine's Vd, T1/2 and clearance?

Back 120

The half-life and volume of distribution are increased, while clearance is decreased because of decreased enzyme activity and shunting.

Front 121

Amides may be manufactured with PABA (methylparaben) added as a preservative. Why is this information important?

Back 121

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).

Front 122

What does the following characteristics of LA determine?
Lipid Solubility, Protein Binding, pKa &Intrinsic Vasodilator Activity

Back 122

Lipid solubility - potency
Protein binding - duration of action;
pKa - onset;
Intrinsic vasodilator - duration of action & affects potency also

Front 123

The rapid onset of procaine and 2-chloropropine blockade [pKa = 9] is due to?

Back 123

A high solution concentration and thus a greater diffusion gradient.

Front 124

After LAs are injected, how much of it is metabolized at the site and how much of it is excreted?

Back 124

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.

Front 125

What fraction of the LA penetrate the brain?

Back 125

The nonionized or free base liophilic fraction.

Front 126

Local anesthetics that are _______(highly/poorly) protein bound have a shorter duration

Back 126

LAs that are poorly protein bound have a shorter duration & vice versa.
Less protein bound = less ionized = quicker onset = quicker off

Front 127

What does the strength of the bond with the site determine?

Back 127

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.

Front 128

Drugs exist in the blood in two forms, what are they?

Back 128

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.

Front 129

How does protein binding affect drug distribution and action?

Back 129

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.

Front 130

How does the protein binding influences clearance of drug?

Back 130

It is the unbound fraction that is available for metabolism and clearance by the liver and kidney.

Front 131

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?

Back 131

Fentanyl & sufentanil

Front 132

How does the degree of protein binding correlate to lipid solubility?

Back 132

Higher lipid solubility = higher degree of protein binding

Front 133

How does Acid-base disturbances affect drug binding?

Back 133

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).

Front 134

Explain:
pKa = Speed of onset

Back 134

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.

Front 135

Total dose =

Back 135

Volume X concentration

Front 136

Absoption is a function of --?

Back 136

Dosage; Site of injection;
Addition of vasoconstrictor;
Specific characteristics of drug used (Lipid solubility,
Protein binding, pKa, intrinsic vasodilator properties).

Front 137

The rate of systemic absorption is proportionate to ---?

Back 137

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

Front 138

What does adding a vasoconstrictor into a mixture with a local anesthetic does?

Back 138

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

Front 139

True/false?
Re-distribution half - time (T1/2 alpha) is very quick related to equilibration with vessel-rich tissue.

Back 139

True

Front 140

True/false?
Local anesthetics rapidly distribute throughout total body water after they reach the bloodstream.

Back 140

True

Front 141

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?

Back 141

Uptake and redistribution by blood.

Front 142

Nerve blocks normally decay in reverse order of their onset. Explain

Back 142

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.

Front 143

Some drugs have first pass ecxtraction by the lungs. Name them. Which one's extraction is dose dependent.

Back 143

Lidocaine
Bupivacaine (dose dependent – saturates quickly)
Prilocaine
Extraction by the lungs limits the concentration of drug that reaches the CNS & CV.

Front 144

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.

Back 144

Lidocaine > Bupivacaine

Front 145

Ester LA are not available to cross the placenta, because?

Back 145

Of their rapid hydrolysis.

Front 146

When LA is used in delivery, if labor is prolonged, how does this affect the fetus?

Back 146

Prolonged labor can result in
fetal acidosis 2° to ion trapping (accumulation of LA).

Front 147

What is ion trapping?

Back 147

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).

Front 148

True/false?
Renal disease usually does not have a significant effect on metabolism of local anesthetics.

Back 148

True

Front 149

How are LAs excreted?

Back 149

LAs are largely eliminated by metabolic conversion to more polar compounds and removed by the kidney.

Front 150

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.

Back 150

Cocaine & Ropivacaine (these cause vasoconstriction).

Front 151

What are isobaric LAs?

Back 151

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).

Front 152

How does the vasodilatory effect of LAs affect potency & duration?

Back 152

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**

Front 153

What are hypobaric LAs?

Back 153

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.

Front 154

What are Hyperbaric LAs?

Back 154

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

Front 155

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?

Back 155

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.
 

Front 156

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?

Back 156

Tetracaine (Pontocaine)

Front 157

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?

Back 157

Lidocaine

Front 158

Small therapeutic window;
Can cause cardiotoxicity (toxicity often results in refractory cardiac arrest);
Concentrations > 0.5% are not recommended.
What LA is this?

Back 158

Bupivacaine (Marcaine) 

Front 159

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?

Back 159

Ropivacaine (Naropin)

Front 160

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?

Back 160

Prilocaine 

Front 161

What is the maximum dose of of lidocaine used in LA (with/without Epi)?

Back 161

w/o Epi = 7mg/kg
with Epi = 5mg/kg

Front 162

What is the primary clinical use of bupivacaine?

Back 162

Infiltration, Neuroaxial Blocks, Peripheral Nerve Blocks

Front 163

What is the primary clinical use of ropivacaine?

Back 163

Epidural, Peripheral Nerve Blocks

Front 164

What is the primary clinical use of chlorprocaine?

Back 164

Epidural Blocks, Nerve Blocks

Front 165

What is the primary clinical use of mepivacaine?

Back 165

Axillary, Peripheral Nerve Blocks

Front 166

What is the primary clinical use of tetracaine?

Back 166

Spinal & Axilllary Blocks

Front 167

What is the primary clinical use of benzocaine

Back 167

Topical anesthetic spray

Front 168

What is the primary clinical use of cocaine?

Back 168

Topical liquid anesthetic

Front 169

Allergies are rare with amides. When a pt say that he/she is allergic to LA, what does he/she most often mean?

Back 169

Metabolism of ester LA yields para-aminobenzoic acid (PABA) which is a known allergen. This is often what the pt is referring to.

Front 170

What is Methylparaben?

Back 170

A preservative in LA that is also metabolized to PABA and may cause allergic reactions.

Front 171

What is the benefit of adding Epinephrine to LA?

Back 171

Maximum dose increased.
Duration prolonged.
Slower absorption into the central circulation decreases toxicity.

Front 172

LA toxicity primarily involves which systems?

Back 172

Central Nervous System (CNS)
Cardiovascular System (CV)

Front 173

Most episodes of local anesthetic toxicity result from?

Back 173

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.

Front 174

Prevention and treatment of local anesthetic toxicity is dependent on..?

Back 174

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.

Front 175

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?

Back 175

The plasma level will be lowered - binding & redistribution decrease drug level in circulation.

Front 176

What is the relationship between total dose of local anesthetic and plasma concentration?

Back 176

It is linear.

Front 177

What is the actual effect of the addition (to LA)of vasoconstrictive agents like epinephrine or phenylephrine?

Back 177

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.

Front 178

Because little metabolism of local anesthetics occurs at the site of injection, what must happen in order for the LA to be metabolized?

Back 178

Absorption and delivery to the site of metabolism (for amides, the liver; for esters, the plasma) is necessary.

Front 179

S/S Systemic LA Toxicity

Back 179

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.

Front 180

If there is rapid absorption & inadvertent rapid intravenous injection, what may happen?

Back 180

May result in CNS toxicity.
LA readily cross the Blood Brain Barrier (BBB) and can produce excitation and depression.

Front 181

True/false?
CNS toxicity is proportional to LA potency.

Back 181

True.
The more potent the more CNS toxicity.)
(Longer-acting drugs tend to be more toxic).

Front 182

How does hypercarbia affect drug toxicity?

Back 182

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.

Front 183

LAs cause a dose-dependent depression in myocardial contractility and they also exhibit vasodilating properties. Which two LAS are exceptions?

Back 183

Cocaine & ropivicaine. They have vasoconstricting properties.

Front 184

What is Cauda Equina Syndrome?

Back 184

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.

Front 185

High concentrations of LA may cause neural toxicity. Which 2 LAs have been implicated?

Back 185

Both 3% chloroprocaine and 5% xylocaine

Front 186

What are recommendations to prevent cauda enquina syndrome when using lidocaine?

Back 186

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

Front 187

What are the stages of LA toxicity?

Back 187

CNS Excitation
CV Excitation
CNS Depression
CV Depression
Death

Front 188

What are the classic early CNS symptoms of LA toxicity?

Back 188

Circumoral Numbness - Earliest Sign;
Metallic Taste;
Lightheadedness;
Dizziness;
Blurred Vision;
Tinnitus.

Front 189

What are the later CNS symptoms of LA toxicity?

Back 189

Disorientation
Shivering
Muscle Twitching
Tonic/Clonic Seizures
Unconsciousness
Apnea

Front 190

What are early CV s/s of LA toxicity?

Back 190

Tachycardia
Hypertension (related to the CNS excitatory effects).

Front 191

What are late CV s/s of LA toxicity?

Back 191

Bradycardia
Hypotension
Dysrhythmias
Asystole
- Direct depression of cardiac and vascular smooth muscle
- Decrease in myocardial electrical activity, conduction rate, and force of contractions.

Front 192

Signs of LA toxicty in order of occurence

Back 192

Disorientation
Metallic taste
Tingling in the mouth & tongue
Tinnitus & auditory hallucination
Muscular spasms
Seizures
Coma
Resp arrest
Cardiac arrest
Death

Front 193

Treatment of LA Toxicity:

Back 193

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

Front 194

How can you raise the seizure threshold?

Back 194

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....

Front 195

Prevention is best, what can you do to prevent an OD?

Back 195

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!

Front 196

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:

Back 196

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).

Front 197

LAs are weak bases(hydrochloric salts) that are poorly soluble in water, with a pH < ____

Back 197

6

Front 198

Both forms of LA (ionized & nonionized) are important in conduction blockade. Explain.

Back 198

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.

Front 199

____ (Nonionized/ionized) form diffuse through cell membrane;
________ (Nonionized/Ionized) form blocks receptors;
Hydrophilic = _____ (nonionized/ionized) molecules;
Lipophilic = ______ (ionized/nonionized)

Back 199

Nonionized form diffuse through cell membrane
Ionized form blocks receptors
Hydrophilic = ionized molecules;
Lipophilic = nonionized molecules.

Front 200

Duration of action is generally correlated to lipid solubility. Explain.

Back 200

Highly lipid soluble LAs have a longer duration of action b/c they are less likely to be cleared away by blood flow.

Front 201

The CNS is the site of premonitory signs of OD in awake pts. What are these signs?

Back 201

Circumoral numbness, tongue paresthesia & dizziness. Sensory complaints may include tinnitus & blurred vision.