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Pharm III Unit I > 4 Local Anesthetics > Flashcards

4 Local Anesthetics Flashcards

1
Q

Choice of local anesthetic is based on …

A

Duration of action

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2
Q

Topical LAs are used to anesthetize…

A

Skin, eye, throat, mucus membranes

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3
Q

Injection of LA into CSF in lumbar region

A

Spinal anesthesia

Blocks sympathetic fibers in the subarachnoid space

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4
Q

Injection into the epidural space

A

Epidural anesthesia

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5
Q

Injection into tissue

A

Infiltration anesthesia

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6
Q

Advantage of infiltration anesthesia

A

Anesthesia w/o disrupting normal body function

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7
Q

Disadvantage of infiltration anesthesia

A

Requires large amounts of drug

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8
Q

Intravenous region anesthesia is also known as…

A

Bier’s block

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9
Q

Local anesthetics are classified as either…

A

“Esters” or “amides”

A lipophilic group connected to a hydrophilic group by either an ester or amide bond

The both have different physiological properties

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10
Q

Esters have ______ duration of action and _______ systemic toxicity

A

Shorter

Increased

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11
Q

Differences in ______ can also affect potency and clinical properties

A

Stereochemistry

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12
Q

Local anesthetics are typically administered as _____ to increase stability and solubility

A

Salts

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13
Q

How are local anesthetics transported across the cell membranes

A

They are weak bases (pKa = 7.5-9) and at physiologic pH they are predominantly IONIZED (LAH+)

Binding site is on inner membrane

Need to be in NON-IONIZED (LA+ H+) form to cross membrane

Once inside, become IONIZED to bind to Na+ channel

Neutral LA can also pass through the membrane via the HYDROPHOBIC PATHWAY

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14
Q

In general, the closer a LA’s pKa is to physiological pH…

A

The higher the concentration of the drug in the non-ionized form

Membrane transport increases, thus a faster onset of action

Ex: Lidocaine (pKa 7.8) has faster onset than bupivacaine (pKa 8.1)

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15
Q

What is the exception to the rule about pKa and membrane transport?

A

BENZOCAINE has a pKa of 3.5

It is ALWAYS in the non-ionized form

It’s used for TOPICAL application ONLY

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16
Q

_________ decreases membrane transport of LAs due to increased acidification

A

Inflammation (infection)

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17
Q

________ makes the pH more basic and may increase non-ionized drug concentrations and thus, the degree of LA transport

A

Bicarbonate

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18
Q

What is the MOA for local anesthetics?

A

Block Na+ channels and inhibit neuronal firing**

Complete block results from the drug binding to more and more Na+ channels - increases the threshold for excitation and impulse conduction slows

As more channels are blocked the rate of the action potential declines and complete block is achieved

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19
Q

Extent of neuronal block is ______ and ______ dependent

A

Voltage (potential) and time (firing)

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20
Q

Local anesthetics have high affinity for channels in ________ and ________ states and low affinity for channels in ________ state

A

High affinity = activated (open) and inactivated states

Low affinity = resting (closed) state

Basically, the block is more effective in rapidly firing axons than in resting axons

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21
Q

____________ LAs have a faster rate of integration with the Na+ channels

A

Smaller and more lipophilic

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22
Q

Long-acting LAs also bind more extensively to _______

A

Proteins

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23
Q

___________ increases the membrane potential (hyperpolarizes), so more channels are in the resting state and the block is diminished

A

Elevated Ca2+

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24
Q

________ depolarizers the membrane, so more channels are in the inactivated state and the block is enhanced

A

Elevated K+

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25
Q

LAs may target a variety of other proteins (potentially affecting their MOA)

A

Ion channels (K+ and Ca2+)

Enzymes (adenylate cyclase)

Receptors (NMDA, 5HT3, neurokinin-1)

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26
Q

Potency of an LA is correlated to _______ and ________, and is measured relative to ________.

A

Lipid solubility and duration of action

Procaine

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27
Q

Increased lipid solubility results in …

A

Increased time at site of action, and hence, increased duration of action

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28
Q

Cocaine and Mepivacaine are _____ as potent as Procaine

A

2x (medium duration of action)

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29
Q

Lidocaine is ______ as potent as Procaine

A

4x (Medium duration of action)

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30
Q

Tetracaine, Bupivacaine, and Ropivacaine are ____ as potent as Procaine

A

16x (long duration of action)

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31
Q

What are the important pharmacokinetic points for LAs?

A

They exert their effect at the site of application

Pharmacokinetics is important for elimination and potential adverse effects (CNS, cardiac)

Rapidly diffuse away from the site of application

Duration of action is dependent on time at site of action

Toxic effects (CNS, cardiac) are dependent on half-life

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32
Q

Systemic absorption of LAs is affected by…

A 
Dosage
Site of injection (vascular area vs fat)
Drug-tissue binding
Chemical properties of the drug
Local blood flow
Vasoconstriction agents (ie Epinephrine)
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33
Q

Why is epi frequently coadministered with local anesthetics?

A

Decreases diffusion of drug
Prolongs duration of action
Decreases systemic absorption
Decreases risk of systemic toxicity

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34
Q

How are amides metabolized?

A

In the liver by the CYP450s

Toxicity is more likely in patients with HEPATIC DISEASE or reduced hepatic blood flow

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35
Q

How are esters metabolized?

A

Rapidly metabolized by butyrylcholinesterases in the plasma

Mutations can affect metabolism of ester LAs

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36
Q

How are LAs excreted?

A

Metabolites excreted through the renal system

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37
Q

In a differential block, the block is …

A

Not limited to intended site

It blocks noxious stimuli but also blocks motor nerves

May lead to motor paralysis, respiratory impairment, and hypotension

Different degrees of sensory and motor nerve block (ie bupivacaine vs etidocaine)

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38
Q

How does anatomic arrangement affect anesthetic action?

A

Effect hits proximal fibers and proceeds to more distal fibers within a nerve bundle

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39
Q

How does the intrinsic susceptibility of nerve fibers to blocks affect anesthetic action?

A

Diameter, degree of myelination and conduction velocity

Smaller diameter fibers are more sensitive than large

Myelinated fibers are less sensitive than unmyelinated of same diameter

The faster the conduction velocity, the less sensitive the fiber

40
Q

CV side effects of LAs

A

(Due to inhibition of Na+ and Ca2+ channels)

Arrhythmias, vasodilation, hypotension

BUPIVACAINE - increased binding to cardiac Na+ channels —> slower dissociative times

COCAINE - increased sympathetic tone

41
Q

What may decrease the cardiac toxicity of LAs?

A

IV lipid administration (“lipid sink”)

42
Q

CNS side effects of LAs

A

Depression of cortical inhibitory pathways

Sedation, visual/auditory disturbances, circumoral numbness, nystagmus, muscle twitching, convulsions, death

43
Q

Are allergic reactions to LAs a thing?

A

They are RARE with AMIDES

p-aminobenzoic acid (PABA) is a metabolite of ESTERS that may cause hypersensitivity

44
Q

Possible blood related side effects of LAs

A

Prilocaine metabolite may produce methemoglobinemia

45
Q

What are the possible PNS side effects of LAs?

A

Prolonged sensory and motor deficit following high doses

46
Q

What are some localized toxicities that can result from LA administration?

A

Neural injury - neurotoxic effects produced by high concentrations or if inadvertently injected intrathecally

Transient neurological symptoms (TNS) - transient pain, dysethesia linked to use of lidocaine for spinal anesthesia

47
Q

If someone develops a hypersensitivity reaction to an LA, it is likely…

A

An ester, not an amide

48
Q

If a patient develops methemoglobinemia following LA administration, it was likely…

A

Prilocaine

49
Q

If a patient develops transient neurological symptoms (transient pain, dysesthesia) following LA administration, it was likely…

A

Lidocaine used for spinal anesthesia

50
Q

What was the first synthetic local anesthetic to be developed?

A

Procaine (Novocain)

It’s an ester-type drug, developed in late 1800s

Short duration of action

Metabolic product is para-aminobenzoic acid (PABA) which can cause allergic reactions and inhibit sulfonamide action

51
Q

How is procaine (Novocain) used today?

A

For infiltration anesthesia and diagnostic nerve blocks (ie in colonoscopy)

Lacks topical activity, but has minimal systemic toxicity and no local irritation

52
Q

Ester-type drug with slow onset but long duration of action, that is approx. 16x more potent and more toxic than procaine

A

Tetracaine (Pontocaine)

Severe toxicity with high volume peripheral blocks

53
Q

How is tetracaine (pontocaine) used?

A

Preferred for ophthalmological use (retrobulbar)

Spinal anesthesia - combined with 10% dextrose to increase the specific gravity (solution is more dense than CSF - hyperbaric)

54
Q

Ester-type drug that is very lipophilic and always in non-ionized form at physiologic pH

A

Benzocaine (Americaine)

Used topically only to treat sunburn, minor burns, and pruritis in OTC preps

55
Q

Why is benzocaine only used topically?

A

B/c it’s readily transported through membrane due to low pKa

56
Q

What is the FDA safety warning for benzocaine?

A

Risk of methemoglobinemia with prolonged use

57
Q

Cocaine is an ________ drug used for _______

A

Ester-type

Topical anesthesia of mucous membranes typically around the upper respiratory tract

Can also reduce bleeding in dental procedures

58
Q

MOA for cocaine

A

Inhibits Na+ channels secondary to its effect on increasing the DA in the CNS and periphery

59
Q

Adverse effects of cocaine as an LA

A

CNS and CV side effects

Use with caution in addicts or with other drugs that increase catecholamines

60
Q

What is the prototype amide drug?

A

Lidocaine

61
Q

Lidocaine is ______ absorbed and has a _______ duration of action

A

Rapidly absorbed (rapid onset)

Intermediate duration

Has greater potency and longer duration of action than procaine

62
Q

What are the uses for Lidocaine?

A

Moderate topical activity and minimal local irritation

Wide range of applications

Preferred for infiltration blocks and epidural anesthesia

NOT preferred for spinal blocks b/c of risk of TNS

Can also be used as an antiarrhythmic agent

63
Q

Amide-type LA with intermediate duration and highest rate of clearance of the amides

A

Prilocaine (Citanest)

64
Q

Most important side effect of Prilocaine?

A

Methemoglobinemia - due to metabolites

Excessive methemoglobin in the blood (chocolate color) —> SOB, fatigue, dizziness, dysrhythmias, seizures, coma death

Do not use in patients with methemoglobinemia

65
Q

A patient comes to the ED with SOB, fatigue, and dizziness. Their EKG shows some minor dysrhythmias. You’re awesome at history taking and discover they had a dental procedure done earlier today. What’s going on and how will you treat it?

A

They have methemoglobinemia from prilocaine

Give em methlylene blue to reverse it

66
Q

Prilocaine use is largely limited to…

A

Dentistry

67
Q

Amide-type drug with long duration of action used primarily for post-op pain control

A

Bupivacaine (Marcaine)

68
Q

How is Bupivacaine used?

A

Post-op pain control

Spinal anesthesia, infiltration blocks and epidural anesthesia

Preferred as epidural during labor and childbirth

69
Q

What is the preferred LA for epidurals during childbirth and why?

A

Bupivacaine

B/c more potent sensory block than motor block (so it reduces pain w/o paralysis so you can push that baby out)

70
Q

Bupivacaine has greater _______ than other amides

A

Cardiotoxicity

Higher degree of lipophilic its, so it diffuses away from cardiac channels more slowly

71
Q

S-enantiomer of bupivacaine that’s also a long-acting amide

A

Ropivacaine

Less lipid soluble and cleared more rapidly than bupivacaine, so less likely to produce adverse events and less cardiotoxic

BUT it’s metabolized by CYP3A4, so possible drug interactions

72
Q

How is Ropivacaine used?

A

For peripheral and epidural blocks (but bupivacaine still preferred for L&D b/c of the differential block)

Vaso-constricting effects at clinical doses (so don’t have to add epi)

73
Q

Which LA is the only one that doesn’t need to be coadministered with epi?

A

Ropivacaine, b/c it’s the only vasoconstrictor

74
Q

Amide-type drug similar to bupivacaine but with intermediate duration of action

A

Mepivacaine (Carbocaine)

Preferred for peripheral nerve blocks but not used topically or in L&D

75
Q

Amide-type drug with long duration but INVERSE differential block

A

Etidocaine (Duranest)

May cause motor block before or without sensory block

So it paralyzes you but you still feel pain 😳🗡😳🗡😳

76
Q

Amide-type LA that also has an additional ester group which subjects it to metabolism by plasma esterases

A

Articaine (Septocaine)

Because of the metabolism, it has a decreased half-life and decreased potential for systemic toxicity

77
Q

How is articaine used?

A

Widespread use in dental medicine due to its large therapeutic window and low potential for systemic toxicity

Allows for the injection of more drug later into the procedure

78
Q

Adverse effects of articaine

A

Rare, but may include the development of persistent paresthesias (3x more likely with articaine than other LAs)

79
Q

Amide-type drug used as a spinal anesthetic outside the US but topical only in US

A

Dibucaine (Nupercainal)

80
Q

Why do we even bother learning about dibucaine (nupercainal)?

A

Dibucaine number test, used as a measure of butyrylcholinesterase activity (to see if a patient can metabolize ester anesthetics due to mutations or deficiencies)

Number 80 or below is considered deficient

81
Q

How are centrally acting muscle relaxants used?

A

For the relief of spastic muscle disorders, including the abnormal function of bowel and bladder

82
Q

An increase in tonic stretch reflexes and flexor muscle spasms, together with muscle weakness

A

Spasticity

Associated with cerebral palsy, MS, and stroke

Difficult to treat without worsening muscle weakness

83
Q

What are the centrally acting spasmolytic agents?

A

Baclofen
Cyclobenzaprine
Diazepam
Tizanidine

84
Q

What are the direct acting spasmolytic agents?

A

Dantrolene

Botulinum Toxin (BoTox)

85
Q

What are the target proteins for spasmolytic agents?

A

GABA-a
GABA-b
Alpha-2
Ca2+ channels

86
Q

How does Diazepam (Valium) work as a spasmolytic?

A

Acts on the GABA-a receptor to facilitate GABA-mediated presynaptic inhibition in the spinal cord

Different alpha subtypes of the GABA receptor mediate different responses. Diazepam affects all the subtypes, so a dose sufficient to act as muscle relaxant produces heavy sedation

87
Q

How is Diazepam (Valium) used?

A

For local muscle trauma and as an adjunct in chronic spasticity

BUT a dose sufficient to act as muscle relaxant produces heavy sedation.

88
Q

Why is Diazepam (Valium) may not the greatest for muscle relaxation?

A

Affects all subtypes of GABA, so a dose sufficient to act as muscle relaxant also produces heavy sedation

89
Q

What is the MOA for Baclofen (Lioresal)?

A

Agonist at GABA-b receptors

Stimulation opens K+ channels —> hyperpolarization and presynaptic inhibition of Ca2+ influx

Inhibits AC and cAMP formation and decreases release of excitatory transmitters in brain/spinal cord

90
Q

How is baclofen (Lioresal) administered?

A

Orally

T1/2 = 3-4 hours

91
Q

Side effects of Baclofen (Lioresal)?

A

Drowsiness
Weakness
Increased seizure activity
Respiratory depression may occur with intrathecal administration

92
Q

MOA for Tizanidine (Zanaflex)

A

Alpha-2 receptor agonist

Produces both pre- and post-synaptic inhibition of spinal cord synaptic activity to decrease muscle spasticity

Inhibits pain transmission in dorsal horn while limiting muscle weakness

93
Q

How is Tizanidine (Zanaflex) used?

A

Chronic and acute muscle spasms

Inhibits pain transmission in dorsal horn with limited muscle weakness

94
Q

Side effects of Tizanidine (Zanaflex)

A

Sedation

Some hypotension

Dry mouth

Weakness

Falls in elderly

Hepatotoxicity

95
Q

MOA for Dantrolene (Dantrium)

A

Inhibits Ca2+ release from the SR by blocking the ryanodine receptor 1 (RyR1) channel

Interferes with excitation-contraction coupling of actin and myosin in skeletal muscle fibers

Minimal effects on cardiac or smooth muscle b/c Ca2+ release is mediated by different receptor (RyR2)

96
Q

How is Dantrolene (Dantrium) used?

A

To treat neuroleptic malignant syndrome and malignant hyperthermia

97
Q

MOA for Botulinum Toxin (BoTox)

A

Inhibits ACh release from nerve at neuromuscular junction

Small amounts injected locally to control muscle spasms following stroke or neurological injury

Effects persist for weeks to months

Large amount scan be very toxic - spread of toxin to unwanted areas may be problematic

Pharm III Unit I (9 decks)

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