Exam #01a (Local Anesthetics)

Question 1

These agents prevent the generation and conduction of nerve impulse via actions on Na+ channels?

Answer 1

Local anesthetics (LA’s)

Question 2

What was the earliest LA?

Answer 2

cocaine (1884)

Question 3

LA’s can be structurally classified into what two categories? Give the prototype LA for each category?

Answer 3

1. Amino-esters (Procaine)

2. Amino-amides (Lidocaine)

Question 4

How do LA’s MOA of blocking conduction of action potentials (AP) in excitable membranes work? How does the ionization affect LA’s MOA?

Answer 4

LA’s block the increase in permeability of excitable membranes to Na+ normally produced by depolarization by interacting with 1 or more binding sites on Na+ channels on the INTRACELLULAR side of cell membranes. Neutral form of LA required to cross membrane and ionized form of LA required to bind to Na+ channel and have activity

Question 5

True or False - at higher concentrations, LA’s can bind to other ion channels like Ca2+ and K+?

Answer 5

True

Question 6

In what state do LA’s exist at physiological pH?

Answer 6

uncharged base and as a cation (+ charged)

Question 7

True or False - since pKa of most LA’s is 7.5-9.5, at physiological pH a > fraction will be charged in cationic form?

Answer 7

True

Question 8

LA onset of action dependent on?

LA duration of action dependent on?

Answer 8

Onset - pKa (the larger the difference between pKa and pH means drug will be more ionized and will take LONGER to cross the membrane)
Duration - lipophilicity

Question 9

Why are LA’s less effective when injected into infected tissue?

Answer 9

Infected tissue has a lower extracellular pH and therefore > amount of ionized LA exists. Since unionized LA is required to cross the membrane, you’ll see a decrease in effectiveness of the LA

Question 10

True or False - highly non-ionized (lipophilic or high partition coefficient) results in poor penetration, but high activity?

Answer 10

False - highly non-ionized results in good penetration but low activity…meaning a high partition coefficient allows the LA to cross the membrane but will be difficult to ionize and have activity

Question 11

What effect would an ortho-substituent have on an amino-ester LA activity?

Answer 11

It would increase duration of action by hindering hydrolysis

Question 12

In general, what effect does adding alkoxy and NH2 substituents to the meta position on aromatic rings of amino-esters have on lipophilicity (DOA)?

Answer 12

meta alkoxy groups increase lipophilicity

meta amino groups decrease lipophilicity (charged compounds increase polarity/decrease lipophilicity

Question 13

Why must amino-amide (lidocaine) LA’s aromatic ring be ortho substituted?

Answer 13

Ortho substitution hinders hydrolysis and contributes to resonance forms that lead to more effective binding and therefore activity

Question 14

True or False - LA ester functional group MUST be in conjugation with aromatic ring for activity?

Answer 14

True - reverse esters are inactive (double bond O is not directly adjacent to aromatic ring)

Question 15

What effect does branching of the intermediate chain (btwn int. chain and hydrophilic group) in both categories of LA’s have on activity?

Answer 15

Branching increases DOA, but has NO EFFECT on activity

Question 16

What effect does methylene insertion between the carbonyl and aromatic have on activity and SE?

Answer 16

Results in poor activity and anticholinergic effects (dry mouth, hypotension, tachycardia)

Question 17

What is the most common type of amine at the hyrophilic region of a LA?

Answer 17

tertiary amine

Question 18

Comment on the size of the N substituent at the hyrophilic region of a LA? What is the optimal range of #’s C’s?

Answer 18

the > C’s, the > potency and toxicity

optimal range is 3-4 C’s (any more would be too lipophilic)

Question 19

What effect would the addition of polar (OH) groups to the N at the hydrophilic region of a LA have on activity?

Answer 19

Decreases activity

Question 20

Fill in the blanks:
A LA with a pKa close to physiologic pH and high partition coefficient will have a BLANK onset and BLANK duration of action?

Answer 20

rapid onset of action (more drug will be in neutral form and able to cross membrane)

long duration of action (high lipophilicity means better penetration and distribution)

Question 21

In general, what onset and DOA do amino-ester LA’s have? Name (3) amino-ester LA (generic and brand)? Indicate which one is considered long acting?

Answer 21

Slow onset and short to intermediate DOA

1. Procaine (Novocain)
2. Chloroprocain (Nesacaine)
3. Tetracaine (Pontocaine) - LONG ACTING

Question 22

In general, what onset and DOA do amino-amide LA’s have? Name (6) amino-amide LA (generic)? Indicate which ones are considered long acting?

Answer 22

Rapid onset and intermediate to long DOA

1. Lidocaine
2. Prilocaine
3. Mepivacaine
4. Bupivacaine - LONG ACTING
5. Articaine
6. Ropivacaine - LONG ACTING

RAMP BL

Question 23

What effect does Epi have on LA DOA (Hiint 2 effects)?

Answer 23

1. Increases DOA

2. decreases probability of CNS toxicity b/c restricts removal from injection site decreasing blood levels

Question 24

What (4) factors influence onset and DOA?

Answer 24

1. pKa of drug
2. pH of environment
3. Lipophilicity of drug
4. rate of drug metabolism

Question 25

True or False - when applied at high concentrations, all LA's can be toxic to nerve tissue?

Answer 25

True

Question 26

Which (2) LA's may be more neurotoxic when used for spinal anesthesia?

Answer 26

1. chloroprocaine | 2. lidocaine

Question 27

True or False - spinal neurotoxicity of LA's results from LA MOA?

Answer 27

False - it is NOT the result of excessive Na channel blockade

Question 28

CNS effects from LA's is dose dependent. What are (2) early symptoms of CNS toxicity from low doses of LA? At higher concentrations, what (2) effects are seen in patients? What are the final stages of high concentration CNS toxicity from LA?

Answer 28

LOW CONCENTRATION EARLY SYMPTOMS 1. tongue numbness 2. metallic taste HIGH CONCENTRATION SIGNS 1. nystagmus (invol eye movement) 2. muscular twitching FINAL STAGES tonic clonic convulsions (excitation) followed by CNS depression/death (excitation b/c of depression of cortical inhibitory pathways allowing unopposed excitatory activity)

Question 29

Which LA is also effective for ventricular arrhythmias and only active parenterally? CNS toxicity of this LA has been attributed to the formation of which metabolite?

Answer 29

Lidocaine | monoethylglycine xylidide metabolite

Question 30

True or False - LA toxicity resulting in CV effects is a result from direct effects on smooth muscle membranes and indirect effects on autonomic nerves?

Answer 30

True

Question 31

Which LA is more cardiotoxic than other LAs?

Answer 31

Bupivacaine

Question 32

The (S)-isomer of which LA has a LOWER propensity for CV toxicity than its racemic mixture?

Answer 32

Levobupivacaine

Question 33

What toxic metabolite of prilocaine can cause cyanosis in which the skin appears blue b/c tissues near skin surface do not have enough oxygen

Answer 33

o-toluidine

Question 34

What metabolite are ester type LAs metabolized to that are responsible for allergic reactions in a small % of population?

Answer 34

PABA

Question 35

True or False - Amide type LAs are metabolized to PABA?

Answer 35

False - therefore allergic reactions are rare

Question 36

Which LA is the only useful TOPICAL agent we discussed in class, but is a weak LA, and doesn't fit the SAR discussed?

Answer 36

Benzocaine

Question 37

Where are the amide type LAs hydrolyzed?

Answer 37

At the carbonyl (C=O)