Local Anesthetics

Question 1

What are 3 features of the “ideal” local anesthetic?

Answer 1

Non-irritating to the tissue to which it is applied.
Short onset.
Duration long enough to be useful, but not so low as to entail a prolonged recovery.

Question 2

What was the first local anesthetic used in “modern medicine”? (How was it discovered?)

Answer 2

Cocaine. (An ophthalmologist hiking in South America chewed on some coca leaves for an energy boost, found it made his mouth numb.)

Question 3

4 features of the chemical structure of local anesthetics?

Answer 3

Weakly basic.
Lipophilic aromatic ring.
Intermediate group that is either an
-amide or
-ester
Hydrophilic cardbon chain bearing amino group.
(the first 3 are directly relevant to them having properties discussed in lecture)

Question 4

How can you tell from a local anesthetic’s generic name whether it has an intermediate group that is an amide or ester?

Answer 4

Amide: two “i”s in the name (e.g. bupivacaine, lidocaine)
Ester: just one “i” (e.g. procaine, cocaine)

Question 5

Does the chirality of local anesthetics matter? Why is that important?

Answer 5

Yup, for some. The R form is more cardiotoxic than the S form. (preparations of S only are now made for some drugs)
(both stereoisomers produce an analgesic effect, though).

Question 6

What’s the target of local anesthetics? Effect?

Answer 6

Voltage gated sodium channels on neurons. Reversibly prevents transmission along the axon.

Question 7

CTB review: What are the 3 states of NaCh?

Answer 7

Closed, open, inactive.

Question 8

To what state(s) of NaCh do local anesthetics bind?

Answer 8

The open and inactive states.

Question 9

Why do local anesthetics affect different nerves differently?

Answer 9

Because the drug binds only the open and inactive states of NaCh (which are only present when the neuron is firing), the drugs first / more easily inhibit nerves that fire more frequently.

Question 10

How does charge / the basicity of local anesthetics affect their activity?

Answer 10

Uncharged drug crosses neuron membrane into cell. There, where it’s more acidic, it picks up a proton / (+) charge and gets trapped. Also the drugs don’t work well when the extracellular environment is acidic.

Question 11

Why might a local anesthetic not work in for pain near an abscess?

Answer 11

If the environment is acidic, the drug will become protonated and positively charged, and thus won’t be able to cross the membrane.

Question 12

What do local anesthetics bind in the blood? (2 things) Is this desirable?

Answer 12

alpha1-glycoprotein and albumin.

Yes, this is desirable because it helps keep the drug from getting to tissues where it could cause toxicity.

Question 13

What affect do differences in blood flow have on the ability to locally anesthetize an area?

Answer 13

More blood flow will get the drug out of there more rapidly (and thus it will be harder to anesthetize).

Question 14

Why is epinephrine often coadministered with local anesthetic?

Answer 14

Causes local vasoconstriction which will decrease blood flow and keep the drug there longer.

Question 15

3 phases of metabolism of local anesthetics?

Answer 15

Alpha phase - drug rapidly distributed in bloodstream to well-perfused tissue (Brain, Heart, Kidney)
Beta phase - distribution to less perfused tissue
Gamma phase - clearance via metabolism and excretion

Question 16

Where are ester-type local anesthetics broken down? What enzyme does this? What is one of its breakdown products?

Answer 16

Hydrolyzed in the plasma by pseudocholinesterase.
Yields PABA (para-aminobenzoic acid) as a breakdown product.

Question 17

Where are amide-type local anesthetics broken down?

Answer 17

In hepatocytes.

Question 18

Which is more likely to cause toxicity: Ester-type or amide-type local anesthetic? Why?

Answer 18

Amide-type, because they aren’t broken down until they reach the liver. Unlike ester-type, which are broken down in the plasma.
(Remember from bioethics the research subject who died from lidocaine OD?)

Question 19

Which are more potent: local anesthetics that are more or less lipid soluble? How about lasting for a longer duration?

Answer 19

More lipid soluble, more potent, longer duration.

can think of them as being harder to wash away

Question 20

How is lipid solubility represented? What does a higher value mean?

Answer 20

Lipid:water partition coefficient. Higher = more lipid soluble.

Question 21

Does protein binding (Kd and all that) affect duration / potency?

Answer 21

No, but it’s important for toxicity.

Question 22

What property of local anesthetics most affects speed of onset? What sort of values will produce the rapidest onset? Why?

Answer 22

pKa. Drugs with a pKa closest to physiological pH (7.3 - 7.4) will have the rapidest onset because a higher proportion will be unionized following Henderson-Hasselbach, and thus be better able to cross membranes. (So not all of gen chem was a waste?)

Question 23

So amide-type are more toxic, but what’s bad about ester-type local anesthetics?

Answer 23

Para-aminobenzoic acid (PABA), a breakdown product of ester-type local anesthetics, is a allergen. Many people are allergic to ester-type local anesthetics.

Question 24

So this guy’s got a recurrent erythematous rash on the shaft of his penis. He uses condoms for birth control. What’s the most likely diagnosis?

Answer 24

Allergy to PABA, which is from a local anesthetic on condom (used to prolong the performance).

Question 25

Why are most OTC anesthetics esters even though many people are allergic to PABA?

Answer 25

Because they’re rapidly metabolized, it’s hard to get toxicity, even if people rub it all over themselves.

Question 26

What are 4 signs CNS toxicity from local anesthetic that appear before unconsciousness? (roughly in order)

Answer 26

Numbness of tongue
Light-headedness
Visual disturbance
Muscular twitching

Question 27

What are 3 signs of CNS toxicity from local anesthetic that may appear with or after unconsciousness?

Answer 27

Convulsions
Coma
Respiratory arrest

Question 28

Do CNS signs appear before cardiovascular depression? Is there an exception?

Answer 28

Yes. Yes. Yes.

Except for bupivacaine.

Question 29

What are the manifestations of local anesthetic toxicity on the cardiovascular system? (name 3)

Answer 29

Reduced contractility
Impaired automaticity
Altered rhythms and conductivity (esp ventricular arrhythmia)

Question 30

Can seizures be a product of local anesthetic CNS toxicity?

Answer 30

Yep.

Question 31

How do you treat local anesthetic toxicity?

Answer 31

Inject intralipid. This lipid emulsion (they same as what’s given in TPN) may work by drawing the drugs into the blood away from the tissue. (Works very well in case reports.)

Question 32

What effect do local anesthetics usually have on vascular smooth muscle? Does it vary with concentration?

Answer 32

Low concentrations - vasoconstriction.
High concentrations - vasodilation
Exception: Cocaine always causes vasoconstriction.

Question 33

What local anesthetic would be best to numb for a procedure that might produce lots of bleed? (eg. a nasal endoscopy)

Answer 33

Cocaine, as the vasoconstriction will reduce bleeding. And there’s a low risk of toxicity.

Question 34

Which local anesthetic can cause methemoglobinema?

Answer 34

Prilocaine. -> reduced O2 carrying capacity of blood -> cyanosis and low O2 sat.

Question 35

What is a formulation used as a topical anesthetic for procedures such as IV placements in kids? What drug with a notable toxicity does it contain?

Answer 35

EMLA (eutectic mixture of local anesthetic). Contains prilocaine, which can cause methemoglobinemia.