Mason Ob Lecture Iii

Front 1

Perinatal Pharmacology involves what 3 important participants? Why?

Back 1

Mother
Placenta
Fetus
Maternal drugs affect fetus directly or indirectly (by impacting placenta)
Most drugs cross placenta and affect fetus to some extent

Front 2

What drugs do not cross placenta?

Back 2

Insulin, heparin, protamine

Front 3

Maternal plasma concentration depends on what?

Back 3

site & amount of drug

Front 4

Concerning Locals, give the routes with the highest to lowest plasma concentration

Back 4

IV > paracervical > caudal > epidural > IM > SAB

Front 5

Volume of distribution in mother

Back 5

1. Increased plasma volume increases Vd
2. Increased clearance of drugs
Highly lipid-soluble drugs (bupivacaine and fentanyl) have ↑ Vd in mom and very little drug free to reach neonate
3.Increased blood volume and CO increase UP blood flow - ? Increase in drug to placenta and fetus
IV drug to mom at beginning of contraction, placental transfer of drug decreased

Front 6

T or F: Highly lipid-soluble drugs (bupivacaine and fentanyl) have ↑ Vd in mom and very little drug free to reach neonate

Back 6

True

Front 7

IV drug to mom at beginning of contraction, what happens?

Back 7

placental transfer of drug decreased

Front 8

Free drug in uterine artery that will reach placenta depends on

Back 8

Total dose
Maternal metabolism and elimination, protein binding, pH and pKa
Addition of epinephrine

Front 9

Metabolism and elimination

Back 9

1. Esters (sux and 2-chloroprocaine) destroyed by cholinesterase
Maternal half-life very short – less to fetus
2. Active metabolites may reach fetus
Normeperidine may lead to decreased Apgars
Infants born more than 4 hours after Mom gets meperidine accumulate more normeperidine in tissue

Front 10

Protein binding

Back 10

drugs more highly protein bound are less available to fetus

Front 11

pH and pKa:
Only ______ form crosses membranes (placenta)

Back 11

nonionized

Front 12

pH and pKa:

Drugs with pKa close to body’s pH remain in ______amount in nonionized form

Back 12

higher

Will cross placenta in higher amounts
Mepivacaine pKa of 7.6 will cross placenta in higher amounts than bupivacaine with pKa of 8.1 (at pH 7.4)

Front 13

Placental transfer depends on
5 things, what are the first 2?

Back 13

1. Area of transfer and diffusion distance
2. MW

Front 14

Explain the MW values and placenta transfer

Back 14

MW:
MW > 1000 will not cross
MW 600-1000 cross with difficulty
MW < 600 freely cross

Front 15

CLINICAL IMPLICATION for placental transfer and concern with MW

Back 15

Anticoagulation

Heparin MW 6000 – won’t cross

Coumadin MW 330 – crosses – anticoagulated fetus

Front 16

Placenta transfer of drugs depends on 5 things, what are the last 3?
What is the signifiance?

Back 16

1.pKa (or degree of ionization)
Only non-ionized form can cross
2.Protein binding
Protein-bound drugs cross with difficulty
3.Lipid solubility
The more lipid soluble, the easier to cross

CLINICAL SIGNIFICANCE – lipid soluble drugs (barbiturates) can reach fetus in high amounts

Front 17

ion trapping in the fetus

Back 17

In acidotic fetus (pH < 7.2) un-ionized drug from mother reaches fetus and becomes ionized

Correction of acidosis when fetus delivers → conversion of drug to un-ionized active form and exaggerated effects in neonate

Front 18

Normal fetal pH

Back 18

Normal fetal pH < Mom’s (7.32-7.42)

Front 19

Is there more or less protein-binding capacity in fetus than mom

Back 19

Protein binding - less protein-binding capacity in fetus than mom

Front 20

fetal tissues will or will not take up highly lipid-soluble drugs

Back 20

Lipid solubility - fetal tissues will take up highly lipid-soluble drugs

Front 21

Blood via umbilical vein from placenta enters liver or bypasses liver thru _____ _____ to IVC

Back 21

ductus venosus

Front 22

T or F: Fetal liver extracts substantial amount of drug

Back 22

True:
Cytochrome p450 system immature but works to some degree
See uptake of thiopental, volatiles, and lidocaine
Prevents high concentrations from reaching fetal brain

Front 23

Concentration of drug in umbilical vein progressively _____ before reaches fetal brain

Back 23

diluted

Front 24

>____% of fetal CO returns to placenta without perfusing fetal tissues

Back 24

50

Extensive R to L shunt of fetal circulation

Front 25

Majority of maternal drugs will cross placenta and reach fetus
T or F: All Volatiles Cross

Back 25

True

Front 26

T or F:
A large amount of drug will reach fetal brain and myocardium

Back 26

False, Only small amount of drug will reach fetal brain and myocardium

Front 27

CLINICAL IMPLICATION: Bupivacaine vs Lidocaine

Back 27

Bupivacaine is more lipid soluble than lidocaine
Bupivacaine is more protein bound than lidocaine (95% vs 50%)
Similar amount of each drug reaches fetus

Front 28

Requirements for L & D

Back 28

-Effective and controllable analgesia
-Maternal safety
-No weakening of maternal powers
>Expulsive forces unaffected
-No alteration of maternal passages
>Muscle tone of birth canal preserved so fetal head rotates normally as presenting part descends
-No depression of passenger
>Safe for fetus

Front 29

Amino-esters (COOCH)

Back 29

O
I ‌
C ― O ― R (alkyl chain)

Front 30

Amino Esters are derivatives of _____

Back 30

para-aminobenzoic acid (PABA)
known as an allergen

Front 31

Amino esters are metabolized by_____

Back 31

Metabolized by plasma cholinesterases

Front 32

Are allergic reactions common with Amino Esters?

Back 32

Allergic reactions may occur

Front 33

Amino-amides (NH-CO)

Back 33

O
I
NH ― C

Front 34

Amino Amides are metabolized by ____

Are allergic reactions common with Amino Amides

Back 34

Metabolized by liver
Allergic reaction rare

Front 35

Mode of action of Locals

Back 35

Block Na+ conductance thru nerve cell membrane

Most bind to Na+ channels in inactivated state to prevent propagation of action potential

Front 36

Physiochemical properties – lipid solubility correlates with what?

Back 36

Correlates with potency – the more lipid-soluble, the more potent

Locals are highly lipid soluble and pass easily thru nerve and placental membranes

Front 37

Protein binding effects what?

Back 37

Effects duration of action

Local binds with protein receptor within Na+ channel

If minimal protein binding – washes away from nerve channel more quickly than highly protein-bound local

Front 38

pKa determines what?

Back 38

Determines speed of onset

Front 39

pKa closest to body’s pH has the fastest or slowest onset?

Back 39

fastest onset

Front 40

What is significance of having nonionized and ionized forms of locals?

Back 40

Un-ionized form crosses membrane but ionized form binds to protein receptor
Both forms important for nerve blockade

Front 41

Locals in OB have Inherent vasoactive properties, explain.

Back 41

1.May have inherent vasodilating property (lidocaine)
Contributes to shorter duration of action
2.May have inherent vasoconstricting property (bupivacaine)
Contributes to longer duration of action

Front 42

T or F: Higher doses and concentrations speed onset and increase duration

Back 42

True

Front 43

Addition of vasoconstrictors
to locals

Back 43

Makes more local available for block
Less absorbed thru vascular beds
Epi ↓ peak plasma concentration of lidocaine and mepivacaine
Bupivacaine inherent vasoconstrictor (none needed)

Front 44

Site of injection affects locals, how?

Back 44

Onset more rapid with SAB and SQ injection
Slower with epidural and brachial plexus blocks

Front 45

Addition of bicarb affects activity of locals

Back 45

May increase onset by 50%
Locals have pH of 3.5-5.0 to increase shelf life
Adding bicarb increases pH & % of un-ionization
Speeds diffusion across nerve membrane (pKa=onset)
Precipitation occurs with bupivacaine if pH > 7

Front 46

Adding bicarb to locals increases pH & % of ______

Back 46

un-ionization

Front 47

How does Mixing locals affect activity of locals?

Back 47

Shorten onset, improve quality of block, reduce risk of toxicity

Front 48

T or F Warming to 100°F speeds onset of epidural

Back 48

True

Front 49

During Pregnancy _____ amounts are required for SAB and epidural

Back 49

smaller

Onset faster in parturient - ?↑ progesterone levels

Front 50

Concerning Toxicity: Severity of symptoms directly R/T _____ ________

Back 50

plasma concentration

Front 51

What can cause toxicity?

Back 51

May be caused by systemic absorption of inadvertent IV injection

Front 52

The more potent, the less it takes to reach toxic levels – name the most to least potent:

Back 52

Bupivacaine > tetracaine > etidocaine > lidocaine > mepivacaine > 2-chloroprocaine

Front 53

S/S Toxicity

Back 53

Circumoral numbness, tinnitus, metallic taste → light-headedness → muscle twitching → unconsciousness → seizures → coma → resp. arrest → CV depression (bradycardia, v-tach, v-fib, asystole)

Front 54

Hypoxic patient may seize more readily, why?

Back 54

Increased PaCO2 and low pH ↓ seizure threshold

Front 55

Severe CV toxicity is rare.

is Bupivacaine cardiotoxic?

Back 55

Potent locals (bupivacaine) have narrow margin of safety

Bupivacaine and lidocaine rapidly block cardiac Na+ channels during systole
Bupivacaine dissociates from channels during diastole much more slowly than lidocaine

Front 56

Prevention of toxicity during epidurals

Back 56

Aspirate epidural catheter EVERYTIME you use it

If aspirate blood thru epidural cath or spinal needle – don’t inject

ALWAYS use test dose for epidural

Give locals via epidural in divided doses
No more than 5mL increments
Wait 30 sec – 1 min between doses

Watch for warning signs each time epidural dosed

Front 57

Epidural Dosing:
No more than ___mL increments
Wait ____-_____between doses

Back 57

No more than 5mL increments
Wait 30 sec – 1 min between doses

Front 58

Treatment of Toxicity:
Diazepam and Thiopental dosing

Back 58

Diazepam 2.5-5 mg or thiopental 50-100 mg IV if obvious signs of toxic reaction

Front 59

What is the number one priority when toxicity occurs?

Back 59

1.Administer oxygen
Pre-oxygenate should seizure occur
2.Oxygenate and ventilate
Seizure not fatal – anoxia and acidosis may be

May have to give SCh
MR does not stop seizure activity in brain – benzo or barb for that

Front 60

Ventilation during Toxicity

Back 60

-Increased PaCO2 and decreased pH decreases seizure threshold

Hypercarbia causes cerebral vasodilation and increases local uptake

Want to avoid hypoventilation – remember that hyperventilation may cause deleterious effects on UBF

Treatment for seizures from local toxicity especially in non-pregnant patient is hyperventilation

Front 61

What position Support circulation

Back 61

LUD

Front 62

You would Treat cardiac arrest as usual for toxicity, explain

Back 62

Bretylium drug of choice in treating bupivacaine induced V-dysrhythmias – not readily available
Amiodarone may block same ion channels as bupivacaine but successful in labs in treating bupivacaine-induced arrhythmias and drug of choice according to Chestnut p. 195
Must maintain LUD or even deliver baby to facilitate effective CPR

Front 63

Treatment of Toxicity with Intralipid

Back 63

Intralipid is the 20% lipid emulsion typically used for TPN
In dogs, return of NSR within 5 minutes
Several case reports in humans

Case report:
58 year-old male in cardiac arrest after interscalene block
No response to conventional resuscitation for 20 min.
100 mL of 20% lipid emulsion and NSR within 30 sec.
Infusion at 0.5 mL/kg/min over 2 hours
Extubated at 2.5 hours without adverse effects

Front 64

Mechanism of action for Intralipids?

Back 64

Lipid emulsion may extract lipid soluble bupivacaine molecules from plasma

May diffuse into tissue and interact with local there

Propofol is a 10% lipid emulsion – NOT INDICATED FOR TREATMENT OF LOCAL TOXICITY

Front 65

Intralipid Proposed protocols

Back 65

1 mL/kg bolus repeated every 3-5 minutes up to total of 3 mL/kg

100 mL bolus followed by 0.25-0.5mL/kg/min infusion until hemodynamically stable

Front 66

Importance of assessing the fetus and mother during CPR/ Toxicity treatment

Back 66

>If maternal CPR not effective in five minutes – C-section must be performed
-Fetus has better chance to survive
-Mom has better chance to survive
----Relief of vena caval obstruction and better CPR

Front 67

2-Chloroprocaine (Nesacaine)

Back 67

Ester
Ester hydrolysis – rapid metabolism and negligible fetal uptake (safest for fetus)
Half-life 21 sec in maternal blood, 43 sec in fetal blood
pKa 8.9
Duration of action 35-50 minutes
Have to top up in 30-45 min
Max dose 12 mg/kg
3% concentration required for surgical anesthesia

Front 68

Why are Infusions of Nesacaine for labor not recommended

Back 68

Tachyphylaxis & neurotoxicity
Arachnoiditis reported after use
Thought from sodium bisulfite preservative
Replaced but backache still common SE if > 23-25mL used
Severe in nature and lasts for several hours
Relieved by 100-200mcg Fentanyl to epidural

Front 69

T or F: Nesecaine can cause serious nerve injury if injected into subarachnoid space

Back 69

True

Front 70

2 important things to remember about nesacaine

Back 70

1. Impairs subsequent actions of other locals and narcotics
2.Useful drug if emergent C-section with existing epidural

Front 71

Lidocaine

Back 71

Amide
Metabolized by liver
Half-life 1.5-2 hours
pKa 7.9
Duration 60 min without epi, 75 min with epi
Max dose – 5 mg/kg without epi, 7 mg/kg with
2% used for C-section and loading epidural dose by some

Front 72

Compare lidocaine to bupivacaine

Back 72

Onset more rapid than bupivacaine
? greater motor block than bupivacaine

Front 73

Carbonated lidocaine

Back 73

May see quicker onset and better penetration
Not available in USA
Make your own by adding 1meq NaHCO3 to 10 mL local
Can carbonate lidocaine and 2-chloroprocaine but bupivacaine precipitates(unless < 0.1 meq/10 mL)

Front 74

Bupivacaine

Back 74

Amide
Metabolized by liver
Half-life 2.7 hours
pKa 8.2
Duration of action – up to 4 hours
Max dose – 2.1 mg/kg or 175 mg plain and 225 mg with epi
Onset of action up to 30 min

Front 75

Bupivacaine Usual technique for labor epidural

Back 75

0.25% epidural loading dose
0.125% infusion

NEVER use 0.75% on OB
Pregnant patients more susceptible to CV toxicity

Front 76

Advantages of bupivacaine

Back 76

Good sensory block with less motor block
Long duration
Good analgesia at low concentrations

Front 77

Ropivacaine & Levobupivacaine

Back 77

Similar to bupivacaine
Reported to preserve more motor function
Greater safety margin


Levobupivacaine not available at this time

Front 78

Ropivicaine

Back 78

Amide
Metabolized by liver
Half-life 1.8 hours
pKa 8.2
Duration of action – up to 4 hours
Max dose – seizures in pregnant sheep at 5.9 mg/kg
Onset of action 15-30 min