Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
78 Cards in this Set
- Front
- Back
Perinatal Pharmacology involves what 3 important participants? Why?
|
Mother
Placenta Fetus Maternal drugs affect fetus directly or indirectly (by impacting placenta) Most drugs cross placenta and affect fetus to some extent |
|
What drugs do not cross placenta?
|
Insulin, heparin, protamine
|
|
Maternal plasma concentration depends on what?
|
site & amount of drug
|
|
Concerning Locals, give the routes with the highest to lowest plasma concentration
|
IV > paracervical > caudal > epidural > IM > SAB
|
|
Volume of distribution in mother
|
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 |
|
T or F: Highly lipid-soluble drugs (bupivacaine and fentanyl) have ↑ Vd in mom and very little drug free to reach neonate
|
True
|
|
IV drug to mom at beginning of contraction, what happens?
|
placental transfer of drug decreased
|
|
Free drug in uterine artery that will reach placenta depends on
|
Total dose
Maternal metabolism and elimination, protein binding, pH and pKa Addition of epinephrine |
|
Metabolism and elimination
|
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 |
|
Protein binding
|
drugs more highly protein bound are less available to fetus
|
|
pH and pKa:
Only ______ form crosses membranes (placenta) |
nonionized
|
|
pH and pKa:
Drugs with pKa close to body’s pH remain in ______amount in nonionized form |
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) |
|
Placental transfer depends on
5 things, what are the first 2? |
1. Area of transfer and diffusion distance
2. MW |
|
Explain the MW values and placenta transfer
|
MW:
MW > 1000 will not cross MW 600-1000 cross with difficulty MW < 600 freely cross |
|
CLINICAL IMPLICATION for placental transfer and concern with MW
|
Anticoagulation
Heparin MW 6000 – won’t cross Coumadin MW 330 – crosses – anticoagulated fetus |
|
Placenta transfer of drugs depends on 5 things, what are the last 3?
What is the signifiance? |
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 |
|
ion trapping in the fetus
|
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 |
|
Normal fetal pH
|
Normal fetal pH < Mom’s (7.32-7.42)
|
|
Is there more or less protein-binding capacity in fetus than mom
|
Protein binding - less protein-binding capacity in fetus than mom
|
|
fetal tissues will or will not take up highly lipid-soluble drugs
|
Lipid solubility - fetal tissues will take up highly lipid-soluble drugs
|
|
Blood via umbilical vein from placenta enters liver or bypasses liver thru _____ _____ to IVC
|
ductus venosus
|
|
T or F: Fetal liver extracts substantial amount of drug
|
True:
Cytochrome p450 system immature but works to some degree See uptake of thiopental, volatiles, and lidocaine Prevents high concentrations from reaching fetal brain |
|
Concentration of drug in umbilical vein progressively _____ before reaches fetal brain
|
diluted
|
|
>____% of fetal CO returns to placenta without perfusing fetal tissues
|
50
Extensive R to L shunt of fetal circulation |
|
Majority of maternal drugs will cross placenta and reach fetus
T or F: All Volatiles Cross |
True
|
|
T or F:
A large amount of drug will reach fetal brain and myocardium |
False, Only small amount of drug will reach fetal brain and myocardium
|
|
CLINICAL IMPLICATION: Bupivacaine vs Lidocaine
|
Bupivacaine is more lipid soluble than lidocaine
Bupivacaine is more protein bound than lidocaine (95% vs 50%) Similar amount of each drug reaches fetus |
|
Requirements for L & D
|
-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 |
|
Amino-esters (COOCH)
|
O
I C ― O ― R (alkyl chain) |
|
Amino Esters are derivatives of _____
|
para-aminobenzoic acid (PABA)
known as an allergen |
|
Amino esters are metabolized by_____
|
Metabolized by plasma cholinesterases
|
|
Are allergic reactions common with Amino Esters?
|
Allergic reactions may occur
|
|
Amino-amides (NH-CO)
|
O
I NH ― C |
|
Amino Amides are metabolized by ____
Are allergic reactions common with Amino Amides |
Metabolized by liver
Allergic reaction rare |
|
Mode of action of Locals
|
Block Na+ conductance thru nerve cell membrane
Most bind to Na+ channels in inactivated state to prevent propagation of action potential |
|
Physiochemical properties – lipid solubility correlates with what?
|
Correlates with potency – the more lipid-soluble, the more potent
Locals are highly lipid soluble and pass easily thru nerve and placental membranes |
|
Protein binding effects what?
|
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 |
|
pKa determines what?
|
Determines speed of onset
|
|
pKa closest to body’s pH has the fastest or slowest onset?
|
fastest onset
|
|
What is significance of having nonionized and ionized forms of locals?
|
Un-ionized form crosses membrane but ionized form binds to protein receptor
Both forms important for nerve blockade |
|
Locals in OB have Inherent vasoactive properties, explain.
|
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 |
|
T or F: Higher doses and concentrations speed onset and increase duration
|
True
|
|
Addition of vasoconstrictors
to locals |
Makes more local available for block
Less absorbed thru vascular beds Epi ↓ peak plasma concentration of lidocaine and mepivacaine Bupivacaine inherent vasoconstrictor (none needed) |
|
Site of injection affects locals, how?
|
Onset more rapid with SAB and SQ injection
Slower with epidural and brachial plexus blocks |
|
Addition of bicarb affects activity of locals
|
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 |
|
Adding bicarb to locals increases pH & % of ______
|
un-ionization
|
|
How does Mixing locals affect activity of locals?
|
Shorten onset, improve quality of block, reduce risk of toxicity
|
|
T or F Warming to 100°F speeds onset of epidural
|
True
|
|
During Pregnancy _____ amounts are required for SAB and epidural
|
smaller
Onset faster in parturient - ?↑ progesterone levels |
|
Concerning Toxicity: Severity of symptoms directly R/T _____ ________
|
plasma concentration
|
|
What can cause toxicity?
|
May be caused by systemic absorption of inadvertent IV injection
|
|
The more potent, the less it takes to reach toxic levels – name the most to least potent:
|
Bupivacaine > tetracaine > etidocaine > lidocaine > mepivacaine > 2-chloroprocaine
|
|
S/S Toxicity
|
Circumoral numbness, tinnitus, metallic taste → light-headedness → muscle twitching → unconsciousness → seizures → coma → resp. arrest → CV depression (bradycardia, v-tach, v-fib, asystole)
|
|
Hypoxic patient may seize more readily, why?
|
Increased PaCO2 and low pH ↓ seizure threshold
|
|
Severe CV toxicity is rare.
is Bupivacaine cardiotoxic? |
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 |
|
Prevention of toxicity during epidurals
|
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 |
|
Epidural Dosing:
No more than ___mL increments Wait ____-_____between doses |
No more than 5mL increments
Wait 30 sec – 1 min between doses |
|
Treatment of Toxicity:
Diazepam and Thiopental dosing |
Diazepam 2.5-5 mg or thiopental 50-100 mg IV if obvious signs of toxic reaction
|
|
What is the number one priority when toxicity occurs?
|
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 |
|
Ventilation during Toxicity
|
-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 |
|
What position Support circulation
|
LUD
|
|
You would Treat cardiac arrest as usual for toxicity, explain
|
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 |
|
Treatment of Toxicity with Intralipid
|
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 |
|
Mechanism of action for Intralipids?
|
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 |
|
Intralipid Proposed protocols
|
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 |
|
Importance of assessing the fetus and mother during CPR/ Toxicity treatment
|
>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 |
|
2-Chloroprocaine (Nesacaine)
|
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 |
|
Why are Infusions of Nesacaine for labor not recommended
|
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 |
|
T or F: Nesecaine can cause serious nerve injury if injected into subarachnoid space
|
True
|
|
2 important things to remember about nesacaine
|
1. Impairs subsequent actions of other locals and narcotics
2.Useful drug if emergent C-section with existing epidural |
|
Lidocaine
|
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 |
|
Compare lidocaine to bupivacaine
|
Onset more rapid than bupivacaine
? greater motor block than bupivacaine |
|
Carbonated lidocaine
|
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) |
|
Bupivacaine
|
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 |
|
Bupivacaine Usual technique for labor epidural
|
0.25% epidural loading dose
0.125% infusion NEVER use 0.75% on OB Pregnant patients more susceptible to CV toxicity |
|
Advantages of bupivacaine
|
Good sensory block with less motor block
Long duration Good analgesia at low concentrations |
|
Ropivacaine & Levobupivacaine
|
Similar to bupivacaine
Reported to preserve more motor function Greater safety margin Levobupivacaine not available at this time |
|
Ropivicaine
|
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 |