Pharmacology Flashcards
- Which of the following physiologic changes of pregnancy would be the LEAST likely factor that affects the bioavailability of a medication during pregnancy?
A. Respiratory mucosa hypervascularity
B. Delayed gastric emptying
C. Increased blood volume
D. Slow bowel transit time
E. Decreased serum albumin
A.
The bioavailability of medications is determined by the main pharmacokinetic parameters of each drug: absorption, distribution, metabolism, and elimination. Pregnancy is characterized by profound physiologic changes that begin early in gestation and may affect the pharmacokinetics of many medications. They include changes in the cardiovascular and gastrointestinal systems, composition of body fluids, changes in renal function, and activity of hepatic metabolizing enzymes and many others. Pregnancy is characterized by prolongation of gastric emptying and small bowel transit times. These are mainly driven by progesterone-mediated inhibition of smooth muscle motility. These changes affect the pharmacokinetics of many orally administered drugs by delaying their absorption and onset of action. In addition, drugs that undergo significant changes/metabolism at the stomach and small intestine level before absorption (eg, antimalarial drugs) may have decreased therapeutic efficacy during pregnancy.
The blood volume increases by almost 40-50% in pregnancy, reaching peak volume at around 32 weeks. This is thought to be related to increased mineralocorticoid activity with water and sodium retention, and increased in vasopressin release during pregnancy. The increase in blood volume is thought to allow adequate perfusion of vital organs including the uteroplacental unit, and may provide survival benefit in anticipation of blood loss during delivery. The increase in blood volume leads to decreased serum albumin concentrations, decreased protein binding ability, and increased drug free (nonprotein bound) levels. In addition, the increase in blood volume leads to increase in the volume of distribution of many drugs especially hydrophilic ones. The most correct answer is therefore respiratory mucosa hypervascularity. The increase in estrogen concentrations during pregnancy leads to edema and hypervascularity of the upper respiratory mucosa. These changes may explain the increased prevalence of rhinitis and epistaxis in pregnant women. Additionally, these changes may increase the absorption of inhaled medications such as inhaled steroids (used in the treatment of asthma). This risk remains theoretical because there have been no studies showing increased toxicity with the use of these or other inhaled agents during pregnancy.
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol. 2014;5:65.
- Your patient had a spontaneous vaginal delivery complicated by a third degree laceration and deep sulcal tears. She does not have an epidural and weighs 220 pounds (110kg). What is the maximum recommended dose of lidocaine you can give during your repair? What is mixed with epinephrine?
A. 200 mg
B. 280 mg
C. 400mg
D. 490mg
E. 700mg
C.
Local anesthetics can be toxic if injected directly into the blood stream or used in excess. Prodromal signs of local anesthesia toxicity are ringing in the ears, excitation, bizarre behavior, and disorientation. These may be followed by seizures or cardiovascular effects (initially hypertension and tachycardia followed by hypotension, arrhythmias, and cardiac arrest). Treatment is mainly supportive but lipid emulsion therapy can also be considered for lipid-soluble anesthetics such as bupivacaine. For lidocaine, the maximal recommended dose is 4 mg/kg. Our patient weighs 100 kg, thus the maximal recommended dose would be 400mg (4x100). If the patient weighed 70 kg the maximal dose would be 4x70 or 280 mg. Epinephrine cases vasoconstriction, which delays and decreases the uptake of the local anesthetic into the blood stream. Thus, more anesthetic can be used if mixed with epinephrine. If the lidocaine was mixed 1:200,000 concentration epinephrine the maximum recommended is 7 mg/kg giving a maximal dose of 700 mg for a 100 kg woman and 490 mg for a 70 kg woman. You can also refer to the package inserts for dosing limits.
Gabbe Chapter 17, Obstetrical Anesthesia, pp 370-371.
. What is the most important factor to consider when assessing drug transfer in human milk?
A. Concentrations in maternal plasma
B. Molecular weight
C. Protein binding
D. Lipid solubility
E. Phase of lactation
A.
The factors that increase drug transfer in milk are high maternal plasma concentrations, low molecular weight, low protein binding, and lipophilic drugs. Drugs enter milk by passive diffusion from maternal plasma into lactocytes. The most important determinant of drug transfer in milk is maternal plasma level. Drugs enter milk by passive diffusion; therefore, drug levels in milk are based on maternal plasma concentrations.
The phase of lactation matters in this transfer because in the first 72 hours there are large gaps between lactocytes. This allows most drugs, immunoglobulins, and inflammatory cells to pass into milk. After the first week, lactocytes swell under the influence of prolactin and these gaps significantly reduce. Although the drug transfer increases in colostrum, the absolute dose is low because the volume of colostrum is small (30-100mL daily).
Hale T, Rowe H. Medications and Mothers’ Milk, 2014
Which of the following is NOT an important consideration in deciding if a drug is safe to use during lactation?
A. Gestational age at birth
B. Gastrointestinal instability
C. Oral bioavailability
D. Infant age
E. Information on packet insert
E.
Prematurity and gastrointestinal instability may affect gut permeability. Older infants have lower risk because they have high metabolic capacity. Oral bioavailability: Some drugs never reach mothers’ plasma due to liver bypass. If a small amount is transferred to the milk, many medications are either not absorbed, destroyed in the gut or metabolized in the liver of the infant. Breastfeeding is beneficial to mother and infant, and should not be discontinued without accurate information about the drug in question. Lactational pharmacology is not understood by many physicians. Many women are asked to discontinue provision of their breast milk to their infant because of information on a package insert. The level of drugs in milk is typically very low and is not hazardous to infants receiving breast milk. A literature search should be performed to obtain accurate, up to date information before discontinuation of breastfeeding.
Hale T, Rowe H. Medications and Mothers’ Milk, 2014.
- Your patient is hospitalized with sickle cell crisis at 34 weeks gestation. In addition to her current medical management, you discuss postpartum contraceptive options and recommend which of the following:
A. Combined oral estrogen/progestin contraceptive
B. Copper intrauterine device (IUD)
C. Levonorgestrel intrauterine device (IUD)
D. Combined estrogen/progestin patch or ring
C.
The World Health Organization (WHO) publication “Medical Eligibility Criteria for Contraceptive Use” includes 4 categories of contraceptive eligibility for a variety of medical conditions:
In women with sickle cell anemia, all combined estrogen/progestin contraceptives are category 2, secondary to the increased risk of venous thromboembolism and cerebrovascular events that accompanies the disease. Copper intrauterine device (IUD) is also category 2 because of the risk of increased menstrual bleeding in a woman with preexisting anemia. Average monthly blood loss may increase by approximately 50% throughout the duration of copper IUD use. Although this rarely leads to anemia in healthy women, this increase in blood loss may be problematic for women with preexisting anemia. Progestin-only methods (including progestin-only pills, depo medroxyprogesterone acetate (DMPA), levonorgestrel/etonorgestrel implants, and levonorgestrel IUD) are category 1 and have no restrictions for use in women with sickle cell anemia. Other forms of anemia, including thalassemia and iron-deficiency anemia, have no restrictions for any form of contraception with the exception of the copper IUD, which may exacerbate preexisting anemia through increased menstrual blood loss (category 2).
The following factors determine the extent of the drug being transferred across the placenta EXCEPT
A. Molecular weight of the drug
B. Pka
C. Myometrial thickness
D. Extent of drug binding to the plasma protein
C.
Factors affecting drug transport across the placenta are generally divided into physical and pharmacological characteristics: Physical: Placental surface area, placental thickness, pH of maternal and fetal blood, placental metabolism, uteroplacental blood flow, and presence of placental drug transporters. Pharmacological: Molecular weight of drug, lipid solubility, pKa, protein binding, and concentration gradient across placenta
From the following drugs which one will have a higher concentration in the fetus in comparison to maternal plasma?
A. Thiopental
B. Succinylcholine
C. Ketamine
D. Ampicillin
C.
The placental transfer of ketamine is more rapid than its distribution within the fetus. It falls under exceeding transfer (type 2 drugs). These drugs cross the placenta to reach greater concentrations in fetal compared with maternal blood.
When administering local anesthetic agents such as lidocaine for a pudendal block, which scenario from the below choices leads to “ion trapping”?
A. Fetal weight >95%
B. Fetal weight <95%
C. Acidotic fetus
D. Fetal anomaly
E. Multiple gestation
C.
Non-ionized drugs tend to cross the placenta more easily than ionized drugs, however the fetus usually has a lower pH than the mother, leading to “ion trapping.” The non-ionized form of the local anesthetic crosses the placental barrier. Since the fetus has a lower pH than is found in the mother, the nonionized form of the local anesthetic is converted to the ionized form (a weak base made more acidic yields more ionized drug), and the ionized form is trapped in the fetus. The more acidotic the fetus, the greater the ion trapping. When fetal pH falls into the range of 7.03-7.23, significant ion trapping occurs.
Most drugs cross the placenta via:
A. Protein binding
B. Simple diffusion
C. Facilitated diffusion
D. Active transport
E. Pinocytosis
Simple diffusion is passive for lipophilic items (CO2 and O2 cross this way as they are lipophilic). Substances or drugs that freely cross the placenta are: non-ionized, lipid soluble, non-protein bound. Drugs with a molecular mass less than 500 Da pass readily through placental tissue by simple diffusion. These are the majority of substances. These include oxygen, carbon dioxide, water, most electrolytes, and anesthetic gases. Most drugs with MW > 1000 Da do not cross the placenta (ex. heparin, protamine, insulin). Neither succinylcholine (highly ionized) or non-depolarizing NMBDs (high molecular weights) cross the placenta. Inhalation agents will pass freely the placenta but when used < 1MAC and delivery is expected to occur < 10mins, very little fetal depression is observed. Other drugs such as: benzodiazepines (significant fetal effects), propofol and thiopental all cross the placenta. Opiates all cross the placenta to some extent (amount is variable) – Morphine can lead to worst fetal respiratory depression. Low doses of fentanyl appear to be safer ( < 1ug/kg dose). Other drugs that pass freely the placenta: beta blockers, vasodilator agents, reglan, atropine and ephedrine. Drugs that do not pass the placenta: Paralytic agents, heparin, insulin and glycopryrolate.
A 30 yo G2 P1 at 36 weeks is taking sertraline for depression and anxiety. She is concerned about the newborn drug effects. What is the risk of persistent pulmonary hypertension of the newborn?
A. All exposed newborns will have component of PPHN
B. 1/100
C. 5/100
D. 5/1000
E. No associated risk
D.
One third of babies born to mothers using SSRIs in late pregnancy will experience transient issues such as jitteriness, mild respiratory distress, transient tachypnea of the newborn, weak cry, or poor tone. A much less frequent but potentially serious complication is persistent pulmonary hypertension of the newborn (PPHN). This occurs when pulmonary vascular resistance remains abnormally elevated after birth, resulting in right-to-left shunt and refractory hypoxemia and a mortality rate of about 10%. PPHN occurs in 0.5-2 newborns per 1000 live births. The use of SSRIs during late pregnancy may be associated with a 2- to 6-fold increased risk of PPHN. Given the low incidence of PPHN in the general population, the absolute risk of PPHN in the setting of SSRI use in late pregnancy remains low (3-6 per 1000 infants). About 350 women would have to be treated with SSRIs in late pregnancy to cause 1 additional case of PPHN. Advising a pregnant woman to discontinue medication exchanges the fetal or neonatal risks of medication exposure for the risks of untreated mental illness. A number of obstetric risks, such as incomplete prenatal care, miscarriage, preterm birth, and low birth weight, have been associated with untreated depression or anxiety.
Laura is a 28 yo G3P1011 at 21 weeks presenting with severe flank pain and blood in her urine. On presentation, she is writhing in bed and requesting pain control. However, she wants to make sure that she gets a medication “that is least likely to pass to my baby.” Which opioid should you prescribe?
A. Meperidine–It crosses the placenta quickly, and exits the body quickly.
B. Remifentanil–It crosses the placenta but is rapidly metabolized by the fetus.
C. Morphine–It is less lipid soluble because of its polarity and crosses the placenta slowly, although it does cross because of its poor protein binding.
D. Fentanyl–It is lipid insoluble so it doesn’t cross the placenta at all.
E. Oxycodone–Quickly metabolized by CYP enzymes, resulting in consistently low placental transfer.
C.
All opioids cross the placenta. The rate at which they cross is dependent on drug properties such a lipid solubility, protein binding, and maternal and fetal pH. However, genetic variation in placental drug transporters such as multidrug-resistant protein-1 (MDR1) and breast cancer resistance protein (BCRP) as well as in metabolizing proteins such as aromatase and CYP proteins may impact placental opioid transport. These in turn dictate the variation in which neonates may experience neonatal abstinence syndrome. Meperidine’s effects may last 72 hours or more after delivery making A incorrect. Remifentanil does cross the placenta but is generally used in epidural anesthesia rather than systemic. Fentanyl is very lipid-soluble. Oxycodone is variably metabolized by CYP enzymes, with large variations in placental transfer between individuals.
Jennifer is a 37 yo G4P2012 at 32 weeks who was started on glyburide for poorly controlled gestational diabetes by her prenatal provider. At birth, the baby is hypoglycemic and requires time in the ICU. What properties of glyburide may have contributed to this outcome?
A. Glyburide does not cross the placenta, and neonatal hypoglycemia was likely due to poor maternal diabetic compliance.
B. Transplacental transport of glyburide is reasonably uniform for all women, but because of variations in maternal glucose levels, fetuses are impacted differentially.
C. Glyburide and glucose are co-transported across the placenta, which results in high fetal levels of glyburide among women with severe hyperglycemia.
D. Glyburide has a high molecular weight, is bound to albumin, and has a short half life with a pKa of 5.3. These properties all promote placental transfer.
E. Polymorphisms in the breast cancer resistance protein placental transporter may alter the placental pharmacokinetics of fetal glyburide transfer among women
E.
Placental transfer of nutrients and drugs are impacted by placental surface area and thickness; pH of maternal and fetal blood; placental metabolism; uteroplacental flow; the presence of placental drug transporters; and drug properties such as the molecular weight of the drug, lipid solubility, pKa, protein binding; and the placental concentration gradient. Drugs of low molecular weight with high lipid solubility, a nonionized status, and not protein-bound cross the placenta by diffusion. Otherwise, a transport mechanism is required. Glyburide was initially felt not to cross the placenta in significant levels but was subsequently found to have variable transplacental passage between women. Glyburide is actively effluxed from the fetal to maternal sides of the syncytiotrophoblast by the placental breast cancer resistance protein transporter. This protein has multiple polymorphisms that impact functionality, which may explain why some neonates experience hypoglycemia after birth. (B) is incorrect because glyburide transport is not uniform between women.
Rosa is a 24-year-old G2P1001 who presents for a routine prenatal visit at 24 weeks of gestation. During the visit, the fetal heart rate is auscultated to be 195 beats per minute. She has a fetal echocardiogram that diagnoses supraventricular tachycardia, and initiation of digoxin is recommended. Which mechanism below best describes why maternally administered digoxin may be used as a treatment for the fetus?
A. Digoxin diffuses along a concentration gradient through the placenta and so fetal levels will never exceed nontoxic maternal levels.
B. Digoxin is metabolized by cytochrome P450 enzymes in the placenta and so uptake to the fetus is self-limited.
C. Digoxin crosses placental syncytiotrophoblast by a combination of passive diffusion and fetal-protective active transport.
D. Digoxin is reliably bound by albumin in the fetal vessels and transported to the fetal heart.
E. Digoxin may not be used for treatment of the fetus due to risk of maternal toxicity.
C.
Placental transfer of drugs occurs when drugs leave the maternal intervillous space, pass through syncytiotrophoblast, placental stroma, and ultimately through villous endothelial cells to a fetal capillary. The primary site of transport is through the syncytiotrophoblast and occurs via four primary mechanisms: passive diffusion, facilitated diffusion, ATP-requiring active transport, and pinocytosis. Some drugs use a combination of these mechanisms. Digoxin is transported across the placenta by both passive diffusion and active transport by P-glycoprotein. The physiologic function of this protein is for fetal-to-maternal transport of hydrophobic cationic compounds. Because this transporter is generally a fetal-to-maternal transporter, it helps regulate fetal levels, which likely contributes to preventing fetal toxicity. P-glycoprotein is also involved in placental regulation of ciclosporin, saquinavir, hydrophobic cationic vincristine, vinblastine, paclitaxel, dexamethasone, sirolimus, quinidine, terfenadine, ondansetron, and loperamide. (B) is partially correct. Digoxin is metabolized, but this does not self-limit digoxin toxicity to the fetus.
The placenta is important in the exchange of substances between the mother and the fetus. It can also be a barrier to prevent certain medications from crossing to the fetus. Which of the following statements is NOT correct?
A. The placenta becomes more permeable to drugs as gestational age increases.
B. Placental enzymes can catalyze the formation of reactive metabolites that might be fetotoxic.
C. Phagocytosis and pinocytosis have not so far been shown to significantly contribute to placental drug transfer.
D. The metabolizing capacity of the placenta is similar to the liver and most drugs are metabolized before reaching the fetus.
E. Most drugs that enter the maternal circulation can cross the placenta to some extent.
D.
The placenta expresses a variety of xenobiotic-metabolizing enzymes from the earlier stages of pregnancy. However, compared to the liver, placental drug metabolism seems to be relatively minor and does not significantly limit the extent of drug delivery to the fetus. On the other hand, placental enzymes can catalyze the formation of reactive metabolites that might be fetotoxic. Drugs that have been shown to undergo significant placental metabolism include azidothymidine, dexamethasone, and prednisolone. The anticonvulsant oxcarbazepine (but not carbamazepine) is also metabolized to some extent by the human placenta.
A pregnant woman was given tea made from blue cohosh. Which of the following has blue cohosh tea been associated with ?
A. No fetal anomalies
B. Clubbed foot
C. Stillbirth
D. Uterine contractions and arterial vasoconstriction
E. Preeclampsia
D.
Blue cohosh is found in herbal teas and is thought to induce labor. It is known to stimulate contractions and cause arterial vasoconstriction. There are case reports of it causing neonatal congestive heart failure and shock, fetal severe multiorgan hypoxic injury, and perinatal stroke.
