Clinical Pharmacology II - OB/GYN RX
Drug Effects on Developing Fetus
Factors influencing drug effects:
Stage of pregnancy during exposure
Use of NSAIDs
Route of administration
Dose, duration, etc.
Effects on the fetus:
Destruction of fetus
Structural anomalies
Growth retardation
CNS abnormalities
General Principles – Placental Transfer
Key Characteristics:
Lipid Solubility: Affects the ability to cross the placental barrier.
Charge: Ionization status of the drug influences transfer.
Ion Trapping: Fetal pH is lower than maternal pH, leading to increased ionization of weak acids in the fetus, which can trap the drug in the fetal compartment.
Molecular Weight (Daltons):
mw = 250 - 500: Very easily crosses the placental barrier.
mw = 500 - 1000: Easily crosses.
mw > 1000: Very poor crossing.
Protein Binding: High protein binding may reduce free drug levels available for transfer.
General Principles – Placental and Fetal Metabolism
Mechanisms that Protect the Fetus:
Placental Function: Acts as a semipermeable barrier.
Drug Metabolism: The placenta has limited drug metabolism capacity:
Drugs typically enter the fetus through the umbilical vein.
40-60% of umbilical blood flow goes to the fetal liver.
FDA Categories for Drug Use in Pregnancy
Category A: Controlled studies in women show no risk in the first trimester; fetal harm is remote.
Category B: Either:
Animal studies show no risk and no controlled studies in humans,
or animal studies indicate risk, but human studies fail to demonstrate risk.
Category C: Animal studies indicate risk with no adequate controlled human studies; risk vs benefit should be considered.
Category D: Positive evidence of fetal risk exists; however, benefits may warrant use in severe situations.
Category X: Definitive fetal risk; the risks involved outweigh any potential benefits in pregnant women; contraindicated.
General Principles – Transfer into Breast Milk
Similar characteristics as placental transfer:
Lipid Solubility: Affects the drug's passage into milk.
Hind Milk: Contains a higher lipid content, which can concentrate certain drugs.
Charge and Ion Trapping: Similar phenomena occur as in placental transfer.
Molecular Size and Protein Binding: Influence the concentration of drug in milk.
Additional Factors - Transfer into Breast Milk
Timing since delivery affects transfer.
Major determinant is maternal serum concentration of the drug.
Feeding can be strategically scheduled to minimize exposure.
pH of Breast Milk: Ranges from 6.35 to 7.67, influencing drug ionization.
Physiological Changes During Pregnancy (Maternal)
Changes start in the first trimester and peak in the second trimester:
Increased Blood Volume: 30-40%.
Increased Renal Blood Flow: 30% increase and a 50% increase in glomerular filtration rate.
Cardiac Output: Increases by 30-35%.
Heart Rate: Increases by 10-15 bpm; blood pressure ideally remains constant.
Physiological Changes During Pregnancy (Continued)
GI Motility: Decreased.
Hypercoagulable State: Increased risk of clotting.
Decrease in Albumin: Affects the volume distribution of drugs.
Weight Gain: Normal physiological process during pregnancy.
Volume of Distribution: Increased for highly protein-bound medications and fat-soluble medications.
Drug Selection in Pregnancy
Aim to avoid use where possible, only using medications when necessary for acute and chronic conditions.
Goals include:
Identifying medication use prior to conception.
Eliminating non-essential medications.
Discouraging self-medication.
Minimizing exposure to known harmful drugs.
Assessing dose, route of exposure, dosage form, etc.
Pregnancy Induced Conditions
Common conditions include:
Nausea and vomiting.
Heartburn.
Constipation.
Hemorrhoids.
Gestational diabetes.
Gestational hypertension.
Coagulation disorders.
Treatment of Acute Conditions
Nausea and Vomiting in Pregnancy
Non-Pharmacological Approaches: Dietary changes.
Medications:
Pyridoxine (Vitamin B6): 10-25 mg orally 3-4 times daily (Category A).
Doxylamine: 12.5 mg orally 3-4 times daily (Category A).
Diclegis: A combination product with delayed release.
Metoclopramide (Reglan): Risk for sedation and extrapyramidal effects.
Promethazine (Phenergan): Risk for sedation.
5-HT3 Antagonists: Ondansetron, granisetron, dolasetron (Category B, more expensive).
Treatment of Acute Conditions (Continued)
Nausea and Vomiting Treatment with 5-HT3 Antagonists
Ondansetron, Granisetron, Dolasetron:
Not recommended during lactation due to lack of data on safety.
Pass into breast milk; risk of harm is not expected but should be considered.
Treatment of Acute Conditions
Heartburn
Non-Pharmacological Approaches:
Frequent, small meals.
Medications:
Antacids in moderation; use low sodium products.
Avoid sodium bicarbonate and magnesium trisilicate.
Sucralfate (Carafate): Safe option.
H2-receptor antagonists (e.g., famotidine) can be used if symptoms persist.
Proton Pump Inhibitors: Likely safe but have less evidence; used if H2 blockers are ineffective.
Treatment of Acute Conditions
Constipation
Non-Pharmacological Approaches:
Increase fiber and water intake, moderate exercise.
Medications:
Bulk-forming Laxatives: First line (e.g., methylcellulose, psyllium husk).
Surfactants (Stool Softeners): e.g., docusate sodium (Category C).
Osmotic Laxatives: For short-term use only (e.g., polyethylene glycol, lactulose, magnesium salts).
Stimulants: Used occasionally (e.g., senna, bisacodyl).
Mineral Oil: Should be avoided due to possible decreased absorption of fat-soluble vitamins.
Treatment of Acute Conditions
Hemorrhoids
Best Practices: Avoiding constipation is critical.
Recommended Products: External topical medications preferred due to lower systemic absorption.
Preparation H: Contains hydrocortisone or phenylephrine is acceptable.
Tucks: Contains witch hazel, is also acceptable.
Sitz baths are encouraged.
Treatment of Acute Conditions
Diarrhea
Preferred Approach: Stool bulking agents.
Loperamide: Category B, works peripherally on GI opioid receptors.
Hypertension During Pregnancy
Nondrug Management:
Activity restriction; bed rest can lead to venous thromboembolism (VTE).
Stress reduction and exercise are encouraged.
Calcium Supplementation: 1-2 g daily reduces hypertension risk by 30% and preeclampsia risk by 48%.
Magnesium Sulfate: Reduces progression from preeclampsia to eclampsia by 60%; used for eclamptic seizures.
Administration: 4-6 g IV over 15-20 minutes, followed by a continuous infusion of 2 g/h.
Avoid Benzodiazepines and Phenytoin.
Hypertension During Pregnancy Continued
Chronic Management of Hypertension
Defined as BP > 150-160/100-110.
First-line agents:
Labetalol: Third-generation beta-adrenergic blocker with some alpha-blocking effects; administered IV for acute treatment and orally for chronic management.
Methyldopa: Previously drug of choice, stimulates alpha-2 receptors to decrease sympathetic outflow.
Additional Agents:
Calcium channel blockers (DHP) are also effective.
Nitroprusside or nitroglycerin for rapid IV treatment when necessary.
Gestational Diabetes (GDM)
Defined as “any degree of glucose intolerance with onset or first recognition during pregnancy.”
Prevalence: Affects 7% of all pregnancies.
Risk Factors: Women at risk should be screened at 24-28 weeks of gestation.
Resolution: Usually resolves after delivery, but women may have a higher risk for type 2 diabetes post-pregnancy.
Diagnosing GDM
Oral Glucose Tolerance Test (OGTT):
Two-step method:
50 g, 1-hour glucose challenge.
100 g, 3-hour glucose challenge.
Some suggest a 2-hour, 75 g OGTT as an alternative screening method.
Diagnosis may be made based on symptoms or based on A1C, fasting glucose, etc.
Treatment of GDM
Key Focus: Dietary modification is the primary treatment strategy.
Medications:
Insulin: Drug of choice during pregnancy and lactation (Category B); does not cross the placenta.
Glyburide (Sulfonylurea): Minimally crosses the placenta; stimulates insulin release from the pancreas.
Metformin: Insulin sensitizer at the liver and skeletal muscle; appears to be free of teratogenic effects.
Thromboembolism in Pregnancy
VTE Risk: Risk is increased 5-10 times in pregnant patients.
Recommended Therapy: Low molecular weight heparin (LMWH) such as enoxaparin is preferred over unfractionated heparin (UFH) and warfarin (known teratogen).
Duration of Treatment: Should continue throughout pregnancy and for at least 6 weeks postpartum, totaling a minimum of 3 months of treatment.
Treatment of Acute Conditions
Urinary Tract Infection (UTI)
Treatment: Always treat even when asymptomatic.
Antibiotic Options:
Nitrofurantoin (Macrocrystal): (Category B); does not cover Proteus species; inhibits carbohydrate metabolism and disrupts cell wall formation.
Amoxicillin: (Category B); increasing risk of resistant E. coli.
Cephalosporin: (Category B); also compatible with breastfeeding.
Treatment of Acute Conditions
Pain Management
Acetaminophen: Drug of choice (Category B) for pain management during pregnancy.
NSAIDs:
Category B in 1st and 2nd trimesters.
Category D in the 3rd trimester due to risk of premature closure of the ductus arteriosus.
Morphine: Category B for short-term use in the first and second trimesters; Category D if prolonged use or high doses are needed at term.
Postpartum Depression - Treatment
Selective Serotonin Reuptake Inhibitors (SSRIs):
Effective agents with expanded literature including case reports.
Very few reported adverse effects in breastfed infants, but potential withdrawal effects and unknown long-term developmental effects.
Example agents include:
Citalopram (Celexa®).
Escitalopram (Lexapro®).
Paroxetine (Paxil®): Associated with a 1.2-2 fold increased risk of cardiac malformations in the first trimester.
Fluoxetine (Prozac®): Known adverse effects include potential increased cardiac sheering.
Postpartum Depression - Treatment Continued
Tricyclic Antidepressants (TCAs): Useful as second-line agents to SSRIs, all excreted into breast milk at low concentrations, with no adverse effects reported. Examples include:
Amitriptyline (Elavil®).
Nortriptyline (Pamelor®).
Desipramine (Norpramin®).
Folic Acid Recommendations
Daily Intake: All women capable of becoming pregnant should consume 400 µg daily to prevent neural tube defects (NTDs).
Effectiveness: Supplementation can prevent >50% of NTDs.
Higher Risk Women: Should consume 4 mg starting at least 1 month prior to conception if they have had a previous NTD-affected pregnancy.
Current Compliance: Less than 30% of women follow this recommendation.
Tocolytic Therapy
Purpose: To postpone delivery in situations of regular uterine contractions with cervical changes.
Classifications of Tocolytics:
Beta Agonists:
Example: Terbutaline (Brethine) – a beta-2 selective agent, given IV or PO.
Magnesium: Limited data for usefulness but may be employed.
Calcium Channel Blockers: Nifedipine may have fewer adverse events and appears to be more efficacious.
NSAIDs: Indomethacin can be preferred if hypotension is a consideration.
Tocolytic Therapy Continued
Progesterone Therapy:
Controversial Use of 17-alpha-hydroxyprogesterone: Given IM weekly from weeks 16-36 of pregnancy for women at high risk of experiencing preterm birth; available as hydroxyprogesterone (Makena).
Labor Induction
Medications for Cervical Ripening and Labor Induction:
Prostaglandin Analogs:
Dinoprostone (Cervidil): Given vaginally, a prostaglandin E2 analog; must be monitored for fetal heart rate.
Misoprostol (Cytotec): Prostaglandin E1 analog; also used for NSAID-induced ulcers and pregnancy termination.
Labor Induction Continued
Oxytocin (Pitocin): Most commonly used agent that facilitates uterine contractions; has potential adverse effects including arrhythmias, bleeding due to afibrinogenemia, and increased uterine tone.
Labor Pain Management
Administration Method: Primarily via epidural infusion of Fentanyl/bupivacaine combination.
Adverse Effects: Hypotension, pruritus, inability to void, and risk of spinal headache due to puncture.
Disturbances in Ovarian Function
Common Causes: May result from inflammatory or neoplastic processes affecting the uterus, ovaries, and/or pituitary.
Self-limiting nature: Minor disturbances are generally self-limited.
Influential Factors: Emotional and physical stress can impact GnRH secretion; extremes in diet and exercise may also have an effect.
Estrogens
Main Estrogens in Women:
Estradiol: Major secretory product from the ovaries.
Estrone and Estriol: Converted in liver or periphery.
Equine Estrogens: Include equilenin and equilin; captured in urine and purified for use in hormone therapies (e.g., Premarin).
Synthetic Estrogens
Examples include:
Ethinyl Estradiol
Micronized Estradiol
Estradiol Cypionate
Estradiol Valerate
Estropipate
Conjugated Estrogens
Estrogens - Pharmacokinetics
Protein Binding: Highly protein-bound, primarily to Alpha2 globulin (sex hormone-binding globulin) and albumin.
Metabolism: Estradiol converts to estrone and estriol, with a high ratio of hepatic to peripheral effects.
Excretion: Conjugated metabolites are excreted in bile and hydrolyzed in the intestine to active, re-absorbable forms.
Estrogens - Mechanism of Action
Action Pathway: Estrogens dissociate from SHBG, cross the cell membrane, and enter the nucleus where they bind to estrogen receptors.
Dimers Formation: Hormone complex forms dimers (mixed ERα and ERβ) that bind to estrogen response elements (EREs), regulating gene transcription and displaying tissue-specific effects.
Clinical Effects of Estrogens
Female Growth and Sexual Maturation: Stimulates development of vagina, uterus, and secondary sex characteristics.
Endometrial Effects: Develops the endometrial lining; helps in regulating the menstrual cycle through interactions with progesterone.
Metabolic Effects: Influence on bone density, adipose tissue development, and lipid profiles (increased HDL and reduced total plasma cholesterol).
Coagulation Effects: Enhances coagulability through increased factors II, VII, IX, and X; decreased antithrombin III.
Possible Mood Effects: May influence mood and libido while producing fluid retention.
Estrogens - Clinical Uses
Primary Hypogonadism Treatment: Replacement therapy may begin at ages 11-13 to stimulate sexual maturation and prevent osteoporosis.
Postmenopausal Hormonal Therapy: Used to manage loss of menstrual periods, menopausal symptoms, and to help prevent osteoporosis.
Consideration of Risks: Assess cardiovascular, breast cancer, and endometrial cancer risks when prescribing; monitor for adverse effects closely.
Estrogens - Adverse Effects
Common Adverse Effects:
Uterine bleeding due to endometrial hyperplasia (smallest dose advised).
Cancer Risks: Increased risk of breast and endometrial cancers identified; progestins can help mitigate endometrial cancer risk.
Mild Effects: Include nausea/vomiting, breast tenderness, cholestasis, hypertension; should use the lowest effective dose.
Estrogens - Contraindications
Clinical Conditions: Contraindicated in patients with estrogen-dependent neoplasms, undiagnosed genital bleeding, significant liver disease, history of thromboembolic disorders, and heavy smoking.
Progestins
Role of Progesterone: Important for human reproduction; serves as a precursor to estrogens, androgens, and adrenocortical steroids, produced in the ovary, testis, and adrenal cortex.
Synthetic Progestins: Exhibit higher variability in physiological effects compared to natural progesterone.
Progestins - Historical Challenges
Certain progestins also act at androgen and mineralocorticoid receptors, presenting varying degrees of activity.
Notable Agents Include:
Norgestrel: High AR activity.
Norethindrone: More PR than AR activity.
Drospirenone: Anti-MR, anti-AR properties.
Progestins - Pharmacokinetics
Absorption and Excretion: Rapidly absorbed with high first-pass effect; primarily excreted in urine.
Progestins - Mechanism of Action
Works similarly to other steroid hormones by binding to progesterone response elements (PRE).
Progestins - Physiological Effects
Metabolic Influence: Causes little effect on lipids yet increases insulin levels and response to glucose. Works against aldosterone in the kidney leading to increased aldosterone release. Physiological variations noted with synthetic agents.
Progestins - Therapeutic Uses
Hormone Replacement Therapy (HRT): Used for long-term ovarian suppression.
Medroxyprogesterone Acetate: Administered intramuscularly every three months; effective in treating conditions where estrogens are contraindicated.
Progestins - Adverse Effects
Common Risks: May increase blood pressure; androgenic progestins potentially lower HDL levels.
Hormone Replacement Therapy (HRT)
FDA Approved Indications: Treatment of moderate to severe vasomotor symptoms, vulvar and vaginal atrophy, and prevention of postmenopausal osteoporosis.
Hormone Replacement Therapy - Estrogen-Progestin Therapy
For patients with an intact uterus, administer estrogen + progestin in either daily or cyclical formats, with varying durations.
Hormonal Dosage Forms
Oral Forms: Undergo first-pass metabolism; stimulate hepatic proteins.
Transdermal Forms: Preferred for women with HTN, increased triglycerides, or risk factors for VTE.
Intravaginal Forms: Preferred for localized symptoms, though systemic absorption must be monitored.
Other Agents for Vasomotor Symptoms of Menopause
Non-hormonal alternatives like SSRIs, venlafaxine, gabapentin, and clonidine can help in managing symptoms of menopause.
Hormonal Contraception
Combination Estrogens and Progestins: Different formulations available (monophasic, biphasic, triphasic), along with continuous progestin-only therapies.
Hormonal Contraception - Mechanism of Action
Selectively inhibits pituitary function to prevent ovulation; alters cervical mucus and uterine endometrium, thus decreasing likelihood of conception.
Hormonal Contraception - Physiologic Effects
Ovary: Depressed ovarian function, menstrual patterns return after discontinuation.
Uterus: Hypertrophy and thickening of endometrial lining observed.
Hormonal Contraception - Clinical Uses
Effective form of contraception when taken as directed with minimal risk of pregnancy; also beneficial in therapy for endometriosis.
Hormonal Contraception - Adverse Effects
Mild: Nausea, breakthrough bleeding, headaches; vary with dosages of estrogen and progestins.
Moderate: Breakthrough bleeding common in progestin-only agents, weight gain an issue with androgenic formulations.
Hormonal Contraception - Severe Adverse Effects
Increased risks of thromboembolic events, myocardial infarction, and stroke, particularly in high-risk groups or when combined with other factors such as smoking.
Miscellaneous Contraceptive Products
Medroxyprogesterone Acetate (Depo-Provera): Injected every 3 months; has extended duration of effect with irregular bleeding patterns.
Levonorgestrel (Mirena): Effective uterine implant that alters uterine lining and cervical mucus to prevent pregnancy.
Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen (Nolvadex): Acts as a competitive, partial agonist, proving effective in breast cancer treatment with potential adverse effects noted.
Raloxifene (Evista): Partial agonist with favorable bone and lipid effects but no stimulation of endometrium or breast.
Aromatase Inhibitors
Examples include Anastrozole and Letrozole: Effective in treating aromatase-resistant conditions, though may increase fracture risk compared to tamoxifen.