DE LA SALLE HEALTH SCIENCES CAMPUS COLLEGE OF MEDICINE

Detoxicol
Subject: Obstetrics and Gynecology Topic: Drugs and Immunization During Pregnancy Lecturer: Dr. Enrique V. Labios Lecture Date: December 07, 2005 Transcriber(s): Jaime Aherrera No. of pages: 19

Medicine for the intoxicated

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DRUGS & IMMUNIZATION DURING PREGNANCY

INTRODUCTION I. ABSORPTION Absorption of Drugs in Pregnancy is affected This is due to the following: A. Gastrointestinal Disturbances o Vomiting (Drugs are vomited out) o Reduced Gastric Secretions o Reduced Motility B. Pulmonary Effects o Increase in the Volume of Inspired Air / Minute o Increase Alveolar Ventilation **NOTE: We should Decrease the doses of Inhaled Drugs during Pregnancy (Dose Adjustment) These Factors Increase the Absorption and Elimination of Drugs C. Enhanced Percutaneous Drug Absorption o Blood Flow Increases Six-Fold in pregnancy **NOTE: We should also Decrease Dose (due to the increased blood flow) II. DISTRIBUTION

Decrease Plasma Albumin by 50% during the Last Trimester (Increases Bioavailability of the drug) Decrease Binding Affinity (Increases Biovailability of the Drug) Competition for Binding Proteins (Variable) Increased Intravascular Volume in the Last Two Trimesters of Pregnancy (Increased Drug Distribution) **NOTE: When Drugs are NOT bound to proteins, they become more Bioavailable

III. DRUG ELIMINATION Drugs are eliminated via Renal / Hepatic Excretion, Sweat Glands, Respiration Most of the Time = Kidney and Liver A. Drug Elimination is Increased due to: o Decrease Protein Binding Affinity o Increase Renal Plasma Flow o Increase Glomerular Filtration Rate o Increase Rate and Minute Volume B. Drug Elimination may be Impaired: o Impaired Metabolism is required prior to elimination o Hepatobiliary Excretion o Decrease Gastrointestinal Motility PHARMACOLOGY & PREGNANCY I. FETAL EXPOSURE Important = TIMING of Intake of the Drugs There are three periods of Pregnancy:

A. Ovum o From Fertilization to Implantation B. Embryo o Period of Organogenesis (2nd to 8th week of Pregnancy) o This is the MOST Vulnerable Period o Potential for causing Limb Malformation may last until the end of the first trimester (14th week) o Muscle Malformation is also possible at this time C. Fetal

o Beyond the 8th Week until Term

o Histogenesis and Functional Maturation

o Diethystilbestrol (DES) = Mullerian Abnormalities include Uterine Agenesis and Vaginal Duplication o Tetracyclein = Brownish Discoloration of the Teeth in Newborns

II. TERATOGENETICS OF DRUGS Some Drugs have Potential for causing Limb Malformation may last to the end of the First Trimester (14 Weeks) Beyond the Period of Organogenesis, the Fetus is STILL Susceptible since Histogenesis and Functional Maturation continue (ex. Tetracycline, Diethylsolbestrol / DES) There is NO information about Long-Term Effect, like learning / behavioral problems (Functional Teratogenesis) III. PRINCIPLES OF COUNSELING Counseling about Teratogenic Exposure should be done in a Sympathetic, Supportive and Informative Manner Ultrasound Examination (we can check for possible Fetal Anomalies) Neural Tube Defects & Midline Ventral Fusion defects may be Detected by Ultrasound or Maternal Serum Screening **NOTE: These Tests are NOT used for Assessing Drug Exposure: o Serologic Testing, Chronic Villus Sampling, Aminocentesis, Fetal Blood Sampling **IMPORTANT Notes: o The Physicians Desk Reference (PDR) Reference o Organization of Teratogen Information Service o TO Avoid Liabililty, Drug Manufacturers DO NOT encourage use of their Drugs during Pregnancy **Standard Series of Statements: o Reproductive Studies, performed in rats and mice at Maternally Toxic Dose Levels, revealed NO evidence of Impaired Fertility or Harm to the Fetus (no human studies yet) o There are, however, NO adequate and well-controlled studies in Pregnant Women o As animal reproduction studies are not always predictive of Human Response, ____ should be used during pregnancy only if clearly indicated IV. FOOD AND DRUG ADMINISTRATION (FDA) CATEGORY OF DRUGS (1979) Based on the Available Information assessing the Risk to the Fetus balanced against the Drugs Potential Benefit to the Mother Most Drugs belong to Class B and C A. Class-A Drug o Well-Controlled Studies show NO Risk o Ex) Supplemental Drugs (Vitamin Preparations, Perisulfate, etc) **NOTE: It DOES NOT Include Pure and High Dose Vitamin-A and/or D Capsules B. Class-B Drug o No Evidence of Risk in Humans BUT, there are no studies yet o Ex) B-Lactams, Paracetamol C. Class-C Drugs o Risk cannot be ruled out o There are studies in animals that show possible risk D. Class-D Drugs o Positive Evidence of Risk
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Ex) Fluoroquinolones

E. Class-X Drugs o There are PROVEN cases that Humans are affected by drugs o Contraindicated in Pregnancy Teratogens with High Risk V. FETAL EFFETS FROM SPECIFIC DRUGS Many Dilemmas exist when Studying a Drug The finding are NOT always conclusive Most Human Data involve small series or case reports, biased or merely reflect the patients background risk for Birth Defects A lack of comparability of the Dose and Route of Administration can limit interpretation Randomized Controlled Trial are UNCOMMON Side Effects may mimic Symptoms of Pregnancy (Nausea, Vomiting, Bloatedness) Many agents contain Multiple Ingredients, Active and Inactive VI. DRUGS OR SUBSTANCES SUSPECTED OR PROVEN TO BE HUMAN TERATOGENS ACE-Inhibitor Alcohol Aminopterin Androgens Busulfan Caramazepine Chlorbiphenyls Coumadins Cyclophosphamide Danazol DES Etretinate Isotretinoin Lithium Methimazole Methotrexate Penicillamine Phenytoin Radioactive Iodine Tetracycline Trimethadione Valproic Acid

VII. PRINCIPLES OF PRESCRIBING IN HUMAN PREGNANCY Evaluate every Drug to be Prescribed Use Drugs with proven Tract Records of Safety Inform the mother of any Potential Risk to the Fetus VS the Benefit to the Mother & Fetus

DRUGS AND PREGNANCY

DRUG
Androgen ACE Inhibitors Anticoagulants (Warfarin) Anticonvulsants

CRITICAL PERIOD
8th to 13th Week = Labial Fusion 2nd and 3rd Trimester = Clitoral Hypertrophy 2nd and 3rd Trimester 6th 9th week Age of Gestation = Fetal Warfarin Syndrome (Facial Anomalies and Epiphyseal Stippling) Throughout Gestation = CNS Defects 1ST Trimester (Malformation) 3rd Trimester (Early HDN)

MAGNITUDE OF RISK
Unknown Unknown Dependent on Dose and Duration 5-10% for FWS 4-5% for CNS and other Defects 2-3-Fold Increase Risk from Epilepsy Alone 12-15% for Anticonvulsant Drug Therapy 1-2% NTD (Valproic Acid) 1% NTD (Carbamazapine) <1 to 8% = Cardiac Risk Less than 1% = Ebstein Anomaly
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Antidepressant (Lithium)

1st Trimester = Cardiac Defects 3rd Trimester = New Born Toxicity

Aminoglycosides (Kanamycin, Streptomycin) Fluconazole Quinine High Dose Tetracycline Corticosteroids (Systemic) Peinicillamine Synthetic Estrogen (DES)

Throughout Pregnancy 1ST Trimester 1st Trimester Beyond 4th Months Before 10 weeks = Oral Clefts Throughout Gestation = IUGR Unknown 10-13 Weeks of Gestation = Highest Risk of Vaginal Adenocarcinoma, but some risk up to 18 weeks Up to 20 weeks = Genital Malformation Highest Risk = 6-8weeks Any time during the 1st Trimester

Low (probably <3%) Dose and Duration Dependent Unknown Dose Related (400mg/day or greater) Observed only after use of Toxic Dose in unsuccessful Abortion Attempts Unknown Duration-Dependent 0.1-0.2% = Cleft Lip (+ / - ) Cleft Palate May increase to seven fold Unknown Probably Less than 5% <1% = about 350-450 cases of Vaginal Cancer Unknown for Genital Malformation 7-times Risk for Mobius Syndrome Almost all Adverse Outcomes have been related to Unsuccessful Abortion Attempts with large, sometimes massive doses 20-50%

Misoprostol

Immunodulators (Thalidomide) Iodine Methimazole / Carbumazole Etretinate & Acitretin Isotretinoin

Days 34-50 days after LMP (20-36days after Conception) Critical Maternal Dose is at least 100mg 2nd and 3rd Trimesters Up to 9weeks after LMP Day 15 after Conception to the End of 1st Trimester Day 15 After Conception to End of 1st Trimester

Dose and Duration Dependent Unknown but probably LOW Unknown May be same as Isotretinoin 30-50% Teratogenic Dose Range is Less Than 0.2 to 1.5mg/kg/day

I. ANDROGEN A. Critical Period o 8th to 13th Week = Labial Fusion o 2nd and 3rd Trimester = Clitoral Hypertrophy B. Magnitude of Risk o Unknown C. Mechanism o Hormonal D. Defects & Toxicity o Masculinization of Female Fetus E. Comments: o No Effect in Reported Male Fetuses o No Fetal Effect if Exposure is STOPPED before onset of Androgen Receptor Sensitivity in 8th Gestational Week II. ACE INHIBITORS A. Critical Period o 2nd and 3rd Trimester B. Magnitude of Risk o Unknown (Dependent on Dose and Duration) C. Mechanism o Decreased Fetal Angiotensin-II resulting in Renal Impairment and Hypotension
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D. Defects & Toxicity o Fetus-Anuria-Oligohydramnios, Growth Restriction (IUGR), Hypocalvaria, Persistent PDA, Stillbirths, Renal Failure in the Newborn o Congenital Hypocalvaria (underdevelopment of the Skull) o Renal Anomaly (anuria) E. Comments o Monitoring of AF-Levels is RECOMMENDED, but Renal Impairment may be IRREVERISBLE III. ANTICOAGULANTS (WARFARIN) A. Critical Period: o 6th 9th week Age of Gestation = Fetal Warfarin Syndrome (Facial Anomalies & Epiphyseal Stippling) o Throughout Gestation = CNS Defects B. Magnitude of Risk o 5-10% for FWS o 4-5% for CNS and other Defects C. Mechanism o Vitamin-K Deficiency in Embryo o Microhemorrhage and Scarring (CNS Effects) D. Defects & Toxicity o FWS-Nasal Hypoplasia, Stippled Hypophysis, IUGR, Eye Defects, Hypoplasia of Extremities, CHD o CNS Damage (MR, Spasticity, Seizures, Scoliosis, Deafness and Hearing Loss, Death) IV. ANTICONVULSANTS A. Critical Period: o 1ST Trimester (Malformation) o 3rd Trimester (Early HDN) B. Magnitude of Risk o 2-3-Fold Increase over Risk from Epilepsy Alone o 12-15% for Anticonvulsant Drug Therapy o 1-2% NTD (Valproic Acid) o 1% NTD (Carbamazapine) C. Mechanism o Multifactorial (Polygene-Drug Interaction) o Folic Acid Deficiency o Carbamazepine, Phenytoin, and Valproic Acid produce Toxic Epoxide Metabolites o If Fetus is Homozygous for Low Epoxide Hydroxylase Activity, then High Risk for Embryopathy o Early HDN may result from Depletion of Vitamin-K Stores in Fetus D. Defects & Toxicity ANTICONVULSTANT
Carbamazepine Phenobarpital / Primidone Phenytoin Trimethadione Valproic Acid

DEFECT
NTD, Craniofacial Defects, Fingernail Hypoplasia, Developmental Delay Cardiac Defects, Cleft Lip / Palate, Hypoplasia of Midface and Fingers, Microcephaly, IUGR, Impaired Cognitive Development, and HDN Craniofacial and Limb Defects, HDN Cardiac Septal, Craniofacial and Genitourinary Defects, IUGR, Postnatal Growth Deficiency, and MR NTD, Craniofacial, Digit & Urogenital Defects, IUGR, Retarded Psychomotor Development

V. ANTIDEPRESSANT (LITHIUM) A. Critical Period o 1st Trimester = Cardiac Defects o 3rd Trimester = New Born Toxicity
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B. Magnitude of Risk o <1 to 8% = Cardiac Risk o Less than 1% = Ebstein Anomaly C. Mechanism o Unknown D. Defects & Toxicity o Cardiac Defects including Ebsteins Anomaly o Transient Toxicity in the New Born (Cyanosis, Hypotonia, Thyroid Suppression with Goiter, Bradycardia, Atrial Flutter, Cardiomegaly, ECG Abnormalities, Hepatomegaly, GI-Bleeding, Diabetes Insipidus, Polyhydramnios, Shock & Seizures VI. AMINOGLYCOSIDES (KANAMYCIN AND STREPTOMYCIN) A. Critical Period o Throughout Pregnancy B. Magnitude of Risk o Low (probably <3%) o Dose and Duration Dependent C. Mechanism o Direct Toxicity of 8th Cranial Nerve (Congenital Deafness) D. Defects & Toxicity o Hearing Loss / Deafness E. Comment: o Although 8th Cranial Nerve Damage and Renal Impairment may occur with ALL Aminoglycosides, this Toxicity has NOT beed associated with other members of this Class VII. FLUCONAZOLE (ANTI-FUNGAL DRUG) A. Critical Period o 1ST Trimester B. Magnitude of Risk o Unknown o Dose Related (400mg/day or greater) C. Mechanism o Unknown D. Defects & Toxicity o Brachycephaly, Craniosynostosis, Low Nasal Bridge, Cleft Palate, Femoral Blowing, Thin Ribs, and Long Bones, Joint Contractures o Cardiac Malformation VIII. QUININE HIGH DOSE (ANTI-MALARIAL DRUG) A. Critical Period o 1st Trimester B. Magnitude of Risk o Observed only after use of Toxic Dose in unsuccessful Abortion Attempts C. Mechanism o Unknown D. Defects & Toxicity o CNS Anomalies (Hydrocephalus, Deafness, Optic Nerve Damage) o Limb Defects MOST Frequent

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IX. TETRACYCLINE A. Critical Period o Beyond 4th Month B. Magnitude of Risk o Unknown o Duration-Dependent C. Mechanism o Chelation: Drug forms a complex with Calcium Orthophosphate and is Incorporated into Bones an Teeth undergoing Calcification o Complex is permanent in TEETH because remodeling and Calcium exchange DO NOT occur after Calcification is Completed D. Defects & Toxicity o Intense Yellow Gold Fluorescence of Mineralized Skeletal Structure and Teeth o Impairment of Bone Growth may occur but it is NOT clinically significant

X. CORTICOSTEROIDS (SYSTEMIC) ALL MEMBERS OF CLASS A. Critical Period o Before 10 weeks = Oral Clefts o Throughout Gestation = IUGR B. Magnitude of Risk o 0.1-0.2% = Cleft Lip (+ / - ) Cleft Palate o May increase to seven fold C. Mechanism o Unknown D. Defects & Toxicity o NONSYNDROMIC CLEFT LIP (with or without Cleft Palate) o IUGR (Intrauterine Growth Retardation)

XI. PEINICILLAMINE A. Critical Period o Unknown B. Magnitude of Risk o Unknown o Probably Less than 5% C. Mechanism o Chelation of Metals (ex. Copper) D. Defects & Toxicity o Cutis Laxa (Limiting Dose to 1g/d or less during Gestation may reduce the Risk) o If Cesarean Section is planned, limit the dose to 250md/day for 6 weeks before delivery and after surgery until Wound Healing is Complete

XII. SYNTHETIC ESTROGEN (DES) A. Critical Period o 10-13 Weeks of Gestation = Highest Risk of Vaginal Adenocarcinoma, but some risk up to 18 weeks o Up to 20 weeks = Genital Malformation B. Magnitude of Risk o <1% = about 350-450 cases of Vaginal Cancer o Unknown for Genital Malformation
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C. Mechanism o Possible Inhibition of Upward Growth of Vaginal Plate of Stimulation of Mullerian Epithelium so that it persists in the Developing Vagina D. Defects & Toxicity (Infertility) 1. Females Lower Mullerian Tract = Vaginal Adenosis, Vaginal & Cervical Clear Cell Adenocarcinoma (more than 90% occur after 14years of age), Cervical and Vaginal Fornix Defect Vaginal Defects = Incomplete Transverse and/or Longitudinal Septum Upper Mullerian = Uterine and Fallopian Structural Defects 2. Males Epididymal Cyst, Hypotrophic Testis, Microphalus, Varicocele, Capsular Induration, Altered Semen XIII. MISOPROSTOL A. Critical Period o Highest Risk = 6-8weeks o Any time during the 1st Trimester B. Magnitude of Risk o Up to 7-times Background Risk for Mobius Syndrome o Almost all Adverse Outcomes have been related to Unsuccessful Abortion Attempts with large, sometimes massive doses (same with Quinine) C. Mechanism o Vascular Disruption caused by Uterine Contractions o Deformation o With Uterine Contractions it Expells the Fetus **Problem: DEFORMATION (because of the compression of the Fetus) D. Defects & Toxicity o Vaginal Bleeding o Abortion o If Abortion does not occur, reported defects include the following: Mobius Syndrome (6th and 7th Nerve Palsies), Defect of Cranium and Scalp, Cleft Lip/Palate, Ocular Hypertelorism, Arthrogryposis (Multiple Nonprogressive Congenital Joint Contractures), Hydrocephalus XIV. IMMUNODULATORS (THALIDOMIDE) Defects will NOT be seen when baby is born These defects will be seen when he is about 40-50y/o A. Critical Period o Days 34-50 days after LMP (20-36days after Conception) o Critical Maternal Dose is at least 100mg **NOTE: 34 14 = 20 days B. Magnitude of Risk o 20-50% C. Mechanism o Intercalates into DNA of Specific Promoter Genes that code for Proteins involved in Normal Limb Development, thereby inhibiting Transcription of these Genes and Disrupting Development of New Blood Vessels, resulting in Truncation of Limbs D. Defects & Toxicity o Limb Defects = Amelia or Phocomelia of Upper & Lower Limbs, Osteochondritis of Femoral Head, Laxity of Cruciate Ligamens in Knee Joints o Craniofacial Defects = Defects of Eye, Ears, Face, Skull, Tongue, Nose (including Choanal Atresia) o CNS Defects = Facial Nerve Palsy, Hydrocephalus, NTD, Epilepsy, Autism, Marcus Gunn Phenomenon (Jaw Winking Syndrome) o Multiple Organ Malformation

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XV. ANTITHYROID DRUGS PTU has No known Cases of Defects (even if used in First Trimester) A. Iodine 1. Critical Period 2nd and 3rd Trimesters 2. Magnitude of Risk Dose and Duration Dependent 3. Mechanism Inhibition of Fetal Thyroid Gland with Compensatory Hypertrophy 4. Defects & Toxicity Hypothyroidism, Goiter May cause Tracheal Compression in the New Born

B. Methimazole / Carbumazole 1. Critical Period Up to 9weeks after LMP 2. Magnitude of Risk Unknown but probably LOW 3. Mechanism Possible Phenotype (Polygene Interaction) 4. Defects & Toxicity A Pattern of Rare Congenital Malformation, possible indicating a Phenotype, that consists of some or all of the Following: Scalp (Aplasia Cutis) or Patchy Hair Defects, Choanal Atresia, Esophageal Atresia with TEF, Minor Facial Anomalies, Hypoplastic or Absent Nipples, Psychomotor Delay, Goiter

XVI. VITAMIN-A DERIVATIVES

A. Etretinate & Acitretin 1. Critical Period Day 15 after Conception to the End of 1st Trimester 2. Magnitude of Risk Unknown May be same as Isotretinoin 3. Mechanism Unknown May be same as Isotretinoin 4. Defects & Toxicity Upper / Lower Limb Reduction Defects Neural Tube Defects and CNS Defects = Meningomyelocele, Meningoencephalocele, Peripheral Facial Nerve Paresis Head Defects = Microcephaly, Small Mandible Facial Dysmorphia = Asymmetric Nares, Microtia or Low Set, Protruding Ears with malformed antihelices, and enlarged keyhole-shaped entrances to External Ear Canal Strabusmus, Cardiac Malformation (TOF), Syndactylies, Poor Head Control 5. Comment Because of Prolonged Elimination Times of Etretinate and Acitretin, Effective Contraception should be used for at least 3years after stopping therapy

B. Isotretinoin 1. Critical Period

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Day 15 After Conception to End of 1st Trimester

2. Magnitude of Risk 30-50% TERATOGENIC DOSE RANGE is LESS THAN 0.2 to 1.5mg/kg/day 3. Mechanism Disruption of Initial Differentiation and Migration of Cephalic Neural Crest Cells 4. Defects & Toxicity Spontaneous Abortion (Most Common) CNS-Hydrocephalus, 7th Nerve Palsy, Posterior Fossa structure defects, Cortical and Cerebellar Defects, Cortical Blindness, Optic Nerve Hypoplasia, Retinal Defects, Microphthalmia, Craniofacial, Cardiovascular, Thymic Gland Defects

DRUGS USED FOR TREATMENT I. HYPERTENSION THERAPY DURING PREGNANCY

Most Common = METHYLDOPA Belong to Classification B and C DRUG

Methyldopa Hydralazine Labetalol Nifedipine Felodipine Thiazide Furosemide Nitroprusside

USUAL NONACUTE DOSING

250-1,500mg bid to max 3,000mg/d 10, 25, 50, 100 tid-qid to max 400mg/d 100, 200, 300mg to max 2,400 mg/d Long Acting: 30-60mg max 120mg/d 5-10mg/d to max 10mg bid 12.5mg increasing to 25mg daily 20-40mg/d to 160mg bid Not usually used in Non-Acute Hypertension

A. Strategies for Control of Chronic Hypertension in Pregnancy / Postpartum o Antepartum = Before Delivery o Postpartum = After Delivery REGIMEN PRIMARY SECONDARY THIRD DRUG

Antepartum (Before Delivery)

I II III IV Methyldopa Felodipine Felodipine Hydralazine Labetalol Diuretic Labetalol Labetalol Hydralazine Labetalol Hydralazine Diuretic

Postpartum (After Delivery)

I II III Hydralazine Ca2+ Blocker ACE Inhibitors Ca2+ Blocker Labetalol Ca2+ Blocker Labetalol Diuretic Beta Blocker

o ACE-Inhibitors are NOT used Ante-Natally (before Delivery) o Diuretics are NOT very popular because if we give Diuretics (even in early pregnancy), there could be a
Decrease in Intravascular Volume Possibility of Decreasing Blood flowing to the Uterine Artery Decreased Blood Flow to the Fetus **IMPORTANT note:
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There are NO Effects on Blood Flow during the THIRD Trimester NO known studies in the First Trimester

B. Acute Severe Hypertension o Most Commonly Used for Acute Hypertension = Hydralazine, Labetalol, Nifedipine, Sodium Nitroprusside o Hydralazine = when there is NO response to Hydralazine (Non-Responders), we may add Labetalol & Nifedipine o Nifedipine = NOT Approved by FDA o Sodium Nitroprusside = LAST Choice (Arterial and Venous Dilator) because Fetal Cyanide Poisoning may occur if used for > 4hours DRUG
Hydralazine Labetalol

RECOMMENDATION
5-10mg IV or IM; Repeat at 20-minute interval 20mg IV-Bolus; If suboptimal Effect, give 40mg q 10min later x3 and 80mg for 20 doses 20, 40, 40, 40, 80, 80 for a total of 300mg Continuous Infusion at 0.5 to 3mg/min 10mg po. Repeat in 30 minutes if necessary NOT Approved by FDA 0.25mg/kg/min max of 5mg/kg/min For Nonresponder or with Encephalopathy NOTE: Fetal Cyanide Poisoning may occur if used for > 4hours

Nifedipine Sodium Nitropruside

**NOTE: DISADVANTAGE of BETA-BLOCKERS: Manifested by GROWTH RESTRICTION among Fetuses We should monitor the Growth Pattern of the Fetus C. Discussion of the Individual Antihypertensive Agents 1. Methylopa Central Acting Alpha Agonist MOA: Weak, Short-Acting, Central Acting Stimulate A2-Receptors decreases Sympathetic Tone and Arterial BP Use: Chronic Hypertension, Hypertensive Crisis **Maternal Side Effects: Lethargy, Dry Mouth, Sedation, Depression, Postural Hypotension, Hemolytic Anemia, Drug Induced Hepatitis 2. Clonidine Alternative Drug to Methyldopa Central Acting Alpha Agonist MOA: Central Acting, Stimulate A2-Receptors Decreases Sympathetic Tone & Arterial BP Use: Chronic Hypertension Dosage: 0.1 to 0.3mg orally two or three times a day, max 2.4mg/d 3. Hydralazine Long Acting, Peripheral Acting MOA: Directly acts on Arterial Smooth Muscle to cause Vasodilation Rapidly absorbed (Peak Plasma in 30minutes) Duration of Effect = 6-8hours Use: Chronic Hypertension, Hypertensive Crisis **Maternal Side Effects: Fluid Retention, Tachycardia, Headache, Depression, Postural Hypotension, Hemolytic Anemia, Drug-Induced Hepatitis 4. Propranolol Beta-Adrenergic Receptor Blocker (Non-Selective) MOA: Short-Acting, (-) Chronotropic Rapidly Use: Use in patients with Cardiac and Thyroid Abnormalities, Chronic Hypertenstion **Maternal Side Effects:
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IUGR, Bradycardia, Fatigue, Depression, Dizziness, Nausea, Vomiting

5. Labetalol Beta Adrenergic Receptor Blockade Short Acting MOA: Has Beta Blockade Actions Onset in 5minutes Rapidly Absorbed (Peak Plasma in 10-20minutes) Half Life: 6 hours Use: Acute Severe Hypertension; Combined with other drugs for Chronic Essential Hyperension **Maternal Side Effects: IUGR, Bradycardia, Fatigue, Depression, Dizziness, Nausea, Vomiting 6. Nifedipine / Felodipine (Calcium Antagonists) MOA: Short or Long Acting Use: Chronic Hypertension **Maternal Side Effects: Peripheral Edema, Headache Potential Concern is its Synergism with Magnesium Sulfate, with Variable Degree of Hypotension, Neuromuscular Blockade, or BOTH 7. Diuretics (Thiazide / Furosemide) MOA: Inhibits Na+ and Corpus Luteum Reabsorption in the Distal Renal Tubules and Collecting System Use: Secondary or Associated Therapy with other Primary Drug Concerns: Blood Volume, Uric Acid **Maternal Side Effects: Hypokalemia, Hypomagnesemia, Hyperuricemia, and Hyponatremia **Neonatal Side Effects: Electrolyte Imbalance, Hyperlycemia, Thrombocytopenia 8. Sodium Nitroprusside MOA: Short-Acting Vasodilator of BOTH Arterial and Venous Smooth Muscle Onset of Action = < 1minute Duration = 1-3 minutes Dose = 0.25 to 1.0ug/kg/min IV Caution when used for > 4 hours Cyanide Poisoning of Fetus may occur Use: Hypertensive Crisis, other agents are NOT effective II. CORTICOSTEROIDS & FETAL LUNG MATURITY Steroids are used for Lung Maturity in the New Born Benefits of Steroids were first reported in 1972 A. Main Benefits: o Decrease Respiratory Distress Syndrome o Decrease IVH o Decrease Neonatal Mortality **IMPORTANT Notes: No Adverse on Long-Term follow up of Children Affect Biochemical Systems within Type-II Pneumocytes: Increased Surfactant Production Increased Compliance & Maximal Lung Volume More Mature Parenchymal Structure Enhanced Response to Surfactant Treatment B. Drugs used: o Betamethasone (12mg q 24hours x 2 doses) o Dexamethasone (6mg q 12 hours x 4 doses)
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**IMPORTANT Note: Since Steroids Action involves mRNA and Protein Synthesis takes time, it is NOT useful to Decrease Dosing Intervals C. NIH Consensus Statement Recommends: o All Fetuses at risk for Preterm Delivery between 24 and 34 weeks o Betamethasone and Dexamethasone o In Preterm PROM, at less than 30 to 32-week gestation in the Absence of Chorioamnionitis III. DRUGS FOR SPECIFIC CONDITIONS ANTIBACTERIALS Penicillins (B) Macrolide (B) Cephalosporins Tetracyclines Aminoglycosides Clindamycin (B) Chloramphenicol Sulfonamides Nitrofurantoin (B) Vancomycin Fluoroquinolones Anti-TB ANTI-FUNGALS Cotrimazole Miconazole Nystatin Fluconazole Itraconazole Butoconazole Amphotericin-B Griseofulvin ANTIVIRALS Zidovudine Zalcitabine Didanosine Stavudine Lamuvudine Acyclovir Ganciclovir Amantadine (C) Ribavirin Alpha-Interferon Idoxuridine Trifuridine Vidarabine ANTI-PARASITIC Metronidazole (B) Lindane Crotamiton Chloroquine Quinine (D) Pyrimethamine Spiramycin (B) Mebendazole Thiabendazole Pyrantel Pamoate

**NOTE: Those with (B) are part of Drug Category-B **Antibacterials: o Tetracyclines = Causes Discoloration of the Teeth o Aminoglycosides = Streptomycin causes Cranial 8th Nerve Palsy o Chloramphenicol = Gray Baby Syndrome o Nitofurantoin = Safe in Pregnancy o Fluoroquinolones = Embryonic Arthropathy o Anti-TB Drugs = Safe to Use

IV. OVER-THE-COUNTER PRODUCTS Nonprescription Medication, Nutraceuticals, and Herbal Agents Over the Counter Drugs are taken 1.5 times more often than prescribed medication during Pregnancy Worrisome because its use are WITHOUT Physicians Knowledge and may not be recognized by the patient as potentially harmful Many agents contain Multiple Ingredients A. Mild Analgesics o Drugs MOST COMMONLY taken during Pregnancy 1. Acetaminophen (+) Pregnancy DOC for Fever and Pain (B) Analgesic and Antipyretic DOC during Pregnancy Side Effects = Hepatotoxicity and Nephrotoxicity among mothers and infants 2. NSAID (Aspirin, Ibuprofen, Mefenamic) Generally DISCOURAGED (particularly in 3rd Trimester) Possibility of Premature Closure of Ductus Arteriosus and Subsequent persistent Pulmonary Hypertention in the Newborn Oligohydramnios, Delayed Labor B. Cold Medications o Agents used are mostly Sympathomimetics = Stimulate Adrenergic Receptor may induce Maternal Hypertension or Reduce Uterine Blood Flow 1. Pseudoephedrine DOC (Drug of Choice)
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Use with Caution during the 1st Trimester and choose a LOW-Dose, Short Acting preparation

2. Oxymethazoline Incorporated in Long-Acting Nasal Sprays 3. Guiafenesin, Dextromethorpan Used as Expectorant Reserved for cases of Significant Maternal Need C. Anti-Histamines o Sedating (LOW RISK) = Brompheniramine, Chlorpheniramine, Diphenhydramine o Less Sedating (Considered Over the Counter) = Loratadine, Fexofenadine, Cetrizine o Nasal Spray = Cromolyn D. Antacids o Moderate use would appear to present MINIMAL Risk to the Fetus o Patients on Low-Sodium Diet should use a Low-Sodium Antacid o Several Large Studies have NOT found an association with Malformations in Infants exposed during the 1st Trimester or Adverse Outcomes in Infants exposed later in pregnancy 1. Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Limited Studies Limited Intestinal Absorption 2. Sodium Bicarbonate Can produce Metabolic Alkalosis and Fluid Overload in BOTH mother and offspring 3. H2-Receptor Antagonists Cimetidine, Ranitidine, and Famotidine = available as Over-the-Counter Preparation 4. Cimetidine Has Antiandrogenic Effects

E. Anti-Diarrheals and Laxatives 1. Bismuth Subsalicylate 2. Aluminum Hydroxide, Magnesium Use for Relief of Indigestion, Nausea, and Vomiting, and Diarrhea Used in SMALL quantities or AVOIDED during Pregnancy 3. Loperamide Antidiarrheal Shares some Opioid-Binding Properties of Meperidine in the Intestine Poorly Absorbed in the Gut MINIMUM Risk for Malformation 4. Docusate Emulsifying Agent used as Stool Softener No Association with Malformation 5. Psyllium Dietary Fiber used as Laxative 6. Phenolphthalein A Laxative / Catharic F. Motion Sickness Preparation 1. Dimenhydrinate Can Increase Level of Uterine Activity & Anecdotally Implicated as a cause of Preterm Labor in the latter part of Pregnancy Avoid using in the First Trimester because it contains MECLIZINE 2. Meclizine Cause Cleft Palate & Other Malformations
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HOWEVER, Studies involving BOTH agents have found the frequency of Congenital Anomalies to be NO Greater than Expected among Children exposed to these agents in the 1st Trimester

G. Topical Preparations: o Many Topical Agents result in Minimal Systemic Levels o Studies are NOT frequent with regard to Reproductive Toxicity: **Topical Preparations Included: Benzoyl Peroxide Zinc Pyrithione Bacitracin Benzocaine Hydrocortisone 1% Cream Terbinafine Miconazole Pytethrin + Piperonyl Butoxide = Pediculicide V. PHARMACOLOGIC INHIBITION OF LABOR Prematurity = Maternal / fetal risk of prolonging Gestations A. Goals of Preterm Labor Inhibition 1. Immediate Goals: Achieve a 24- to 48- hour delay to administer Glucocorticoids Transfer Antepartum Patient to a Tertiary Care Facility for a Higher Level of Neonatal Intensive Care 2. Long Term Goals Maintain labor suppression for a sufficient time to enable the fetus to mature in utero Reduce duration of hospital stay and number of Hospital Admissions for Recurrent Preterm Labor B. Criteria for Labor Inhibition o A Diagnosis of Preterm Labor o A Gestational age greater than 15 weeks and less than 34 weeks o An Absence of medical or Obstetrical Contraindication to Labor Inhibition (FDU, fetal Anomaly, Fetal Distress, Severe IUGR, Chorioamnionitis, Severe Maternal Hemorrhage, Eclampsia or Severe Preeclampasia) o An Absence of Contraindication To specific labor inhibiting agents C. Labor Inhibiting Agents o Beta Adrenergic Receptor Agonist o Magnesium Sulfate o Prostaglandin Synthetase Inhibitors o Calcium Channel Antagonist o Oxytocin Receptor Antagonist o Nitric Oxide Donor 1. Beta Adrenergic Receptor Agonist (Ritodrine, Terbutalline, Sabutamol, Fenoterol, Isoxsuprine) MOA: Binds to receptor and this complex acts via the Guanyl Nucleotide Regulatory Protein to Activate Adenyl Cyclase The resultant Increase in Cytoplasmic cAMP Decreases Intracellular Calcium and Inhibits MLCK Decreased Activity of MLCK Decreases Phosphorylation of Myosin = Decrease Myocyte Contractility **Maternal Side Effects: hypotension, Tachycardia, Arrhythmia, Pulmonary Edema, Hyperglycemia, Hypokalemia **Fetal / Neonatal Effects: Tachycardia, Hyperinsulinemia with Hypoglycemia 2. Magnesium Sulfate MOA: Competitive Inhibition of Calcium at the Voltage Operated Calcium Channels at the Plasma Membrane leading to Hyperpolarization of the Membrane May directly compete with intracellular calcium by decreasing the Calcium-Calmodulin Binding Affinity to MLCK **Maternal Side Effects: Flushing, Warmth Sensation, Nausea, Emesis, Dizziness, Nystagmus, Lethargy, Pulmonary Edema
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**Fetal / Neonatal Effects: Nonreactive Heart Rate, Fetal Breathing, Hypotonia, Lethargy 3. Prostaglandin Synthetase Inhibitor (Indomethacin) MOA: Reversible Competitive Inhibitor of Cyclooxygenase, thereby Reducing Level of Prostaglandin and Diminishing Myometrial Contractility NOTE: Prostaglandin stimulates Myometrial Gap Junction Formation and raise Intracellular Ca Levels = by Increasing Ca2+ Flux across the cell membrane and stimulating release from Sarcoplasmic Reticulum **Maternal Side Effects: Nausea, Dyspepsia, Vomiting **Fetal / Neonatal Effects: Fetal Constriction of Ductus Arteriosus - AVOID giving after 32-week gestation Oligohydramnios by Decreasing Urinary Output 4. Calcium Channel Antagonist (Nifedipine) MOA: blocks the Voltage-Dependent Calcium Channels in the Plasma Membrane It may also Inhibit Release of Intracellular Calcium from Sarcolemmal Stores and Increase Calcium Efflux from the cell The resultant Decrease in Intracellular Calcium inhibits MLCK Decreased Activity of MLCK Decreases Phosphorylation of Myosin = Decrease Myocyte Contractility **Maternal Side Effect: Flushing, Nausea, Headache, Dizziness, Palpitations Hypotension, Tachycardia **Fetal / Neonatal Effects: Possible decrease in Uterine Blood Flow 5. Oxytocin Receptor Antagonist (Atosiban) MOA: Competitive Inhibition of Oxytocin Receptors in the Myometrium and Decidua This results to Decrease in Intracellular Free-Calcium **Maternal Side Effects: Injection-Site Reaction **Fetal / Neonatal Effects: Not yet approved by FDA; Used only in Europe. 6. Nitric Oxide Donors (Nitroglycerin) MOA: Activate the cGMP pathway involved in Muscle Relaxation, leading to Decrease in Intracellular Calcium and Inhibits MLCK. Decreased activity of MLCK Decreases Phosphorylation of Myosin = Decreased Contractility **Maternal Side Effect: Headache, Light-Headedness, Nausea, Emesis, Hypotension **Fetal / Neonatal Effects: No Reported Adverse Effects VI. DRUGS FOR SPECIFIC CONDITIONS A. Bronchial Asthma (No Change in Management during Pregnancy) o Epinephrine o Terbutalline o Metaproterenol o Albuterol o Aminophylline o Cromolyn o Corticosteroids (Beclometasone, Betamethasone, Prednisone) B. Anticonvulsant: o Phenytoin
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o o o o

Carbamazepine Trimethadione Valproic acid Phenobarbital **Side Effects: Impedes Folic Metabolism, causes Cleft Lip, Cardiac and Limb Defects

C. Psychiatric: o Benzodiazepines o Antidepressant o Lithium o MAO Inhibitors = Isocarboxid, Phenelzine o SSRI (B) = Fluoxetine, Sertraline o Antipsychotic = Chorpromazine, Halperidol **Side Effects: Causes Cardiac Defects NOTE: SSRI is the only group of Psychiatric Drugs SAFE in Pregnancy (prenotes) D. Anesthetics (Non-Teratogenic): o Thiopental o Ketamine o Succinylcholine, curare o Nitrous oxide o Halothane o Isoflurane o Lidocaine, tetracaine, procaine, bupivacaine VII. CHEMOTHERAPY AND PREGNANCY Cancer complicates 1 in 1,000 pregnancies Most common = Cervical, Breast, Melanoma, Ovarian, Thyroid, Leukemia, Lymphoma, and Colorectal Chemotherapeutic agents are usually given in combination because it provides the maximum tumor cell kill rate Chemotherapy treats the mother but may damage the fetus. This dilemma requires compromises and makes the management of pregnant women one of the most challenging areas in all of medine Chemotherapeutic agents generally fall into the C or D Categories X is NOT assigned to these drugs because their use may be Life Preserving to Mother A. Alkylating Agents: o Cyclophosphamide (D) o Thiotepa (D) o Chlorambucil (D) o Melphalan (D) o Busulfan (D) o Cisplatin (D) o Carboplatin (D) o Dacarbazine (C) o B. Antibiotics: o Dactinomycin (C) o Bleomycin (D) C. Antimetabolites: o Methotrexate (D) o 5-Fluouracil (D) D. Ducleoside Analogues: o Cytarabine (D) o Gemcitabine (D) E. Topoisomerase-I Inhibitors
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o o

Topotecan (D) Irinotecan (D)

F. Topoisomerase-II Inhibitors: o Etoposide (D) o Doxorubicin (D) o Daunorubicin (D) G. Vinca Alkaloids: o Vincristine (D) o Vinblastine (D) o Vinorelbine (D) H. Taxanes: o Paclitaxel (D) VIII. THERAPY OF DIABETES IN PREGNANCY Diet = 30 kcal/kg (40-50 % CHO; 20%CHON; 30-40% Fat) Insulin A. Target Plasma Glucose Concentration: o Fasting - under 95 mg/dL o Postprandial - under 120 mg/dL B. Insulin Formulations: ONSET
Lispro Regular NPH Lente Ultralente Lantus 15-20min 30-60min 1-2 1-2 1-2 1-2

PEAK
1-2 2-4 5-7 10-12 None None

DURATION
4 4-6 10-12 14-18 20-24 20

IMMUNIZATIONS DURING PREGNANCY Prevention of Disease Eradication of the Disease I. ACTIVE VS PASSIVE IMMUNIZATION A. Active Immunization (Vaccination) o Elicits an Immununologic Response o Duration of effect could be life-long or partial o Agent: Live Virus Vaccine, Killed or Inactivated Bacterial or Viral Vaccine B. Passive Immunization o Administration of Preformed Antibody o Immediate protection is possible o Duration is brief because the half-life of IgG is 20 to 30 days **Indication: Defective immune system Exposure to the disease Therapeutic purpose/amelioration of disease
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II. CURRENTLY AVAILABLE ACTIVE IMMUNIZING AGENT

BACTERIA Live: Bacille Calmette-Guerin Tularemia Typhoid Killed Cholera Meningococcus Pertussis Yersinia Pneumococcus Typhoid H-Influenza Type-B Lyme Disease Toxoid Anthrax Diphtheria

VIRUSES Measles Mumps Poliomyelitis, Oral Rubella Vaccinia Varicella-Zoster Yellow Fever Hepatitis-A Hepatitis-B Influenza Japanese Encephalitis Poliomyelitis Rabies

III. ADVERSE REACTION TO VACCINE/ IMMUNOGLOBULIN Discomfort and pain at the injection site Local irritation/abscess Arthralgias or frank arthritis (eg, rubella) Headache Chills, Fever, Encephalopathy (eg, pertusis) Nausea Chest pain Bronchoconstriction Anaphylaxis Flushing Convulsion IV. ADMINISTRATION OF VACCINES Storage Appropriate solvent Use of plastic syringe for live vaccine Avoidance of light exposure Aseptic administration Appropriate measures to counteract side effect V. IMMUNIZATIONS DURING PREGNANCY A. Tetanus o Recommended for Routine Use During Pregnancy o 2 Vaccine Preparation: **Tetanus Vaccine (Adsorbed) 0.5 ml IM, at lease 2 doses, preferably 3 doses at 3-8 weeks interval for primary immunization 1st injection = at least 60 days, preferably 90 days or more before delivery 2nd injection = 20 days or more before delivery B. Rubella o Accidental vaccination up to 3 months before conception places the pregnant women at high risk o Appropriate counseling is warranted o Abortion is not warranted o First Trimester Maternal Infection = 20 -35% risk o By 4th month = 4-5% risk **Rubella Contact Confirm the diagnosis
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If close contact and there is desire to continue pregnancy - give 750 mg Ig IM, then repeat the dose within 3 -4 days If no desire to continue = DONT give Ig Take a 2nd Blood Sample after 3-4 weeks to Check Seroconversion - (Rubella IgM)

**Rubella Positive Confirm the diagnosis Appropriate counseling is warranted for proven case First Trimester Maternal Infection = 20 -35% risk By 4th month - 4-5% risk 2 IM injections, 750 mg within 4 days **Rubella vaccine Contraindicated During Pregnancy Given to Seronegative Women Postpartum After vaccination, prevent pregnancy for the next 3 months Other C/I: after blood transfusion, within 3 months of Ig injections, high fever, allergic diathesis, steroid and immunosuppresive therapy C. Varicella (Chicken Pox) o No reported birth defects after vaccine exposure during pregnancy o May cause maternal pneumonia and preterm labor o 1st trimester = 10% fetal risk o Within 2 weeks before delivery = neonatal varicella may be seen **Varicella Vaccine Vaccine is given to non-pregnant women 2 doses, 4 to 8 weeks apart **Varicella Contact Anti-Varicella-Zoster Ig, 1000 mg within 3 days of exposure **Varicella Infected Admit Acyclovir 0.5 mg/kg IV/1 hour, repeated every 8 hours for 5 days Neonate should receive Ig

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