Drug therapy in pregnancy and lactation

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Changes during pregnancy,drugs used in pregnancy and their side effects,drugs used in lactation

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chalapathi institute of pharmaceutical sciences 1 Drug therapy in pregnancy & lactation BY T.VIJAYA, I/II M.PHARMACY, PHARMACOLOGY .

Physiological changes in pregnancy: 

Physiological changes in pregnancy Weight gain & altered body shape Frequent urination Mouth and tooth changes Aches and pains Shortness of breath Constipation Heartburn and gas Leg cramps Nausea and vomiting (morning sickness) chalapathi institute of pharmaceutical sciences 2

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Pharmacokinetics in pregnancy: 

Pharmacokinetics in pregnancy ↑ plasma volume (30-50%)  in cardiac output  in renal blood flow and GFR  in body fat  hepatic metabolism  progesterone levels ↓ plasma albumin concentration chalapathi institute of pharmaceutical sciences 4

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chalapathi institute of pharmaceutical sciences 6 The placenta provides an interface between mother and baby, allowing exchange of materials useful for growth and development, gas exchange, and removal of waste products.

Placental drug Transfer: 

Placental drug Transfer Drugs pass placenta by passive diffusion Factors effecting placental drug transfer: Protein binding P H difference Lipid solubility Molecular weight chalapathi institute of pharmaceutical sciences 7

Pregnancy & drug use: 

Pregnancy & drug use 8% pregnant women need drug treatment 59% pregnant women prescribed other than vitamin or mineral supplement 13% pregnant women take dietary supplement More than 90% pregnant women take prescription / non prescription drugs /use social drugs /illicit drugs chalapathi institute of pharmaceutical sciences 8

FDA categorization of drugs in pregnancy: 

FDA categorization of drugs in pregnancy Category Description Examples A Controlled human studies show no risk Vitamins B,C,D,E,Folic acid,Tyroxine, Inj.mag.sulfate B No evidence of risk in humans Metronidazole,Paracetamol,Piperazine,penicillin,erythromycin C Risk cannot be ruled out Most drugs D Positive evidence of risk Antiepileptics X Contraindicated in pregnancy Teratogenic drugs chalapathi institute of pharmaceutical sciences 9

DRUGS PRESCRIBING DURING PREGNANCY:: 

DRUGS PRESCRIBING DURING PREGNANCY: DISEASE/CONDITION DRUGS TO BE USED Nausea & vomiting Cyclizine, Meclizine, Metoclopromide(safe in 3 rd trimester of pregnancy) Hypertension Methyldopa Cough Diphenhydramine, Codiene, Dextromethorphan Headache Paracetamol, Codiene, Benzodiazepines Aspirin and other NSAID s(1 st & 2 nd trimesters) Anti coagulants Heparin S.C Constipation Milk of Magnesia, DocusateSodium, Glycerin, Mineral oil, Bisacodyl Peptic ulcer Sucralfate, H 2 blockers, Bismuth Sub Salicylate, Non Systemic Antacids Tuberculosis Isoniazid & Ethambutol, Rifampin Anti-amoebic drugs Metronidazole, Diloxanides Chalapathi institute of pharmaceutical sciences 10

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CONDITION DRUGS TO BE USED Anti Asthmatic Drugs β Agonists, Gluco Corticoids, Aminophylline Cardiac drugs Digoxin, Quinidine Anti malarial drugs Chloroquine, Quinine, Fansidar Anti microbial drugs Pencillins, Cephalosporins Anti helmintics Piperazine, Biphenium Anti migraine Ergotamine, Propranolol, Amitryptiline Anti diabetics Purified Insulin Heart burns Non systemic Antacids, Metoclopromide Allergigic rhinitis Glucocorticoids ( locally), Diphenhydramine (systemically) chalapathi institute of pharmaceutical sciences 11

TERATOGENESIS : 

TERATOGENESIS Terato –"monster" Genesis -"producing“ A teratogen is any infectious agent drug,chemical or radiation that alters fetal morphology or fetal function if the fetus is exposed during a critical stage of development. Examples- cleft lip/palate, clubfoot, neural tubal defects, missing or malformed limbs/fingers. Also- behavorial and/ or biochemical abnormalities. Teratogenesis maybe direct- i.e ,-malformations of structures Or indirect-such as interfering with oxygen or nutrients. chalapathi institute of pharmaceutical sciences 12

History Thalidomide:: 

History Thalidomide: Thalidomide was originally developed in Germany in 1954 by the pharmaceutical company Chemie Grunenthal . Marketed in 1957 & spread to many countries in Europe, Asia, Australia, America and Africa "WONDER DRUG " for insomnia, coughs, colds, headaches & morning sickness. Thousands of pregnant women took the drug to relieve their symptoms. It was an anticonvulsive drug, but instead it made users sleepy and relaxed. It seemed a perfect example of newly fashionable tranquilisers . chalapathi institute of pharmaceutical sciences 13

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First affected child born in \West Germany on December 25, 1956 Dr McBride in Sydney Australia published a letter in Lancet in December 1961 Rare limb and ear defects noticed in unprecedented numbers 60% of mothers gave a history of taking Contergan 10,000 affected children were born world-wide 40% of victims died before their first birthday. Thalidomide was withdrawn in Germany by the end of November 1961. chalapathi institute of pharmaceutical sciences 14 1962: FDA pharmacologistFrances Oldham Kelsey receives the President's Award for Distinguished Federal Civilian Service f rom President John F. Kennedy for blocking sale of thalidomide in the United States.

Teratogenic mechanism : 

Teratogenic mechanism Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The (R) enantiomer is effective against morning sickness. The (S) is teratogenic and causes birth defects. The enantiomers can interconvert in vivo –that is, if a human is given pure (R)-thalidomide or (S)-thalidomide, both isomers can be found in the serum – therefore, administering only one enantiomer will not prevent the teratogenic effect in humans. Thalidomide intercalates(inserts itself) into DNA in guanine-cytosine-rich regions. Its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA at purine sites Intercalation impacts upon the promoter regions of the genes controlling the development of limbs, ears, and eyes, such as IGF- Iand FGF-2. chalapathi institute of pharmaceutical sciences 15

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Thalidomide malformations: Phocomelia: It is from the Greek words phoco means “seal” and melos means “limb” to indicate that a limb is like a seal's flipper. No ears or deafness Missing or extra fingers or toes Partial or total loss of sight Improper formation of heart, kidney & other internal organs Flattening of the bridge of the nose chalapathi institute of pharmaceutical sciences 16

NSAIDS:: 

NSAIDS: Risks of NSAID used from 30 weeks of pregnancy onwards Premature closure of the ductus arteriosus Oligohydramnios Deficiency of amniotic fluid chalapathi institute of pharmaceutical sciences 17

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Phenytoin: F etal hydantion syndrome Craniofacial abnormalities Hypoplasia of distal phalanges Growth deficiency Mental deficiency Cleft palate Chalapathi institute of pharmaceutical sciences 18

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Valproic acid: ↓ absorption of folic acid Neural tube defects Carbamazepine (Tegretol) Craniofacial defects Spina bifida. Hypoplasia of distal phalanges chalapathi institute of pharmaceutical sciences 19

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Trimethadione: Simian creases in the hands Cardiac anomalies Irregular teeth Mental retardation Phenobarbital: Neonatal withdrawal Neonatal coagulopathy chalapathi institute of pharmaceutical sciences 20

DES (diethylstilboestrol):: 

DES (diethylstilboestrol): Increased risks of clear cell Adenocarcinoma of the vagina and cervix and of breast cancer have been found for daughters of women who took DES during pregnancy. Fertility problems are also more common among these daughters. Women who took DES during pregnancy have an increased risk of breast cancer. chalapathi institute of pharmaceutical sciences 21

LITHIUM SALTS:: 

LITHIUM SALTS: Ebstein's anomaly : It is a rare heart defect in which parts of the tricuspid valve are abnormal. chalapathi institute of pharmaceutical sciences 22

Paroxetine: : 

Paroxetine: chalapathi institute of pharmaceutical sciences 23 selective serotonin reuptake inhibitor

Isotretinoin:: 

Isotretinoin : Vitamin A derivative-fetal defects chalapathi institute of pharmaceutical sciences 24

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Sulphonamides Hyperbilirubinemia Jaundice Kernicterus Primaquine G6PD deficiency chalapathi institute of pharmaceutical sciences 26

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Warfarin : Fetal warfarin syndrome Nasal hypoplasia Hypoplasia of the extremities Developmental retardation Other: Central nervous system defects Spontaneous abortion Stillbirth Prematurity Hemorrhage Ocular defects chalapathi institute of pharmaceutical sciences 27

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chalapathi institute of pharmaceutical sciences 28 Toco agents Tocolytic agents ↑ strength and frequency of uterine contractions Uses: Induction of labour Augmentation of labour Prevention of PPH ↓ strength and frequency of uterine contractions Uses: premature labour uterine hyper stimulation

Drugs affecting uterine contractility: 

Drugs affecting uterine contractility Toco agents: Oxytocin Prostaglandin Ergometrine Mifepristone Misoprostol Carboprost Tocolytic agents: Magnesium Sulfate Ritodrine Terbutaline Calcium antagonists Indomethacin Atosiban (oxytocin receptor antagonist) chalapathi institute of pharmaceutical sciences 29

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Social Drugs: Cigarette smoking A reduction in birth weight Birth defects of heart, brain & face Risk of sudden infant death syndrome(SIDS) Mis-located placenta Preterm labor Miscarriages Uterine infections spontaneous abortions chalapathi institute of pharmaceutical sciences 30

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Alcohol: Foetal alcohol syndrome: Effects: Risk of miscarriage Inadequate growth before or after birth Facial defects A small head Mental retardation Nail dystrophy chalapathi institute of pharmaceutical sciences 31

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Caffeine: ↓ blood flow across placenta ↓ the absorption of iron ↑ risk of anemia ↑ risk of fetal death Advice: limit coffee to 3cups/day Illicit drugs: Cocaine and opioids Neonatal abstinence syndrome Inadequate growth of fetus Premature birth defects Reducing blood flow to the fetus (cocaine ) Miscarriage chalapathi institute of pharmaceutical sciences 32

Drug Passage into Breast Milk: 

Drug Passage into Breast Milk Diffusion : the movement of the drug from a high concentration area (blood) to a low concentration area (breast milk). Active transport : the movement of the drug from blood with a low concentration to breast milk with a high concentration. This mechanism concentrates the drug in the breast milk. After diffusion or active transport, drugs pass through spaces between alveolar cells into the milk chalapathi institute of pharmaceutical sciences 33

Drug transfer into breast milk: 

Drug transfer into breast milk Ionization of the drug - Drugs that are not protein bound and nonionized are more likely to be transferred into breast milk. Molecular weight of the drug - Lower molecular weight drugs are more likely to be transferred to the breast milk than higher molecular weight drugs. Solubility of the drug in lipids and waters - Lipid soluble drugs pass more freely into breast milk than water soluble drugs. The pH of the plasma and the milk - Weakly alkaline drugs have higher breast milk levels than weak acids. chalapathi institute of pharmaceutical sciences 34

Drug Concentration in Breast Milk: 

Drug Concentration in Breast Milk Lower pH than serum Varying degrees of fat concentrations Foremilk Hind milk Milk/Plasma ratio chalapathi institute of pharmaceutical sciences 35

Calculating Drug Exposure: 

Calculating Drug Exposure The infant's dose ( D infant ) is calculated by Milk consumption – 150 ml/kg/d Relative infant dose - < 10% better Infant dose/maternal dose using mg/kg/d chalapathi institute of pharmaceutical sciences 36 D infant (mg/kg/day) = C maternal (mg/L) x M/P AUC x V infant (L/kg/day)

Neonatal Factors:: 

Neonatal Factors: Volume of milk consumed Higher gastric pH Differences in GI flora GI transit time Higher concentrations of free drug Higher percentage of body water Lower rates of metabolism and excretion chalapathi institute of pharmaceutical sciences 37

Relatively safe drugs in nursing mothers: 

Relatively safe drugs in nursing mothers CATEGORY EXAMPLES Antimicrobials Pencillin,ampicillin,kanamycin,amoxycillin,cefadroxil,cefotoxime,cephalexin,carbenicillinoxacillin Analgesics Paracetamol ,Morphine, Pentazocine Anti hypertensives β - blockers , Ca 2+ channel blockers Antimalarials Quinine,chlorquine Anti tubercular drugs Rifampin,ethambutol,pyrazinamide Bronchodilators Theophylline,salbutamol Antiepileptics Phenobarbitone , diphenylhydantoin,valproic acid,carbamazepine Diuretics Chlorthiazide,furosemide,spironolactone Hypoglycemics Insulins,tolbutamide,isoniazid chalapathi institute of pharmaceutical sciences 38

Drugs to be avoided in during lactation:: 

Drugs to be avoided in during lactation: Drug Effects Amiodarone Neonatal hypothyroidism Barbiturates Drowsiness Benzodiazepines Lethargy Carbimazole Hypothyroidism Contraceptives Diminish milk supply, ↓ nitrogen & protein content Cytotoxic drugs Netropenia, immune suppression Aspirin Reye’s syndrome Ephedrine Irritability Tetracyclines Tooth discoloration chloramphenicol Gray baby syndrome chalapathi institute of pharmaceutical sciences 39

Drugs absolutely contraindicated in nursing mothers:: 

Drugs absolutely contraindicated in nursing mothers: Anti cancer drugs Radiopharmaceuticals Ergot & its derivatives (methysergide ) Lithium Chloramphenicol Phenyl butazone Atropine Thiouracil Iodide Mercurials Sulphonamides chalapathi institute of pharmaceutical sciences 40

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Drugs which suppress /inhibit lactation Bromocriptine Bendroflumethazide Estradiol Oral contraceptives Levodopa Trazodone Drugs which are hazardous to the infant Large doses of Alcohol Caffeine Theophylline chalapathi institute of pharmaceutical sciences 41

Considerations in Breastfeeding: 

Considerations in Breastfeeding Withhold or delay therapy if possible Use a drug with poor penetration into milk Use an alternate route of administration Avoid nursing at peak drug concentrations Give drug before infants longest sleep Pump and dump milk Discontinue breastfeeding chalapathi institute of pharmaceutical sciences 42

Conclusion:: 

Conclusion: Completely avoid alcoholic beverages in pregnancy & lactation. Cut down or eliminate food and drinks which contain caffeine such as coffee, tea, colas and other soft drinks, cocoa and chocolate. Stop smoking or cut down your smoking when pregnant. Avoid smokers and smoking areas whenever possible. Check with your physician for his/her recommendations before using drugs. The responsibility of all clinicians including pharmacists to counsel the patients with complete & current information on the risks & benefits of using drugs during pregnancy & lactation. chalapathi institute of pharmaceutical sciences 43

REFERENCES:: 

REFERENCES: Drug use in pregnancy; a point to ponder! - http://www.ijpsonline.com/ Pharmacology and Pharmacotherapeutics R.S.Sathoskar , S.D .Bhandarkar, Nirmala N.Rege KD Tripathi. Essentials of Medical Pharmacology 6 th edition Text book of pharmacology by P.D SETH chalapathi institute of pharmaceutical sciences 44

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