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CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION SOMESHWAR.K M.Pharm 1st sem DEPARTMENT OF PHARMACEUTICS UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES KAKATIYA UNIVERSITY WARANGAL-506009 • CONTENTS Introduction Alterations in pharmacokinetic parameters Index of fetal drug exposure Compartment characterisation Teratogens Drug transfer Pharmacokinetics of Antiepileptics Antidepressants Antiinfectives References INTRODUCTION • Pharmacokinetics deals with the description of • concentration changes of drugs in the body as a function of time. In pregnancy and labour the body becomes a complex physiological unit which consists of mother, placenta and fetus. • This unit is complicated not only because of integrated • parts of the system are interrelated but also because considerable changes occur as pregnancy advances. These changes may lead to important variations in the pharmacokinetic processes of absorption,distribution and elimination of drugs. • Alterations in pharmacokinetic parameters in pregnancy Absorption GI absorption - reduced intestinal motility; increased gastric and intestinal emptying time; reduction in gastric acid secretion; increased mucus secretion; total perfusion is increased Pulmonary absorption – haemodynamic and ventilatory factors . Hyperventilation increased alveolar drug uptake Intramuscular absorption – increased peripheral tissue perfusion due to vasodilation. in late pregnancy blood flow is decreased to lower limbs . • Drug distribution increased blood volume and cardiac output • Drug elimination Renal Drug elimination – creatinine clearance and drug elimination. Hepatic Drug elimination increased rate of metabolism decreased rate of metabolism - ethylmorphine • INDEX OF FETAL DRUG EXPOSURE • It is an index of the fetus to the drug taken by the • mother. It is the ratio of the total area under the drug concentration time curve for the fetus to that of the mother-from the time of drug administration to the mother to the time when all drug has been eliminated. • Drugs that are intended to reach the fetus should have a high index of relative exposure, while that should preferably not reach the fetus, but are intended for the mother, should have a low index of relative exposure to the fetus. COMPARTMENT CHARACTERISATION OF FETAL-MATERNAL UNIT In simple terms,mother and fetus can be regarded each as a single compartment. More complicated models include further compartments for the amniotic fluid or the drug eliminating placenta. • Various computer simulations have been introduced for • better understanding of these pharmacokinetic characterisations,in which the fetal-maternal unit functions as one-,two-or more compartment systems. In these models,it is assumed that all distribution,transfer and elimination processes should be apparent first-order. • Single compartment maternal fetal system the drug equilibrates with great speed so that a fetal:maternal drug concentration ratio of about unity is reached. Rapid i.v. injection or constant i.v. infusion of THIOPENTONE. If the fetal tissue is slowly accessible,the drug enters relatively slowly. • Elimination from maternal compartment. • Results in higher concentration in the fetus than in the mother. • Fetal:maternal ratio will be lower during infusion than post infusion or after rapid i.v. injection. • SALICYLATE,SACCHARIN,DIAZEPAM. • TWO COMPARTMENT MATERNAL FETAL SYSTEM • Consisting of central compartment,which corresponds to • • blood-plasma and site drug elimination and additional peripheral tissue compartment. If fetal system is rapidly accessible –TETRACYCLINE If the fetal system is slowly accessible – AMPICILLIN,GENTAMYCIN. MATERNAL-PLACENTAL-FETAL SYSTEM • Placenta and fetus are capable of metabolising drugs • Fetal :maternal drug concentration will be considerably decreased –lignocaine,lidocaine. US FDA pharmaceutical pregnancy classification • category A- careful tests in humans have shown no harm. • Category B- animal studies have shown an adverse effect, but adequate and well controlled studies in pregnant women have failed to demonstrate any risk to the fetus. • Category C- animal studies show some harm and there are no good studies in humans. • Category D- adequate well controlled studies in pregnant women have demonstrated a risk to the fetus. • Category X- adequate well controlled studies in animals or in pregnant women have shown that the drug causes fetal abnormalities. Use of FDA drug classification • Category A- not perfectly safe. • Category B- often prescribed in pregnancy, research • • • shown some risk of birth defects in animals. Category C- should be avoided in pregnancy unless there is clear need. Category D- should be avoided in pregnancy when possible. Category X- should never be used in pregnancy. TERATOGENS • A substance, organism, physical agents or deficiency state capable of inducing abnormal structure or function such as: – – – – – Gross structural abnormalities Functional deficiencies Intrauterine growth restriction Behavioral aberrations Demise TERATOGENIC FACTORS • • • • • • Timing of exposure Developmental stage during exposure Maternal dose and duration Maternal pharmacokinetics Genetic factors/phenotypes Interactions between agents Nature of drug effects on fetal development • Stage gestation period • Blastocyst 0-16days fomation • Organoge -nesis 17-60days • Histogenesis, 60days to term functional maturation main cellular process altered by celldivision cytotoxic drugs division migration differentiation same as above teratogens miscellaneous alcohol,nicotine • DRUG TRANSEFER TO THE FETUS • Placental transfer may occur by: – Passive diffusion – Facilitated diffusion – Active transport • Placental surface area • Placental metabolism • DRUG PASSAGE INTO MILK • Diffusion from maternal plasma into milk • Higher maternal plasma levels mean higher breast milk concentrations • Equilibrium will be established with most drugs between milk and plasma • DRUG TRANSFER • Across Placenta – – – – – Molecular weight Lipid solubility Ionization Protein binding Chemical Structure • Across Placenta – Size < 400 daltons – High blood concentration – Similar configuration • DRUG TRANSFER • Into Breast Milk – – – – – – Molecular weight Lipid solubility Ionization Protein binding Drug concentration Drug equilibrium • Into Breast Milk – – – – Size < 200 daltons Drug pKa Equilibration speed High blood concentration • ANTIEPILEPTICS • Uncontrolled epilepsy in a pregnant woman is a serious and • • • • , potentially life threatening condition for both mother and child. Fetal abnormalities CHF, Neural tube defects, Neuro genital defects. • VALPROATE • Should be avoided in reproductive women. • Major malformations including spina bifida. • Compatible with breastfeeding. • LAMOTRIGINE • Plasma concentrations of lamotrigine fall early in pregnancy,so dose increases may be necessary to control seizures • At the post partum lamotrigine concentration rises with • in a few days and dose reduction may be required to prevent toxicity. Excreted in considerable amounts into breast milk. • CARBAMAZEPINE • Structural birth defects. • Compatible with breastfeeding. • PHENYTOIN • Less frequently used because of increased malformations. • Increased clearance,decreased plasma concentrations lead to loss of seizure control. • Post partum monitoring of plasma concentrations helps in preventing phenytoin toxicity. • CLONAZEPAM • No particular pregnancy risks. • Causes drowsiness in breastfeeded neonate. • Withdrawal effects • PHENOBARBITONE • Marked increase in plasma clearance. • Neonatal drowsiness and apathy. ANTIDEPRESSANTS Harmful effects: In pregnancy –Shorter gestational length and lower birth weight in new born. Raised cortisol levels with the increased vulnerability to psychopathology In lactation-women who develop post natal depression are most likely to stop breastfeeding. • SSRIs during pregnancy First trimester-no teratogenic effects. Paroxetine - Cardiovascular abnormalities. Second trimester-significant risk of shorter gestational length and lower birth weight in infants. Third trimester-increased respiratory distress,irritability and feeding problems. Persistent pulmonary hypertension in new born and possibly intraventricular haemorrhage. SSRIs during lactation: Compatible with breastfeeding. Highly protein bound so less drug is transferred from mother to the infant during lactation. ANTI- INFECTIVES • • • • • • Penicillins Cephalosporins Carbapenems Fluoroquinolones Macrolides Aminoglycosides • Sulfonamides • Miscellaneous Antibiotics • Antivirals • Antiretrovirals • Antifungals PENICILLINS • Category B in pregnancy – Cross the placenta easily and rapidly – Concentrations equal maternal levels • Lactation – Crosses in low concentrations – Compatible with breastfeeding CEPHALOSPORINS • Category B in pregnancy – Cross the placenta during pregnancy – Some reports of increased anomalies with specific cephalosporins (cefaclor, cephalexin, cephradrine) – Primarily cardiac and oral cleft defects • Lactation – Excreted into breastmilk in low concentrations – Considered compatible with breastfeeding CARBAPENEMS (ertapenem,Imipenem,meropenem) • Category B/C/B in pregnancy – Likely cross the placenta – Very little human data • Lactation – Excreted into breastmilk in low amounts – Unknown effects but likely low clinical significance MACROLIDES (azithromycin,Clarythromycin,eryhtromycin) • Pregnancy Categories B/C/B – Cross the placenta in low amounts – Limited data with azithromycin and clarithromycin • Lactation – Erythromycin compatible – Others probably compatible AMINOGLYCOSIDES (Amikacin,gentamicin) • Pregnancy Category C – Rapidly cross placenta – Enter amniotic fluid through fetal circulation • Lactation – Compatible with breastfeeding – Not absorbed through GI tract SULFONAMIDES • Pregnancy Category C – Readily cross the placenta – Concerns of use at term • Lactation – Excreted into breastmilk in low levels – Use should be avoided in premature infants TETRACYCLINES (Doxycycline,minocycline) • Pregnancy Category D – Can cause problems with teeth and bone and other defects/effects – Have been linked to maternal liver toxicity • Lactation – Compatible with breastfeeding – Serum levels in infants undetectable • MISCELLANEOUS ANTIBIOTICS • Aztreonam – Pregnancy Category B, likely safe in pregnancy, little human data – Lactation – Compatible per AAP • Clindamycin – Pregnancy Category B, commonly used – Lactation – Compatible per AAP MISCELLANEOUS ANTIBIOTICS • Nitrofurantoin – Pregnancy Category B, possible hemolytic anemia with use at term – Lactation – Compatible, avoid with G-6-PD deficiency • Trimethoprim – Pregnancy Category C, potentially problematic early in pregnancy – Lactation – Compatible as combination drug ANTI VIRALS (Acyclovir,valaciclovir,famciclovir) • Pregnancy Category B – Acyclovir and valacyclovir readily cross the placenta – Can be used for HSV treatment and suppression • Lactation – Acyclovir and valacyclovir are compatible – Famciclovir should be avoided ANTIRETROVIRALS/NRTI (Lamivudine,stavudine) • Pregnancy Category C – Maternal benefit usually outweighs fetal risk – Cross the placenta by simple diffusion – Data with lamivudine show no increased risk of anomalies – Stavudine has been associated with severe lactic acidosis w/ or w/o pancreatitis – All NRTIs have been possibly linked to mitochondrial dysfunction postnatally • ANTIRETROVIRAL/NNRTI (Efavirenz,nevirapine) • Pregnancy Category C – Maternal risk usually outweighs fetal risk – Likely cross into fetus (nevirapine readily) – Delavirdine has possible VSD risk, but limited human data – Efavirenz is associated with anomalies in monkeys, limited human data, possible NTD – Nevirapine can cause hepatotoxicity and rash – Nevirapine can be used as a single dose in labor to prevent HIV transmission Antiretrovirals/PI • Pregnancy Category B/C – – – – – Maternal benefit usually outweighs fetal risk Likely cross the placenta All PIs can cause hyperglycemia ( GDM?) Atazanavir can cause hyperbilirubinemia Indinavir can cause nephrolithiasis Antifungals (Fluconazole,itraconazole,ketoconazole,voriconazole) • Pregnancy Categories C/C/C/D – Likely cross placenta – Fluconazole > 400mg/day seems to be associated with cranio-facial abnormalities – Itraconazole appears to have low risk – Ketoconazole can impair testosterone and cortisol synthesis – No data in humans is available for voriconazole, increased risk in animals • Antifungals (Fluconazole,itraconazole,ketoconzole,voriconazole) • Lactation – Fluconazole is compatible per AAP – Itraconazole could concentrate in milk and body tissues, not recommended – Ketoconazole is compatible per AAP – No data with voriconazole, not recommended ANTIFUNGALS / POLYENES • Amphotericin B – Pregnancy Category B, compatible, lipid complexes also compatible – Lactation – no data available ADVERSE EFFECTS OF SOME DRUGS ON FETAL DEVELOPMENT • Thalidomide -heart defects,gut atresia • Warfarin -retarded growth,defects in limbs, • • • • • • Eyes,CNS Androgens -musculinisation in female Estrogens -testicular atrophy in males ACE inhibitors -deafness Ethanol -fetal alcohol syndrome Retinoids -hydrocephalus Nicotine -reduced birth weight;premature delivery CONCLUSION • Pharmacokinetic analyses in humans during pregnancy and labour are complicated for technical reasons and must be limited for obvious legal and ethical considerations. • Serial determinations of the maternal and fetal drug conc-time course through out pregnancy, although hardly feasible, would be of far greater relevance for the better understanding of the pharmaceutical behaviour of drugs in the fetal-maternal unit and the important clinical question of assessing effects of fetal drug exposure. REFERENCES Hand book of clinical pharmacokinetics; Milo Gibaldi and Prescott Applied biopharmaceutics and pharmacokinetics ;Leon shargel,Susanna wu-pong,Andrew B.C.YU Clinical pharmacokinetics ; Rowland and Tozer Clinical pharmacology and pharmacotherapeutics; Roser walker Pharmacological basis of therapeutics; Goodmann and Gilmann www.spingerlink.com www.wikipedia.org www.pubmed.gov www.pharmainfo.net www.lovetoknowpregnancy.htm THANK YOU