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CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION

CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION. SOMESHWAR.K M.Pharm 1 st sem DEPARTMENT OF PHARMACEUTICS UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES KAKATIYA UNIVERSITY WARANGAL-506009. CONTENTS Introduction Alterations in pharmacokinetic parameters

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CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION

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  1. CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION SOMESHWAR.K M.Pharm 1st sem DEPARTMENT OF PHARMACEUTICS UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES KAKATIYA UNIVERSITY WARANGAL-506009

  2. CONTENTS Introduction Alterations in pharmacokinetic parameters Index of fetal drug exposure Compartment characterisation Teratogens Drug transfer Pharmacokinetics of Antiepileptics Antidepressants Antiinfectives References

  3. 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.

  4. 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.

  5. 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

  6. . • Pulmonary absorption – haemodynamic and ventilatory factors . Hyperventilation increased alveolardrug uptake • Intramuscular absorption – increased peripheral tissue perfusion due to vasodilation. in late pregnancy blood flow is decreased to lower limbs

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. MATERNAL-PLACENTAL-FETAL SYSTEM Placenta and fetus are capable of metabolising drugs Fetal :maternal drug concentration will be considerably decreased –lignocaine,lidocaine.

  16. 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.

  17. 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.

  18. TERATOGENS

  19. TERATOGENIC FACTORS

  20. Nature of drug effects on fetal development • Stage gestation periodmain cellularprocess altered by • Blastocyst 0-16days celldivision cytotoxic drugs fomation • Organoge 17-60days division teratogens -nesis migration differentiation • Histogenesis, 60days to term same as above miscellaneous functional alcohol,nicotine maturation

  21. DRUG TRANSEFER TO THE FETUS

  22. DRUG PASSAGE INTO MILK

  23. DRUG TRANSFER

  24. DRUG TRANSFER

  25. 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. ,

  26. 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

  27. 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.

  28. 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.

  29. CLONAZEPAM No particular pregnancy risks. Causes drowsiness in breastfeeded neonate. Withdrawal effects PHENOBARBITONE Marked increase in plasma clearance. Neonatal drowsiness and apathy.

  30. 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.

  31. 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.

  32. SSRIs during lactation: Compatible with breastfeeding. Highly protein bound so less drug is transferred from mother to the infant during lactation.

  33. ANTI- INFECTIVES

  34. PENICILLINS

  35. CEPHALOSPORINS

  36. CARBAPENEMS (ertapenem,Imipenem,meropenem)

  37. MACROLIDES (azithromycin,Clarythromycin,eryhtromycin)

  38. AMINOGLYCOSIDES (Amikacin,gentamicin)

  39. SULFONAMIDES

  40. TETRACYCLINES (Doxycycline,minocycline)

  41. MISCELLANEOUS ANTIBIOTICS

  42. MISCELLANEOUS ANTIBIOTICS

  43. ANTI VIRALS (Acyclovir,valaciclovir,famciclovir)

  44. ANTIRETROVIRALS/NRTI (Lamivudine,stavudine)

  45. ANTIRETROVIRAL/NNRTI (Efavirenz,nevirapine)

  46. Antiretrovirals/PI

  47. Antifungals (Fluconazole,itraconazole,ketoconazole,voriconazole)

  48. Antifungals (Fluconazole,itraconazole,ketoconzole,voriconazole)

  49. ANTIFUNGALS / POLYENES

  50. 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

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