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

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

 INTRODUCTION Pharmacokinetics deals with the description of concentration changes of drugs in the body as a function of time. 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. 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. 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. These changes may lead to important variations in the pharmacokinetic processes of absorption,distribution and elimination of drugs.

Alterations in pharmacokinetic parameters in pregnancy Alterations in pharmacokinetic parameters in pregnancy Absorption Absorption  GI absorption - reduced intestinal motility; increased gastric and intestinal emptying time; increased gastric and intestinal emptying time; reduction in gastric acid secretion; reduction in gastric acid secretion; increased mucus secretion; increased mucus secretion; total perfusion is increased total perfusion is increased

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

Drug distribution Drug distribution increased blood volume and cardiac output increased blood volume and cardiac output Drug elimination Drug elimination Renal Drug elimination – Renal Drug elimination – creatinine clearance and drug elimination. creatinine clearance and drug elimination. Hepatic Drug elimination - Hepatic Drug elimination - increased rate of metabolism increased rate of metabolism decreased rate of metabolism - ethylmorphine decreased rate of metabolism - ethylmorphine

INDEX OF FETAL DRUG EXPOSURE INDEX OF FETAL DRUG EXPOSURE It is an index of the fetus to the drug taken by the mother. 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. 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. 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. 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. In these models,it is assumed that all distribution,transfer and elimination processes should be apparent first-order.

Single compartment maternal fetal system Single compartment maternal fetal system the drug equilibrates with great speed so that a fetal:maternal drug concentration ratio of about unity is reached. 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. 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. Elimination from maternal compartment. Results in higher concentration in the fetus than in the mother. 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. Fetal:maternal ratio will be lower during infusion than post infusion or after rapid i.v. injection. SALICYLATE,SACCHARIN,DIAZEPAM. SALICYLATE,SACCHARIN,DIAZEPAM.

TWO COMPARTMENT MATERNAL FETAL SYSTEM TWO COMPARTMENT MATERNAL FETAL SYSTEM Consisting of central compartment,which corresponds to blood-plasma and site drug elimination and additional peripheral tissue compartment. 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 fetal system is rapidly accessible –TETRACYCLINE If the fetal system is slowly accessible – AMPICILLIN,GENTAMYCIN. If the fetal system is slowly accessible – AMPICILLIN,GENTAMYCIN.

 MATERNAL-PLACENTAL-FETAL SYSTEM Placenta and fetus are capable of metabolising drugs Placenta and fetus are capable of metabolising drugs Fetal :maternal drug concentration will be considerably decreased –lignocaine,lidocaine. 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 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 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 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 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. 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 Use of FDA drug classification Category A- not perfectly safe. Category A- not perfectly safe. Category B- often prescribed in pregnancy, research shown some risk of birth defects in animals. 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 C- should be avoided in pregnancy unless there is clear need. Category D- should be avoided in pregnancy when possible. Category D- should be avoided in pregnancy when possible. Category X- should never be used in pregnancy. Category X- should never be used in pregnancy.

TERATOGENS TERATOGENS

TERATOGENIC FACTORS TERATOGENIC FACTORS

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

DRUG TRANSEFER TO THE FETUS DRUG TRANSEFER TO THE FETUS

DRUG PASSAGE INTO MILK DRUG PASSAGE INTO MILK

DRUG TRANSFER DRUG TRANSFER

ANTIEPILEPTICS ANTIEPILEPTICS Uncontrolled epilepsy in a pregnant woman is a serious and potentially life threatening condition for both mother and child. Uncontrolled epilepsy in a pregnant woman is a serious and potentially life threatening condition for both mother and child. Fetal abnormalitiesFetal abnormalities CHF,CHF, Neural tube defects, Neural tube defects, Neuro genital defects. Neuro genital defects.,

VALPROATE VALPROATE Should be avoided in reproductive women. Should be avoided in reproductive women. Major malformations including spina bifida. Major malformations including spina bifida. Compatible with breastfeeding. Compatible with breastfeeding. LAMOTRIGINE LAMOTRIGINE Plasma concentrations of lamotrigine fall early in pregnancy,so dose increases may be necessary to control seizures 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. 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. Excreted in considerable amounts into breast milk. CARBAMAZEPINE CARBAMAZEPINE Structural birth defects. Structural birth defects. Compatible with breastfeeding. Compatible with breastfeeding.

PHENYTOIN PHENYTOIN Less frequently used because of increased malformations. Less frequently used because of increased malformations. Increased clearance,decreased plasma concentrations lead to loss of seizure control. Increased clearance,decreased plasma concentrations lead to loss of seizure control. Post partum monitoring of plasma concentrations helps in preventing phenytoin toxicity. Post partum monitoring of plasma concentrations helps in preventing phenytoin toxicity.

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

ANTIDEPRESSANTS Harmful effects: In pregnancy –Shorter gestational length and lower birth weight in new born. In pregnancy –Shorter gestational length and lower birth weight in new born. Raised cortisol levels with the increased vulnerability to psychopathology Raised cortisol levels with the increased vulnerability to psychopathology In lactation-women who develop post natal depression are most likely to stop breastfeeding. In lactation-women who develop post natal depression are most likely to stop breastfeeding.

SSRIs during pregnancy SSRIs during pregnancy First trimester-no teratogenic effects. First trimester-no teratogenic effects. Paroxetine - Cardiovascular abnormalities. Paroxetine - Cardiovascular abnormalities. Second trimester-significant risk of shorter gestational length and lower birth weight in infants. Second trimester-significant risk of shorter gestational length and lower birth weight in infants. Third trimester-increased respiratory distress,irritability and feeding problems. Third trimester-increased respiratory distress,irritability and feeding problems. Persistent pulmonary hypertension in new born and possibly intraventricular haemorrhage. Persistent pulmonary hypertension in new born and possibly intraventricular haemorrhage.

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

ANTI- INFECTIVES

PENICILLINS

CEPHALOSPORINS

CARBAPENEMS (ertapenem,Imipenem,meropenem )

MACROLIDES ( azithromycin,Clarythromycin,eryhtromycin)

AMINOGLYCOSIDES (Amikacin,gentamicin)

SULFONAMIDES

TETRACYCLINES (Doxycycline,minocycline)

MISCELLANEOUS ANTIBIOTICS MISCELLANEOUS ANTIBIOTICS

MISCELLANEOUS ANTIBIOTICS

ANTI VIRALS (Acyclovir,valaciclovir,famciclovir)

ANTIRETROVIRALS/NRTI (Lamivudine,stavudine) (Lamivudine,stavudine)

ANTIRETROVIRAL/NNRTI ANTIRETROVIRAL/NNRTI (Efavirenz,nevirapine) (Efavirenz,nevirapine)

 Antiretrovirals/PI

 Antifungals (Fluconazole,itraconazole,ketoconazole,voriconazole)

Antifungals Antifungals (Fluconazole,itraconazole,ketoconzole,voriconazole)

ANTIFUNGALS / POLYENES ANTIFUNGALS / POLYENES

ADVERSE EFFECTS OF SOME DRUGS ON FETAL DEVELOPMENT Thalidomide -heart defects,gut atresia Thalidomide -heart defects,gut atresia Warfarin -retarded growth,defects in limbs, Warfarin -retarded growth,defects in limbs, Eyes,CNS Eyes,CNS Androgens -musculinisation in female Androgens -musculinisation in female Estrogens -testicular atrophy in males Estrogens -testicular atrophy in males ACE inhibitors -deafness ACE inhibitors -deafness Ethanol -fetal alcohol syndrome Ethanol -fetal alcohol syndrome Retinoids -hydrocephalus Retinoids -hydrocephalus Nicotine -reduced birth weight;premature delivery Nicotine -reduced birth weight;premature delivery

CONCLUSION CONCLUSION Pharmacokinetic analyses in humans during pregnancy and labour are complicated for technical reasons and must be limited for obvious legal and ethical considerations. 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. 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

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