CLINICAL PHARMACOKINETICS IN PREGNANCY AND LACTATION

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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

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

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• 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.

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• 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.

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• 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

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• 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

• .

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• 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

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• 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.

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• 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.

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• 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.

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• 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.

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• Single compartment maternal fetal system
• the drug equilibrates with great speed so that a
  fetalmaternal 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.

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• Elimination from maternal compartment.
• Results in higher concentration in the fetus than
  in the mother.
• Fetalmaternal ratio will be lower during
  infusion than post infusion or after rapid i.v.
  injection.
• SALICYLATE,SACCHARIN,DIAZEPAM.

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• 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.

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

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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.

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• 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.

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• TERATOGENS

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• TERATOGENIC FACTORS

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Nature of drug effects on fetal development

• Stage gestation period main cellular
  process 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

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• DRUG TRANSEFER TO THE FETUS

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• DRUG PASSAGE INTO MILK

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• DRUG TRANSFER

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• DRUG TRANSFER

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• 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.
• ,

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• 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

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• 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.

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• 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.

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

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• 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.

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• 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.

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

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• ANTI- INFECTIVES

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• PENICILLINS

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• CEPHALOSPORINS

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• CARBAPENEMS
• (ertapenem,Imipenem,meropenem)

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• MACROLIDES
• (azithromycin,Clarythromycin,eryhtromycin)

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• AMINOGLYCOSIDES
• (Amikacin,gentamicin)

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• SULFONAMIDES

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• TETRACYCLINES
• (Doxycycline,minocycline)

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• MISCELLANEOUS ANTIBIOTICS

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• MISCELLANEOUS ANTIBIOTICS

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• ANTI VIRALS
• (Acyclovir,valaciclovir,famciclovir)

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• ANTIRETROVIRALS/NRTI
• (Lamivudine,stavudine
  )

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• ANTIRETROVIRAL/NNRTI
• (Efavirenz,nevirapine)

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• Antiretrovirals/PI

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• Antifungals
• (Fluconazole,itraconazole,ketoconazole,voriconazol
  e)

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• Antifungals
• (Fluconazole,itraconazole,ketoconzole,voriconazole
  )

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• ANTIFUNGALS / POLYENES

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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 weightpremature
  delivery

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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.

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• 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

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THANK YOU