Transcript clinical pharmacokinetics in pregnancy and lactation

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
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 INTRODUCTION
• Pharmacokinetics deals with the description of
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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
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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
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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
• INDEX OF FETAL DRUG EXPOSURE
• It is an index of the fetus to the drug taken by the
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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
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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
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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
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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
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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:
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Gross structural abnormalities
Functional deficiencies
Intrauterine growth restriction
Behavioral aberrations
Demise
TERATOGENIC FACTORS
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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
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Molecular weight
Lipid solubility
Ionization
Protein binding
Chemical
Structure
• Across Placenta
– Size < 400 daltons
– High blood
concentration
– Similar
configuration
• DRUG TRANSFER
• Into Breast Milk
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Molecular weight
Lipid solubility
Ionization
Protein binding
Drug concentration
Drug equilibrium
• Into Breast Milk
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Size < 200 daltons
Drug pKa
Equilibration speed
High blood
concentration
• ANTIEPILEPTICS
• Uncontrolled epilepsy in a pregnant woman is a serious and
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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
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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
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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
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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,
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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
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Pharmacokinetic analyses in humans during
pregnancy and labour are complicated for technical
reasons and must be limited for obvious legal and ethical
considerations.
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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;
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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