Pk-PD changes in pregnancy

Changes in Pharmacokinetics and Pharmacodynamics of various drugs in pregnancy.

1. A SEMINAR ON
PHARMACOKINETIC & PHARMACODYNAMIC
CHANGES IN PREGNANCY
•By Dr. Nidhi Maheshwari
PG 1
ST
yr student

2. Introduction…
•Every minute a woman is giving birth to a baby
•Each pregnancy is a precious pregnancy
• Mother and fetus are non-separable unit
•Maternal well being is absolute prerequisite
•Important to treat the mother while protecting the
unborn fetus.

3. Drugs are used for…
• Conceiving
• Maintaining pregnancy
• Preventing diseases
• Treating ailments and illness in pregnancy

4. Intake of Drugs During Pregnancy
•A prescription for a pregnant female contains 4
drugs on an average.
•Increased incidence of Hypertension and
Diabetes in late age pregnancy, for which
treatment is imperative

5. Unsupervised use of drugs and environmental
agents in expectant mothers can lead to
spontaneous abortions, low birth weight or….
Fetal Malformations

6. The facts are ..
•Only 2-3% of birth defects are due to drug
exposure
•60-70% of birth defects are due to unknown
reasons.

7. On the other hand…
•Scarcity of data about safety and PK of various
drugs in mother and fetus.
•Fetal effects of drugs differ widely between
animals and humans.
•As pregnant females are excluded from clinical
trials on ethical grounds, case control and cohort
studies are the main sources of information.
•Unnecessary termination of wanted pregnancies
due to fear about drug intake in pregnancy.

8. Topics for discussion

9. Definitions
•Pharmacokinetics means “ what body does to
the drug”
•Includes absorption, distribution, metabolism and
elimination of drugs
• It tells you how and when drug reaches the site
of action

10. •Pharmacodynamics means “ what a drug does
to the body”
• Study of biochemical and physiological effects
of drugs and their mode of action
•It deals with the relationship between the plasma
concentration of the drug and its response as
well as its duration of action

11. Changes in Maternal Pharmacokinetics
•A result of physiological changes
•Progressive in nature
•High intra and interindividual variability
•Therapeutic drug monitoring in case of doubt

12. •Cmax: Highest drug concentration observed in plasma
after administration of an extravascular single dose.
•Tmax: time taken to reach Cmax
•T1/2 means the time duration in which the plasma
conc. of the drug falls by 50% of the earlier value.
•Vd (volume of distribution) is the total space
apparently available in the body to contain the known
amount of the drug. If a drug has high Vd, then it is
widely distributed and attains a lower plasma conc.

13. Physiological Changes in Pregnancy
Body System Physiological changeExtent of change
Cardiovascular System Cardiac output
Heart rate
Stroke volume
Blood Pressure
40%
20%
10%
Blood Flow
Uterus
Kidney & Liver
Skin
15 times
60-80%
600-700%
Hematological System Plasma volume
Red cell mass
Plasma albumin conc
50%
18-30%
30%
Respiratory System Tidal Volume
RR
Oxygen consumption
40%
15-20%

14. Body System Physiological changeExtent of change
Respiratory SystemCompensated respiratory
Alkalosis, pH 7.4
Lowered PaCO2
Gastrointestinal
system
Gastric motility
Intestinal motility
Relaxation of LES
Kidney Function GFR
BUN
Creatinine
50%
8-9 mg/dL
0.5-0.6 mg/dL
Body Composition Water
Fat
(6-8 Lit)
25%

15. Absorption
↑ Progesterone
↓
Reduces gastric and small intestine motility
↓
Reduces absorption
↓
↓ Cmax and↑ Tmax
•Total bioavailability may remains almost
constant

16. ↓H+ secretion
↓
↑ gastric PH & ↑ mucus production
↓
Weak acids ionize and their absorption ↓
↓
Multiple dose weak acids shows no change
but
Single dose (analgesic, antiemetic) shows ↓ Cmax
and↑ Tmax
Weak bases show less ionization so no effect

17. Nausea and vomiting
↓
↓ absorption
↓
If single oral dose to be given, administer in the
evening, when nausea is less
Vasodilatation
↑ tissue perfusion so IM absorption ↑
↑ transdermal absorption

18. ↑ cardiac output, ↑ tidal volume, ↑ alveolar
uptake
↓
↑ absorption of drugs by inhalation
E.g.: low dose halothane is required for
anesthesia

19. Distribution

23. Metabolism
•Estrogen/progesterone induces cyP450 so
elimination ↑ e.g. Phenytoin
• Inhibit some other isoenzymes so elimination ↓
e.g. theophylline, caffeine
•Estrogen causes cholestasis and so reduced
clearance of some drug eg. Rifampicin
•Less activity of cholinesterase

24. Excretion
•Renal blood flow ↑ by 60-80%
•GFR ↑ by 50 % in 1
st
trimester and 80 % in 2
nd

trimester
•Elimination of penicillin and digoxin ↑
•Also of amino glycosides and cephalexin ↑
•Required increase in dose

25. Placental excretion
•Mainly by simple diffusion
•Facilitated diffusion e.g. is cephalexin, glucose
•Active transport e.g. is 5- FU, alpha methyl dopa

26. •Follow Fick’s Equation
∆q/∆t = KA (Cm-Cf)/d
K – Diffusion constant
A – Area of absorption
Cm – Cf – Conc. gradient
d – thickness of the membrane

27. Placental transport affected
by…
a)Lipid solubility
b)Molecular size
c)Transporters

28. Lipid solubility
•Thiopental (anaesthetic) crosses placenta and
causes sedation and apnea in newborn
•Highly ionized drug doesn’t cross placenta e.g.
tubocurarine, scholine
•Salicylates (highly ionized) metabolites or free
fraction is highly lipid soluble and readily crosses
placenta

29. Molecular size
Molecular size crossing of
placenta
< 500 D Very easily
500-1000 D With difficulty
>1000 D poorly
• controls rate and amount of drug transfer

30. Placental transporters
•Increased number of specific drug
transporters identified
• P-glycoprotein transporter encoded by MDR-
1 gene e.g. vinblastin, doxorubicin, digoxin

31. Few points…
•Placental blood flow is a rate limiting step
•Placenta not crossed by
1) high mol. Wt 2) protein bound
e.g. heparin, insulin
•Metabolism by placenta and fetal liver.
Develop in fetus by 8 weeks post conception

32. Metabolism in placenta…
•Prednisolone & hydrocotisone will be converted
to prednisone and cortisone respectively and
thus, they are harmless to the fetus
•Ethanol and benzpyrine toxicity is augmented by
metabolism in placenta

33. Factors affecting placental drug
transfer and effects on fetus
•Stage of gestation
•Uterine blood flow
•Conc. gradient
•Physicochemical properties of
drug and its metabolites of
protein binding
•Metabolism
•Placental absorption of
drugs e.g. coccaine

34. Hepatic metabolism in fetus
•All enzymes for phase I and phase II metabolism
are present
•By 11-18 weeks, CYP450 level reaches adult
value
•CYP3A4 absent and CYP3A7 present (30%)
•Glucoronisation absent and sulphation present

35. Fetal drug accumulation reasons

36. •Changes in maternal physiology during
pregnancy impact on pharmacokinetics with a
tendency to reduced plasma concentrations.
•Definitive information from studies that could be
used to formulate therapeutic guidelines for the
safe use of drugs in pregnancy is, however,
limited.
•At present there is little evidence to formulate
clear-cut guidelines with respect to dosing
schedules for individual drugs.

37. •In order to design evidence-based guidelines for drug-
dosing in pregnancy, high-quality pharmacokinetic
studies of adequate sample size which incorporate a
non-pregnant control group are required.
•On current evidence, dose requirements are likely to
be higher for drugs with increased clearance during
pregnancy.
• Dose titration for protein-bound drugs should be
based on monitoring of free drug concentration.

38. Drugs in pregnancy…
Fever and pain
Paracetamol
•It crosses placenta
•Reduces t1/2 with increased
clearance
•PCM toxicity occurs after hepatic
oxygenation by cyto P450

39. •At week 18-23 of gestation the mean activity of
CYP450 in fetal liver is 10% of adult values, which
increase with gestation
•So potential for fetal toxicity increases with
gestational age
•N acetylcysteine can be given to pregnants as
neglible placental transfer and no teratogenicity
•If maternal PCM conc. are in toxic range, then
delivery of mature fetus is considered to allow for
direct extrauterine acetylcysteine therapy

40. Aspirin
•Avoided in 3
rd
trimester
•Salicylic acid crosses placenta
•Conc. in fetus is more than mother as salicylic acid
has more affinity for fetal proteins
•Being weak acid gets less ionized in fetal acidic P
H

41. •Crosses cell membrane and causes CNS toxicity
•It interfere with thromboxane A2 synthesis of
maternal platelets and may interfere with fetal
prostaglandin synthesis
•Can cause peripartum bleeding and CND
haemorrhage
•40-150 mg/day can be given for the prevention of
PIH, Eclampsia and pre-eclampsia

42.  Other NSAIDs
•Avoided in 3
rd
trimester as it can inhibit fetal COX
•May be assosciated with oligohydramnios,
constriction of the ductus arterious, PDA, and PPH
after birth
•Indomethacin is given as tocolytic

43. Opiod analgesics
Pethidine:
• Most commonly used during delivery (1
st
phase of labour)
•Longer T1/2 in pregnancy
•Maternal –fetal equilibrium reaches in 6 mins after i.v
administration

44. •hypertonic uterine constriction may occur with its use
•So, given intrathecally with/without LA during labour
or IM

•Morphine can be used for the same purpose
•Prolnged use of them causes resp. depression and
addiction in pregnancy

45. •Pentazocine, fentanyl, oxymorphone can be
used as analgesics in late pregnancy
•Codeine , oxycodone and hydromorphone are
safe when used in pharmacological dose during
pregnancy

•Naloxone used to couneract resp depresssion in
neonate caused by opioid agonist

46. Anticaogulants
•Heparin and Aspirin are given
Heparin
•Do not cross placenta as large size
•On the day of delivery, the dosage should be
reduced to 7500 U or less every 12 hrs to reduce the
danger of excessive bleeding
•If Aptt if prolonged , then administer protamine
suplhate

47. Anaesthesia
•Pre mixed Nitrous oxide and O2(entonox) is used
as inhalational agent
•Enflurane and halothane is also safe
•Dose requirement may be less

48. •Duration of anaesthesia before delivery is kept as
low as possible as fetal conc. of nitrous oxide
increases with continuous administration
•During labor i.v. thiopental and methohexital
•Peak fetal conc. in 2 mins
•Bupivacaine or lignocaine are given for regional
anaesthesia

49. Thrombophebitis or DVT
•Heparin( <12 wks and > 36 weeks)
•Warfarin( 2
nd
+3
rd
trimester)
•Streptokinase
Rheumatoid arthritis
•Aspirin
•NSAIDs
•Corticosteroids

50. Bacterial infection
Penicillin
•Safe and preferred Antibiotic
•Dose need to be increased during pregnancy as
renal clearance is increased
Ampicillin, amox and methicillin (i.v.)
•Clerance ↑ so dose need to be ↑
•

51. •Β lactams are low protein bound and crosses
placenta and reaches amniotic fluid and
reabsorbed in the gut of fetus
 Cephalosporins
•Increased dose is required of 1
st
and 2
nd
gen.
•Unchanged dose of 3
rd
gen like ceftriaxone
Erythromycin
•Erythrmycin esolate is hepatotoxic in pregnants

52. Clindamycin,
•Can be given in anaerobic infections as it
crosses placenta
Nitrofurantin
•Given in UTI in femlaes
Metronidazole and cotrimoxazole are safe
Tertacyclines and sulphonamides are avoided

53. Asthma
•Inhalational salbutamol, corticosteroids, sodium
cromoglycate and ipratropium bromide
•Systemic theophylline and corticosteroids
Diabetes mellitus
Human insulin
Antacid & Antiemetic
H2 blocker and Metoclopramide are choices

54. Antihypertensives
Methyldopa
•Easily crosses placenta and drug of choice
Labetaolol
•T1/2 is shorter in pregnants, so frequent doses are
required as compared to non-pregnants
Nifedipine
•Clearance of nifedipine ↑ in pregnants than non-
pregnants


55. Others: ppnl, hydralazine, nitroglycerine
Anticonvulsants
BZD e.g. diazepam
Carbamazepine
Ethosuximide
Lamotrigine( ≤ 200 mg/day)
Mgso4

56. •Maternal plasma conc. of phenytoin,
phenobarbital, primidone, valproic acid
decreases during pregnancy as
•↑ hepatic and renal function, ↑ Vd, ↓ protein
binding
•Carmazepine and ethosuximide conc. Remains
stable

57. Anxiety
BZD
Depression
Tricyclic anti depressants
Fluoxetine
Insomnia
Diphenhydramine, dimenhydrinate, BZD

58. Arrythmia
Digoxin
Quinidine
• accumulate in amniotic fluid
Procainamide
• Weak base and low protein so placental
transport and ion trapping occurs

59. Pharmacodynamics

60. •Drug
use
Benefits mother or fetus
Dangers to mother or
fetus
Fetal adverse effects are difficult to manage
• They are difficult to diagnose
• Most of the effects are irreversible

61. So our objectives should be
• Prevent the adverse effects
• Diagnose these effects as soon as possible
• Treat them before they reach an irreversible state

62. Teratogenicity

63. Teratology
•Definition: The study of all environmental
contributions to abnormal development
Teratogen
‘ Any agent that acts during embryonic or fetal
development to produce a permanent alteration
of form or function.’

64. Principles of teratogenicity
1 Time of exposure (window of opportunity)
•Thalidomide – 22 to 36 post conceptional day
•Carbamazepine – 1
st
week
2 Dose and duration
•Severity of teraotogenicity increase with dose
and duration
•e.g. Alkylating agents, Actinomycin D etc.

65. 3. Species difference
• Coumarins - teratogenic in man only
• Thalidomide – teratogenic in higher primates
4.Mechanism
a)Direct fetal toxicity
e.g. chemotherapeutic agents, radiation
b) Genetic suseptibility
Fetal hydantoin syndrome is associated with the
expression and activity of epoxide hydrolase

66. C) Maternal-fetal unit dysfunction
Cadmium interferes with placental zinc transport
d) Multifactorial effects
e.g. Fetal hydantoin syndrome caused by alcohol
e) Other factors
Concurrent exposures
Concurrent illness
Degree of organ specificity

67. Slice 1
Slice 2
Slice 3
•Incidence -
Environmental
65-70%
Genetic 25%
Drug
exposure3%

68. Mechanisms
•Folic acid deficiency
•Epoxides or arenaoxides- metabolites(CBZ)
•Environment & genes
•Maternal disease and drugs-ex. Epilepsy
•Homeobox genes –regulate normal development
& growth (Hox gene) affected by teratogen

69. Slice 1
Slice 2
Slice 3
Fetal period
Embryonic period
(organogenesis)
Pre-
implantation
period
Gestational clock

70. Stages of fetal growth & development
Period of cell division( pre-implantation period)
•The period of one week from fertilisation to
implantation of fertilized egg is called the
preimplantation period
•Zygote transforms into embryonic disk
•No birth defects as systems not developed
•But fetal loss can occur
•So called ‘all-or-none’ period i.e. an insult can either
cause death or complete recovery can occur

71. Embryonic period
•The period from 8
th
day to the end of 8
th
week(2
nd

month) is the period of organogenesis during which
organs are formed in the fetus
• most vulnerable for major birth defects

72. Fetal period
• from 3
rd
month 1
st
week to the end of 9 months s
the period of fetal maturation.Intake of drugs
during this period may modify the function of the
fetal organs rather than causing gross structural
malformation in the fetus
•Period of growth
•Birth defects usually not severe.

73. Criteria for proof of human
teratogenicity
•Careful delineation of clinical cases
•Rare exposure a/w rare defect (at least 3
reported cases)
•Proof of embryopathic action direct or indirect
•Proven exposure at critical stages
•Association must be biological plausible.
•Epidemiological studies consistency
•Teratogenicity in experimental animals

74. Evaluation of Teratogenicity
•Pregnant animals treated with drugs during
embryonic period (organogenesis)
•Mice & rats – 6-15 days of gestation
•Rabbits – 6-18 days of gestation
•Fetuses removed few days before parturition.

75. Evaluation parameters
•Litter size (no of implantation)
•Lethal effect (no. of resorbed embryo & dead
fetuses
•Teratogenic effects (no. of malformed live fetuses)

76. Deficiencies of animal studies
•Dosage
•PK :Different metabolic pathway
•Predictability of teratogenic potential
•False positve drugs are: Chlorpheniramine,
Hydroxyzine, Propoxyphene
•False Negatives: Captopril, enalapril,
Carbimazole, methimazole , Misoprostol

77. List of Teratogens
DRUGS TERATOGENIC
EFFECTS
Alcohol Fetal alcohol syndrome
carbamazepine Neural tube defect
Coumarin Fetal warfarin syndrome
DES Clear cell adenoca.
Lead Mental retardation
Lithium Ebstein anomaly
phenytoin Fetal hydantoin syndrome

78. Tetracycline Bone & teeth defect
Valproic acid CNS defects
Isotretinoin Craniofacial
malformation
ACE inhibitors Renal & lung anomalies
Methimazole Fetal aplasia cutis
Cocaine Vascular infarcts
Tobacco Growth retardation
Anticancer drugs Multiple organ anomalies
Methyl mercury CNS anomalies
Aminoglycoside Ototoxicity

79. Fetal hydantoin syndrome
•Upturned nose,

mild midfacial
hypoplasia,
•long upper lip
with thin
vermillon
borders.
•Lower
distal digital
hypoplasia

80. Fetal Alcohol Syndrome

81. Warfarin embryopathy
•Nasal hypoplasia
•Depressed nasal bridge
•Flat face
•Altered calcification

82. Isotretinoin embryopathy
•Flat nasal bridge,
•Ocular hyperteleorism

83. Do’s and Don’ts of prescription
Do’sDo’s
•Only prescribe for valid indications.
•Use lowest therapeutic dose.
•Treat minor ailments without drugs.
•Avoid medications during the first trimester when the
fetus is at greatest risk from teratogens.
•Do not use combinations of drugs. Use one agent at a
time.
•Use topical treatments when available as you get less
systemic absorption.
•Use the medication only if the benefits outweigh the
risks.

84. Don’ts Don’ts -
•Do not add drugs
unnecessarily.
•Never be the first one to
use the new & the last
one to use old drugs.
•If decision to treat, do
not use sub-therapeutic
doses.
•Don’t encourage pt. to
take OTC or herbal
preparations.

85. US-FDA GUIDELINES
CATEGORY DESCRIPTION
A Well controlled studies show no fetal
risk. ex. Niacin, riboflavine, thiamine
B Animal studies indicated no fetal risk,
but human inadequate or animal
studies show some risk not supported
by human studies. Ex. Metro.,
cefotaxime, penicillin
C Animal studies shows risk but human
studies inadequate of no studies in
humans or animals. Ex. mebendazole,
acyclovir

86. US-FDA GUIDELINES
CATEGORY DESCRIPTION
D Definite fetal abnormalities human
studies but potential benefits may
outweigh risks. Ex. Phenytoin,
alprazolam
X Contraindiacated in pregnancy. Fetal
abnormalities in animals or humans
proven. Risks clearly outweigh any
benefits. Ex. Isotretinoin, danazol

87. NWCPT 12/03/2013
Clinical trials in Pregnant Women
NWCPT 12/03/2013

88. Justification
Should not be deprived of beneficial drugs,
vaccines, investigations because of lack of
data
88

89. General Ethical Consensus
Pregnant or nursing women should in no
circumstances be the subject of any research
unless the research carries no more than
minimal risk to the fetus or nursing infant
89

90. Ethical aspects
NWCPT 12/03/2013
Should only be included if object of the research is to
obtain new knowledge about the fetus, pregnancy and
lactation
trials as are designed to protect or advance the health of
pregnant or nursing women or fetuses or nursing infant
Data obtained from the non-pregnant are not suitably
extrapolated to pregnant women
No discontinuation of nursing for the sake of
participating in trial
90

91. Recommended safeguards
NWCPT 12/03/2013
–All female reproduction toxicity studies and
genotoxicity studies should be complete
–All female reproduction toxicity data to be
reviewed
91

92. Are they Therapeutic orphans
NWCPT 12/03/2013
•Actively excluded from the studies evaluating
safety and efficacy of NCEs
•Very few data available to decide
The right drug
The right dose and
The right dosing regimen
92

93. NWCPT 12/03/2013
•Safety and efficacy data :
observational studies
Pregnancy registries
• Studies on women who desire to undergo
MTP
93

94. Typical Clinical Trials (1/2)
NWCPT 12/03/2013
•Randomized controlled trials
– Two preparation of iron for anemia
•Placebo-controlled trials
–Antidepressant drug Vs placebo
–TRH Vs placebo for threatened premature delivery
–Vit D supplementation Vs placebo
94

95. Typical Clinical Trials (2/2)
NWCPT 12/03/2013
•PK studies, PK-PD studies
–Normal pregnant volunteers ?
–Pre-requisites for initiation
–A typical study:
Study of PK-PD of anti HT drug on a woman who
is already taking the drug for PIH
95

96. Trials related to Prenatal diagnostic
techniques
NWCPT 12/03/2013
•Prenatal Diagnostic Techniques (Regulation
and Prevention of Misuse) Act, GOI, 1994
96

97. Conclusion
•Pregnancy not a disease which require
multidrug therapy.
•Based on reliable info. drug use should be
cautious & minimal.
•Systematic generation of reliable data is
desperately sought commodity .
•Always strive for better & safer therapies in
years to come.