A SEMINAR ON

PHARMACOKINETIC & PHARMACODYNAMIC

CHANGES IN PREGNANCY

• By Dr. Nidhi MaheshwariPG 1ST yr student

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.

Drugs are used for…• Conceiving

• Maintaining pregnancy

• Preventing diseases

• Treating ailments and illness in pregnancy

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

Unsupervised use of drugs and environmental agents in expectant mothers can lead to

spontaneous abortions, low birth weight or….

Fetal Malformations

The facts are ..

• Only 2-3% of birth defects are due to drug exposure

• 60-70% of birth defects are due to unknown reasons.

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.

Topics for discussion

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

• 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

Changes in Maternal Pharmacokinetics

• A result of physiological changes

• Progressive in nature

• High intra and interindividual variability

• Therapeutic drug monitoring in case of doubt

• 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.

Physiological Changes in PregnancyBody System Physiological change Extent of changeCardiovascular System Cardiac output

Heart rateStroke volumeBlood Pressure

40%20%10%

Blood FlowUterus

Kidney & LiverSkin

15 times60-80%

600-700%Hematological System Plasma volume

Red cell massPlasma albumin conc

50%18-30%

30%Respiratory System Tidal Volume

RROxygen consumption

40%

15-20%

Body System Physiological change Extent of change

Respiratory System Compensated respiratoryAlkalosis, pH 7.4Lowered PaCO2

Gastrointestinal system

Gastric motilityIntestinal motility

Relaxation of LESKidney Function GFR

BUNCreatinine

50%8-9 mg/dL

0.5-0.6 mg/dLBody Composition Water

Fat (6-8 Lit) 25%

Absorption

↑ Progesterone↓

Reduces gastric and small intestine motility↓

Reduces absorption↓

↓ Cmax and↑ Tmax

• Total bioavailability may remains almost constant

↓H+ secretion↓

↑ gastric PH & ↑ mucus production↓

Weak acids ionize and their absorption ↓↓

Multiple dose weak acids shows no changebut

Single dose (analgesic, antiemetic) shows ↓ Cmax and↑ Tmax

Weak bases show less ionization so no effect

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

↑ cardiac output, ↑ tidal volume, ↑ alveolar uptake

↓

↑ absorption of drugs by inhalation

E.g.: low dose halothane is required for anesthesia

Distribution

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

Excretion

• Renal blood flow ↑ by 60-80%

• GFR ↑ by 50 % in 1st trimester and 80 % in 2nd trimester

• Elimination of penicillin and digoxin ↑

• Also of amino glycosides and cephalexin ↑

• Required increase in dose

Placental excretion• Mainly by simple diffusion

• Facilitated diffusion e.g. is cephalexin, glucose

• Active transport e.g. is 5- FU, alpha methyl dopa

• 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

Placental transport affected by…

a)Lipid solubility

b)Molecular size

c)Transporters

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

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

Placental transporters

• Increased number of specific drug transporters identified

• P-glycoprotein transporter encoded by MDR-1 gene e.g. vinblastin, doxorubicin, digoxin

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

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

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

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

Fetal drug accumulation reasons

• 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.

• 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.

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

• 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

Aspirin

• Avoided in 3rd 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 PH

• 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

Other NSAIDs • Avoided in 3rd 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

Opiod analgesics

Pethidine:• Most commonly used during delivery (1st phase of labour)

• Longer T1/2 in pregnancy

• Maternal –fetal equilibrium reaches in 6 mins after i.v administration

• 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

• 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

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

Anaesthesia

• Pre mixed Nitrous oxide and O2(entonox) is used as inhalational agent

• Enflurane and halothane is also safe

• Dose requirement may be less

•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

Thrombophebitis or DVT• Heparin( <12 wks and > 36 weeks)• Warfarin( 2nd +3rd trimester)• Streptokinase

Rheumatoid arthrit is• Aspirin• NSAIDs• Corticosteroids

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 ↑

•

• 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 1st and 2nd gen.

• Unchanged dose of 3rd gen like ceftriaxone

Erythromycin• Erythrmycin esolate is hepatotoxic in pregnants

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

Asthma• Inhalational salbutamol, corticosteroids, sodium

cromoglycate and ipratropium bromide

• Systemic theophylline and corticosteroids

Diabetes mell itus Human insulin

Antacid & Antiemetic H2 blocker and Metoclopramide are choices

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

Others: ppnl, hydralazine, nitroglycerine

Anticonvulsants BZD e.g. diazepam Carbamazepine Ethosuximide Lamotrigine( ≤ 200 mg/day) Mgso4

• 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

Anxiety BZD

Depression Tricyclic anti depressants Fluoxetine

Insomnia Diphenhydramine, dimenhydrinate, BZD

Arrythmia Digoxin

Quinidine• accumulate in amniotic fluid

Procainamide• Weak base and low protein so placental

transport and ion trapping occurs

Pharmacodynamics

• 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

So our objectives should be

• Prevent the adverse effects

• Diagnose these effects as soon as possible

• Treat them before they reach an irreversible state

Teratogenicity

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.’

Principles of teratogenicity

1 Time of exposure (window of opportunity)

• Thalidomide – 22 to 36 post conceptional day

• Carbamazepine – 1st week

2 Dose and duration

• Severity of teraotogenicity increase with dose and duration

• e.g. Alkylating agents, Actinomycin D etc.

3. Species dif ference

• Coumarins - teratogenic in man only

• Thalidomide – teratogenic in higher primates

4.Mechanism

a)Direct fetal toxicity

e.g. chemotherapeutic agents, radiation

b) Genetic suseptibi l i ty

Fetal hydantoin syndrome is associated with the expression and activity of epoxide hydrolase

C) Maternal-fetal unit dysfunction

Cadmium interferes with placental zinc transport

d) Multifactorial effects

e.g. Fetal hydantoin syndrome caused by alcohol

e) Other factorsConcurrent exposures Concurrent illnessDegree of organ specificity

Slice 1

Slice 2

Slice 3

• Incidence -

Environmental

65-70%

Genetic 25%

Drug exposure 3%

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

Slice 1

Slice 2

Slice 3

Fetal period

Embryonic period

(organogenesis)

Pre-implantation period

Gestational clock

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

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

month) is the period of organogenesis during which organs are formed in the fetus

• most vulnerable for major birth defects

Fetal period • from 3rd month 1st 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.

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

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.

Evaluation parameters • Litter size (no of implantation)

• Lethal effect (no. of resorbed embryo & dead fetuses

• Teratogenic effects (no. of malformed live fetuses)

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

List of Teratogens

DRUGS TERATOGENIC EFFECTS

Alcohol Fetal alcohol syndromecarbamazepine Neural tube defectCoumarin Fetal warfarin syndromeDES Clear cell adenoca.Lead Mental retardationLithium Ebstein anomalyphenytoin Fetal hydantoin syndrome

Tetracycline Bone & teeth defectValproic acid CNS defectsIsotretinoin Craniofacial

malformationACE inhibitors Renal & lung anomaliesMethimazole Fetal aplasia cutisCocaine Vascular infarctsTobacco Growth retardationAnticancer drugs Multiple organ anomaliesMethyl mercury CNS anomaliesAminoglycoside Ototoxicity

Fetal hydantoin syndrome

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

Fetal Alcohol Syndrome

Warfarin embryopathy

• Nasal hypoplasia • Depressed nasal bridge• Flat face• Altered calcification

Isotretinoin embryopathy

• Flat nasal bridge,• Ocular hyperteleorism

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.

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.

US-FDA GUIDELINESCATEGORY 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

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

NWCPT 12/03/2013

Clinical trials in Pregnant Women

NWCPT 12/03/2013

Justification

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

88

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

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

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

Are they Therapeutic orphans

NWCPT 12/03/2013

• Actively excluded from the studies evaluating safety and efficacy of NCEs

• Very few data available to decideThe right drugThe right dose and The right dosing regimen

92

NWCPT 12/03/2013

• Safety and efficacy data : observational studies

Pregnancy registries

• Studies on women who desire to undergo MTP

93

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

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

Trials related to Prenatal diagnostic techniques

NWCPT 12/03/2013

• Prenatal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, GOI, 1994

96

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.