Prescribing in Pregnancy

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Prescribing in Pregnancy

• Prof Louise Kenny PhD MRCOG
• Professor of Obstetrics and
• Consultant Obstetrician and Gynaecologist
• Cork University Maternity Hospital
• UCC

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Aims

• Awareness of physiology of pregnancy
• How pregnancy alters pharmacokinetics
• Placental transfer
• Teratology
• Drugs utilised in pregnancy

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Terms and definitions

• Pharmacokinetics
• Study of the time course of drug absorption,
  distribution, metabolism and excretion
• Pharmacodynamics
• Study of the biochemical and physiological
  effects of drugs and their mechanisms of action

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Terms and definitions

• Plasma half-life
• The time taken for drug concentration to fall by
  50
• Steady state
• Occurs when the amount of the drug administered
  during the dosage interval equals the amount of
  drug eliminated during the dosage interval. This
  is dependent on the half-life. The actual steady
  state concentration is directly proportional to
  the size of the dose and indirectly proportional
  to the volume of distribution and the eliminator
  constant

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Terms and definitions

• Clearance
• The volume of plasma cleared of drug in unit time
  (ml/min)
• First pass effect
• Metabolic breakdown of drugs before entering the
  systemic circulation on iniial passage through
  the liver (e.g. lidocaine, pethidine and
  oestrogen), the intestinal mucosa (e.g. L-dopa,
  chlorpromazine and ethanol) or lungs (e.g.
  isoprenaline).

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Terms and definitions

• Bioavailability
• Extent to which a drug is absorbed systemically.
  It is dependent upon tablet formulation, gut
  motility, disease states and first pass effect.
• Volume of distribution
• The theoretical fluid volume which would contain
  the total body content of a drug at a
  concentration equal to the plasma concentration.
  Drugs that are highly lipophilic and extensively
  tissue bound have a large volume of distribution
  (e.g. nortriptyline)

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Terms and definitions

• Drug elimination
• First order (linear) elimination.
• Most common type for drug absorption and
  elimination.
• The rate of reaction is directly proportional to
  the amount of drug available (i.e. constant
  fraction of drug absorbed or eliminated in unit
  time)
• Zero order elimination
• Proceeds at a constant rate independent of the
  amount of drug available.

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Terms and definitions
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Pharmacokinetics and Pharmacodynamics in Pregnancy
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Physiological changes of Pregnancy

• ? in plasma volume
• ? in cardiac output
• ? in renal blood flow and GFR
• Induction of liver enzyme pathways
• ? in plasma protein content
• Delayed gastric emptying

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Resulting changes in pharmacokinetics

• ? volume of distribution
• ? plasma concentration
• ? excretion renal excretion
• ? hepatic metabolism

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Placental Transfer

• Golden rule is that every drug crosses the
  placenta and under normal circumstances most
  drugs equilibrate between maternal and fetal
  compartments. The only exception is heparin,
  which because of its large molecular weight and
  polarity, does not cross

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Teratology

• (the study of monsters)

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Teratogens

• An agent that causes physical and/or
  developmental abnormalities by preventing the
  developing embryo or fetus reaching its full
  genetic potential

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Potential of drug teratogenicity

• dose
• exposure time
• bioavailability
• degradation products
• drug interactions

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Drugs in Pregnancy

• Most pregnancies are unexpected
• Even planned pregnancies are not detected until
  8-10 weeks gestation
• Many women take vitamin supplements and over the
  counter medications

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The Lesson of Thalidomide
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Thalidomide
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History

• Synthesised by Ciba in 1953
• Taken over by Chemie Gruenthal in 1954
• Trials indicated it had mild sedative properties
• Marketed in 1957 for nausea and morning sickness
• drug of choice to help pregnant women
• Known as Contergan but also incorporated into
  many over the counter preparations
• Licensed in Europe and Australia and Japan

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History II

• First affected child born in \West Germany in
  1956
• Dr McBride in Sydney Australia published a letter
  in Lancet in December 1961
• Rare limb and ear defects noticed in
  unprecedented numbers
• 60 of mothers gave a history of taking Contergan
• Drug was withdrawn between 1962-1963
• 10,000 affected children were born world-wide
• 40 of victims died before their first birthday

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Evidence of teratogenicity of a drug

• double blind randomised control trials in humans
• isolated case reports
• epidemiological studies
• laboratory experiments

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Laboratory experimental work

• testing on cell lines
• testing on tissue culture models
• in vitro embryo culture models
• e.g. whole rat embryo culture
• pregnant mammalian studies

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Limitations of laboratory experimental work

• what dose to study?
• what exposure window?
• which experimental model to use?
• does evidence of toxicity provide evidence of
  teratogenicity?
• different species sensitivity and bioavailability
• Classic example - thalidomide!

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Early development Main embryonic
period (weeks) Fetal
period (weeks)
1 2 3 4 5 6
7 8 9 16 32 38
Neural tube defects Mental
retardation
CNS
TA, ASD, and VSD
HEART
Amelia/Meromelia
LIMBS
Cleft lip
UPPER LIP
Low-set malformed ears and deafness
EARS
Microphthalmia, cataracts,glaucoma
EYES
Enamel hypoplasia
TEETH
Cleft palate
PALATE
Masculinsation
GENITALIA
Embryo Death
Major congenital anomalies
Functional minor anomalies
Highly sensitive period
Less sensitive period
Common site(s) of action
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Abnormal limb development secondary to
thalidomide ingested by pregnant mother

• Thalidomide is a tranquiliser,
• sedative immunosuppressant
• Critical exposure window
• 24 to 36 days post fertilisation
• Defects
• amelia - no limbs
• micromelia - short limbs
• cardiac defects
• haemangiomas
• defects of urinary tract
• defects of digestive tract

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FDA Classification of Drugs Risk to Fetus

• Cat A
• Controlled studies in women fail to demonstrate a
  risk to the fetus in the 1st trimester (and there
  is no evidence of risk in later pregnancy) and
  the possibility of fetal harm is remote
• Cat B
• Either animal studies have not demonstrated a
  fetal risk but there are no controlled studies in
  women, or animal studies have shown an adverse
  effect but this has not been confirmed in
  controlled studies in women
• Cat C
• Either studies in animal have shown an adverse
  fetal effect and there are no contolled studies
  in women or studies in women and animals are not
  available

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FDA Classification of Drugs Risk to Fetus

• Cat D
• There is positive evidence of an adverse risk in
  the human fetus but the benefits from use in
  pregnant women may outweigh the risk
• Cat X
• Studies in animals or humans have demonstrated
  significant fetal abnormalities and the risk of
  the use of the drug in pregnant women clearly
  outweighs any potential benefit

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Anticonvulsants

• Phenytoin
• craniofacial abnormalities
• hypoplasia of distal phalanges
• growth deficiency
• mental deficiency
• Valproic acid
• associated with neural tube defects
• Carbamazepine (Tegretol)
• similar to phenytoin but decreased risk and
  therefore drug of choice

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Neural tube closure

• Posterior view

• Transverse section

Developing embryo day 17 to 21 Showing closure of
neural tube
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Various degrees of Spina Bifida
Spina bifida meningocele
Spina bifida occulta
Spina bifida with meningomyelocele
Spina bifida with myeloschisis
Normal lower limbs
Affected lower limbs
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Neural tube Defects of the Brain

• Hydranencephaly
• (Closed cranium)

• Anencephaly
• (Open cranium)

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Formation of the upper lip and palate
Inferior view of palate showing fusion of palatal
plates of maxillary prominences
Fusion of facial bones
Scanning electron micrograph of facial bones
before fusion
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Abnormal formation of upper lip and palate

• phenolbarbitone (anticonvulsant)
• trimethadione
• ? isotretinoin (retinoid)
• ? methotrexate
• ? valproic acid

Cleft palate
Cleft lip palate
Cleft lip
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Tetracycline teeth

• Discolouration of the
• tooth enamel
• Exposure
• 14 weeks gestation to 10th postnatal month -
  primary teeth
• 14 weeks gestation to 16th postnatal year -
  permanent teeth

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Genital abnormality (8 -10 weeks)

• 
  FEMALE MALE
• Genital tubercle (GT) - Clitoris
  Penis
• Genital swelling (GS) - Labia majora
  Scrotum
• Urethral fold (UF) - Labia minora
  Dorsum of penis
• Anal fold (AF) - Anus
  Anus
• Masculinisation of female genitalia
• (enlarged clitoris and labia majora)

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Fetal Alcohol Syndrome

• thin upper lip
• short palpebral fissures
• flat nasal bridge
• short nose
• elongated philtrum
• microcephaly
• mental retardation
• cardiac abnormalities
• joint abnormalities

Spectrum of signs, the greater the intake the
more severe the signs
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Congenital Goiter(enlargement of the Thyroid
gland)

• Excessive administration of antithyroid drugs to
  the mother during pregnancy

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Drugs affecting uterine contractility

• Toco agents

• Tocolytic agents

• ? strength and frequency of uterine contractions
• Uses
• termination of pregnancy
• induction of labour
• augmentation of labour
• prevention of PPH

• ? strength and frequency of uterine contractions
• Uses
• premature labour
• uterine hyperstimulation

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Drugs affecting uterine contractility

• Toco agents
• oxytocin
• ergometrine
• prostaglandin
• mifepristone
• misoprostol
• carboprost

• Tocolytic agents
• Ritodrine (ß2adrenoceptor
  agonist)
• analgesics
• calcium antagonists
• indamethacin
• Atosiban (oxytocin receptor antagonist)

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Coagulation and pregnancy

• Pregnancy produces a thrombophilic state in the
  mother
• helps prevent post partum haemorrhage
• thrombophilia, decreased venous return due to
  the gravid uterus and immobility during labour
• Risk of DVT and Pulmonary embolus
• Warfarin is Teratogenic
• chondroplasia punctata
• optic atrophy
• mental retardation

Heparin and Low molecular weight heparins are safe
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Cytotoxic Drugs
G0
G0 latent phase G1 resting pase G2 premitotic
phase S synthesis of DNA M mitosis and
division
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Drugs and Lactation

• Drugs excreted in breast milk
• Antibiotics, e.g. aminoglycosides, sulphonamides,
  tetracycline, metronidazole, chloramphenicol
• Anti-TB drugs, e.g. isoniazid
• CNS drugs, e.g. narcotic analgesics,
  benzidiazepines, chlorpromazine
• Anti-thyroid drugs, e.g. carbimazole, radioactive
  iodine
• Anti-convulsant drugs, e.g. phenytoin,
  phenobarbitone
• Anticoagulation, e.g. phenindiones (warfarin and
  heparin)
• Cytotoxic drugs and high dose corticosteroids

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Drugs and the endocrine system

• Galactorrhoea
• Methyldopa, L-dopa, phenothiazines,
  metoclopramide, cimetidine, benzodiazepines,
  oestrogens, tricyclic antidepressants
• Gynaecomastia
• Spironolactone, cimetidine, methyldopa,
  phenothiazines, tricyclic antidepressants,
  cytotoxic drugs, digoxin, oestrogens
• Hypothyroidism
• Iodides, lithium, amiodarone
• Vaginal carcinoma
• Diethystilboestrol

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