Lecture 13 The Physiology, Pharmacology and Toxicology of Pregnancy Collier

DEVELOPMENTAL PHARMACOLOGY:

• “Developmental Pharmacology” = pharmacology (and toxicology)

of substances from conception to adulthood

• In the past, drugs were tested (and hence most human

pharmacology data pertains to) healthy white males aged 18-60

• Because of moral, ethical, and legal issues, the pharmacology of

pregnancy and childhood remain relatively undefined

PREGNANCY, ANATOMY & PHYSIOLOGY:

1. Pregnancy is established when an egg (ovum) is fertilized by sperm

in the fallopian tube zygote

2. Zygote travels to uterus & implants at blastocyst stage (~ 8 cells)

3. At the morula stage (12-16 cells):

a. ¼ of cells become the placenta (vascular unit that provides

blood & nutrients and removes wastes)

b. ¾ of cells becomes the embryo

4. The embryo then grows and differentiates for period of 12 wks

5. After 12 weeks, the embryo become a fetus, and while higher

structures (brain, digestive tract) continue to develop, this is

primarily a time of growth

MOST PREGNANCIES, ONCE ACHIEVED, PROCEED NORMALLY AND ARE

UNCOMPLICATED

PRESCRIBING DRUGS IN PREGNANCY:

• Pregnant women are usually only prescribed drugs if the therapeutic benefits

outweigh the potential adverse effects on the fetus

• The consideration of drug use in pregnancy is of concern in two main scenarios:

1. The prescribing of therapeutics to any woman of childbearing age who has

the potential to become pregnant

2. Prescribing to a woman who is known to be pregnant

• Most important issue surrounding drug use in pregnancy is risk of congenital birth

defects, although miscarriage, prematurity & neonatal withdrawal are concerning

• Despite generally held view that pregnant women should abstain from medication if

at all possible, drug use in pregnancy is still common

o 80 - 90% of women take a prescription or OTC drug in pregnancy

FDA GRADING SYSTEM FOR DRUG SAFETY IN PREGNANCY:

CRITERIA FOR RISK ASSESSMENTS

A • Controlled human studies have demonstrated no risk

B • Animal studies indicate no fetal risk but there are no human studies

• Animal studies indicate fetal risk but controlled human studies don’t

C • No adequate human or animal studies

• Animal studies indicate risk but no human studies are available

D • Evidence of fetal risk but benefits of drug outweigh the risk

X • Evidence of high fetal risk, risk to fetus outweighs therapeutic benefit

AMENDMENTS TO A/B/C/D/X: has limitations

• Category C provides little guidance to health professionals –

broadly interpretable category and places the onus on

prescribing on the HCP’s clinical judgment, accumulated

experience and medical need of the patient

• FDA published “Pregnancy & Lactation Labeling Rule” (final rule)

o PLLR requires changes to the content and format for

information presented in prescription drug labeling to

assist HCPs in assessing benefit versus risk and in

counselling of pregnant/nursing mothers who need to

take the medication

o Progressively removes pregnancy letter categories

o Requires labels to be updated when information

becomes outdated

• PLLR has great promise for prescribing novel drugs, although it

does not solve the problem for older drugs and formulations

that exist under the former classification

MECHANISMS OF TERATOGENESIS:

• Mutation and chromosomal abnormalities

• Mitotic interference

• Nutritional deficiency

• Ultrastructural changes (cell membranes, placental changes)

• Functional changes (enzymes, nucleic acids)

MATERNAL PHYSIOLOGY CHANGES AFFECTING PK:

• Before defaulting to physiologic mechanisms, consider patient compliance

o Up to 60% of pregnant women do not take their medications as prescribed

KIDNEY • 50% increase in renal plasma flow, GFR and endogenous CrCl increased clearance of renally eliminated drug may require increased dosage to maintain therapeutic concentrations

GI • Rate of gastric emptying & motility in small intestine decreased up to 50% (due to effects of progesterone on smooth muscle contractility) greater drug exposure due to increased GIT time

CV • Cardiac output increased by 30% greater pulmonary flow and favoring uptake of substances across alveolar membranes of lungs

• Increased breaths/min (caused by greater progesterone levels and increase in tidal volume) promote alveolar passage of substances

• Could amplify fetal drug exposure to inhaled drugs

BLOOD VOLUME

• Total blood volume increases proportionally with cardiac output, BUT increase in plasma volume (50%) >> in packed RBC (25%)

• Hemoglobin lowered by dilution = decreases blood viscosity

PLASMA PROTEIN

• Plasma albumin decreases to approx. 75% of normal by end of 1st trimester higher plasma unbound fraction for drugs that bind to albumin (generally weak bases)

• Significant only for highly protein bound drugs (potential for drug toxicity, although is rare)

HEPATIC • CYP1A2, 2B6, 2C9 = INDUCED CYP2C19 = SUPPRESSED

• CYP2D6 = induced up to 200% in third trimester

MULTI EFFECTS

• Clearance changes over time may not relate to changes in single organ clearance, but can result from the sum of changes for the different routes of elimination

PLACENTAL ROLE IN FETAL EXPOSURE:

• The womb is not a preserved environment, and both exogenous and endogenous

substances can cross the placenta and affect the fetus

• Passage across the placenta is dependent on the physiological characteristics of the

placenta as well as the physicochemical properties of the drug or compound

o Lipophilic compounds – cross the placenta rapidly by diffusion

▪ Ex// diamorphine (opioid) sometimes used during delivery in the UK

which can cause respiratory depression in newborns

o Placental transfer of hydrophilic drugs is 20% of similar Mw lipophilic ones

• Fetal compartment is slightly more acidic than maternal compartment and

ionization may differ slightly on either side of membrane placental partitioning of

drugs to some extent is based on compounds’ acid:base properties

• No clear pattern for transfer of ionized, weak electrolytes – even within drug classes

o Ex// penicillin antibiotic family: dicloxacillin, cefoxitin, methicillin and

ampicillin are all highly ionized at physiological pH

▪ Methicillin & ampicillin have rapid transfer rates

▪ Dicloxicilln and cefoxitin are slow to cross the placenta

• Active transporters exist in the placenta – remove some drugs and metabolites

o May explain differences in rate of transfer of penicillins

ESTABLISHING DRUG SAFETY IN PREGNANCY:

• 1962 Kefauver-Harrison Act (USA): drug must be demonstrated to be safe for prescribed use, which Supreme Court ruled includes testing in pop of intended users

o BUT studies in pregnant women considered to be unethical due to risk of fetus

o Only method for measuring fetal drug exposure in utero is umbilical cord blood sampling (used to assess genetic abnormalities; risk of miscarriage)

o Legislation intended to protect mothers and children led to pregnant women becoming “therapeutic orphans” stopped developing therapeutics for them

• 2003 Pediatric Research Equity Act (FDA): requires companies to assess safety and effectiveness of certain products in pediatric patients

Lecture 13 The Physiology, Pharmacology and Toxicology of Pregnancy Collier

PREDICTING TERATOGENESIS:

ANIMAL STUDIES AND PRECITING TERATOGENESIS:

• Teratogens vary markedly in their ability to affect fetuses

between species

o Thalidomide does not cause birth defects in rodent

species, yet does in rabbits and humans

o Anti-HIV drug AZT causes transplacental and neonatal

carcinogenicity in mice, yet no teratogenic effects in

humans have been reported over 20+ yrs of clinical use

• It is difficult to “time” the exposure in another species to the

same or similar developmental phase in a human, due to

different physiological development

• Identification of teratogens has primarily occurred in clinic

after mothers have ingested a drug during pregnancy and

similar birth defects have been observed by the same doctor

o Often initial identification is via a single case report or is

an unforeseen finding of a small cohort study

EPIDEMIOLOGOICAL STUDIES AND PREDICTING TERATOGENESIS:

• Studies, regardless of size, can only predict teratogenesis in drugs which cause

between 2- and 4-fold increases in the overall rate of birth defects

o Even known teratogens (ex// phenytoin) cause at most 2-fold increases in

total rate of birth defects

• Detecting causal events also complicated because many teratogens don’t cause an

increase in overall rate of defects, but have their own syndromes (ex// warfarin

embryopathy) or increase rate of only one type of defect (ex// VPA and spina bifida)

• Teratogens show massive inter-individual differences in ability to affect progeny

o Example: Fetal Alcohol Syndrome may affect the baby of a moderately

drinking woman but not occur to the baby of another heavily drinking woman

o Reasons unknown, but may be related to:

▪ Metabolizing enzyme activities of mother, fetus or placenta

▪ Immune responses

▪ Maternal age and parity (# of previous pregnancies)

▪ Physiological characteristics of the parents

RECOGNIZING TERATOGENIC EFFECTS – TIMING IS EVERYTHING

• Diethylstilbestrol (DES) = synthetic estrogen administered to maintain pregnancy

and prevent miscarriage from 1938-1971

• Effects of DES do not occur in offspring until adolescence (average age 14 yrs)

o Clear cell adenocarcinoma of vagina, endometrium or cervix in women

o Epididymal cysts and undescended testes in men

• Drug was administered for MANY years before effects were correlated with its use

EXPOSURE TO TERATOGENS:

MEDICATIONS

Valproic acid • Epileptics may spontaneously abort during fitting, may die, or suffer irreversible brain damage due to fitting o Valproic acid = anti-epileptic medication used for its anti-convulsant properties

• VPA causes cranio-facial abnormalities and skeletal defects o Maternal risk vs. fetal risk

Gentamycin • 8th nerve toxicity (hearing deficit)

Tetracyclines • Causes discoloration of teeth, may cause cataract, liver nerosis, or morphologic abnormalities

RADIATION • Exposure to radiation in utero produces a high level of pre-natal death but data on levels of congenital malformations conflicting o Japan: conflicting associations o Scandinavia: mental retardation, microcephaly

DIET (folic acid) • Low levels of folic acid in maternal circulation can cause Spina Bifida in children (neural tube defect in 1/1000 children) o Caused by failure of spine to close properly during first 4 weeks of pregnancy o Commonly, syndrome includes paralysis, hydrocephalus, developmental delay and GU problems o In severe cases, spinal cord may protrude through the neck

• Controversially, fetal surgery in utero has been used recently to mitigate the effects of Spina Bifida

FATHERS CONTRIBUTE • Folate deficiency in males (usually due to poor diet) may cause DNA damage to sperm fertilized embryos carrying mutant genes

• Many childhood cancers may be mediated through paternal spermatozoic chromosomal abnormalities and are congenital

Dichlorobromopropane • A nematocide sprayed on by hand – exposed men have normal testosterone but lowered gonadotropin levels

• Fathers are 3x more likely to have a female child

VIRUSES Syphilis • Infants exposed in utero are at risk of rhinitis, hepatosplenomegaly, “mulberry molars”, “saber shins,” saddle nose deformity, interstitial keratitis, 8th nerve deafness, peg-shaped incisors, hydrocephaly and congenital retinitis

HSV II • Uncommon syndrome (skin lesions, chorioretinitis, microcephaly, hydranecephaly, microphthalmia)

• Primary HSV infections in first trimester associated with higher rates of spontaneous abortion and stillbirth

• Later infection appears more likely to be associated with preterm labor or growth restricition

Toxoplasmosis • Contracted from family pets (cats)

• Parovirus associated with neonatal anemia and fetal loss, toxoplasmosis, chorioretinitis, hydrocephaly, microcephaly, aqueductal stenosis, agenesis of corpus callosum, cerebral calcifications, non-immune

Lecture 13 The Physiology, Pharmacology and Toxicology of Pregnancy Collier

BREAST MILK AND DRUG EXPOSURE:

LACTATION:

• Most drugs are safe for breastfed babies

• Dose received via milk is small and less than the known safe doses of the same drug

given directly to neonates and infants

PK CONSIDERATIONS FOR EXPOSURE VIA MILK:

Maternal plasma concentration

• Passive diffusion is primary pathway for drugs to enter breast milk

• Good concordance between time-course of maternal plasma-drug concentration and milk-drug concentration

• Maternal plasma concentration is also affected by drug’s distribution into different tissues o HIGH VOLUME OF DISTRIBUTION will contribute to a

LOWER MATERNAL PLASMA CONCENTRATION and a subsequent LOWER CONCENTRATION IN MILK

Maternal plasma protein binding

• Free unbound drug diffuses readily, while highly protein-bound drugs are unable to diffuse in significant amounts o Sertraline = 98% protein bound, so overall will be minimally

transferred to breastfed baby o Venlafaxine has lower protein binding = more drug in milk

• Unbound fraction is dynamic – so beware

• Any drug that competes for binding to plasma proteins would be contraindicated in combination

Molecular mass

• Most drug molecules are small enough to enter milk

• Exceptions – drugs with high molecular weights o Heparin, monoclonal antibodies

Ionization • Drugs cross membranes in an unionized form by passive diffusion

• Milk is generally slightly more acidic (pH 7.2) than mother’s plasma (pH 7.4), so weak bases show ion-trapping in milk

• For weak organic acids, ionization is higher in blood so there is a greater percentage in the maternal compartment

Lipid solubility • Lipid-soluble drugs (in addition to passive diffusion) may have co-secretion by dissolution in the fat droplets of milk

• Fat content of milk varies according to infant age and phase of the feed, particularly in early neonate o PK considerations based on fat distribution are difficult to

study and there’s no conclusive evidence of this

PHARMACOGENOMICS: example of codeine (CYP2D6)

• Ultra-rapid metabolizer phenotype for codeine morphine

occurs in up to 10% of Western Europeans and up to 30% of

North Africans

• Repeated codeine doses in these women produce significant

amounts of morphine

• Rapid distribution from maternal plasma into milk may result

• Codeine should be avoided during breastfeeding, and

alternative analgesia is recommended

OTHER CONSIDERATIONS FOR NEONATAL RISK:

Timing of dose vs. breastfeeding

• Feeding the baby at trough concentrations, before the mother takes the next dose, means the neonate receives the lowest possible drug concentration

• This doesn’t apply as well for the drugs with a long half-life

Oral bioavailability

• A drug’s being in milk may not cause significant exposure o Infant gut may degrade or

destroy a drug o Ka may be poor in infant due to

different GI transit time, permeability and pH

o May be high first pass metabolism in the neonate

Amount of breast milk

• Amount of milk a baby receives varies

• Intake of breastfed baby 150 mL/kg/day

• However, if breast milk is being supplemented by other liquid or solid foods and/or only offered as a comfort to older baby, the amount (in mL) of milk ingested is small

Scaled (relative) dose

• Scaled or relative infant dose is the amount received via breast milk (mg/kg/day) relative to the mother’s dose (mg/kg/day) = a %

• Relative dose of 10% is “rule of thumb” for concern, but this is uncommon

LEGAL AND ETHICAL ISSUES:

• In countries such as New Zealand and the USA where abortion is legal, even in healthy fetuses, a precedent is inferred that either the fetus has no rights under the

law or that their rights are secondary to those of the mother

• The complex legal issues of autonomy and personal freedom mean that legislation ahs not been enacted to prevent pregnant mothers from knowingly exposing

fetuses to teratogens

o In some countries, claims have been bought by the children of mothers who knowingly exposed their fetuses to substances which caused congenital defects

or withdrawal (over 60 cases in USA alone)

o In almost every case, these charges have been dismissed

▪ Fetus = not a minor = did not come under protection of child abuse laws

▪ Fetus = not a human being and therefore the rights of the mother were paramount