Medication use during pregnancy Uzoma Samuel Ikonne Ph.D. uikonne@atsu.edu 480-248-8133

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Learning Objectives 1. Discuss pharmacokinetic factors that affect drug transfer during pregnancy: Lipid solubility, Molecular size and pH, Placental Transporters, Protein Binding, and Placental and Fetal Drug Metabolism 2. Discuss changes to pregnancy categories 3. Describe Therapeutic Drug Action 4. Describe Toxic drug action on Fetus: ACE inhibitors and Opioids 5. Discuss Teratogen and Teratogenic mechanisms: Folic Acid, Thalidomide, Tobacco Smoking/Nicotine, Fetal Alcohol Distress Syndrome

Recommended Reading Koren G (2015). Special Aspects of Perinatal & Pediatric Pharmacology. InKatzung B.G., Trevor A.J. (Eds), Basic & Clinical Pharmacology, 13e. 

Lipid Solubility Drugs in Cesarean section Lipophilic drugs tend to cross placenta easier i.e. Thiopental Highly ionized i.e Succinylcholine moves slowly Staud, F., Cerveny, L., & Ceckova, M. (2012). Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. Journal of drug targeting, 20(9), 736-763.

Molecular size and pH Molecular weight 250-500 easier 500-1000 more difficult >1000 very difficult Heparin vs Warfarin pH Maternal blood pH 7.4 Placenta blood pH 7.3

Placental Transporters Staud, F., Cerveny, L., & Ceckova, M. (2012). Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. Journal of drug targeting, 20(9), 736-763.

Protein Binding Highly-Lipid Soluble – not affected as much by protein binding Lower-Lipid Soluble affected more Differences in maternal and fetal protein binding affinities

Placental and Fetal Drug Metabolism Monticone, S., Auchus, R. J., & Rainey, W. E. (2012). Adrenal disorders in pregnancy. Nature Reviews Endocrinology, 8(11), 668-678.

Therapeutic Drug Action: Respiratory Distress Syndrome http://3.bp.blogspot.com/-PYJTDnbbk-s/UNSMfAagwJI/AAAAAAAAABk/_ZirKTbsOec/s1600/Infant's+Respiratory+system.jpg

Toxic Drug Action: Angiotensin-Converting Enzyme (ACE) Inhibitors “–prils-” Contraindicated in Pregnancy: significant renal failure in infants http://www.nature.com/nrd/journal/v7/n5/images/nrd2550-f2.jpg

Toxic Drug Action on Fetus: Opioids Neonatal Abstinence Syndrome (NAS) Tremors (trembling) Irritability (excessive crying) High-pitched crying Seizures Vomiting (not exhaustive) http://tpeantidouleurs.e-monsite.com/medias/images/1.jpg http://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=90&ContentID=P02387

https://www. drugabuse https://www.drugabuse.gov/publications/research-reports/heroin/how-does-heroin-abuse-affect-pregnant-women

A B C D

Teratogen Characteristics Effects Result in characteristic set of malformations Selectivity for target organs Exerts its effects at a particular stage of fetal development Dose-dependent incidence Major malformations Thalidomide Growth restriction Cigarette smoking Miscarriage Alcohol Stillbirth Cigarette smoke Neurocognitive delay Courtesy Dr. Thompson

Human Development

FDA Teratogenic Risk Categories (OLD) http://daley-design-test.com/wp3/wp-content/uploads/2012/07/fda-pregnancy-categories2.png

New Pregnancy Labels http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425317.htm

Examples: Old vs New Versus

Teratogenic Mechanisms Direct effects on maternal tissue affecting the fetus Interference with passage of oxygen/ nutrients through the placenta Direct effects on differentiation of tissues Vitamin A Deficiency of critical substances Folic acid Multifactroial Courtesy Dr. Thompson

Thalidomide: Malformations Phocomelia – malformation of limbs Risk: 4-7 weeks gestation https://helix.northwestern.edu/sites/helix/files/styles/16by9/public/field/image/GettyImages_50674351_helix.jpg?itok=e0Q8QVUQ

Tobacco Smoking/Nicotine: Growth Restriction Symptoms: Intrauterine growth restriction Stillbirth Neurobehavioral deficiency Risk Factor for SIDS Wickstrom, R. (2007). Effects of nicotine during pregnancy: human and experimental evidence.Current neuropharmacology, 5(3), 213-222.

Fetal Alcohol Spectrum Disorder Symptoms: Poor Growth Decreased muscle tone and poor coordination Delayed development: thinking, speech, movement, or social skills (3 of 4) Heart Defects (heart murmur) Alcohol Use Increases risk of Miscarriage http://pubs.niaaa.nih.gov/publications/AA82/images/figure01.jpg http://www.nlm.nih.gov/medlineplus/ency/article/000911.htm

Vitamin A (retinoic acid): Differentiation Cunningham, T. J., & Duester, G. (2015). Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nature reviews Molecular cell biology, 16(2), 110-123.

Folic Acid: Deficiency Neural Tube Defects i.e. Spina bifida http://38.media.tumblr.com/tumblr_lrbtkbV4YH1qgrnh8o1_400.jpg

References