Perinatal Pharmacology Drug Toxicology PDF

Perinatal Pharmacology Drug Toxicology Readings: Ch 30 in Pharmacology Revealed © Dr. E. Cates, Fall2021 2 Agenda • PART I • • • • Review Last Week Drug Metabolism Drug Excretion Clinical Pharmacokinetics • PART II • Perinatal pharmacology • Toxicology • Drug Hypersensitivity © Dr. E. Cates,...

Perinatal Pharmacology Drug Toxicology Readings: Ch 30 in Pharmacology Revealed © Dr. E. Cates, Fall2021 2 Agenda • PART I • • • • Review Last Week Drug Metabolism Drug Excretion Clinical Pharmacokinetics • PART II • Perinatal pharmacology • Toxicology • Drug Hypersensitivity © Dr. E. Cates, Fall2021 3 Perinatal Pharmacology Review: Pharmacokinetic Parameters Image Sourced From: www.slideshare.net © Dr. E. Cates, Fall2021 4 Perinatal Pharmacology Changes in Pregnancy that Affect Pharmacokinetic Parameters: Absorption Factors Affecting Absorption Change in Pregnancy Effect Gastric emptying and intestinal motility Decreased (progesterone) What happens to slowly absorbed drugs? What happens to rapidly absorbed drugs? Gastric Acidity Decreased (estrogen & HCl) What happens to weak acids? Weak bases? Pulmonary function Increased (progesterone) Hyperventilation can increase drug uptake across alveoli Cardiac output Increased (more blood) Increased blood flow increases blood flow across various organs (e.g., alveoli GI tract Blood flow to the skin Increased Effect on absorption? © Dr. E. Cates, Fall2021 5 Perinatal Pharmacology Changes in Pregnancy that Affect Pharmacokinetic Parameters: Distribution Factors Affecting Distribution Change in Pregnancy Effect Plasma volume Increased Total body water Increased Plasma proteins Decreased More free drug Body fat Increased Lipophilic drugs dissolve in body fat © Dr. E. Cates, Fall2021 Vd = D C0 6 Perinatal Pharmacology Changes in Pregnancy that Affect Pharmacokinetic Parameters: Metabolism Factors Affecting Metabolism Hepatic metabolism Change in Pregnancy Effect Some enzyme activities (e.g., CYP3A6) increased Some enzyme activities (e.g., CYP1A2) decreased In General: • Because most drugs are cleared by CYP1A2 (which is decreased) AND • Because there is decreased blood flow to the liver • Due to uteroplacental circulation Drugs that are metabolized by the liver are cleared more slowly in pregnancy © Dr. E. Cates, Fall2021 7 Perinatal Pharmacology Changes in Pregnancy that Affect Pharmacokinetic Parameters: Elimination Factors Affecting Elimination Change in Pregnancy Renal blood flow Increased (Kidney length increases by 1cm – so renal volume increases, leading to an increased in renal blood flow) Glomerular filtration rate Increases due to: • Decrease in colloidal osmotic pressure (from fewer plasma proteins) • Increased hydrostatic pressure • • Effect If drug is eliminated by GF, then elimination is increased Plasma volume increases in pregnancy (40%) In pregnancy, GFR is much higher, thus increases in doses of drugs eliminated by this route may be justified 8 © Dr. E. Cates, Fall2021 Placental Transfer of Drugs Maternal Transfer • Antibodies • Drugs • Hormones In general, transfer across the placenta follows the same kinetics as any other tissue: • Nutrients • Oxygen • Pathogens (including viruses) • Vitamins • Lipid soluble (non-ionized) • Low molecular-weight • Low protein binding in the parturient’s plasma • Water © Dr. E. Cates, Fall2021 9 Placental Transfer of Drugs DRUGS CAN CROSS THE PLACENTA BY: Passive Diffusion • Oxygen, carbon dioxide, fatty acids, steroids, electrolytes, fatsoluble vitamins, drugs MOST DRUGS CROSS THE PLACENTA BY DIFFUSION Facilitated Diffusion • Sugars Solvent Drag • Electrolytes (bulk flow, paracellular (passing through the intercellular space between cells in the epithelium – passive diffusion process) Active Transport • Amino acids, some cations (calcium, iron, iodine, phosphate), water-soluble vitamins © Dr. E. Cates, Fall2021 10 Placental Transfer of Drugs FACTORS AFFECTING PLACENTAL TRANSFER: • Surface area of the placenta and diffusing distance • Physicochemical properties of drugs • Lipid solubility • Molecular weight (most drugs above 1000 Da will not cross the placenta) • Degree of ionization (pH) • Protein binding • Concentration gradients © Dr. E. Cates, Fall2021 11 Placental Transfer of Drugs As placental surface area increases, the diffusing distance decreases Image Sourced From: © Dr. E. Cates, Fall2021 Image Sourced From: http://biology4isc.weebly.com/2-human-embryonic-development.html 12 Placental Transfer of Drugs Maternal metabolites can also cross the placenta • Most metabolites are polar (phase I and II), so if they reach the fetus, the fetus can eliminate them by transferring metabolites back to maternal circulation, but transfer is slow • The majority of fetal elimination occurs by transfer across the placenta, but drugs can also be eliminated by: • Placental metabolism • Placenta expresses CYP enzymes and some enzymes for phase II reactions (drug then excreted via maternal systems) • Fetal metabolism • Some by fetal liver and kidney metabolism (to amniotic fluid, where it gets re-swallowed), returned to maternal circulation via umbilical arteries and placenta © Dr. E. Cates, Fall2021 13 Summary of factors affecting placental transfer of drugs Cross Easily • Lipid solubility • Non-ionized substances • Molecular weight <500 Da • Low Protein Binding • High maternal-fetal gradient • Increased placental blood flow • Increased fetal acidity • Larger surface area © Dr. E. Cates, Fall2021 Cross Slowly • • • • Increased diffusion distance Highly charged High molecular weight Drug bound to maternal RBCs or plasma proteins • Drug altered or bound by placental enzymes • Decreased maternal blood flow • Drugs highly metabolized by the mother 14 Pharmacology and Toxicology • Pharmacology and toxicology closely related • Pharmacology – treatment of disease with a drug • Toxicology – disease caused by a drug • The study of the damaging effects of chemicals on all types of organisms • Pharmacokinetics and pharmacodynamics applicable to toxicology • Merely looking at the toxic effects as opposed to the therapeutic effects © Dr. E. Cates, Fall2021 16 Drug Toxicity 3 types of toxicity: i. Drug exerts more effect than expected, e.g., GAs and sedation, coma, death ii. Drug toxicity that is unrelated to intended effect, e.g., acetaminophen and acute hepatic failure iii. Drugs damage DNA, e.g., cause genetic mutation © Dr. E. Cates, Fall2021 17 Developmental Toxicology Concerned with how chemicals, infectious agents and other factors cause abnormalities in prenatal development. • There is a very high degree of suspicion RE: drug use in pregnancy • Pregnancy is a time of increased drug use • E.g., NVP, UTIs, GBS, PUPPs 4 TYPES: 1. Death 2. Altered Growth • Growth restriction • Low birth weight 3. Conception Embryonic period (1st trimester) Fetal period (3-9 months) death Max teratogenic effect, major deformities Minor deformities, functional anomalies Neonatal anomalies Functional impairments • Neurological deficits 4. Developmental malformations (terata) © B Waiman • Agents which lead to developmental malformations are called teratogens (cause physical change e.g., cleft palate, phocomelia) © Dr. E. Cates, Fall2021 18 Drugs as Developmental Toxins Please see TABLE 30-1 in your text DRUG THERAPEUTIC USE ADVERSE EFFECTS Thalidominde Treatment of Hansen’s Disease (leprosy) and historically was used to treat NVP phocomelia Statins Lower cholesterol levels Skeletal defects and gastroschisis Tetracycline Antibacterial Stained teeth, enamel hypoplasia © Dr. E. Cates, Fall2021 19 Drugs as Developmental Toxins DRUG THERAPEUTIC USE ADVERSE EFFECTS Ethanol Recreational; CNS sedative-hypnotic drug Fetal alcohol syndrome Warfarin Anticoagulant Nasal hypoplasia, stippled epiphyses, CNS defects Phenytoin Anticonvulsant Fetal hydantoin syndrome © Dr. E. Cates, Fall2021 20 Labeling drugs for use in Pregnancy • Canada does not have a coherent system for providing information RE: the safety of drugs during pregnancy and lactation • Rely on the FDA out of the U.S. for such information • Drugs used to be classified for safety in pregnancy from proven safe in human clinical trials (Category A) to completely contraindicated (Category X) • You may still come across these letter “Pregnancy Categories” • This labelling system was changed in 2015 to the “Pregnancy and Lactation Labelling Rule” • More transparency and more detailed information • Allow clinicians and consumers to make more informed decisions © Dr. E. Cates, Fall2021 21 Labeling drugs for use in Pregnancy Image Sourced From: www.fda.gov © Dr. E. Cates, Fall2021 22 Labeling drugs for use in Pregnancy Requirements of the New Labeling: • Information RE: pregnancy exposure registry for the drug and contact info to enroll • General statement RE: risks of adverse outcomes for ALL pregnancies • Followed by if/how exposure to the drug increases the risk • Fetal risk summary with a description of risk conclusions based on human data • Human data to be prioritized over animal data where it exists • A statement RE: systemic absorption of the drug and downstream consequences to fetus • E.g., “(Name of drug) is not absorbed systemically from (part of body) and cannot be detected in the blood. Maternal use is not expected to result in fetal exposure to the drug.” • If human data exist RE: a drug causing fetal developmental abnormalities, the specific nature of the abnormality must be listed • When human data are available, but not sufficient to determine a drug’s effect on fetal development, the risk of abnormality must be stated as low, moderate, or high • When only animal data are available, similar classifications are used but are expressed in terms of “likelihood” • “Contraindications” and/or “Warnings and Precautions” © Dr. E. Cates, Fall2021 23 Labeling drugs for use in Pregnancy Requirements of the New Labeling (cont’d): • “Clinical Considerations” • What is known about inadvertent fetal exposure to drug • Dosing adjustments for pregnancy • Maternal adverse events unique to pregnancy • “Data” • Describing positive and negative experiences during pregnancy • “Lactation” • Whether or not the drug affects the quantity or quality of human milk • If the drug is detectable in human milk • If that amount will affect the breast-fed child © Dr. E. Cates, Fall2021 24 Labeling drugs for use in Pregnancy © Dr. E. Cates, Fall2021 25 Calculation of Fetal Age • One of the most important criteria for evaluating risk of drug exposure in pregnancy is the age of the fetus • Two ages can be calculated: • Gestational age • Date from first day of last menstrual period (the first day of previous menstrual cycle) • Relatively easy to calculate in women with regular menstrual cycles • Conceptional age • Date from conception (fusion of sperm and ova) which occurs about 14 days after the first day of menstrual bleeding in women with a 28day cycle • This date is the true age of the embryo/fetus • Gestational age is usually 2 weeks greater than conceptional age • Typically used by care providers © Dr. E. Cates, Fall2021 26 Embryonic and Fetal Development This phase from 14 days to about 8 weeks is where embryo/fetus is particularly sensitive to exposure to toxins. Why? © Dr. E. Cates, Fall2021 27 Embryonic and Fetal Development There are 3 main phases of development: 1. The pre-embryonic phase • Lasts for 14 days after fertilization • The conceptus is about 1.5 mm in length by the end of this phase as embryonic disk and placenta consists of trophoblast cells • Zona pellucida is still present for earlier parts of this phase and the embryo is isolated from the maternal environment 2. Embryo • • • • • 2-8 weeks after fertilization Period of organogenesis: all major organs are assembled The embryo grows to about 28 mm The placenta is far larger than the embryo Complete access to materials in maternal circulation 3. Fetus © Dr. E. Cates, Fall2021 • >8 weeks to term • Histogenesis phase: the organs grow 28 Teratogens and Timing • The timing of the exposure is critical • In general terms the more immature an organism the greater susceptibility to damage • Pre-embryonic Phase • Not particularly susceptible to insult • Zona pellucida, surrounds conceptus, which is largely impermeable layer of protein • Isolates the pre-embryo from the maternal environment • Cells are not differentiated so loss of a few usually leads to other cells filling in the gaps • If enough cells are damaged, then the pregnancy ends • “All or none” period © Dr. E. Cates, Fall2021 29 Teratogens and Timing • Embryo and early fetus are the most susceptible to teratogens since damage at this time leads to malformed organs • Embryonic Phase • Complete access to chemicals in the maternal circulation during this time • Damage caused at this point typically alters an entire organ in an irreversible way • E.g., limb bud abnormalities, major cardiac defects, neural tube defects • Embryopathy = a disorder resulting from abnormal development of the embryo • Damage in the embryonic/early fetal phase occur at very specific times in development • Thalidomide damage (phocomelia or hypoplastic limb disorder) occurs between 20-36 days • Anencephaly must occur before 25-26 days when the anterior neural tube closes © Dr. E. Cates, Fall2021 30 Teratogens and Timing • Fetal Phase • Basic structure of the organs established, but they have to grow • Developmental toxins can result in incomplete or abnormal growth of an organ or functional changes in the function of an organ • E.g., fetal alcohol syndrome neurological deficit • Fetopathy = A disorder resulting from the abnormal development of the fetus • Damage to the fetus during histogenesis can cause functional changes but gross damage to organs is impossible • Functional changes include brain damage, deafness and growth restriction- but basic organ is there © Dr. E. Cates, Fall2021 31 Teratogens and Timing Image Sourced From: The Developing Human. Moore © Dr. E. Cates, Fall2021 32 Rate of Major Developmental Malformations • Rate of major developmental malformation is 2.5 to 3 % of live births • Rate varies depending on definitions and reporting systems used • Many causes of congenital malformations • 20% due to single gene abnormalities • 5-10% due to chromosomal abnormalities • 2-10% due to maternal exposure to infections and chemicals • Majority of fetuses with major abnormalities spontaneously abort • E.g., 92% of fetuses with neural tube defects are lost; also, high numbers for fetuses with cleft palate and polydactyly © Dr. E. Cates, Fall2021 33 Rate of Major Developmental Malformations © B Wainman © Dr. E. Cates, Fall2021 34 The Loss of Mother Risk At this time, there is no word on the re-development of a Canadian organization that could replace Motherisk. Mothertobaby.org is a U.S.based organization of specialists offering a comparable service. Clients can be referred to this website. May 2019, Counselling services were rendered unavailable to Canadian residents d/t overwhelming demand. © Dr. E. Cates, Fall2021 35 Summary • Many developmental abnormalities occur: 2.5-3% of newborns will have some sort of anomaly • About 2% of these developmental defects appear to be due to drugs and chemicals • Perhaps 5- 10% of these are due to environmental causes • The majority of developmental abnormalities are of unknown cause • Exposure to toxin in the organogenesis phase of development is likely to show the highest degree of damage • Acute or chronic exposures to developmental toxins need to be minimized wherever possible © Dr. E. Cates, Fall2021 36 Drug Allergy • Drug toxicity can also manifest as allergic reactions • Drug acts as allergen and triggers immune system • 4 TYPES OF HYPERSENSITIVITY REACTIONS: 1. Type I: mediated by IgE, can cause anaphylaxis e.g., bee sting 2. Type II: drug modified endogenous protein  triggers immune response with IgG, IgM and complement proteins which attach cells of circulatory system, e.g., penicillin can lead to hemolytic anemia 3. Type III: formation of Ab-Ag complexes activating complement leading to destructive inflammatory response in blood vessels; rare, e.g., sulfa drugs 4. Type IV: mediated by T lymphocytes, e.g., dermatitis after poison ivy exposure; takes days to hours to develop © Dr. E. Cates, Fall2021 38 Importance of Understanding Allergy… https://brighterworld.mcmaster.ca/articles/youprobably-dont-have-a-penicillin-allergy/ CMAJ Podcast: http://www.cmaj.ca/content/191/8/E231 © Dr. E. Cates, Fall2021 39 Hypersensitivity Reactions Type I • Mediated by IgE on the surface of mast cells • Underlying mechanism of allergic asthma, rhinitis, acute urticaria, food allergy and systemic anaphylaxis • Antibody cross-linking causes mast cells to release a variety of mediators • increase blood vessel permeability, affect smooth muscle contraction • Ingested antigens cause a variety of symptoms through their action on mucosal mast cells • Systemic antigens most likely to result in anaphylaxis via activation of connective tissue mast cells © Dr. E. Cates, Fall2021 40 Hypersensitivity Reactions © Dr. E. Cates, Fall2021 41 Image Sourced From: Immunobiology 6th Ed. Janeway Hypersensitivity Reactions Type II • Antibody-mediated destruction of red blood cells or platelets • Drug binds to the cell surface and serves as a target for anti-drug IgG antibodies • Antibodies target the cell for destruction © Dr. E. Cates, Fall2021 42 Image Sourced From: Pathologic Basis of Disease 6th Ed. Robbins Hypersensitivity Reactions Type III • Sometimes called immune-complex disease or serum sickness • Rare, evoked by large IV doses of antigen (antibiotics) • Dose and route of Ag delivery determines pathology • Experimental model called the Arthus Reaction • Large doses of Ag evoke a robust IgG response • IgG:Ag complexes activate complement • Complement proteins stimulate histamine release, inflammation, and blood clotting • Small blood vessels become plugged with clots, producing hemorrhage in the skin © Dr. E. Cates, Fall2021 43 Hypersensitivity Reactions Type III © Dr. E. Cates, Fall2021 Images Sourced From: Immunobiology 6th Ed. Janeway 44 Hypersensitivity Reactions Type IV • Also called delayed-type hypersensitivity reactions • Mediated by antigen-specific effector T cells instead of antibodies • Model example = tuberculin test • Small amounts of tuberculin injected ID • In people previously exposed to the bacterium a local T-cellmediated inflammatory response evolves over 24-72h • Mediated by TH1 cells that release inflammatory mediators at the site when Ag is recognized • Similar reaction happens in response to pentadecacatechol (poison ivy) • Contact hypersensitivity reaction © Dr. E. Cates, Fall2021 45 Hypersensitivity Reactions Type IV 46 © Dr. E. Cates, Fall2021 Images Sourced From: Immunobiology 6th Ed. Janeway Hypersensitivity Reactions © Dr. E. Cates, Fall2021 Image Sourced From: Immunobiology 6th Ed. Janeway 47 Self-Study Check your course-outline each week for case studies associated with each topic! This week: #5 – Heather’s Headaches #20 – Hilda’s Headaches #21 – Hattie’s Hives © Dr. E. Cates, Fall2021 48