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Pharmacodynamics in pregnancy and placenta.pptx

  1. Pharmacokinetics and dynamics in pregnancy – Placental barrier Dr. Inunil Piyadigama Consultat Obstetrician and Gynaecologist Acting director BH Kahawatta
  2. Introduction • Maternal physiology have evolved to favour the development and growth of the placenta and the fetus • Variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect • Detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy • Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk
  3. Problems • Most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk • Over two-thirds of women receive prescription drugs while pregnant • Treatment and dosing strategies based on data from healthy male volunteers with little adjustment for the complex physiology of pregnancy and its unique disease states
  4. Concepts of pharmacology • Fundamental concept in pharmacology • A drug must reach the target tissues at sufficient concentration to exert its therapeutic effects • This should not cause significant adverse events • Pharmacokinetics (PK) describes the time course of drug concentration in the body • This involves the evaluation of drug absorption, distribution, metabolism, elimination, and transport
  5. Drug absorption • The movement of drug from the site of administration into the systemic circulation
  6. Bioavailability • Bioavailability, the fraction or percentage of active drug medication that reaches the systemic circulation intact by any route • IV drugs are 100% bioavailable • Intramuscular and subcutaneous administration may lead to a delay in time to reach maximal concentration but has less effect on bioavailability • Increased local blood flow and vasodilation are thought to facilitate drug absorption following intramuscular or subcutaneous drug delivery
  7. Oral route • The greatest variability in drug absorption is seen when a medication is administered orally • For orally administered medications, the bioavailability is affected by • The amount absorbed across the intestinal epithelium • First-pass metabolism as the drug crosses the intestine and the liver on its way to the systemic circulation • Stomach pH, food, gut transit time, gut metabolism, uptake, and efflux transport processes may impact oral drug bioavailability
  8. Pregnancy changes affecting drug absorption • Nausea and vomiting in early pregnancy • Gastric acid production is decreased • Mucus secretion is increased • Overall leads to increase in gastric pH • Reduce intestinal transit time • Increased cardiac output and intestinal blood flow may allow for increased drug absorption overall
  9. Pregnancy effects on drug absorption
  10. Drug distribution • Reversible transfer of a drug between different locations following its entry into the systemic circulation • Drug distribution is influenced by various factors including • Tissue perfusion • Tissue binding • Lipid solubility • Plasma protein binding
  11. Volume of distribution (Vd) • Indicates how extensively a systemic dose of medication is ultimately dispersed throughout the body • A theoretical volume that an administered drug would occupy if it was uniformly distributed at a concentration observed in plasma • Vd is important to determine the loading dose of a drug needed to achieve a certain therapeutic concentration • Variations in Vd mainly affect the plasma concentration of the drug • This can directly impact a drug’s therapeutic and adverse effects
  12. • Drugs that are highly bound to plasma proteins and/or have a large molecular weight will tend to concentrate intravascularly and will have a small Vd • Drugs that predominantly remain within the vascular system will have a Vd estimate close to plasma volume • Drugs that are not bound to any proteins in the body will have a Vd estimate close to total body water • Drugs that are highly bound to tissues, with a small proportion remaining in the intravascular space, will have a very high Vd
  13. Pregnancy and Vd • Increase in cardiac output starting in early pregnancy, plateauing by 16 weeks of gestation 7 L/min and remaining elevated until delivery • Stroke volume starting at 20 weeks of gestation and a gradual increase occurs with maternal heart rate reaching 90 beats per min at rest in the third trimester • 42% increase in plasma volume, reaching over 3.5 L at 38 weeks of gestation • increases in total body water and in all body fluid compartments • Expanded extracellular volume and total body water will increase volume of distribution for hydrophilic drugs, leading to lower plasma concentrations
  14. • Maternal body fat expands by approximately 4 kg, increasing the volume of distribution for lipophilic drugs • Plasma protein binding of drugs decreases during pregnancy due to reduced concentrations of both albumin and alpha 1-acid glycoprotein • Albumin concentrations decrease on average by 1% at 8 weeks, 10% at 20 weeks, and 13% at 32 weeks • Decreased protein binding leads to higher concentrations of free drug • This favours more distribution to tissues • Ex - Phenytoin and Tacrolimus, efficacy and toxicity are expected to be related to unbound drug concentration in plasma
  15. • Blood flow to the uterus increases 10-fold from 50 to 500 mL/min at term • Small-molecular-weight and lipophilic drugs readily cross the placenta • Fetus and the amniotic fluid can act as additional compartments, leading to increased drug accumulation and an apparent increase in volume of distribution of certain drugs
  16. Drug metabolism • Chemical modification of a drug through specialized enzymatic systems • Inactive pro-drugs, metabolism is necessary to convert the drug into an active compound • For most drugs, metabolism leads to loss of drug activity • Liver accounts for the metabolism of a vast majority of drugs • Intestine and the placenta can also contribute to the clearance of certain drugs
  17. Clearance • Clearance is the volume of blood/plasma that is completely cleared off the drug in a unit of time • Determines drug exposure as measured by the area under the plasma concentration vs time curve and a body’s overall ability to eliminate a drug
  18. • The clearance of a drug in the liver is determined by hepatic blood flow and the extraction ratio of the drug in the liver • The extraction ratio (ER) refers to the proportion of a drug taken up from the hepatic arterial circulation into hepatocytes, making it available for subsequent metabolism. • For high ER drugs (e.g., morphine and propranolol), overall hepatic elimination is limited only by hepatic perfusion (blood flow). • In contrast, hepatic clearance of low ER drugs (e.g., diazepam, fluoxetine, or caffeine) is limited by intrinsic metabolic capacity of hepatic cells and the unbound fraction of the drug in plasma, and it would be changed little by changes in hepatic perfusion
  19. Hepatic drug metabolism • Phase I (oxidation, reduction, or hydrolysis) reactions that introduce more polar or reactive moieties into drug molecules • Carried out by the cytochrome P450 (CYP) family of enzymes • CYP3A4 (50–100%), CYP2A6 (54%), CYP2D6 (50%), and CYP2C9 (20%) are all increased during pregnancy • Leads to lower levels of Nifedipine, Indinavir, Glyburide • CYP1A2 and CYP2C19 appear to undergo a gradual decrease in activity with advancing gestation • Phase II (conjugation) reactions to glucuronic acid, sulfate, or other moieties that favour excretion into urine or bile • Uridine 5’-diphosphate glucuronosyltransferases (UGTs), is also altered during pregnancy, with a 200% increase in UGT1A4 activity during the first and second trimesters and a 300% increase during the third trimester • Lamotrigine levels are significantly reduced
  20. Variations in metabolism • Metabolic enzyme activity is highly variable, affected by • Ethnicity • Gender • Age • enzyme polymorphisms • Certain enzymes are involved in the metabolism of numerous drugs and create a potential for co-administered medications to impact drug clearance • PK of nifedipine, used for tocolysis, noted differences in drug clearance due to genetic variability in a specific allele of the CYP3A5 coding gene • 17-hydroxyprogesterone caproate (17-OHPC) (a drug used to prevent preterm delivery) modestly increased the activity of CYP2C19. • It follows that dosage of CYP2C19 substrates, for example, tricyclic antidepressants, proton pump inhibitors, and propranolol, may have to be increased
  21. Summary of metabolism For drugs with a narrow therapeutic window, an increased clearance during pregnancy can lead to sub- therapeutic concentrations and worsening disease control Conversely, to avoid increased toxicity, drug doses may need to be adjusted in the postpartum period, when pregnancy-related metabolic enzyme activity changes resolve
  22. Drug elimination • Renal drug excretion depends on GFR, tubular secretion, and reabsorption • GFR is 50% higher by the first trimester and continues to increase until the last week of pregnancy • If a drug is solely excreted by glomerular filtration, its renal clearance is expected to parallel changes in GFR during pregnancy. • For example, cefazolin and clindamycin exhibit increased renal elimination during pregnancy • Differences in renal tubular transport (secretion or reabsorption) can result in differing effects on renally cleared drugs • clearance of lithium is doubled during the third trimester compared to preconception • digoxin, which is 80% renally-cleared, is merely 20–30% higher during the third trimester compared to postpartum • clearance of atenolol is only 12% higher across pregnancy
  23. Drug transport • Transporters in hepatic sinusoids determine drug uptake into hepatocytes where they may undergo biotransformation • Transporters in biliary canaliculi govern secretion into bile • Transporters on both the apical and the basolateral surfaces of renal epithelial cells govern tubular secretion and reabsorption • Drug transporter distribution, substrate specificity, and activities are important determinants governing • Drug absorption • Drug excretion • The extent of drug entry into target organs
  24. Placenta • Fetal development is dependent upon the transport of nutrients by the placenta toward the fetal side and that of products of fetal metabolism for elimination by the mother • Placenta produces and secretes hormones that affect the maternal physiology and endocrine state • Transfers immunoglobulins providing immunity to the fetus
  25. • late 1950s and early 1960s, the devastating series of thalidomide-induced birth defects raised awareness of the imperfect state of the placenta as a barrier to drug transfer • There has also been increasing interest in the deliberate use of maternally administered drugs designed to cross the placenta and provide therapeutic effects on the fetus.
  26. Placental structure At term, the placenta weighs almost 500 g Has a diameter of 15–20 cm A thickness of 2–3 cm A surface area of almost 15 m2 The basic structural unit of the placenta is the chorionic villus
  27. Chorionic villus • Transport role is mediated by the syncytiotrophoblasts, the functional cell of the placenta • These cells have a polarized plasma membrane consisting of a brush border at the maternal side and a border membrane on the fetal side • At term, only a single layer of syncytiotropho- blast separates maternal blood and fetal capillary endothelium • Most xenobiotics cross the placental barrier by simple diffusion
  28. Placental blood flow • The pressure is about 80 – 100 mm Hg in the uterine arteries, 70 mm Hg in the spiral arteries and only 10 mm Hg within the intervillous space • The umbilical arteries divide into chorionic arteries and end as capillaries within the villi • Substances in the maternal blood pass from the intervillous space through the syncytiotrophoblast, fetal connective tissue, and the endothelium of the fetal capillaries into the fetal blood • Maternal uterine blood flow at term is 600 ml min21, 80% of which passes to the placenta • There is no autoregulation in the uteroplacental circulation • Flow is directly related to the mean uterine perfusion pressure and inversely related to uterine vascular resistance
  29. Placental drug transfer • Almost all drugs will eventually cross the placenta to reach the fetus • The effects of drugs on the fetus may be either direct or may be mediated via the alteration of uteroplacental blood flow. • Three types of transfers occur
  30. Placental drug transfer types I. Complete transfer (type1drugs): for example, thiopental Drugs Rapidly cross the placenta with pharmacologically significant concentrations equilibrating in maternal and fetal blood II. Exceeding transfer (type 2 drugs): for example, ketamine These drugs cross the placenta to reach greater concentrations in fetal compared with maternal blood. III. Incomplete transfer (type 3 drugs): for example, succinylcholine These drugs are unable to cross the placenta completely, resulting in higher concentrations in maternal compared with fetal blood.
  31. Factors determining placental transfer • Physical Placental surface area Placental thickness pH of maternal and fetal blood Placental metabolism Uteroplacental blood flow Presence of placental drug transporters • Pharmacological Molecular weight of drug Lipid solubility pKa Protein binding Concentration gradient across placenta
  32. Mechanisms of drug transfer across the placenta • A – Simple diffusion • B – Facilitated diffusion using a carrier • C – Active transport using ATP • D - Pinocytocis
  33. Simple diffusion – Midazolam, paracetamol • Transfer is either transcellularly through the syncytiotrophoblast layer or paracellularly through water channels incorporated into the membrane • Dependent on a concentration gradient • In the normal placenta, the villous surface area and blood flow to the placenta increase with gestation • The placental membranes also thin out and the cytotrophoblast layer almost completely disappears • Dependent on the diffusion constant of the drug
  34. Determinants of diffusion constant • Molecular weight • Most of the drugs used are < 500 Da • Lipid solubility • Degree of ionization • Neuromuscular blocking agents are highly ionized and do not cross • pH of maternal blood reduces in labour • Protein binding • Free fraction is able to transfer
  35. Facilitated diffusion - cephalosporins and glucocorticoids • Drugs structurally related to endogenous compounds are often trans- ported by facilitated diffusion • Energy input is not required since drug transfer occurs down a con- centration gradient • Facilitated diffusion will be inhibited if the carrier molecules become saturated by both drug and endogenous substrates
  36. Active transport - norepinephrine and dopamine • Active transport utilizes energy • Transport substances against a concentration or electrochemical gradient • Transport is carrier-mediated and saturable and there is competition between related molecules
  37. Placental drug transporters • A number of placental drug transporters have been identified • The family of multi-drug resistance protein (MRPs) • Phosphoglycoprotein (P-gp) • Breast cancer resistance protein (BCRP) • These are the most studied so far • P-gp is expressed on the apical microvillous surface • BCRP is mostly identified on the basolateral membrane and fetal blood vessels • P-gp include endogenous compounds such as cortisol, aldosterone, and bilirubin as well as various drugs such as antibiotics, antiretrovirals, and steroids • Substrates of BCRP include antibiotics, antiretrovirals, calcium channel blockers, estrogen, and porphyrins
  38. Factors affecting placental transporters • Both oestrogen and progesterone appear to increase expression of P-gp and BCRP in trophoblast cell lines • Hypoxia reduces expression • Prolonged exposure to dexamethasone reduces expression • Inflammatory cytokines • SSRI - Maternal SSRI use in the first and the third trimesters has been linked to congenital anomalies and neonatal complications, respectively • P-gp and BCRP expression was lower in placentas from women with preeclampsia compared to term placentas from uncomplicated pregnancies
  39. Thank you
  40. Which drugs can easily pass the placental barrier a) Drugs having molecular weight less than 1000 Dalton b) Moderate to high lipid solubility c) Drugs having a molecular weight less than 1000 Dalton and moderate to high lipid solubility, analgesics and antibiotics d) Analgesics, antibiotics etc
  41. All of the following drugs cross the placenta except a) Phenytoin b) Diazepam c) Morphine d) Heparin
  42. Which of the normal physilogical changes in pregnancy is associated with slower drug metabolism? a) Delayed gastric emptying b) Increased body fat volume c) Increased cardiac output d) Increased GFR e) Increased third space volume
  43. A 27 year old woman is treated for severe bronchiolitis at 38 weeks. Her baby born at 41 weeks of gestation has neonatal haemolysis Which drug taken by the mother for bronchitis is the cause of the baby’s neonatal haemolysis? a) Chloramphenicol b) Co-trimoxazole c) Doxycycline d) Erythromycin e) Streptomycin