PHARMACOKINETICS IN PREGNANCY Pharmacokinetics describes the handling of a drug by the body.

Over the last several decades, the consumption of medicines either shortly before or during pregnancy has been increasing. CHRONIC: Pregnancy occurs among female patients undergoing regular treatment for such disorders as diabetes, circulatory problems, epilepsy, psychiatric disorders, and those who are HIV-positive. (18-19 million in the world) SYMTOMS AND PATHOLOGY: Pregnancy itself, including its pathological course, has become an object of medical intervention. OTC USE: Increased drug consumption among them, often without medical consultation and solely due to the pressure of aggressive advertisements in the media. Pregnancy is a special physiological condition where drug treatment presents a special concern because the physiology of pregnancy affects the pharmacokinetics of medications used and certain medications can reach the fetus and cause harm. The unique nature of physiology of pregnancy presents challenges for pharmaceutical treatment of chronic and acute disorders and for symptom management of many complaints associated with pregnancy. ABSORPTION Oral Slowed gastric emptying/Decreased motility due to progesterone results in: Slower onset Decreased absorption resulting in decreased plasma concentration of drug Increased gastric pH (alkaline) due to decrease in H+ results in: Increased ionization of weak acids resulting in decreased absorption. (example NH4OH = NH4+/OH-) Nausea and vomiting as an effect the hormone HCG results in decreased absorption. Give during the evening for once a day medications. Inhalational due to increase in cardiac output there is increased lung perfusion resulting in more rapid absorption of drugs. (example: volatile anesthesia) Intrathecal Intramuscular Due to increase in tissue perfusion secondary to vasodilation resulting in increased absorption DISTRIBUTION

Hydrophilic: Increase in total body water by up to 8 liters results in the increase Plasma Volume There is increased space for hydrophilic drugs for distribution but decreased plasma concentration. Lipophilic: Increase in body fat by 4 kg results in increase Protein bound drug: Increase in total body water results in hemodilution results in decreased plasma concentration. Decrease in plasma albumin concentration results and with the steroid and hormones compete with protein binding site results in increased FREE or UNBOUND drugs thereby increasing the drug effect. BUT free or unbound drugs are rapidly metabolized and excreted.

METABOLISM: Increased progesterone levels resulted to increase liver enzyme activity resulting to increased drug metabolism and degradation. Hepatic cytochrome P450 induced by estro/proges increase metabolism thereby increasing elimination (phenytoin). Other enzymes are inhibited by estro and proge thereby decreasing elimination (theophylline).

ELIMINATION: Renal blood flow is increased by 60 to 80 percent and the GFR increased by 50 percent thereby increasing elimination. SUMMARY: Most drugs : Decreased absorption + Increased elimination = Decreased Plasma Concentration. There are relatively few specific data on pharmacokinetics in pregnancy compared to non-gravid states, because of the obvious ethical issue surrounding studies during pregnancy. Data is limited due to small sample size and the incorporation of results from subjects of different gestational ages.

There is limited evidence to formulate clear cut guidelines with respect of dosing of individual drugs.

PLACENTAL TRANSPORT Placenta: The major function of the placenta is to transfer nutrients and oxygen from the mother to the fetus and to assist in the removal of waste products from the fetus to the mother. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false.

Factors affecting the rate of transport: Thickness of the surface area of the placental membrane (known to decrease in later gestational age) Placental blood flow pH of blood

1. PASSIVE: Simple Diffusion-process by which most drugs crosses the placenta. Movement of substance from hi area to low area. Lipid solubility:molecules that are hydrophilic, such as mannitol , most cephalosporins and streptomycins, have difficulty diffusing through the placenta. most drugs are lipophilic and only slightly acidic or basic (ionized). Mol. Weight: >500 dalton-incomplete >100 dalton-extremely difficult to pass 2. Passage through the membrane pores only molecules that measures 10 angioms or 1 nanometer or those with molecular weight of less than 100 can pass through this method. 3. Active Transport: USE OF ATP Pinocytosis-for passage of very small macromolecules. Scale of transfer f drug too small. Transporters: has ATP BINDING CASSETE (ABC) Drugs are only carried this way if theyhave certain specificity of structure. Usually is thru the use of Placental Transporters.

Mode of transport:

PLACENTAL TRANSPORTERS Placental anatomy

Transporters: They use the energy produced as a result of ATP hydrolysis for the transportation of many substrate in defiance of the concentration gradient. Placenta expresses several transporters that are relevant to drug distribution across the maternal-fetal interface. Most of these transporters perform vital physiological functions in facilitating the transfer of nutrients and other normal metabolites across the placenta. The specificity of these transporters is, however, not restricted to their physiological substrates (A substrate is a solid substance or medium to which another substance is applied and to which that second substance adheres). Many of them also recognize xenobiotics (foreign substance) as substrates due to structural resemblance to the physiological substrates. As a consequence, these transporters also mediate the transfer of xenobiotics across the placenta. In the course of pregnancy, the expression of the active transporters in the particular cells and structures of the placenta evolves. Some of them dominate in the first trimester of gestation, others gradually increase their activity as the organ matures, yet others are characterized by a stable action throughout the whole gestational period. INFLUX OR EFFLUX except for Pglycoprotein which is efflux only. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. The fetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the fetus with these drugs in utero. 1. Monoamine Transporters LOCATION brush-border membrane SUBSTRATE serotonin XENOBIOTIC amphetamine

serotonin transporter (SERT), norepinephrine transporter (NET), extraneuronal monoamine transporter (OCT3).

dopamine and amphetamine norepinephrine Likely located at monoamines neurotoxin 1placental basal serotonin, methyl-4membrane dopamine, phenylpyridinium, norepinephrine, and K+-channel blocker histamine. tetraethylammonium

Note: Also transports cimetidine and clonidine

Tricyclic and nontricyclic antidepressants interact with SERT/NET, these compounds bind to the transporters with high affinity and are not translocated across the membrane. 2. Carnitine Transporter location substrate the placental carnitine brush-border membrane xenobiotic tetraethylammonium, quinidine, verapamil, pyrilamine, and the -lactam antibiotic cephaloridine b-lactam antibiotics

3. Ttransporter for monocarboxylates (e.g., lactate and pyruvate) and dicarboxylates (e.g., succinate and -ketoglutarate location brush-border membrane brush-border membrane substrate xenobiotic

monocarboxylate transporter dicarboxylate transporter

4. Sodium/Multivitamin Transporter location placental brushborder membrane vesicles substrate xenobiotic biotin, pantothenate, and lipoate

5. Equilibrative Nucleoside Transporters location substrate placental brush- purine and border membrane pyrimidine nucleosides such as adenosine and uridine not known purine and pyrimidine nucleosides such as adenosine and uridine xenobiotic Antineoplastic drugs cladribine, cytarabine, gemcitrabine, and fludarabine Antineoplastic drugs cladribine, cytarabine, gemcitrabine, and fludarabine

ENT1

ENT2

NOTE: Coronary vasodilators dilazep and dipyridamole, which bind to these transporters and block their transport function.

6. Folate Receptor and Folate Transporter location brush-border membrane substrate Influx of folate xenobiotic interact with variety antifolates such methotrexate interact with variety antifolates such methotrexate

Folate Receptor

a of as a of as

folate transporter basalolateral (FOLT1) membrane

Efflux of folate

7. P-glycoprotein efflux of lipophilic xenobiotics not the influx thus protecting the cell from the potential toxic effects of xenobiotics location brush-border membrane the intestinal tract, kidney, liver, and blood-brain barrier substrate xenobiotic anticancer drugs (e.g., vincristine, vinblastine, anthracyclines, etoposide, taxol, and mithramycin), cytotoxic agents (e.g., colchicine and emetine), HIV protease inhibitors (e.g., sequinavir, indinavir, and ritonavir) , and abusable drugs (e.g., morphine)

8. Organic Cation/Proton Antiporters to facilitate the efflux of cationic drugs location substrate placental brush- cimetidine, border membrane clonidine, amiloride, imipramine, benzamil. xenobiotic

and

9. Organic Anion Transporter location Basal membrane Basal membrane Syncytiotrophoblast cell substrate xenobiotic Efflux Efflux

OAT 1 OAT 3 OAT 4

Efflux conjugated steroid

10. Organic Cation Transporter OCTN1 location substrate Microvilli of Bile salts syncytiotrophoblast xenobiotic Efflux of antiviral drugs

11. Prostaglandin Transporter location not known substrate xenobiotic Prostaglandins and furosemide thromboxanes

12. Amino Acid Transporters location substrate differential amino acids localization in the brush-border membrane and the basal membrane of the syncytiotrophoblast 13. Carboxylate transporters location substrate Basilar membrane Efflux of lactate and apical surface of syncytiotrophoblast xenobiotic ASA xenobiotic gabapentin (an antiepileptic drug), arginine analogs (inhibitors of nitric oxide synthases), and thyroid hormone

PLACENTAL AND FETAL DRUG METABOLISM

PLACENTA the placenta expresses a wider variety of enzymes during the first trimester than at term Although placental metabolism is more restricted than liver metabolism, placental enzymes are capable of metabolizing several drugs and foreign chemicals Metabolites are the products of enzyme-catalyzed reactions that occur naturally within cells. Sometimes metabolism produces a pharmacologically active metabolite, as with the angiotensin receptor antagonist losartan and the antihistamine ebastine, which are converted from inactive prodrugs to the active drugs E3174 and carebastine, respectively In other cases, a drug metabolite can have an adverseeffect. A clinically significant example is that of acetaminophen, a commonly used analgesic and antipyretic. In its therapeutic dose range, acetaminophen is metabolized predominantly predominantly by glucuronidation and sulfation, and these conjugated products account for approximately 95% of the total excreted metabolites. P450 enzymes oxidize a small percentage of acetaminophen to a reactive intermediate, Nacetyl-benzoquinoneimine, which is immediately conjugated to glutathione. However, when the level of acetaminophen exceeds the therapeutic range, the glucuronidation and sulfation pathways become saturated and the stores of glutathione in the liver become depleted. This results in excessive accumulation of N-acetylbenzoquinoneimine, an electrophile that reacts with nucleophilic groups on proteins to produce covalent protein derivatives.

FETUS Immature phase I and phase II metabolism can occur in the fetus 8 weeks postconception. However, metabolic enzyme activity is low, and this coupled with the fact that 50% of the fetal circulation from the umbilical vein bypasses the fetal liver to the cardiac and cerebral circulations contributes to the problem of fetal drug accumulation. Elimination from the fetus is by diffusion back to the maternal compartment. Because most drug metabolites are polar, this favours accumulation of metabolites within the fetus, although as the fetal kidney develops more drug metabolites are excreted into the amniotic fluid. Another process leading to accumulation of drugs within the fetus is the phenomenon of `ion trapping'. The basis for this is the (slightly) more acidic nature of fetal plasma pH compared to maternal plasma. Weak bases, which are mainly non-ionized (lipophilic), diffuse across the placental barrier and become ionized in the more acidic fetal blood, leading to a net movement from the maternal to fetal systems. The fetal liver and the kidneys are capable of metabolizing many substrates by oxidation. However, due their immaturity, there is a very limited metabolizing capacity.

drugs such as aminoglycosides, digoxin, chloropromide, penicillin, salicylic acid, indomethacin, paracetamol and several sulfonamides are cleared very slowly by the neonate. Repeated administration of these drugs can cause neonatal toxicity.

Practically all lipid-soluble xenobiotics enter the conceptus through placental transfer. Many xenobiotics, including a number of clinically used drugs, are known to cause unwanted effects in the embryo or fetus, including in utero death, initiation of birth defects, and production of functional abnormalities. It is well established that numerous xenobiotics are not necessarily toxic as such, but are enzymatically transformed in the body to reactive and toxic intermediates. The cytochrome P450 (CYP) enzymes are known to catalyze oxidative metabolism of a vast number of compounds, including many proteratogens, procarcinogens, and promutagens. About 20 xenobioticmetabolizing CYP forms are known to exist in humans. Most of these forms are most abundant in the liver, but examples of exclusively extrahepatic CYP forms also exist. Unlike rodents, the liver of the human fetus and even embryo possesses relatively welldeveloped metabolism of xenobiotics. There is experimental evidence for the presence of CYP1A1, CYP1B1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7 in the fetal liver after the embryonic phase (after 8 to 9 weeks of gestation). Significant xenobiotic metabolism occurs also during organogenesis (before 8 weeks of gestation). Also, some fetal extrahepatic tissues, most notably the adrenal, contain substantial levels of CYP enzymes. The full-term human placenta is devoid of many CYP activities present in liver. Placental CYP1A1 is highly inducible by maternal cigarette smoking. Other forms present in full-term placenta include CYP4B1 and CYP19 (steroid aromatase), which also contribute to the oxidation of some xenobiotics. At earlier stages of pregnancy, the placenta may express a wider array of CYP genes, including CYP2C, CYP2D6, and CYP3A7. Due to the small size of the fetus and low abundance of CYPs in placenta, the contribution of feto-placental metabolism to overall gestational pharmacokinetics of drugs is probably minor. In contrast, several toxic outcomes have been ascribed to altered metabolic patterns in the feto-placental unit, including a putative association between reduced placental oxidative capacity and birth defects. Examples of human teratogens that are substrates for CYP enzymes include thalidomide, phenytoin, ethanol, and several hormonal agents. Recent studies have improved our understanding of the expression and regulation of individual CYP genes in the fetus and placenta, and the stage is set for applying this knowledge with more precision to the role of xenobiotic metabolism in abnormal intrauterine development in humans