Endocrinology

Effects of pregnancy and lactation

The placenta can synthesize and secrete proteins but cannot syn­thesize steroids. Several maternal serum hormone changes occur during pregnancy (Figure 1.33).

Placental proteins: human chorionic gonadotropin (hCG) peaks at 10 weeks. Human placental lactogen (hPL) rises with placental weight. It induces insulin resistance. Oestrogens (oestradiol, oestriol, and oestrone) are synthesized in the placenta from DHEA produced by the fetus and increase to term. Androgens are derived from the fetoplacental unit and testosterone levels rise tenfold. Progesterone is mainly synthesized by the corpus luteum in the first 2-3 months of pregnancy. Levels rise up to term.

Pituitary hormones: LH and FSH decline while prolactin rises to term. Thyroid hormones (total T4 and T3) rise during the first trimester and then plateau. Cortisol increases to three times prepregnancy values and aldosterone plateaus at 34 weeks.

Several hormones during pregnancy stimulate breast growth (oestrogen, progesterone, hPL, prolactin, cortisol, and insulin). High concentrations of oestrogens inhibit lactation. After de­livery, when the oestrogen levels fall, lactation is initiated by pro­lactin. Prolactin promotes milk formation and is released from the anterior pituitary. Prolactin is also released in response to suckling.

Box 1.2 Pituitary hormones

• Luteinizing hormone

• Follicle-stimulating hormone

• Proopiomelanocortin (POMC)

• Adrenocorticotropin

• Beta-endorphin

• Melanocyte-stimulating hormone (MSH)

• Thyrotropin

• Prolactin

• Growth hormone

Pharmacokinetics

Pharmacokinetics refers to how a drug moves through an individual's body (22). A drug's pharmacokinetics includes absorption, distribu­tion, metabolism, and elimination, which affect the drug's concen­tration at the site of action and its effect.

Clearance is the volume of blood from which a drug is completely eliminated in a period of time. It depends on liver metabolism or renal blood flow. Volume of distribution is the volume of fluid into which a drug distributes. It depends on protein binding and liquid solubility. Half-life is the time taken for the concentration of drug in blood to fall by half.

Pharmacodynamics

Pharmacodynamics refers to an individual's therapeutic response to a drug and is determined by the drug's affinity and activity at its site of action.

Drugs mainly act on four different targets:

1. Receptors

2. Enzymes

3. Membrane ionic channels

4. Metabolic processes such as DNA synthesis.

Drug metabolism

Most drugs are metabolized in the liver. Water-soluble drugs are ex­creted by the kidneys. Lipid-soluble ones pass across the cell mem­brane of the hepatocytes and then access microsomal P450 enzymes.

Drug metabolism in the liver involves simple oxidation, which creates hydroxyl groups and conjugation of these with various sul­phate, acetyl, methyl, and glycyl groups. These processes increase solubility and facilitate renal excretion.

The mechanisms involved in renal excretion are filtration at the glomerulus, transport through the epithelium of the kidney tubules, and diffusion. Renal clearance is important as it affects the plasma concentration of the drug.

Drug interactions

Drugs can interact with each other. Enzyme inducers and enzyme inhibitors are common examples of such interactions.

Enzyme inducers: carbamazepine, phenobarbitone, phenytoin, griseofulvin, and rifampicin belong to this category. These drugs increase the activity of enzyme systems. Drugs metabolized by the same enzymes are metabolized and eliminated more rapidly. As a result, their plasma concentrations will fall with possible clinical implications. Efficacy of oral contraceptives is reduced by enzyme inducers.

Enzyme inhibition: drugs such as erythromycin, metronida­zole, sulphonamides, and cimetidine have the potential to increase

Figure 1.31 The cellular processes involved in the synthesis and subsequent release of the thyroid hormones.

Reproduced from Neil Herring and Robert Wilkins, Endocrinology, in: Basic Science for Core Medical Training and the MRCP, Oxford University Press (2015) with permission from Oxford University Press.

the efficacy of other drugs by enzyme inhibition. For example, sulphonamides can lead to phenytoin toxicity.

Effect of pregnancy and breastfeeding on drug metabolism

Drugs can affect the developing fetus by direct action on the fetus causing birth defects, by affecting the placenta and limiting the supply of nutrients and oxygen to the fetus, and by causing prema­ture labour (Table 1.3) (23). Drugs that do not cross the placenta are heparin, insulin, and curare.

Fluid retention and decreased protein concentrations tend to in­crease the volume of distribution, which in turn causes a decrease in the plasma concentration of the drug. In pregnancy, renal blood flow increases and liver metabolic pathways get induced. Anticonvulsants such as phenytoin and carbamazepine undergo increased drug clearance. Plasma levels fall significantly. Lithium and ampicillin are both eliminated by the kidney and their clearance increases by 100% during pregnancy, requiring increased doses.

Commonly used drugs, which can be safely administered to a breastfeeding mother, are non-narcotic analgesics, penicillins, ceph­alosporins, methyl-dopa, beta-blockers, phenytoin, carbamazepine, and sodium valproate.

Drugs which should be avoided during breastfeeding include:

• laxatives: can cause diarrhoea in neonates

• amiodarone: may affect the neonatal thyroid

• barbiturates: can cause drowsiness

• benzodiazepines can cause drowsiness and failure to thrive

• lithium: can cause hypotonia and cyanosis

• carbimazole and methimazole: can suppress the neonatal thyroid.

Teratogens and organogenesis

Drugs that are commonly implicated in fetal malformations include:

• cytotoxic anticancer drugs

• antiepileptic drugs

• some antirheumatic drugs

• antibiotics

• oral hypoglycaemic agents

• some antihypertensives

• tranquilizers.

Retinoic acids are vitamin A analogues, which are used in the treatment of acne. These drugs can cause major malformations in­cluding craniofacial, cardiac, thymic, and central nervous system defects.

Cytotoxic anticancer drugs: these inhibit rapid cell growth and are detrimental to fetal growth. Methotrexate and antifolate drugs may cause cleft palate and other abnormalities. Thalidomide should also be avoided in pregnancy.

Phenytoin causes a variety of abnormalities including cleft lip/ palate, microcephaly, hypertelorism, and fingernail hyperplasia as well as growth deficiency. Sodium valproate is associated with neural tube defects. Carbamazepine causes similar defects as pheny­toin. The incidence of fetal abnormality is around 10% with the anticonvulsants.

Aspirin is not the analgesic of choice but may still be used in pregnancy (24, 25). However, doses higher than 500 mg/day are contraindicated after 24 weeks of gestation. Aspirin administration during the last weeks of pregnancy may be associated with post­partum haemorrhage and intracranial bleeding of the newborn. Cyclooxygenase-2 inhibitors should be avoided during pregnancy.

Figure 1.32 Steroidogenesis.

Reproduced from Neil Herring and Robert Wilkins, Endocrinology, in: Basic Science for Core Medical Training and the MRCP, Oxford University Press (2015) with permission from Oxford University Press.

The use of non-steroidal anti-inflammatory drugs is contraindicated as it may cause closure of the ductus arteriosus in utero, prolonged pregnancy, and postpartum haemorrhage.

Lithium can cause cardiac abnormalities when given in the first trimester, such as Ebstein's anomaly. The antiviral agent ribavirin is contraindicated in pregnancy and ciprofloxacin is not recom­mended. The antibiotics streptomycin, kanamycin, and gentamicin may cause deafness in the fetus. Tetracyclines may damage tooth growth in children under the age of 8. They may also lodge in the bone and should be avoided in pregnancy. Statins are not recom­mended in pregnancy. Angiotensin-converting enzyme inhibitors can damage the fetal kidney and cause oligohydramnios and neo­natal anuria. Warfarin is a coumarin anticoagulant. Fetal warfarin syndrome has been associated with warfarin exposure in pregnancy, with the highest risk between 6 and 12 weeks of gestation. Warfarin is associated with chondrodysplasia punctata, central nervous system defects, intracerebral haemorrhage, intellectual disability, and eye anomalies (optic atrophy).

In summary, the following rules should be considered when pre­scribing in pregnancy or lactation (26, 27):

• Prescribe only when absolutely necessary.

• Do not prescribe lower or higher doses than necessary.

• Avoid medications known to be contraindicated or newly released medications.

• Choose drugs that do not cross the placenta.

Figure 1.33 Hormonal changes during the three trimesters of pregnancy. DHEA, dehydroepiandrosterone; hCG, human chorionic gonadotrophin; hPL, human placental lactogen.

Reproduced from Austin Ugwumadu, Endocrinology, in: Basic Sciences for Obstetrics and Gynaecology, Oxford University Press (2014) with permission from Oxford University Press.

Source data from Rubin P. Prescribing in pregnancy. In: Warrell DA, Cox TM, Firth JD (eds) Oxford Textbook of Medicine. Oxford: Oxford University Press; 2010.

Ultrasound is an ideal means for imaging soft tissues and fluid collections commonly encountered in obstetric and gynaecological clinical practice.

The interaction between ultrasound waves and tissues can be de­scribed in terms of reflection, scattering, refraction, and attenuation. The last three factors decrease the magnitude of the ultrasound wave.

Reflection occurs when a wave front reaches a tissue boundary/ interface with another medium, causing the wave front to return into the medium from which it originated (the transducer). The magnitude of the reflected wave is dependent on the acoustic im­pedance of the tissue:

Acoustic impedance = tissue density ? propagation velocity

Tissues with increased density reflect a greater proportion of the ultrasound beam. The magnitude of the reflected beam received by the transducer is also dependent upon the angle between the ultra­sound beam and tissue interface.

Refraction occurs when a wave front travelling through a medium reaches an interface with another medium of different acoustic im­pedance and then passes through it (Figure 1.34).

Diffraction occurs when a wave encounters an obstacle that has a diameter comparable to its wavelength. There is bending of waves around small obstacles and spreading out of the waves as they pass through small openings (Figure 1.35).

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