Physiological Background for Pregnant

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Obstetric and Perinatal Pharmacology

I. Physiological Background for Pregnant

Introduction

Physiological and anatomical alterations develop in many organ systemsduring the course of pregnancy and delivery. Early changes are due, in part, tothe metabolic demands brought on by the fetus, placenta and uterus and, inpart, to the increasing levels of pregnancy hormones, particularly those ofprogesterone and estrogen. Later changes, starting in mid-pregnancy, areanatomical in nature and are caused by mechanical pressure from theexpanding uterus. These alterations create unique requirements for thepharmaceutical management of the pregnant woman.

Cardiovascular System

The pregnancy-induced changes in the cardiovascular system developprimarily to meet the increased metabolic demands of the mother and fetus.

Blood Volume

Blood Volume increases progressively from 6-8 weeks gestation(pregnancy) and reaches a maximum at approximately 32-34 weeks with littlechange thereafter. Most of the added volume of blood is accounted for by anincreased capacity of the uterine, breast, renal, striated muscle and cutaneousvascular systems, with no evidence of circulatory overload in the healthy

pregnant woman. The increase in plasma volume (40-50%) is relativelygreater than that of red cell mass (20-30%) resulting in hemodilution and adecrease in hemoglobin concentration. Intake of supplemental iron and folicacid is necessary to restore hemoglobin levels to normal (12 g/dl).

The increased blood volume serves two purposes. First, it facilitatesmaternal and fetal exchanges of respiratory gases, nutrients and metabolites.Second, it reduces the impact of maternal blood loss at delivery. Typical lossesof 300-500 ml for vaginal births and 750-1000 ml for Caesarean sections arethus compensated with the so-called "autotransfusion" of blood from thecontracting uterus.

Blood Constituents

Red cell mass is increased 20-30%. Since plasma volume increases early inpregnancy and faster than red blood cell volume, the hematocrit falls until theend of the second trimester, when the increase in the red blood cells issynchronized with the plasma volume increase. The hematocrit then stabilizesor may increase slightly near term. Leukocyte counts are variable duringgestation, but usually remain within the upper limits of normal. Marked


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elevations, however, develop during and after parturition (delivery).Fibrinogen, as well as total body and plasma levels of factors VII, X and XIIincreases markedly. The number of platelets also rises, yet not above theupper limits of normal. Combined with a decrease in fibrinolytic activity, thesechanges tend to prevent excessive bleeding at delivery. The placenta may be

partially responsible for this alteration in fibrinolytic status. Plasminogen levelsincrease concomitantly with fibrinogens levels, causing an equilibration ofclotting and lysing activity. Thus, pregnancy is a relatively hypercoagulablestate, but during pregnancy neither clotting nor bleeding times are abnormal.

Cardiac Output

Cardiac Output increases to a similar degree as the blood volume.During the first trimester cardiac output is 30-40% higher than in the non-pregnant state. Steady rises are shown on Doppler echocardiography, from anaverage of 6.7 liters/minute at 8-11 weeks to about 8.7 liters/minute flow at

36-39 weeks; they are due, primarily, to an increase in stroke volume (35%)and, to a lesser extent, to a more rapid heart rate (15%). There is a steadyreduction in systemic vascular resistance (SVR) which contributes towards thehyperdynamic circulation observed in pregnancy.

During labor, further increases are seen with pain in response toincreased catecholamine secretion; this increase can be blunted with theinstitution of labor analgesia. Also during labor, there is an increase inintravascular volume by 300-500 ml of blood from the contracting uterus tothe venous system. Following delivery this autotransfusion compensates forthe blood losses and tends to further increase cardiac output by 50% of pre-delivery values. At this point, stroke volume is increased while heart rate is

slowed.

Cardiac Size/Position/ECG

There are both size and position changes which can lead to changes inECG appearance. The heart is enlarged by both chamber dilation andhypertrophy. Dilation across the tricuspid valve can initiate mild regurgitantflow causing a normal grade I or II systolic murmur. Upward displacement ofthe diaphragm by the enlarging uterus causes the heart to shift to the left andanteriorly, so that the apex beat is moved outward and upward. The size ofthe heart appears to increase by about 12%. These changes lead to common

ECG findings of left axis deviation, sagging ST segments and frequentlyinversion or flattening of the T-wave in lead III.

Blood Pressure

Systemic arterial pressure is never increased during normal gestation. Infact, by midpregnancy, a slight decrease in diastolic pressure can berecognized. Pulmonary arterial pressure also maintains a constant level.


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in the lateral recumbent position. Central venous pressure increases in directrelationship to the intensity of uterine contraction and increased intra-abdominal pressure. Additionally, cardiopulmonary blood volume increases300-500mLduring contractions. At the time of delivery, hemodynamicalterations vary with the anesthetic used.

Respiratory System

Respiratory Tract

Hormonal changes to the mucosal vasculature of the respiratory tractlead to capillary engorgement and swelling of the lining in the nose,oropharynx, larynx, and trachea. Symptoms of nasal congestion, voice changeand upper respiratory tract infection may prevail throughout gestation. Thesesymptoms can be exacerbated by fluid overload or edema associated withpregnancy-induced hypertension (PIH) or pre-eclampsia. In such cases,manipulation of the airway can result in profuse bleeding from the nose ororopharynx; endotracheal intubation can be difficult; and only a smaller thanusual endotracheal tube may fit through the larynx. Airway resistance isreduced, probably due to the progesterone-mediated relaxation of thebronchial musculature. The high level of progesterone, a hormone producedcontinuously during pregnancy, signals the brain to lower the level of carbondioxide in the blood. As a result, a pregnant woman breathes slightly fasterand more deeply to exhale more carbon dioxide and keep the carbon dioxidelevel low. She may breathe deeper and faster also because the enlarginguterus limits how much the lungs can expand when she breathes in. Thecircumference of the woman's chest enlarges slightly. Virtually every pregnantwoman becomes somewhat more out of breath when she exerts herself,especially toward the end of pregnancy. During exercise, the breathing rateincreases more when a woman is pregnant than when she is not.

Lung Volumes

Alterations occurring in lung volumes and capacities during pregnancyinclude the following: Dead volumes increases owing to relaxation of themusculature of conducting airways. Tidal volumes increases gradually (35-

50%) as pregnancy progresses. Total lung capacity is reduced (4-5%) by theelevation of the diaphragm. Functional residual capacity, residual volume, andrespiratory reserve volume all decrease by about 20%.Larger tidal volume andsmaller residual volume cause increased alveolar ventilation (about 65%)during pregnancy. Inspiratory capacity increases 5-10%.

Functional respiratory changes include a slight increase in respiratoryrate, a 50% increase in minute ventilation, a 40% increase in tidal volume, anda progressive increase in oxygen consumption of up to 15-20% above non-


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pregnant levels by term. With the increase in respiratory tidal volumeassociated with a normal respiratory rate, there is an increase in respiratoryminute volume of approximately 26%. As the respiratory minute volumeincreases, hyperventilation of pregnancy occurs, causing a decrease inalveolar CO2 . This decrease lowers the maternal blood CO2 tension; however

alveolar oxygen tension is maintained within normal limits. Maternalhyperventilation is considered a protective measure that prevents the fetusfrom the exposure to excessive levels of CO2.

Ventilation and Respiratory Gases

A progressive increase in minute ventilation starts soon after conceptionand peaks at 50% above normal levels around the second trimester. Thisincrease is effected by a 40% rise in tidal volume and a 15% rise in respiratoryrate (2-3 breaths/minute). Since dead space remains unchanged, alveolarventilation is about 70% higher at the end of gestation. Arterial and alveolar

carbon dioxide tensions are decreased by the increased ventilation. Anaverage PaCO2 of 32 mmHg (4.3 kPa) and arterial oxygen tension of105 mmHg (13.7 kPa) persist during most of gestation. The development ofalkalosis is forestalled by compensatory decreases in serum bicarbonate. Onlycarbon dioxide tensions below 28 mmHg (3.73 kPa) will lead to a respiratoryalkalosis.

During labor, ventilation may be further accentuated, either voluntarily(Lamaze method of pain control and relaxation) or involuntarily in response topain and anxiety. Such excessive hyperventilation results in markedhypocarbia and severe alkalosis, which can lead to cerebral and uteroplacentalvasoconstriction and a left shift of the oxygen dissociation curve. The latter

reduces the release of oxygen from hemoglobin with consequent decreasedmaternal tissue oxygenation as well as reduced oxygen transfer to the fetus.Furthermore, episodes of hyperventilation may be followed by periods ofhypoventilation as the blood carbon dioxide tension (PaCO2) returns to normal.This may lead to both maternal and fetal hypoxia.

Oxygen consumption increases gradually in response to the needs of thegrowing fetus, culminating in a rise of at least 20% at term. During labor,oxygen consumption is further increased (up to and over 60%) as a result ofthe exaggerated cardiac and respiratory work load.

Effects of Labor on the Pulmonary System

There is a further decrease in functional residual capacity (FRC) duringthe early phase of each uterine contraction, resulting from redistribution ofblood from the uterus to the central venous pool. Because this decrease inFRC occurs without a concomitant change in dead space, there is little residualdilution and, therefore, presumably more efficient gas exchange.

Clinical Implications


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The changes in respiratory function have clinical relevance for theanesthesiologist. Most importantly, increased oxygen consumption and thedecreased reserve due to the reduced functional residual capacity, may resultin rapid falls in arterial oxygen tension despite careful maternal positioning

and preoxygenation. Even with short periods of apnea, whether fromobstruction of the airway or inhalation of a hypoxic mixture of gas, the gravidahas little defense against the development of hypoxia. The increased minuteventilation combined with decreased functional residual capacity hastensinhalation induction or changes in depth of anesthesia when breathingspontaneously.

Gastrointestinal System

Since aspiration of gastric contents is an important cause of maternalmorbidity and mortality in association with anesthesia, an examination of thecontroversy surrounding gastrointestinal changes in pregnancy is justified.

Mechanical Changes

The enlarging uterus causes a gradual cephalic displacement of stomachand intestines. At term the stomach has attained a vertical position ratherthan its normal horizontal one. These mechanical forces lead to increasedintragastric pressures as well as a change in the angle of thegastroesophageal junction, which in turn tends toward greater esophagealreflux.

Physiological Changes

The hormonal effects on the gastrointestinal tract are an issue of debateamong anesthetists. Relaxation of the lower esophageal sphincter has beendescribed, but there have been differing views about the effect on motility ofthe gastrointestinal tract and the times at which it is most prominent. Manybelieve that there is also retardation of gastrointestinal motility and gastricemptying, producing increased gastric volume with decreased pH, beginningas early as 8-10 weeks of gestation. Recent studies, however, have shed adifferent light on the subject. Measuring peak plasma concentrations of drugsabsorbed exclusively in the duodenum in both non-pregnant and pregnant

volunteers, at different times of gestation, it was shown that peak absorptionoccurred at the same interval in all women with the exception those in labor.This suggests that gastric emptying is delayed only at the time of delivery.Thus, the raised risk of aspiration is due to an increase of esophageal refluxand decreased pH of gastric contents. The heightened incidence of difficultendotracheal intubations worsens the situation.

Oral Cavity


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Salivation may seem to increase due to swallowing difficulty associatedwith nausea, and, if the pH of the oral cavity decreases, tooth decay mayoccur. Tooth decay during pregnancy, however, is not due to lack of calcium inthe teeth. Indeed, dental calcium is stable and not mobilized during pregnancy

as is bone calcium.The gums may become hypertrophic, hyperemic and friable; this maybedue to increased systemic estrogen. Vitamin C deficiency also can causetenderness and bleeding of the gums. The gums should return to normal in theearly puerperium.

Gastrointestinal Motility

Gastrointestinal motility may be reduced during pregnancy due toincreased levels of progesterone, which in turn decrease the production ofmotilin, a hormonal peptide that is known to stimulate smooth muscle in the

gut. Transit time of food throughout the gastrointestinal tract may be so muchslower that more water than normal is reabsorbed, leading to constipation.

Stomach and Esophagus

Gastric production of hydrochloric acid is variable and sometimesexaggerated, especially during the first trimester. More commonly, gastricacidity is reduced. Production of the hormone gastrin increases significantly,resulting in increased stomach volume and decreased stomach pH. Gastricproduction of mucus may be increased. Esophageal peristalsis is deceased,accompanied by gastric reflux because of the slower emptying time and

dilatation or relaxation of the cardiac sphincter. Gastric is more prevalent inlater pregnancy owing to elevation of the stomach by the enlarged uterus.Besides leading to heartburn, all of these alterations as well as lying in thesupine lithotomy position make the use of anesthesia more hazardousbecause of the increased possibility of regurgitation and aspiration.

Small and Large Bowel and Appendix

The large and small bowel moves upward and laterally, the appendix isdisplaced superiorly in the right flank area. These organs return to the normalpositions in the early puerperium. As noted previously, motility is generally

decreased and gastrointestinal tone is decreased.

Gallbladder

Gallbladder function is also altered during pregnancy because of the hypotoniaof the smooth muscle wall. Emptying time is slowed and often incomplete. Bilecan become thick, and bile stasis may lead to gallstone formation.


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Liver

There are no apparent morphologic changes in the liver during normalpregnancy, but there are functional alterations. Serum alkaline phosphataseactivity can double, probably because of increased placental alkaline

phosphatase isoenzimes. Thus, a decrease in the albumin/globulin ratio occursnormally in pregnancy.

Pulmonary Aspiration of gastric contents can occur either followingvomiting (active) or regurgitation (passive). Aspiration of solid material causesatelectasis, obstructive pneumonitis or lung abscess, while aspiration of acidicgastric contents results in chemical pneumonitis (Mendelson's syndrome). Themost serious consequences follow aspiration of acidic materials containingparticulate matter as may follow swallowing certain antacids such asmagnesium trisilicate. Clear antacids such as sodium citrate (0.3 Mol) orbicarbonate should be used. While the incidence of pulmonary aspiration of

solid food has decreased due to patient education, that of gastric acid hasremained constant.

Clinical Implications

The danger of aspiration is almost eliminated when regional anesthesiaor inhalational analgesia is used. During general anesthesia airway protectionby means of a cuffed endotracheal tube is mandatory. Although awakeintubation is safest, discomfort and the lack of patient cooperation and

discomfort prevent it being the routine method for securing the airway. Theendotracheal tube is placed immediately following loss of consciousness afterinduction of general anesthesia.

The acidity and volume of gastric content can be reduced bypharmacologic interventions which may prove invaluable. Most importantly, anonparticulate oral antacid, 30ml of sodium citrate 0.3 Mol or bicarbonate,should be given immediately prior to induction of general anesthesia to allwomen. In addition, if available, metoclopramide, 10 mg IV, should beadministered 15-30 minutes before induction to promote gastric emptying andincrease the lower esophageal sphincter tone. This is especially beneficial in

women in labor who have not been starved and and require emergencysurgery. Lastly, histamine H2-receptor antagonist the night before and themorning of delivery may reduce secretion of hydrochloric acid (ranitidine150mg orally).

Metabolism


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All metabolic functions are increased during pregnancy to provide forthe demands of fetus, placenta and uterus as well as for the gravida'sincreased basal metabolic rate and oxygen consumption. Protein metabolismis enhanced to supply substrate for maternal and fetal growth. Fat metabolismincreases as evidenced by elevation in all lipid fractions in the blood.

Carbohydrate metabolism, however, demonstrates the most dramaticchanges. Metabolically speaking, pregnant women live in a state of"accelerated starvation." First, nutritional demands of the growing fetus aremet by the intake of glucose and, second, secretion of insulin in response toglucose is augmented. As early as 15 weeks of gestation, maternal bloodglucose levels after an overnight fast are considerably lower than in thenongravid state.

As the fetus and placenta grow and place increasing demands on themother, phenomenal alterations in metabolism occur. The most obviousphysical changes are weight gain and altered body shape. Weight gain is duenot only to the uterus and its contents but also to increase breast tissue, blood

and water volume in the form of extravascular and extracellular fluid.Deposition of fat and protein and increased cellular water are added to thematernal stores. The average weight gain during pregnancy is 12,5Kg.

During normal pregnancy, approximately 1000g of weight gain isattributable to protein. Half of this is found in the fetus and the placenta, withthe rest being distributed as uterine contractile protein, breast glandulartissue, plasma protein, and hemoglobin. Plasma albumin levels are decreasedand fibrinogen levels increased.

Total body fat increases during pregnancy, but the amount varies withtotal weight gain. During the second half of pregnancy, plasma lipids increase,but triglycerides, cholesterol and lipoproteins decrease soon after delivery.

The ratio of low density lipoproteins to high density lipoproteins increasesduring pregnancy.

Hypoglycemia

Optimal blood glucose levels in pregnant women range between 4.4 to5.5 mmol/1 (80 to 100mg/dl). In healthy non-pregnant individuals, signs ofhypoglycemia usually begin when the blood glucose level declines toapproximately 2.2 mmol/1 (40mg/dl); in pregnant women, however,hypoglycemia is defined as a concentration below 3.3 mmol/1 (60mg/dl).Hypoglycemia initiates the release of glucagon, cortisol and, importantly,

catecholamines. In the anaesthetized state, however, these compensatorymechanisms, particularly the release of epinephrine (adrenaline), are blocked.Autonomic derangements in the form of hypotension and tachycardia tend toensue during high regional blockade or deep general anesthesia, which maymask the symptoms and signs of hypoglycemia.

Renal Physiology


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Renal Dilatation

During pregnancy, each kidney increases in length by 1-1,5cm, with aconcomitant increase in weight. The renal pelvis is dilated. The ureters aredilated above the brim of the bony pelvis. The ureters also elongate, widen,

and become more curved. Thus there is an increase in urinary stasis, this maylead to infection and may make tests of renal function difficult to interpret.The absolute cause of hydonephrosis and hydroureter in pregnancy is

unknown, there may be several contributing factors:1. Elevated progesterone levels may contribute to hypotonia of the smooth

muscle in the ureter.2. The ovarian vein complex in the suspensory ligament of the ovary may

enlarge enough to compress the ureter at the brim of the bony pelvis,thus causing dilatation above that level.

3. Dextrorotation of the uterus during pregnancy may explain why the rightureter is usually more dilated than the left.

4. Hyperplasia of smooth muscle in distal one-third of the ureter may causereduction in the luminal size.

Renal Function

The glomerular filtration rate (GFR) increases during pregnancy by about50% .The renal plasma flow rate increases by as much as 25-50%. Urinary flowand sodium excretion rates in late pregnancy can be altered by posture, beingtwice as great in the lateral recumbent position as in the supine position.

Even though the GFR increased dramatically during pregnancy, thevolume of the urine passed each day is not increased. Thus, the urinary

system appears to be even more efficient during pregnancy.With the increase in GFR, there is an increase in endogenous clearance

of creatinine. The concentration of creatinine in serum is reduced in proportionto increase in GFR, and concentration of blood urea nitrogen is similarlyreduced.

Glucosuria during pregnancy is not necessarily abnormal, may beexplained by the increase in GFR with impairment of tubular reabsorptioncapacity for filtered glucose. Increased levels of urinary glucose alsocontribute to increased susceptibility of pregnant women to urinary tractinfection.

Proteinuria changes little during pregnancy and if more than 500mg/24h

is lost, a disease process should be suspectedLevels of the enzyme renin, which is produced in kidney, increase early in thefirst trimester, and continue to arise until term. This enzyme acts on itssubstrate angiotensinogen, to first form angiotensin1 and then angiotensin2,which acts as a vasoconstrictor. Normal pregnant are resistant to the pressoreffect of elevated levels of angiotensin2 but those suffering from preeclampsiaare not resistant, this is one of the some theories to explain this disease.


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Bladder

As the uterus enlarges; the urinary bladder is displaced upward and

flattened in the anterior-posterior or diameter. Pressure from the uterus leadsto increase in urinary frequency. Bladder vascularity increases and muscletone decreases, increasing capacity up to 1500ml.

Drug Responses

The response to anesthetic and adjuvant drugs is modified duringpregnancy and the early puerperium. The most pertinent alteration is areduced drug requirement, manifest in both regional and general anesthesia.

Regional Anesthesia

From the late first trimester to the early puerperium, a smaller dose oflocal anesthetic is required to obtain the desired level of spinal or extraduralblockade. During the last months of gestation, approximately two-thirds of thenormal dose is adequate. This altered response, which is due to CSF andhormonal changes and an increase in volume of the epidural veins, subsidesprogressively in the early postpartum period.

General Anesthesia

Induction and changes in depth of inhalation anesthesia occur with

greater rapidity in pregnant women than in non-pregnant subjects. Pregnancyenhances anesthetic uptake in two ways. The increase in resting ventilationdelivers more agent into the alveoli per unit time, while the reduction infunctional residual capacity favors rapid replacement of lung gas with theinspired agent. In addition, there is a reduction in anesthetic requirements,with a fall in the minimum alveolar concentrations (MAC) of halogenatedvapors. When measured in ewes MAC was 25-40% lower in gravid ascompared with nonpregnant animals.The decreased functional residual capacity has a further effect on themanagement of general anesthesia. As referred to earlier, the resultantreduction in oxygen storage capacity, together with the elevated oxygen

consumption, leads to an unusually rapid decline in arterial oxygen tension inthe apnoeic anaesthetized gravida.There are also alterations in the response to intravenous agents, in particularprolongation of their elimination half-lives consequent to the greaterdistribution volume (resulting from the pregnancy-induced increase in plasmavolume). Thus, the mean elimination half-life for thiopentone in gravid womenis more than doubled in comparison with that in nongravid young patients.


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Serum CholinesteraseSerum cholinesterase levels fall by 24-28% during the first trimester

without a marked change for the remainder of gestation. However, even lowerlevels (about 33% reduction) develop during the first 7 postpartum days. Thedecreased levels of the enzyme are still sufficient for normal hydrolysis of

clinical doses of suxamethonium or chloroprocaine during gestation.Postpartum, however, approximately 10% of women will be at risk of aprolonged reaction to suxamethonium.

Clinical Implication

These altered drug responses must be taken into considerationwhenever a patient is pregnant or in the early puerperium.


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References

Internet Articles

1. http://www.patient.co.uk/doctor/Physiological-Changes-In-Pregnancy.htm

2. http://www.medstudents.com.br/ginob/ginob5.htm3. http://www.nda.ox.ac.uk/wfsa/html/u09/u09_005.htm4. http://www.merckmanuals.com/home/sec22/ch257/ch257d.html

Document Readings

1. Thornburg KL, Jacobson SL, Giraud GD, et al; Hemodynamicchanges in pregnancy.; Semin Perinatol. 2000 Feb;24(1):11-4. [abstract]2. Chesnutt AN; Physiology of normal pregnancy.; Crit CareClin. 2004 Oct;20(4):609-15. [abstract]3. Oxford Textbook of Nephrology by Davison, Grunfeld, Cameron

and Stewart. OUP 2nd edition ISBN 019262413X
http://www.patient.co.uk/doctor/Physiological-Changes-In-Pregnancy.htmhttp://www.medstudents.com.br/ginob/ginob5.htmhttp://www.nda.ox.ac.uk/wfsa/html/u09/u09_005.htmhttp://www.merckmanuals.com/home/sec22/ch257/ch257d.htmlhttp://www.merckmanuals.com/home/sec22/ch257/ch257d.htmlhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10709851http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10709851http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15388191http://www.patient.co.uk/doctor/Physiological-Changes-In-Pregnancy.htmhttp://www.medstudents.com.br/ginob/ginob5.htmhttp://www.nda.ox.ac.uk/wfsa/html/u09/u09_005.htmhttp://www.merckmanuals.com/home/sec22/ch257/ch257d.htmlhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10709851http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15388191


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II. Pharmacodynamics In Pregnant PatientMa Lourdes Arquiza

PHARMACODYNAMICS

The science dealing with interactions between the chemical componentsof living systems and the foreign chemicals, including drugs that enterthose systems.

PHARMACOKINETICS

Involves the study of absorption, distribution, metabolism and excretionof drugs.

MATERNAL DRUG ACTION

Because any medication can present risks in pregnancy, and becausenot all risks are known, the safest pregnancy-related pharmacy is aslittle pharmacy as possible.

A single intrauterine exposure to a drug can affect structuresundergoing rapid development at the time exposure. Thalidomide is anexample of a drug that profoundly affects the development of the limbsafter the only brief exposure. This exposure, however must be at acritical time in the development of limbs.

The greatest risk is during the 1st 3 months of gestation. Drugs have adirect effect on maternal tissues with secondary or indirect effects on

fetal tissues. Drugs may interfere with the passage of oxygen ornutrition through the placenta and have direct effects on the fetus.

PREGNANCY CATEGORY

The pregnancy category of a pharmaceutical agent is an assessment ofthe risk of fetal injury due to the pharmaceutical, if it is used as directedby the mother during pregnancy. It does not include any risks conferredby pharmaceutical agents or their metabolites that are present in breastmilk.

Every drug has specific information listed in its product literature. In the

UK, while no preset categories are applied, the British NationalFormulary gives a table of drugs to be avoided or used with caution inpregnancy, and does so using a limited number of key phrases.

In 1979, the United States Food and Drug Administration (FDA)introduced a classification of fetal risks due to pharmaceuticals. This wasbased on a similar system that was introduced in Sweden one yearearlier.


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Different Pregnancy categories in the United States

FDA Pharmaceuticals Pregnancy CategoriesPregnancy Category A Adequate and well-controlled human studies have

failed to demonstrate a risk to the fetus in the firsttrimester of pregnancy (and there is no evidence ofrisk in later trimesters).

Pregnancy Category B Animal reproduction studies have failed todemonstrate a risk to the fetus and there are noadequate and well-controlled studies in pregnantwomen OR Animal studies have shown an adverseeffect, but adequate and well-controlled studies inpregnant women have failed to demonstrate a risk tothe fetus in any trimester.

Pregnancy Category C Animal reproduction studies have shown an adverseeffect on the fetus and there are no adequate andwell-controlled studies in humans, but potentialbenefits may warrant use of the drug in pregnantwomen despite potential risks.

Pregnancy Category D There is positive evidence of human fetal risk basedon adverse reaction data from investigational ormarketing experience or studies in humans, butpotential benefits may warrant use of the drug inpregnant women despite potential risks.

Pregnancy Category X Studies in animals or humans have demonstratedfetal abnormalities and/or there is positive evidenceof human fetal risk based on adverse reaction datafrom investigational or marketing experience, andthe risks involved in use of the drug in pregnantwomen clearly outweigh potential benefits.

Australia has a slightly different pregnancy category system from theUnited States - notably the subdivision of Category B. The system, as outlinedbelow, was established by the Congenital Abnormalities Sub-committee of theAustralian Drug Evaluation Committee (ADEC).

ADEC Pregnancy Categories

Pregnancy Category A Drugs which have been taken by a large number of


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pregnant women and women of childbearing agewithout an increase in the frequency ofmalformations or other direct or indirect harmfuleffects on the fetus having been observed.

Pregnancy Category B Drugs which have been taken by only a limitednumber of pregnant women and women ofchildbearing age, without an increase in thefrequency of malformation or other direct or indirectharmful effects on the human fetus having beenobserved.Studies in animals have not shown evidence of anincreased occurrence of fetal damage.

Pregnancy Category B2 Drugs which have been taken by only a limitednumber of pregnant women and women ofchildbearing age, without an increase in thefrequency of malformation or other direct or indirectharmful effects on the human fetus having beenobserved.Studies in animals are inadequate or may be lacking,but available data show no evidence of an increasedoccurrence of fetal damage.

Pregnancy Category B3 Drugs which have been taken by only a limitednumber of pregnant women and women ofchildbearing age, without an increase in thefrequency of malformation or other direct or indirectharmful effects on the human fetus having beenobserved.Studies in animals have shown evidence of anincreased occurrence of fetal damage, the

significance of which is considered uncertain inhumans.Pregnancy Category C Drugs which, owing to their pharmaceutical effects,

have caused or may be suspected of causing,harmful effects on the human fetus or neonatewithout causing malformations. These effects may bereversible.

Pregnancy Category D Drugs which have caused, are suspected to havecaused or may be expected to cause, an increasedincidence of human fetal malformations orirreversible damage. These drugs may also haveadverse pharmacological effects.

Pregnancy Category X Drugs that have such a high risk of causingpermanent damage to the fetus that they should NOTbe used in pregnancy or when there is a possibility ofpregnancy.

CATEGORY OF SELECTED AGENTS


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The data presented is for comparative and illustrative purposesonly, and may have been superseded by updated data

Classification of some agents, based on different national bodies

Pharmaceutical agent Australia United States

Acetaminophen/Paracetamol

A B

Amoxicillin A BAmoxicillin withclayulanic acid

B1 B

Cefotaxime B1 BDiclofenac C C

Isotretinoin X X

Leflunomide X X

Loperamide B3 B

Paroxetine C DPhenytoin D D

Rifampicin C C

Thalidomide X X

Theophylline A C

Tetracycline D D

Triamcinolone (skin) A C

THERAPEUTIC DRUG ACTIONS IN THE FETUS

A substance that has healing or preventive properties in relationto certain diseases, or is administered to enable a medical diagnosis. Any product that is claimed to cure or prevent a disease is atherapeutic drug. Before it can be sold in France, it must obtain a Frenchor European marketing authorization, following tests that prove its

quality, harmlessness and efficacy. A therapeutic drug can only be soldin a pharmacy, and those that are classed as dangerous are onlysupplied on prescription.

TOXIC DRUG ACTION TO THE FETUS

The absence of drug- induced toxicity in the mother does not assure usof the drugs relative safety for her developing fetus.
http://en.wikipedia.org/wiki/Isotretinoinhttp://en.wikipedia.org/wiki/Leflunomidehttp://en.wikipedia.org/wiki/Loperamidehttp://en.wikipedia.org/wiki/Paroxetinehttp://en.wikipedia.org/wiki/Phenytoinhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Theophyllinehttp://en.wikipedia.org/wiki/Tetracyclinehttp://en.wikipedia.org/wiki/Triamcinolonehttp://en.wikipedia.org/wiki/Isotretinoinhttp://en.wikipedia.org/wiki/Leflunomidehttp://en.wikipedia.org/wiki/Loperamidehttp://en.wikipedia.org/wiki/Paroxetinehttp://en.wikipedia.org/wiki/Phenytoinhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Thalidomidehttp://en.wikipedia.org/wiki/Theophyllinehttp://en.wikipedia.org/wiki/Tetracyclinehttp://en.wikipedia.org/wiki/Triamcinolone


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Drugs taken during the first trimester of pregnancy, as little as thesingle dose has been demonstrated to produce severe physicaldeformities (teratogenic effects) in the human fetus. Teratogenesis is aprenatal toxicity characterized by structural or functional defects in thedeveloping embryo or fetus.

DRUG TRIMESTER EFFECT

AMINOPTERIN First Multiple gross anomaliesAMINOGLYCOSIDES All Eighth nerve toxicityAMPHETAMINES All Cystic cerebral cortical

lesions, abnormaldevelopmental patterns,decreased schoolperformance

ANDROGENS 2nd and 3rd MASCULINIZATION OFFEMALE FETUS

CHLORAMPHENICOL 3rd Increased risk of graybaby syndrome

COCAINE All Increased risk of spontaneous abortion,abruptio placenta, andpremature labor

CORTISONE 1st Cleft palateDIAZEPAM All Chronic use leads to

neonatal dependenceDISULFIRAM 1st Malformations of lower

ext.ETHANOL All High risk of fetal alcoholsyndrome

HEROIN All Chronic use leads toneonatal dependence

IODIDE All Congenital goiter,hypothyroidism

LITHIUM 1st Cardiovascular defectsMETRONIDAZOLE 1st May be mutagenic ( from

animal studies; there isno evidence for

teratogenic effects inhumans

PENICILLAMINE 1st Cutis laxa, othercongenitalmalformations

PHENCYCLIDINE All Abnormal neurologicexamination, poor suck


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reflex and feedingPHENYTOIN All Cleft lip and palatePROGESTIN All Ambiguous genitalia,

cardiovascular defectsTETRACYCLINE All Discoloration and

defects of teeth andaltered bone growth

VACCINES AND LIVEVIRUS

All Risk of fetal infectionwith attenuated viruses

VALPROIC ACID All Various congenitalanomaliesEspecially spina bifida

WARFARIN FirstThird

Hypoplastic nasal bridgeRisk of bleeding

TERATOGENIC DRUG ACTIONS

Teratogens any substance that interferes with the normal fetaldevelopment causing one or more developmental abnormalities

Selected Established and Suspected Human Drug Teratogens

Drug /Class Therapuetic uses Primary types ofteratogenesis

Adrenocorticosteroids(DEXAMETHASONE)

Inflammatory disorders Cleft palate

ALCOHOL Alcoholic beverages Fetal alcohol syndrome

ANDROGENS Gynecological disordersand cancer in woman

Masculinization ofexternal genitalia of thefemale offspring

ANTICANCER AGENTS Cancer chemotherapy Very high incidence ofteratogenesis

ANTICOAGULANTS(WARFARIN)

Retard blood clotting Eye and nose defects

ANTICONVULSANTS(PHENYTOIN)

Epilepsy Mental retardation, heartdefects, celft palate

ESTROGENS Threatened abortion Females: no menstrualcycle at pubertyMale: defects in genitalorgans

OXYGEN Premature infants Blindness (@ o2concentrations > 40%)

VITAMIN D Prevention or tx ofvitamin deficiencies

Bone deformities


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III. NURSES ROLE IN DRUG ADMINISTRATION TO PREGNANTWOMEN

Kishia Olarte

When a woman becomes pregnant, it is very important for her to lead a

healthy life: to eat plenty of nourishing food, get plenty of rest, and exerciseregularly. It is also vital that she avoid anything that might harm her or herbaby-to-be. It is especially important to give up alcohol, cigarettes, and drugs.

For a pregnant woman, drug abuse is doubly dangerous. First, drugsmay harm her own health, interfering with her ability to support thepregnancy. Second, some drugs can directly impair prenatal development.

Virtually all illegal drugs, such as heroin and cocaine, pose dangers to apregnant woman. Legal substances, such as alcohol and tobacco, are alsodangerous, and even medical drugs, both prescription and over-the-counter,can be harmful. For her own health and the health of her baby-to-be, a womanshould avoid all of them as much as possible, from the time she first plans to

become pregnant or learns that she is pregnant.Many medications have side effects that are potentially harmful during

pregnancy, but their benefits may outweigh their risks. A woman shouldconsult her doctor or midwife before taking any drug, even one sold over thecounter. Below are a few examples of medical drugs that must be used withextreme caution or avoided altogether.

Isotretinoin (Accutane) and etretinate (Tegison) are used to treat chronicacne and psoriasis. They may cause chronic malformations during the stage oforgan development. Anticonvulsants, such as phenytoin (Dilantin) and carbamezapine

(Tegretol), are used to prevent epileptic seizures. They are associated withdefects of the heart and face, as well as mental retardation. Antimigraine drugs, such as ergotamine and methysergide, are used tohead off migraine attacks but raise the risk of premature labor. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs(NSAIDs) interfere with blood clotting and increase the risk of uncontrolledbleeding for both mother and baby. Toward the end of pregnancy, they hinderproduction of the hormones that stimulate labor, so that labor may bedangerously delayed or extended. Anticoagulant drugs based on coumarin are used in the treatment ofheart disease and stroke, to slow blood clotting. Taken during early

pregnancy, they are associated with facial malformations and mentalretardation. Later on they raise the risk of uncontrolled bleeding.

Antepartum Drugs

Assessment:

Gather comprehensive medical, drug (illicit, non-pharmacologic andpharmacologic), and herbal history.


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Obtain baseline vital signs. Identify client risk for substance abuse and collaborate with other

professionals to plan strategies to minimize risks. Assess drug history to determine whether antacid use will interfere with

absorption.

Review history of aspirin use when admitting a client in labor. If aspirinhas been used, alert the staff and monitor for increased bleeding.

Ascertain any medical history of alcoholism, liver disease, viral infection,and renal deficiencies. Acetaminophen should be used cautiously inthese clients.

Nursing Interventions:

General Be cognizant that drug use may be part of multiple substance abuse and

may also involve maternal-neonatal infections. Stress the importance of prenatal care, and discuss fears client may

have about health care professionals and concerns about legal action inthe event of substance abuse.

Specific Instruct on nonpharmacologic and pharmacologic measures to relieve

common pregnancy discomforts. Refer to tobacco, alcohol, or drug treatment program if appropriate. Instruct on nutritional and therapeutic supplements needed during

pregnancy.

Monitor hemoglobin/hematocrit of prenatal clients per agency protocol.Iron

Question client about nausea, constipation and bowel habit changes iftaking iron preparations.

Give diluted liquid iron preparation through a plastic straw to preventdiscoloration of teeth.

Store iron in a light-resistant container. Be cognizant that client may have false-positive result of occult blood in

stool if taking iron.

Client Teaching:

General Advise pregnant woman that tobacco, alcohol, and heavy caffeine use

may have adverse effects on the fetus. Instruct client that before taking drugs (illicit, OTC, prescribed) to

discuss with health care provider secondary to teratogenic potential.


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Aspirin/Acetaminophen

Advise client not to take aspirin, during pregnancy particularly duringthe third trimester.

Instruct client not to take nonsteroidal anti-inflammatory drugs (NSAIDs)with acetaminophen.

Caffeine/Alcohol/Nicotine

Advise client to limit coffee and caffeine ingestion from none to 1 to 2cups per day and to limit other sources of caffeine (tea, cola, soft drinks,chocolate, and certain drugs).

If caffeine is allowed by the health care provider, teach client to spacelimited caffeine intake evenly throughout the day because caffeinepasses readily to the fetus that cannot metabolize it. Caffeine candecrease intervillious placental blood flow.

Advise client to use decaffeinated products or dilute caffeinatedproducts.

Instruct client not to drink alcohol if she is pregnant because no safelevel of alcohol has been determined and even minimal exposure haveresulted in fetal alcohol effect and moderate/excess exposure hasresulted in fetal alcohol syndrome.

Advise client that smoking can cause the loss of nutrients such asvitamins A and C, folic acid, cobalamin and calcium. Tobacco use maycontribute to a shortened gestation and low birth weight infants.

Antacids

Advise that antacids should not be taken within one hour of taking anenteric-coated tablet because the acid-resistant coating may dissolve inthe increased alkaline condition of the stomach, and the medication willnot be released in the intestine as needed. Stomach upset may result.

Advise client to store antacid liquid suspension at room temperature,not to let it freeze, and to shake the bottle well before pouring.

Iron Instruct client about dietary sources of iron, which include organ meats

(liver), red meat, nuts and seeds, wheat germ, spinach, broccoli, prunes,and iron fortified cereals.

Explain to client that if supplemental iron is taken between meals,increased absorption (and also increased side effects) may result.Taking iron one hour before meals is suggested. Give with juice or waterbut not with milk or antacids.

Self-Administration for Iron and Antacids


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Advise client to swallow the iron tablets whole, not to crush them. Liquidiron preparations should be taken with a plastic straw to avoid stainingthe teeth.

Caution client not to take antacids with iron because antacids impairabsorption and are generally discouraged during pregnancy. Iron and

antacids should be taken two hours apart if both are prescribed.

Side Effects for Iron and Antacids

Advise client that there may be a change in bowel habits when takingantacids. Aluminum products can cause constipation, whereasmagnesium products can cause diarrhea. Many antacids contain bothingredients.

Advise client to keep iron tablets away from children. Iron tablets looklike candy, and death has been reported in small children who haveingested 2 g or less of ferrous sulfate.

Beta2-adrenergic agonists: Brethine (Terbutaline)

Beta-sympathomimetic drugs act by stimulating beta2-receptors onsmooth muscle. The frequency and intensity of uterine contractions decreaseas the muscle relaxes. Terbutaline (Brethine) is commonly used. It is approvedfor medicinal use but not specifically as a tocolytic. Terbutaline can effectivelydecrease uterine contractions; however, the literature indicates thatknowledge about the long-term effects of this drug is still lacking.

Assessment:

Identify risks for preterm labor (PTL) early in pregnancy. When a client has preterm uterine contractions, obtain a history,

complete physical assessment, vital signs, fetal heart rate (FHR), andurine specimen for screening for intrauterine infection and urinary tractinfection.


Monitor and assess uterine activity and FHR. Maintain client in left lateral position as much as possible to facilitate

uteroplacental perfusion. Monitor vital signs per unit protocol, specifically maternal pulse. Report

maternal heart rate greater than 110beats/min. Report auscultated cardiac dysrhythmias. An electrocardiogram (ECG)

may be ordered.


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Auscultate breath sounds every 4 hours. Notify health care provider ifrespirations are more than 30 per minute or if there is a change inquality (wheezes, rales, coughing).

Monitor daily weight to assess fluid overload: strict input and output (Iand O) measurement.

Report baseline FHR that is more than 180 beats/min or any significantincrease in uterine contractions from pretreatment baseline.

Report persistence of uterine contractions despite tocolytic therapy. Report leaking of amniotic fluid, any vaginal bleeding or discharge, or

complaints of rectal pressure. Be alert to presence of hypoglycemia and hyperglycemia in the newborn

within 5 hours of discontinued beta-sympathomimetic drugs. Assist clients on bed rest and home tocolytic therapy to plan for

assistance with self-care and family responsibilities.

Client Teaching:

General Inform client of the signs and symptoms of PTL (menstrual-type cramps,

sensation of pelvic pressure, low backache, increased vaginal discharge,and any abdominal discomfort).

Instruct client that if she experiences PTL contractions, initially sheshould void, recline on her left side to increase uterine blood flow, anddrink extra fluids. Emphasize that she should notify her health careprovider if the uterine contractions do not cease or if they increase infrequency.

Explain side effects of beta-sympathomimetic drugs. Report heartpalpitations or dizziness to health care provider. Instruct client to take drugs regularly and as prescribed. Advise client to contact the health care provider before taking any drugs

while on tocolytic drug therapy.

CORTICOSTEROID THERAPY IN PRETERM LABOR

The desired outcome from tocolytic therapy is prevention or cessation ofPTL. Clients (24 to 34 weeks gestation) at risk for preterm delivery shouldreceive antenatal corticosteroid therapy with betamethasonbe (Celestone) or

dexamethasone. Administration of corticosteroids accelerates lung maturationwith resultant surfactant development in the fetus in utero, therebydecreasing the incidence and severity of respiratory distress syndrome (RDS)with increased survival of preterm infants. Antenatal therapy decreases infantmortality, RDS and intraventicular bleeds in neonates born between 24 to 34gestational weeks. The effects and benefits of corticosteroid administrationare believed to begin 24 hours after administration and last for up to 1 week.


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Betamethasone (Celestone)

When PTL occurs before the 33rd week of gestation, corticosteroid therapywith betamethasone may be prescribed, 12 mg intramuscularly (IM) every 24hours for two doses.

Adverse Reactions

Side effects of betamethasone are rare but include seizures, headache,vertigo, edema, hypertension, increased sweating, petechiae, eccymoses, andfacial erythema.

Assessment:

Assess for history of hypersensitivity. Assess vital signs; report abnormal findings.

Assess fetal heart rate (FHR)


Shake the suspension well. Avoid exposing to excessive heat or light. Inject into large muscle, but not the deltoid, to avoid local atrophy. Monitor maternal vital signs. Maintain accurate intake and output. Check blood glucose if used for client with diabetes.

DRUG FOR PREGNANCY-INDUCED HYPERTENSION

Pregnancy-induced hypertension (PIH), the most common seriouscomplication of pregnancy, can have devastating maternal and fetal effects.However, with proper management, the prognosis for both mother and infantis good. Hypertensive disorders are reported in 6% to 30% of all pregnantclients, with 3% to 8% of all pregnancies reflecting incidence of PIH. Thecondition is most often observed after 20 weeks gestation intrapartum andduring the first 72 hours postpartum. The cause of PIH remains unknown,although numerous hypotheses exist.

Assessment:

Review baseline vital signs from early pregnancy and BP readings duringprenatal visits.

Identify client history that may predispose client to pregnancy-inducedhypertension (PIH).


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Magnesium Sulfate Continuous electronic fetal monitoring. Monitor for maternal toxicity. Lethargy and weakness result from the

blocking of the neuromuscular transmission .Diaphoresis, flush feeling ofwarmth, and nasal congestion are the results of the vasodilation fromrelaxation of smooth muscle.

Have airway suction, resuscitation equipment and emergency drugsavailable.

Have antidote available Calcium gluconate (1g) IV is given over 3minutes.

Maintain client in left lateral recumbent position in low-stimulationenvironment. provide close observation

For IM administrator, use Z-track technique and rotate sites (drug ispainful and irritating) . Infrequent administration

Monitor BP, pulse, and respiratory rate per agency protocol, DTR, clonusand hourly I & O with urimeter for output

Monitor temperature breath sound and bowel sound every 4 hours Check urine for protein every hour Asses for epigastric pain (heralds impending seizure), headache, visual

symptoms (blurred vision and scotoma), sensory changes, edema, levelof consciousness, and seizure activity on ongoing basis.

Monitor serum magnesium levels according to agency protocol for rangebetween 4 and 7 mg/dl.

Notify physician if following are observed:

Respiratory less than 12/min Absence of DTR Urinary output less than 30 ml/h Systolic BP greater than or equal to 160 mm Hg, unless ordered

otherwise Magnesium level greater than 7 mEq/L Absent bowel sounds or altered breath sound Epigastric pain, headache, visual symptoms (blurred vision and

scotoma), sensory changes, change in affect or level of consciousness,seizure activity

Monitor laboratory reports: evidence of low platelet count, and, ifpresent, observe for excessive bleeding.

Monitor fetal status. FHR baseline should remain to 110 to 160. Monitor laboratory results: 24 hours urinary protein result if ordered

(>300 mg/24 h is abnormal). Monitor client for magnesium toxicity. Monitor newborn for effects of placental exposure to excess magnesium

sulfate. Although infrequent, newborn side effects include lethargy,neurologic or respiratory depression, and muscle hypotonia.


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Hydralazine

Take pulse and BP every 5 minutes when drug is administered ormonitor with electronic BP device until stabilized and then every 15

minutes, Maintain diastolic BP between 90 and 110 mm HG or as ordered. Observe for change in level of consciousness and headache. Monitor I and O to avoid hypotensive episodes or overload. Monitor fetal heart rate (FHR).

Client Teaching:

General Instruct client to avoid exposure to infection. Remind client with diabetes to check her glucose level as ordered.

Side Effects Instruct client to report immediately any breathing difficulty, weakness,

or dizziness. Instruct client to report changes in stool, easy bruising, bleeding blurred

vision, unusual weight gain and emotional changes.


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PHARMACOKINETICS IN PREGNANT PATIENTSAaron Alvarez

Pharmacokinetics describes the handling of a drug by the body how the

drug is absorbed, distributed and eliminated and how these processes determine

plasma concentrations of the drug. Changes in maternal physiology duringpregnancy influence pharmacokinetics, and this may have important sequelae for

drug dosing, especially for drugs for which adverse effects occur at concentrations

within, or just above, the therapeutic range.

For many drugs absorption is decreased and elimination increased, thus

tending to reduce plasma concentrations. There are, however, relatively few

specific data on pharmacokinetics in pregnancy, compared to the non-gravid

state, because of the obvious ethical issues surrounding studies during pregnancy.

Most therapeutic guidelines are thus based on observational studies and

basic principles. The therapeutic actions of most drugs, and often their adverse

effects, are determined by the concentration of the drug in plasma. An

understanding of pharmacokinetics is thus essential in determining practical

aspects of drug delivery dose, dose frequency and route of administration in order

to achieve plasma concentrations that are sufficient to produce desired

therapeutic effects while minimizing the risk of dose-related adverse or toxic

effects.

In the case of physiological changes in drug handling, such as those

occurring during pregnancy, a detailed knowledge of the pharmacokinetics of a

drug potentially provides the necessary information to modify dose schedules to

ensure efficacy and minimize the risk of toxicity.

ORAL ABSORPTION AND BIOAVAILBILITY

When drugs are delivered via the oral route, as is usually the case,

absorption occurs mainly by passive diffusion of the drug through the small

intestine. The bioavailability of a drug is a measure of the proportion of the drug

that reaches the systemic circulation in comparison with the amount that would

reach the systemic circulation were the drug to be given intravenously.

It is usually less than 100% as a result of incomplete absorption. In some

cases delivery to the systemic circulation may be greatly attenuated as a result of

first-pass metabolism-the drug being metabolized within the liver before reaching

the systemic circulation.

Opioids are examples of drugs that have low bioavailability due to a high first-pass metabolism, and they are often given by intramuscular injection to avoid

this problem.

It is important to note that bioavailability only gives information regarding the

total extent of absorption, not the rate of absorption, so that the peak plasma

concentration (Cmax) and time of peak plasma concentration (Tmax) following

an oral dose may differ even though bioavailability may remain constant.


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DISTRIBUTION AND VOLUME OF DISTRIBUTION

Drugs reaching the systemic circulation are distributed to varying degrees

within the intravascular, interstitial and intracellular spaces.

The relative distribution of a drug within these compartments depends upon

its relative solubility in water and within cell membranes, polar drugs beingcontained mainly within the extracellular space and lipophilic drugs being more

widely distributed.

The degree to which drugs are bound to plasma proteins also influences

their distribution. It is the volume that the drug would be distributed in if it were

uniformly and instantaneously distributed at a concentration equal to that in the

plasma.

Drugs that are confined to the intravascular compartment (e.g. by virtue of

their large molecular weight as in the case of heparin) have the lowest Vd, with Vd

then approximating total plasma volume. Widely distributed lipophilic drugs have

a large Vd.

DRUG CLEARANCE

Polar drugs tend to be eliminated by the kidneys whereas lipophilic drugs

are usually metabolized by the liver to more polar metabolites which are then

eliminated by the kidneys. Metabolism is a two-stage process, phase I usually

involving modification (e.g. oxidation, reduction and hydrolysis) and phase II

conjugation (e.g. acetylation and methylation).

Other routes of elimination, such as excretion in bile or via the airways,

tend to be of minor importance. The clearance of a drug is the amount of plasma

cleared of drug per unit time. Drugs are cleared mainly by the liver or kidneys orboth and the total clearance (Cls) is the sum of clearance by the liver and by the

kidneys.

For the vast majority of drugs clearance remains approximately constant

irrespective of the concentration of drug in the plasma. Such drugs obey a

condition known as linear or first-order kinetics and, for these drugs, it is possible

to predict how, given a particular dose schedule, plasma concentrations will vary

over time.

RELATIONSHIP BETWEEN DRUG DOSE AND PLASMA CONCENTRATION

For drugs obeying first-order kinetics, and if it is assumed that the drug iscontained within a single compartment, then there is a simple relationship

between drug dose, Vd, Cls and plasma concentrations of the drug over time.

When a single dose is given, plasma concentrations rise to a maximum

(Cmax) dependent on the dose of drug and volume of distribution; thereafter

plasma concentrations fall over time.


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The time taken for the concentration to fall by 50% is constant (given the

provision of one-compartment first-order kinetics) and is called the half-life (t1/2)

of the drug;

Usually drugs are given at repeated intervals. In this case plasma

concentrations rise over the course of approximately three half-lives to fluctuate

around an average steady state concentration determined by the daily dose (D)and the clearance of the drug.

Fluctuation of the plasma concentration around this level is determined by

dose interval and t1/2. The shorter the dose interval in comparison to t1/2, the

smaller the fluctuation (which may be quantified by the peak/trough ratio).

Depending upon the clinical urgency of a situation it may not be expedient

to wait three half-lives to reach the desired therapeutic concentration at steady

state. In such cases an initial loading dose can be given followed by a

maintenance dose.

The size of the loading dose is determined by Vd whereas that of the

maintenance dose is determined by Cls. These considerations are strictly true only

for drugs distributed within a single compartment which obey first-order kinetics.

In reality, most drugs are distributed across many compartments with

different equilibrium constants. Despite this, the simple single-compartment

model provides a useful description for most drugs.

There are, however, important exceptions. For those drugs for which Cls is

not constant, such as phenytoin and alcohol, which exhibit saturation kinetics, the

relationship between dose and plasma concentration is more complex. In

particular, the average steady state concentration is not proportional to daily dose

and a small increase in dose per unit time can lead to a large increase in plasma

concentrations.

PHYSIOLOGICAL CHANGES IN PREGNANCY

Physiological changes in pregnancy, beginning during the first trimester, and

most marked during the third trimester, alter the absorption, distribution and

clearance of drugs.

In addition, most drugs gain access to the feto-placental unit. These changes

are detailed below before considering specific effects for individual classes of

drugs.

Absorption

Gastric emptying and small intestine motility are reduced in pregnancy due

to elevation of progesterone. This may increase Tmax and reduce Cmax, although

effects on total bioavailability may be relatively minor. An increase in gastric pH,

due to a reduction in secretion and an increase in mucus production, may increase

the ionization of weak acids, tending to reduce their absorption more than that of

weak bases. Such effects are unlikely to be important during repeated dosing.


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They may, however, reduce the effie cacy of a single dose of an oral drug such as

an analgesic or anti-emetic for which Tmax and Cmax are important. A more

practical problem for drug absorption is the nausea and vomiting associated with

pregnancy. If nausea is reduced in the evening its effects on absorption can be

minimized by deferring dosing until the evening (in the case of once-daily dosing).

Absorption of drugs administered by inhalation may be enhanced due to increasedcardiac output and tidal volume increasing alveolar uptake.

Distribution

During pregnancy there is an expansion of intravascular (plasma volume)

and extra vascular (breasts, uterus, peripheral oedema) water content. Thus, total

body water increases by up to 8 litres, creating a larger space within which

hydrophilic drugs may distribute.

As a result of this apparent dilution, Cmax of many hydrophilic drugs is

reduced, although the clinical effect of this is compensated by changes in protein-

binding. Total plasma concentration of albumin-bound drugs decreases as a result

of haemodilution and the subsequent fall in plasma albumin concentration.

In addition, steroid and placental hormones displace drugs from their

protein-binding sites. There is thus the possibility of a rise in free (active) drug

concentration of agents that are normally albumin-bound. This would be expected

to produce an increased drug effect. However, unbound drug is distributed,

metabolized and excreted, and so free concentration of drug is little influenced.

These changes in protein binding are of clinical importance when

monitoring plasma concentrations of drugs, for example, phenytoin, as most

laboratories report total (rather than free) drug concentration. Body fat increases

by approximately 4 kg, creating a larger volume of distribution for lipophilic drugsbut this has little practical importance.

Metabolism

Some enzymes of the hepatic cytochrome P-450 system are induced by

oestrogen/ progesterone, resulting in a higher rate of metabolism (and hence

elimination) of drugs, for example, phenytoin, whereas other isoenzymes are

competitively inhibited by progesterone and oestradiol, leading to impairedelimination, for example, theophylline. Clearance of drugs, such as rifampicin, that

are secreted via the biliary system, may be attenuated due to the cholestatic

property of oestrogen. Some extra-hepatic enzymes, such cholinesterase, have

diminished activity during pregnancy.

Elimination


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Renal blood flow is increased by 60-80% during pregnancy, and glomerular

filtration rate rises by 50%, leading to enhanced elimination of drugs that are

normally excreted unchanged for example, penicillin and digoxin. This leads to

slightly lower steady-state drug concentrations, although this rarely necessitates

increasing the dosage.

Feto-placental unit

Drug transfer occurs mainly via diffusion across the placenta, thus

favouring the movement of lipophilic agents, and the rate-limiting step is placental

blood flow. Protein-bound drugs, and drugs of large molecular weight, for example

heparin and insulin, do not cross the placenta.

Both the immature fetal liver and the placenta can metabolize drugs.

Immature phase I and phase II metabolism can occur in the fetus 8 weeks post-

conception. 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.

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.

SUMMARY

Changes in maternal physiology during pregnancy impact on

pharmacokinetics with a tendency to reduced plasma concentrations.

Definitive information from studies that could be used to formulate

therapeutic guidelines for the safe use of drugs in pregnancy is, however, limited

and at present there is little evidence to formulate clear-cut guidelines with

respect to dosing schedules for individual drugs.

Documents

Physiological Background for Pregnant