The physiological changes that occur during pregnancy in the cardiovascular, renal,gastrointestinal and endocrine systems influence the pharmacokinetics of drugs administered during pregnancy. These two factors affecting the drug kinetics are maternal factors and the placental-fetal unit, These two factors affect the process of a) absorption, b) distributions, c) protein binding, and d) elimination of the drug.
Factors affecting Pharrnacotherapy during Pregnancy Maternal Factors
Absorption
The intestinal motility is reduced due to increased plasma progesterone level resulting in about 30-50 per cent decrease in gastric and intestinal emptying and hence increases absorption of the drug administered. The gastric pH is also increased.Distribution During pregnancy the increase in plasma volume expansion can result in altered volume of distribution of some drugs. Hence higher loading doses may be needed to produce expected serum concentration.
Protein Binding
Dilulional hypoalbuminaemia occurs during pregnancy resulting in decreased protein binding of some drugs. This will affect the estimation of serum concentration of total drug in pregnant women, which may lead to unnecessary increase in drug dosage.Greater fluctuation in the unbound concentration within a dosing interval can produce toxic effects at the beginning of a dosing interval and hence frequent dosing without change in daily dosage may be required.
Progesterone and other endogenous substances can increase or decrease in hepatic metabolism of certain drugs e.g., phenytoin nletabolism is increased while theophylline melrtbolism is decreased. Similarly increase in renal plasma flow and glomerular filtration rate can increase renal nletabolisnl of drugs.
Placental Fetal Unit
Absorption
Unbound free drug only can cross the placental barrier. Non-ionized lipid soluble molecules can cross placenta than less lipid soluble ionized molecdes. Maternal and fetal pH influences the crossing of placenta.
Distribution
Nearly 50 per cent of fetal circulation directly reaches the heart and brain by passing the liver. The affinity of drug to bind to fetal plasn~a proteins may bc different from that of maternal protein and hence can iilfluence the concentration of free drug.
Elimination
Most of the drugs are prinlarily eliminated by diffusion of the dlug back to the malernal coinpartment, although there is evidence of nletabolis~n in placenta and fetus to some extent.Congenital malfortnations are generally caused by drug loxicity during the first hiinester and depend on the nature of the drug, duration of fetal exposure and the genetic susceptibility of the fetus. Hence d n ~ g adminislration in the first trimester should be avoided as much as possible. In the second and third trimesters, interference with fetal growth and developnlent is the major potenlial hazard of d t ~ l g exposure.Mothers requiring continuation of drugs and who want breastfeeding also pose potential problems. Many dnlgs taken by the mother may appear in huinan milk and drug level in milk depends on the properties of the drug, degree of plasma binding and the maternal senlm concentration. Unionized clrugs, with minimal protein binding and high lipid solubility are found more readily in breast milk.
Commonly Used Drugs
Beta-Blockers
Beta-adrenergic blocking agcnts act by blocking 1 and 2 receptors. Cardiac effects are mediated primarily by beta1 rcceptors while two receptors are found in the bronchi and the blood vessels. Myornetrial relaxation mediated by two receptors occurs in pregnancy. Non-selective beta-blockers are: propanolol, nadolol, pindolol,sotalol, carvedilol and labetalol. Carvedilol and labetalol also have alpha blocking activity. One selective antagonist are: atenolol, metoprolol and esmolol. Beta-blockers are indicated in hypertension, ischemic heart disease, control of ventricular rate in atrial fibrillation and atrial flutter, in the management of supraventricular tachycardia. During pregnancy they are used to control hypertension, hereditaty long Q-T syndrome, thyrotoxicosis, idiopathic hypertrophic sub aortic stenosis and fetal tachycardia. Beta-blockers do not cause fetal malformation. Beta-blockers readily cross the placenta.
i)Propranolol: Propranolol has been used in pregnancy over several years with favorable reports. However, adverse fetal effects have been described including bradycardia, birth apnea, hypoglycemia, intrauterine growth retardation, and f are not reported consistently in chronic therapy prolonged labour. ~ u they studies. It is also excreted in the milk but the amount excreted is far less to cause
adverse effects in the infant.
ii) Metoprolol: It is a selective Beta-blocker. It crosses placenta. Metoprolol administered to treat hypertensive pregnant women was effective and did not cause any significant adverse effect. It has also been used to control supraventricular tachycardia in pregnant women with safety with no adverse effect on fetal heart rate. However, the use of beta-blockers in general should be avoided in those who are likely to give birth to very low birth weight infants because of poor outcome seen in these circumstances.
iii) Atenolol: Atenolol is one selective blocker with relatively long half-life. It readily crosses placenta. Effective in treatment of hypertension during pregnancy with no significant adverse effects. However it is better to avoid in mothers who are likely to give birth to very low birth weight infants. Atenolol has shown beneficial effects in women with risk of pre-eclampsia by decreasing
the incidence of pre-eclampsia from 18 per cent to 3.8 per cent. Atenolol is also excreted in breast milk but the infants breast-fed by atenolol treated mothers demonstrated negligible plasma drug levels. Atenolol provides a good blood pressure control and well tolerated by mother and fetus. However, therapy in the first trimester is to be avoided because atenolol could cause low birth
weight.
iv) Pindolol: It is a non-selective beta-blocker approved by US Food and Drug-Administration (FDA) in pregnancy risk classification category B. It has intrinsic sympathommetic activity. It is relatively safe to use in pregnancy to control blood pressure.
v) Acebutolol: Selective one receptor blocker and approved by US FDA in pregnancy risk classification category B. It does not cause low birth weight or any significant side effects in pregnancy when used for treatment of hypertension.It is also excreted in milk.
vi) Esrnolol: It is ultra short acting selective 1 receptor blocker used intravenously to control heart rate in pregnancy with thyrotoxicosis and to treat supraventricular tachycardia, and in hypertension. It has a rapid action (within 5-10 min) with plasma half-life of only 9 rnin. It is relatively safe to use in pregnancy. However a few side effects like weak cry of new born, poor muscle tone heart rate of 120 beats per minute in new born have been reported.
vii) Sotalol: It is a non-selective beta-blocker with class III electrophysiological properties. It is protein bound. It is used to treat hypertension and to treat maternal and fetal arrhythmias. Transplacental therapy to treat fetal arrhythmias shas been used with success. It is also excreted in milk but no significant side effects reported in infants.
In general beta-blockers are relatively safe to be used in pregnancy. However, the following factors need to be considered:
a) Try to avoid initiating beta-blockers if possible, during first trimester.
b') Lower doses need to be used.
c) It is preferable to discontinue beta-blockers 2 to 3 days before delivery to limit di-ugs effect on uterine contraction.
d) Neonates born to mothers receiving beta-blockers need to be monitored for 72 to 96 hrs.
e) Bela-blockers with intrinsic sympathoinmelic activity or with alpha blocking propertics inay be preferred. Better to avoid blocking of two mediated uterine relaxation and vasodilatation.
f)Avoid breastfeeding 3-4 hours after the dose of beta-blockers at the time of expected peak concentralion of the dmg.
Digitalis
Digitalis preparations cross the placenta but no tcratogenic effects are reported.However adverse effects on the fetus have been reported in the fetus of the mothers who developed digitalis toxicity. Electrocardiographic changes and subsequent death of infants has been reported with maternal digitalis intoxication, miscarriage and low birth weight of new born have also been reported. Digitalis preparations are the mainstay in the treatment of fetal arrhythmias providing nearly 80 per cent of success rates in supraventricular tachycardias and considered by some as the routine drug of choice in treating fetal arrhythmias. In pregnancy with fetal hydrops higher doses of digitalis is needed because of reduced transplacental passage of digitalis but needs close monitoring of matei~lal loxlcity. The eftjcacy of digitalis in atrial flutter diminishes and Wolf-Parkinson - White syndrome could worsen with digitalis.
Digitalis is indicated in congestive cardiac failure particularly associated with atrial fibrillation. Digitalis preparations are excreted in breast milk in similar concentrations as ll~at found in maternal serum. However, the total amount of daily maternal excretion is minute and do not cause significant effect on the breast fed infant. Hence digitalis is considered safe in lactating inothers. Digoxin is the drug preferred among other digitalis preparations because of its extensive use in pregnancy. Digitalis
preparation are important in treating heart fililure in pregnancy, since angiotensin converting enzyme inhibitors are contraindicated in pregnancy as they may cause renal failure in the fetus or newborn.
Anti-Arrhythmic Drugs
According to Vaughan-Williams antiarrhythmic drugs are classified as follows:
Class IA: Dnlgs that reduce the rate of rise of action potential upstroke and prolong action potential duration e.g., quinidine, procainamide, disopyramide.
Class IB: Drugs that shorten action potential duration do not reduce rate of rise of action potential e.g., mexiletine, phenytoin 'and lidocaine.
Class IC: Drugs that reduce the rate of rise of action potential, priinarily slow conduction and can prolong refractoriness minimally e.g., flecanide, prop,afenone, and morcizine. .
Class 11: Drugs that block beta-adrenergic receptors e.g., propranolol, timolol,metaprolol, atenolol.
Class III: Drugs that block potassium channels e.g., sotalol, amiodarone, bretylium.
Class IV: Drugs that block slow calcium channels e.g., verapamil, diltiazem. The use of some of the commonly prescribed drugs during pregnancy is discussed.
Class IA
- Quinidine: Class IA drug reduces the rate of rise of action potential by blocking sodium channel. Used in treatment of ventricular and supra ventiicular arrhythmias, including those associated with Wolf-Parkinson White (WPW) syndrome. Quinidine is also used for termination of atrial flutter, atrial fibrillation, it is also used for transplacental treatment of fetal supraventricular tachycardia, fetal atrial flutter1 1. It is relatively safe, but fetal thrombocytopenia,eight-nerve toxicity have been reported. Quinidine is also excreted in milk but the amount likely to be ingested by infant is low and hence safe to use in lactating mothers.
- Procainamide: Its action is similar to that of quinidine, used to prevent or terminate supraventricular and ventricular arrhythmias and to maintain sinus rhythm after cardioversion of atrial fibrillation. There are only a few reports of its use in pregnancy, most of them are for treatment of fetal supraventricular tachycardias. Both procai~mmide and its metabolite N- Acetyl Procainamide (NAPA) are excreted in milk but the amount ingest by infant is low and hence safe. It does not cause any teratogenic effect. However, long-term therapy may cause lupus like syndrome.
- Disopyramide: It is used for treatment of venllicular mhythmias. Indications and actions are similar to procainamide. Also used in supraventricular arrhythmias. It is not teratogenic but can cause low birth weight in higher dose. Initiation of premature labour has been reported by use of disopyramide for cardiac arrhythmiasl2. It is also excreted in breast milk but no side effects reported in infant and hence its use is safe in lactating mothers.
Class IB
Lidocaine: Lidocaine has been used p imarily for epidural or local anesthesia during pregnancy and data of its use as antiarrhythmic agent in pregnancy is scanty. No teratogenic effect reported. It is excreted in milk but the amount reaching the infant is low and safe. Respiratory tract anomalies, hernias in the newborn have been reported. Cautious use with hepatic dysfunction is advocated as it is metabolized in the liver.
Class IC
Flecanide: It has been used with clinical effectiveness to treat maternal tachyarrhythmiasl3. 1t readily crosses placenta and has been used to treat fetal tachycardias. It has been found that the fetus can metabolize the dnlg to avoid accumulation to produce toxicity. Flecanide has been coilsidered by some as rtreatment of choice in fetal supraventricular tachycardia, particularly refractory to digitalis. Use of flecanide is conlpatible with breastfeeding. It is proa~hythmic drug in that it may aggravate existing arrhythmia and may cause new ventricular arrhytlunias.
Propafenone: Its use in pregnant women+as been documented. It crosses placenta and is also excreted in milk but is safe for breastfeeding as the ingested amount by infant is low.Although Class IC drugs are reported favorably during pregnancy, there are no randomized controlled studies involving the use of these drugs in pregnancy and breastfeeding. Their routine use in pregnancy is not recomn~ended at this timel4.
Class I1
a) Beta-blockers - It is described above.
Class I11
Amiodarone: After an oral dose absorption is slow and incomplete and unpredictable. Approximalely 50 per cent of drug is absorbed. Although peak concentration is reached in 2-10 hours, therapeutic steady state levels could take up to 4 weeks. Drug tieposits could bc found in nearly evely tissue, including skin, coniea and liver. The rnain metabolile is desethylamiodarone (DEA) the elimination half-life is I3 to 100 days with an average of 40-50 days rind about 96 per cent of the drug is protein bound. Amiodarone and its metabolites pass through placenta. There we illany reports of use of amiodarone in the treatmenl o l maternal tachya~hylhmias like atrial flutter, atrial fibrillation, supraventricular tachycardia and also in the treatment of fetal tacllyarrllythn~ias. Some have reported amiodarone therapy early in gestation with no adverse effects, while others have reported adverse efSect including bradycardia, QT prolongation in the newborn. Tlle high content of iodine in amiodarone - approximately 40 per cent weight has been inlplicated in causing fetal hypotllysoidism in a of its molecular number of pregnant womcn receiving amiodarone therapy. It may also cause neurodevelopmental problems, and prcmaturity. It is also secreted in nlilk. In view o l side effects of amiodarone during pregnancy it should be used with,caution as a seconti line drug in incessant arrhythmias. Although some reports have shown safety ol' amiodarone for breast feeding, high accumulation of drug in breast milk occurs and hence not recommended in nursing mothers.
Class IV
Anti nrrhythmic Drugs
Calcium channel antagonists
Verapamil: Verapamil is very effective in the cardioversion of paroxysmal supraventricular tachycardia to sinus rhythm and in slowing the ventricular rate in atrial flutter or fibrillation. It has been used in the treatmenl of mateinal supraventricular tachycardias, preclainpsia, severe matcrnal hypertension and tachycardia without severe adverse effects. It crosses fetal s~~praventricular placenta and in chronic therapy for hyperlension with verapamil, lower birth weight in infants have been reported. Maternal second degree atrioventricular block can occur. It is also excreted in milk and although some studies have shown no adverse effects in breast fed infants, others have reported high concentration in milk and cautioned against breastfeeding while on verapamil therapy.
- Diltiazem: The electrophysiological aclion $ similar to verapamil. No adverse effect is reported for its use in pregnancy. It is also excreted in milk.
- Nifedipine: It is a lipophylic dihydropyridine derivative. It has a potent vasodilating effect on vascular smooth muscle and minimal effect on cardiac conduction system. It reduces systemic arterial and pulmonary arterial pressures, its use as an anti-hypertensive agent is effective and safe. It has also been used in primary dysrnenoirhea, bladder instability and Raynaud's phenomenon. 11 can cross the placenta, fetus can metabolize the drug. It is no1 teratogenic. It has also been used as a tocolytic agent to delay labour, It is excreted in milk but breastfeeding is safe.
- Amlodipine: This is less lipid soluble, has a slow, smooth onset and ultra-long duration of action (plasma half life of 36 hrs), it is a vasodilator and may be used as once daily antihypertensive agent and also in angina pectoris. It is effective and well tolerated. It has little if any negative inotropic action and inay be used in angina or hypertension with left ventricular dysfunction. The Prospective Randornised Amlodepine Survival Evalualion (PRASE) Study with class 11 to IV (New York Heart Association Class) in patients with ischemic cardiornyopathy,showed that arnlodipine can be safely used to control hypertension or angina without adverse effect on survival. Side efrects include edema of the legs. In the treatment of hypertension in pregnancy calcium channel antagonists are also acceptable on the basis of limited data.
- Nicardipine: It is dihydropyl-idine calcium antagonist used in treatment of angina and hypertension. It is similar to nifedipine and also used as a tocolytic agent,more potent, but slow in action compared to other drugs.
Adenosine
It is a purine nucleoside and is effective in treating paroxysmal supraventricular tachycardias. It is a natural compound and has a very short half-life of seven seconds and hence an attractive drug to use in pregnancy. However the data on its use in pregnancy is limited. Several case reports of its use in pregnancy with supraventricular tachycardias have shown good results showing efficacy and lack of adverse or teratogenic effects on the fetus. Though data is not available of its secretion in milk, because of its short action it may be safe to use in lactating mothers.
Diuretics
By definition diuretics are drugs that increase urine flow. They are mainly used to treat medical conditions where there is excess accumulation of fluid and salt in the body, as in patients with heart failure, liver disease and kidney disease. These drugs act on the kidneys to increase urine output. Diuretics are also used in the treatment of hypertension. All diuretics initially lower the blood pressure by increasing urinary sodium excretion and by reducing plasma volume, extra cellular fluid voluine and cardiac output. In later stages (6-8 weeks) diuretics acl by reducing the peripheral resistance which may involve potassium channel activation. Diuretics are generally classified as
1 ) Loop Diuretics: Such as bumetanide, filrosemide and torsemide act on the loop of Henle and inhibit sodium, potassium and chloride co-transporter.
2)Thiazide and Thiazide: Thiazide and Thiazide like diuretics which inhibit sodium and chloride cotransporter. They act on the distal convoluted tubules. The drugs include hydrochlorothiazide, chlorothiazide and chlorthalidone.
3) Potassium Sparing Diuretics: They prevent the loss of potassium. Amiloride and triarnterene belong to this group. Inhibitors of mineralocorticoids, like spionolactone is also included in this group, together called 'potassium sparing diuretics'.Use of Diuretics in Pregnancy
1)Hydrochlorothiade: Not commonly used drug in the treatment of hypertension in pregnancy. Usual dose is 25 to lOOmg orally. Prevents nolmal physiologic volume expansion that occurs in pregnancy and may reduce uterine blood flow. It should be restricted in its use in women with volume overload states.
2 ) Furosemide: It is used to treat pulmonary edema associated wilh pre-eclampsia.The usual dose is 10 mg IV initial dose. 20-80 mg per day orally.
3) Spironolactone: Anti aldosterone agent, used to treat hypertension and congestive cardiac failure. Recently, it has been shown to reduce mortality in severe heart failure patients. However its use in pregnancy and safety has not been documented.ACE1 (Angiotensin Converting Enzyme Inhibitors)This group of drugs are inclicated in non-pregnant patients in the management of hypertension, congestive cardiac failure, left ventricular dysfunction, and in ischemic heart diseases and particularly indicated in diabetics to prevent proteinuria. However they are contraindicated in pregnancy because of fetal toxicity and cleath.
Antibiotics
Antibiotics are used to treat concurrent infections during pregnancy. In general every medication is assigned to a category based on whether it is safe or risky to use duiing pregnancy.
Category A
Only a few medications fall in category A, which means that human studies have shown no evidence of fetal harm in the first trimester or later in the pregnancy. Very few medications fall in this categoly. Example Nystatin vaginal prepswations(Mycostatin).
Category B
Most antibiotics are category B, which means that there is no known association with birth defects or other pregnancy related conlplications and the dlvg is probably safe.These include Amoxycillin, Anlpicillin, Amoxycillin-clavulinate, Dicloxacillin, nitrofurantoin, metronidazole. (Controversial over oral use in first tiimester).Cephalosporins, clindamycin, erythromycin, azithromycin, sulfa-drugs (until near term) acyclovir, valacyclovir.
Category C
No enough information about their use in pregnancy or there are concerns arising from animal studies, but no confirlnation of problems like birth defects in humans,These include trimethoprim, clarithroinycin, ciprofloxacin, tluconazole, terconazole,isoniazid, rifampicin, mebendazole, tetanus toxoid, vaccines- hepatitis A, hepatitis B,influenza, polio, measeles, mumps and rubella.
Category D
Medications have clear cut problems in pregnancy and should not be used unless there are no better alternatives. The category D includes, tetracycline derivatives, which can cause discoloration of teeth, tetracycline, doxycycline, sulfa dn~gs. If near delivery, because they can increase the chance of serious newboil1 jaundice.
-
Nifedipine: It is a lipophylic dihydropyridine derivative. It has a potent vasodilating effect on vascular smooth muscle and minimal effect on cardiac conduction system. It reduces systemic arterial and pulmonary arterial pressures, its use as an anti-hypertensive agent is effective and safe. It has also been used in primary dysmenorrhea, bladder instability and Raynaud's phenomenon. It can cross the placenta, fetus can metabolize the drug. It is not teratogenic. It has also been used as a tocolytic agent to delay labour. It is excreted in Inilk but breastfeeding is safe.
- Amlodipine: This is less lipid soluble, has a slow, smooth onset and ultra-long duration of action (plasma half life of 36 hrs), it is a vasodilator and may be used as once daily antihypertensive agent and also in angina pectoris. It is effective and well tolerated. It has little if any negative inotropic action and may be used in angina or hypertension with left ventricular dysfunction. The Prospective Randornised Amlodepine Survival Evaluation (PRASE) Study with class I1 to IV (New York Heart Association Class) in patients with ischemic cardiomyopathy,showed that arnlodipine can be safely used to control hypertension or angina without adverse effect on survival. Side effects include edema of the legs. In the treatment of hypertension in pregnancy calcium channel antagonists are also acceptable o n the basis of limited data.
-
Nicardipine: It is dihydropyridine calcium antagonist used in treatment of angina and hypertension. It is similar to nifedipine and also used as a tocolytic agent, more potent, but slow in action compared to other drugs.
Adenosine
It is a purine nucleoside and is effective in treating paroxysmal supraventricular tachycardias. It is a natural compound and has a very short half-life of seven seconds and hence an attractive di-ug to use in pregnancy. However the data on its use in pregnancy is limited. Several case reports of its use in pregnancy with supraventricular tachycardias have shown good results showing efficacy and lack of adverse or teratogenic effects on the fetus. Though data is not available of its secretion in milk, because of its short action it may be safe to use in lactating mothers.
Diuretics
By definition diuretics are drugs that increase urine flow. They are mainly used to treat medical conditions where there is excess accumulation of fluid and salt in the body, as in patients with heart failure, liver disease and kidney disease. These drugs act on the kidneys to increase urine output. Diuretics are also used in the treatment of hypertension. All diuretics initially lower the blood pressure by increasing urinmy sodium excretion and by reducing plasma volume, extra cellular fluid volume and cardiac output. Ln later stages (6-8 weeks) diuretics act by red~zcing the peripheral resistance which may involve potassium channel activation.Diuretics are generally classified as
1) Loop Diuretics: Such as bumetanide, furosemide and torsemide act on the loop of Henle and inhibit sodium, potassium and chloride co-transporter.
2)Thiuzide and Thiazide: Thiazide and Thiazide like diuretics which inhibit sodium and chloride cotransportera They act on the distal convoluted tubules. The drugs include hydrochlorothiazide, chlorothiazide and chlorthalidone.
3 ) Potassium Sparing Diuretics: They prevent the loss of potassium. Alniloride and triamterene belong to this group. Inhibitors of mineralocorticoids, like spionolactone is also included in this group, together called 'potassium sparing diuretics'.Use of Diuretics in Pregnancy
1) Hydrochlorotltiade: Not commonly used drug in the treatment of hypertension in pregnancy. Usual dose is 25 to l0Omg orally. Prevents normal physiologic volume expansion that occurs in pregnancy and may reduce uterine blood flow. It should be restricted in its use in women with volume overload states.
2 ) Furosemi.de: It is used to treat pulmonary edema associated with pre-eclampsia.The usual dose is 10 mg IV initial dose. 20-80 mg per day orally.
3) Spironolactone: Anti aldosterone agent, used to treat hypertension and congestive cardiac failure. Recently, it has been shown to reduce mortality in severe heart failure patients. However its use in pregnancy and safety has not been documented.
ACE1 (Angiotensin Converting Enzyme Inhibitors)
This group of drugs are indicated in non-pregnant patients in the management of hypertension, congestive cardiac failure, left venlricular dysfunction, and in ischemic heart diseases and particularly indicated in diabetics to prevent proteinuiia. However ;hey are contraindicated in pregnancy because of fetal toxicity and death.
Antibiotics
Antibiotics are used to treat concurrent infections during pregnancy. In general every medication is assigned to a category based on whether it is safe or risky to use during pregnancy.
Category A
Only a few medications fall in category A, which means that human studies have shown no evidence of fetal harin in the first trimester or later in the pregnancy. Veiy few medications fall in this catcgoiy. Example Nystatin vagii~al preparations(Mycostatin).
Category B
Most antibiotics are category B, which means that thcre is no known association with birth defects or other pregnancy related co~nplications and the drug is probably safe.These include Amoxycillin, Ampicillin, Ainoxycillin-clavulinate, Dicloxacillin, nitrofurantoin, metronidazole. (Controversial over oral use in first trimester). Cephalosporins, clindaniycin, erythromycin, azithromycin, sulfa-diugs (until near term) acyclovir, valacyclovir.
Category C
No enough infomation about their use in pregnancy or there are concerns arising from animal studies, but no confirmation of problems like birth defects in humans,These include trimethoprim, clarithromycin, ciprofloxacin, fluconazole, terconazole,isoniazid, iifampicin, mebendazole, tetanus toxoid, vaccines- hepatitis A, hepatitis B,influenza, polio, measeles, mumps and rubella.
Category D
Medications have clear cut problems in pregnancy and should not be used unless there are no better alternatives. The category D includes, tetracycline derivatives, which can cause discoloration of teeth, tetracycline, doxycycline, sulfa drugs. If near delivery,because they can increase the chance of serious newborn jaundice,
Aspirin
Aspirin is an antiplatelet d u g that has used over 100 years in various conditions. It acts by inhibiting cyclooxygenase, inhibiting the production of thromboxane A2 which is a powerful vasoconstrictor: The dose recommended is 75 325 mg daily and is used in ischemic heart disease as a primary prophylaxis in stable angina, in unstable angina, in acute myocardial infarction and as a secondary prophylaxis after myocardial infarction. It is also used before and after percutaneous coronary interventions, after coronary artery bypass surgery, in coronary ectasia and aneurysms, Kawasaki disease and in prevention of rectal cancer.
Aspiiin can cause gastric erosion particularly in high doses. At term of pregnancy aspirin need to be avoided because of its risk of bleeding. Other side effects include allergic phenomenon, precipitation of bronchial asthma, aspirin resistance can occur in some individuals.
Warfarin
Warfarin is a coumariii derivative, produces an anticoagulation effect by interfering with cyclic interconversion of vitamin K and its 2, 3 epoxide (Vitamin K epoxide) Vitamin K is a cofactor for the carboxylation of glutamate residues to gamma-carboxy glutamates (Gla) on the N terminal regions of vitamin K dependent proteins. Warfarin also interferes with the carboxylalion of G l a proteins synthesized in the bone. This can cause fetal bone abnormalities when mothers are treated with warfarin during pregnancy but do not affect bone metabolism in children or adults. When administered orally, it is rapidly absorbed from gastrointestinal tract and reaches peak concentration in 90 minutes and has a half life of 36 to 42 hrs, circulates bound to plasma proteins, mainly albumin and accumulates in the liver. Genetic factors, drugs, diet and various disease states interfere with the response to warfarin. Warfarin is a racernic mixture of two optically active isomers R and S forms in equal proportion.Certain drugs like phenylbutazone, sulphinpyrazone, metronidazole inhibit clearance of S isomer and potentiate the effect of warfarin on the Prothrombin Timc (PT). Drugs like cimetidine, inhibit clearance of R isomer and only modestly affects the PT in patients treated with warfain. Amiodarone inhibits clearance of botli R and S isomers and hence potentiates warfarin anticoagulation. Patients receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary Vitamin K derived froin plant material. Aspirin and nonsteroidal anti-inflammatory agents can increase the risk of warfarin associated bleeding. Eiythromycin can also potentiate anticoagulant effect of warfarin. The practice of giving loading dose initially is not necessary. The usual maintenance dose of 5 mg daily is started and prothrombin time is measured International Normalized Ratio (INR) is calculated and dose of warfarin is adjusted to maintain INR between 2 and 3. Frequent checking is needed. The larget INR also varies depending on the clinical usage of warfarin e.g., for preventing deep vein thrombosis, or for mechanical heart valves.
Inotropes
Inotropic drugs slimulate the myocardium, particularly used ik treating pal'ients with congestive cardiac failure. The cornillonly used inotropic drugs are:
1) Digitalis Glycosides.
2) Adrenergic Agonists: Dopamine, ~obut'arnine, Epinephrine, Isoproterenol, nor Epinephrine.
3) Phospho-diesterase Inhibitors: ~nwinone, Milrenone, Enoximone, Vestarenone.
4) Phospho-diesterase Inhibitors with Calci~lm Sensiliser Activity: pimobendon,levosemindon.
1) Digitalis Glycosides
Digitalis has been used as an inotropic agent in treatment of heart failure for more than 200 years. It stimulates the n~yocardium while depressing sinoahial and ahioventricular nodal functions and this action is pat-licularly useful in treating patients with heart l'ailure and ahial fibrillation. Digitalis inhibits sodium and potassium ATPase in the sarcoleminal membrane of cardiac myocytes, which result in Pregnancy arm increase of calcium available for contractile proteins causing increased force of contracGon. Digitalis preparations are used in pregnancy to treat ml~ythmias and also in congestive heart failure. It belongs to Category C for use in pregnancy (Details already discussed).
2) Adrenergic Agonists
In the failing human heart beta-adrenergic pathways undergo desensitization regulato~y changes that occur in receptors, G proteins and adenylcyclase. All beta-adrenergic agonist are given intravenously for short term support in decompensated heart failure. However they are also arrhythmogenic.
a) Dobutamine: It is an extremely useful agent for moderately decompeilsated heart failure. It increases cardiac output, decreases systemic vascular resistance, and is also a vasodilator. At higher dose it exhibits alpha1 adrenergic agonist action causing vasodilatation, with minimal change in after load and preload. Another advantage is that it does not produce much increase in heart rate at doses of 10 rnicrogm/kg/min. Dobutamine infusions are initiated at 2-3 microgm/kg/min and dose is tiitrated. The limitations of Dobutamine are:
1) It is a weak beta agonist.
2) Only moderately lowers elevated pulmonary artery pressure.
3) May produce desensitizing phenomenon when used chronical1y:In
pregnancy it is usually safe and belongs to Category B.
b) Dopamine: Doparnine is a catecholamine which is the~recursor of nor epinephrine in the catecholamine synthesis pathway. It stimulates both adrenergic and dopamine receptors. Haemodynarnic effect is dose dependent. Low dose is associated with renal and spl$chnic vasodilatation resulting in enhanced diuresis. Moderate doses enhance cardiac contractility and heart rate. High doses .cause increased peripheral vasoconstriction. Used in severe heart failure particularly with hypo-tension. Usual dose is 5 rnicrogm/kg/min by continuous infusion arid titration of dosage which should not exceed 20 rnicrogm/kg/min. Its safety in pregnancy has not been established and belongs to category C.
c) Nor Epinephrine: Naturally occurring catecholamine, potent alpha-receptor and mild beta receptor activity, causes increase in myocardial contractility, heart rate and &soconstriction, increase pressure and after load. Generally reserved for patients with severe hypotension. Dose is 0.5 to 1 microgm/kg/min IV infusion. It belongs to category C, Safety in pregnancy not established.
3) Phospho-diesterase Inhibitors
The ~hoi~ho-diesterase
type III enzyme is associated with the sarcoplasrnic reticulum in the cardiac myocytes and vascular smooth muscles where L
i breaks down cyclic AMP (Adenosine Monophosphate) in to AMP. The phosphodiesterase inhibitors(PDEI) inhibit this enzyme and increase systolic calcium in+the myocyte. They are also vasodilators. and inhibit platelet aggregation.
a) Amrinone: It produces vasodilatation and also tachycardia. It produces thromboyictopenia and may be associated with subsensitivity in subjects with advanced heart failure, it is not widely used. It belongs to category C use in pregnancy and safety not established.
b) Milrenone: It does not cause thrombocytopenia commonly, incidence being 0.4 per' cent, it produces sustained inoko~ic and vasodilator effects whenadministered intravenously. The PROMISE trial, Prospective Randomized Milreiione Survival Evalulation, showed increase in mortality in patients with lieart failure receiving oral milrenone and hence development of oral milrenone was abandoned. However the dosage used in this trial was high. IV milrenone is used for short-term circulatory support in patients with heart failure.
C) Vesnwinone is an oral form of inotropic agent but this also has dose related increase in mortality.Use of milrenone and arnrinone in pregnancy, safety has not been established and belollgs to category C.
4) Phospho-diesternse Inhibitors with Calcium Sensitizer Drugs belonging to this group are Pimobendan and Levosemendan, Pimobendan
is a weak inotropic agent and oral form is available. Levosemindan is available both oral and intravenous forms. Data on safety of their use in pregnancy is not available.
Factors affecting Pharrnacotherapy during Pregnancy Maternal Factors
Absorption
The intestinal motility is reduced due to increased plasma progesterone level resulting in about 30-50 per cent decrease in gastric and intestinal emptying and hence increases absorption of the drug administered. The gastric pH is also increased.Distribution During pregnancy the increase in plasma volume expansion can result in altered volume of distribution of some drugs. Hence higher loading doses may be needed to produce expected serum concentration.
Protein Binding
Dilulional hypoalbuminaemia occurs during pregnancy resulting in decreased protein binding of some drugs. This will affect the estimation of serum concentration of total drug in pregnant women, which may lead to unnecessary increase in drug dosage.Greater fluctuation in the unbound concentration within a dosing interval can produce toxic effects at the beginning of a dosing interval and hence frequent dosing without change in daily dosage may be required.
Progesterone and other endogenous substances can increase or decrease in hepatic metabolism of certain drugs e.g., phenytoin nletabolism is increased while theophylline melrtbolism is decreased. Similarly increase in renal plasma flow and glomerular filtration rate can increase renal nletabolisnl of drugs.
Placental Fetal Unit
Absorption
Unbound free drug only can cross the placental barrier. Non-ionized lipid soluble molecules can cross placenta than less lipid soluble ionized molecdes. Maternal and fetal pH influences the crossing of placenta.
Distribution
Nearly 50 per cent of fetal circulation directly reaches the heart and brain by passing the liver. The affinity of drug to bind to fetal plasn~a proteins may bc different from that of maternal protein and hence can iilfluence the concentration of free drug.
Elimination
Most of the drugs are prinlarily eliminated by diffusion of the dlug back to the malernal coinpartment, although there is evidence of nletabolis~n in placenta and fetus to some extent.Congenital malfortnations are generally caused by drug loxicity during the first hiinester and depend on the nature of the drug, duration of fetal exposure and the genetic susceptibility of the fetus. Hence d n ~ g adminislration in the first trimester should be avoided as much as possible. In the second and third trimesters, interference with fetal growth and developnlent is the major potenlial hazard of d t ~ l g exposure.Mothers requiring continuation of drugs and who want breastfeeding also pose potential problems. Many dnlgs taken by the mother may appear in huinan milk and drug level in milk depends on the properties of the drug, degree of plasma binding and the maternal senlm concentration. Unionized clrugs, with minimal protein binding and high lipid solubility are found more readily in breast milk.
Commonly Used Drugs
Beta-Blockers
Beta-adrenergic blocking agcnts act by blocking 1 and 2 receptors. Cardiac effects are mediated primarily by beta1 rcceptors while two receptors are found in the bronchi and the blood vessels. Myornetrial relaxation mediated by two receptors occurs in pregnancy. Non-selective beta-blockers are: propanolol, nadolol, pindolol,sotalol, carvedilol and labetalol. Carvedilol and labetalol also have alpha blocking activity. One selective antagonist are: atenolol, metoprolol and esmolol. Beta-blockers are indicated in hypertension, ischemic heart disease, control of ventricular rate in atrial fibrillation and atrial flutter, in the management of supraventricular tachycardia. During pregnancy they are used to control hypertension, hereditaty long Q-T syndrome, thyrotoxicosis, idiopathic hypertrophic sub aortic stenosis and fetal tachycardia. Beta-blockers do not cause fetal malformation. Beta-blockers readily cross the placenta.
i)Propranolol: Propranolol has been used in pregnancy over several years with favorable reports. However, adverse fetal effects have been described including bradycardia, birth apnea, hypoglycemia, intrauterine growth retardation, and f are not reported consistently in chronic therapy prolonged labour. ~ u they studies. It is also excreted in the milk but the amount excreted is far less to cause
adverse effects in the infant.
ii) Metoprolol: It is a selective Beta-blocker. It crosses placenta. Metoprolol administered to treat hypertensive pregnant women was effective and did not cause any significant adverse effect. It has also been used to control supraventricular tachycardia in pregnant women with safety with no adverse effect on fetal heart rate. However, the use of beta-blockers in general should be avoided in those who are likely to give birth to very low birth weight infants because of poor outcome seen in these circumstances.
iii) Atenolol: Atenolol is one selective blocker with relatively long half-life. It readily crosses placenta. Effective in treatment of hypertension during pregnancy with no significant adverse effects. However it is better to avoid in mothers who are likely to give birth to very low birth weight infants. Atenolol has shown beneficial effects in women with risk of pre-eclampsia by decreasing
the incidence of pre-eclampsia from 18 per cent to 3.8 per cent. Atenolol is also excreted in breast milk but the infants breast-fed by atenolol treated mothers demonstrated negligible plasma drug levels. Atenolol provides a good blood pressure control and well tolerated by mother and fetus. However, therapy in the first trimester is to be avoided because atenolol could cause low birth
weight.
iv) Pindolol: It is a non-selective beta-blocker approved by US Food and Drug-Administration (FDA) in pregnancy risk classification category B. It has intrinsic sympathommetic activity. It is relatively safe to use in pregnancy to control blood pressure.
v) Acebutolol: Selective one receptor blocker and approved by US FDA in pregnancy risk classification category B. It does not cause low birth weight or any significant side effects in pregnancy when used for treatment of hypertension.It is also excreted in milk.
vi) Esrnolol: It is ultra short acting selective 1 receptor blocker used intravenously to control heart rate in pregnancy with thyrotoxicosis and to treat supraventricular tachycardia, and in hypertension. It has a rapid action (within 5-10 min) with plasma half-life of only 9 rnin. It is relatively safe to use in pregnancy. However a few side effects like weak cry of new born, poor muscle tone heart rate of 120 beats per minute in new born have been reported.
vii) Sotalol: It is a non-selective beta-blocker with class III electrophysiological properties. It is protein bound. It is used to treat hypertension and to treat maternal and fetal arrhythmias. Transplacental therapy to treat fetal arrhythmias shas been used with success. It is also excreted in milk but no significant side effects reported in infants.
In general beta-blockers are relatively safe to be used in pregnancy. However, the following factors need to be considered:
a) Try to avoid initiating beta-blockers if possible, during first trimester.
b') Lower doses need to be used.
c) It is preferable to discontinue beta-blockers 2 to 3 days before delivery to limit di-ugs effect on uterine contraction.
d) Neonates born to mothers receiving beta-blockers need to be monitored for 72 to 96 hrs.
e) Bela-blockers with intrinsic sympathoinmelic activity or with alpha blocking propertics inay be preferred. Better to avoid blocking of two mediated uterine relaxation and vasodilatation.
f)Avoid breastfeeding 3-4 hours after the dose of beta-blockers at the time of expected peak concentralion of the dmg.
Digitalis
Digitalis preparations cross the placenta but no tcratogenic effects are reported.However adverse effects on the fetus have been reported in the fetus of the mothers who developed digitalis toxicity. Electrocardiographic changes and subsequent death of infants has been reported with maternal digitalis intoxication, miscarriage and low birth weight of new born have also been reported. Digitalis preparations are the mainstay in the treatment of fetal arrhythmias providing nearly 80 per cent of success rates in supraventricular tachycardias and considered by some as the routine drug of choice in treating fetal arrhythmias. In pregnancy with fetal hydrops higher doses of digitalis is needed because of reduced transplacental passage of digitalis but needs close monitoring of matei~lal loxlcity. The eftjcacy of digitalis in atrial flutter diminishes and Wolf-Parkinson - White syndrome could worsen with digitalis.
Digitalis is indicated in congestive cardiac failure particularly associated with atrial fibrillation. Digitalis preparations are excreted in breast milk in similar concentrations as ll~at found in maternal serum. However, the total amount of daily maternal excretion is minute and do not cause significant effect on the breast fed infant. Hence digitalis is considered safe in lactating inothers. Digoxin is the drug preferred among other digitalis preparations because of its extensive use in pregnancy. Digitalis
preparation are important in treating heart fililure in pregnancy, since angiotensin converting enzyme inhibitors are contraindicated in pregnancy as they may cause renal failure in the fetus or newborn.
Anti-Arrhythmic Drugs
According to Vaughan-Williams antiarrhythmic drugs are classified as follows:
Class IA: Dnlgs that reduce the rate of rise of action potential upstroke and prolong action potential duration e.g., quinidine, procainamide, disopyramide.
Class IB: Drugs that shorten action potential duration do not reduce rate of rise of action potential e.g., mexiletine, phenytoin 'and lidocaine.
Class IC: Drugs that reduce the rate of rise of action potential, priinarily slow conduction and can prolong refractoriness minimally e.g., flecanide, prop,afenone, and morcizine. .
Class 11: Drugs that block beta-adrenergic receptors e.g., propranolol, timolol,metaprolol, atenolol.
Class III: Drugs that block potassium channels e.g., sotalol, amiodarone, bretylium.
Class IV: Drugs that block slow calcium channels e.g., verapamil, diltiazem. The use of some of the commonly prescribed drugs during pregnancy is discussed.
Class IA
- Quinidine: Class IA drug reduces the rate of rise of action potential by blocking sodium channel. Used in treatment of ventricular and supra ventiicular arrhythmias, including those associated with Wolf-Parkinson White (WPW) syndrome. Quinidine is also used for termination of atrial flutter, atrial fibrillation, it is also used for transplacental treatment of fetal supraventricular tachycardia, fetal atrial flutter1 1. It is relatively safe, but fetal thrombocytopenia,eight-nerve toxicity have been reported. Quinidine is also excreted in milk but the amount likely to be ingested by infant is low and hence safe to use in lactating mothers.
- Procainamide: Its action is similar to that of quinidine, used to prevent or terminate supraventricular and ventricular arrhythmias and to maintain sinus rhythm after cardioversion of atrial fibrillation. There are only a few reports of its use in pregnancy, most of them are for treatment of fetal supraventricular tachycardias. Both procai~mmide and its metabolite N- Acetyl Procainamide (NAPA) are excreted in milk but the amount ingest by infant is low and hence safe. It does not cause any teratogenic effect. However, long-term therapy may cause lupus like syndrome.
- Disopyramide: It is used for treatment of venllicular mhythmias. Indications and actions are similar to procainamide. Also used in supraventricular arrhythmias. It is not teratogenic but can cause low birth weight in higher dose. Initiation of premature labour has been reported by use of disopyramide for cardiac arrhythmiasl2. It is also excreted in breast milk but no side effects reported in infant and hence its use is safe in lactating mothers.
Class IB
Lidocaine: Lidocaine has been used p imarily for epidural or local anesthesia during pregnancy and data of its use as antiarrhythmic agent in pregnancy is scanty. No teratogenic effect reported. It is excreted in milk but the amount reaching the infant is low and safe. Respiratory tract anomalies, hernias in the newborn have been reported. Cautious use with hepatic dysfunction is advocated as it is metabolized in the liver.
Class IC
Flecanide: It has been used with clinical effectiveness to treat maternal tachyarrhythmiasl3. 1t readily crosses placenta and has been used to treat fetal tachycardias. It has been found that the fetus can metabolize the dnlg to avoid accumulation to produce toxicity. Flecanide has been coilsidered by some as rtreatment of choice in fetal supraventricular tachycardia, particularly refractory to digitalis. Use of flecanide is conlpatible with breastfeeding. It is proa~hythmic drug in that it may aggravate existing arrhythmia and may cause new ventricular arrhytlunias.
Propafenone: Its use in pregnant women+as been documented. It crosses placenta and is also excreted in milk but is safe for breastfeeding as the ingested amount by infant is low.Although Class IC drugs are reported favorably during pregnancy, there are no randomized controlled studies involving the use of these drugs in pregnancy and breastfeeding. Their routine use in pregnancy is not recomn~ended at this timel4.
Class I1
a) Beta-blockers - It is described above.
Class I11
Amiodarone: After an oral dose absorption is slow and incomplete and unpredictable. Approximalely 50 per cent of drug is absorbed. Although peak concentration is reached in 2-10 hours, therapeutic steady state levels could take up to 4 weeks. Drug tieposits could bc found in nearly evely tissue, including skin, coniea and liver. The rnain metabolile is desethylamiodarone (DEA) the elimination half-life is I3 to 100 days with an average of 40-50 days rind about 96 per cent of the drug is protein bound. Amiodarone and its metabolites pass through placenta. There we illany reports of use of amiodarone in the treatmenl o l maternal tachya~hylhmias like atrial flutter, atrial fibrillation, supraventricular tachycardia and also in the treatment of fetal tacllyarrllythn~ias. Some have reported amiodarone therapy early in gestation with no adverse effects, while others have reported adverse efSect including bradycardia, QT prolongation in the newborn. Tlle high content of iodine in amiodarone - approximately 40 per cent weight has been inlplicated in causing fetal hypotllysoidism in a of its molecular number of pregnant womcn receiving amiodarone therapy. It may also cause neurodevelopmental problems, and prcmaturity. It is also secreted in nlilk. In view o l side effects of amiodarone during pregnancy it should be used with,caution as a seconti line drug in incessant arrhythmias. Although some reports have shown safety ol' amiodarone for breast feeding, high accumulation of drug in breast milk occurs and hence not recommended in nursing mothers.
Class IV
Anti nrrhythmic Drugs
Calcium channel antagonists
Verapamil: Verapamil is very effective in the cardioversion of paroxysmal supraventricular tachycardia to sinus rhythm and in slowing the ventricular rate in atrial flutter or fibrillation. It has been used in the treatmenl of mateinal supraventricular tachycardias, preclainpsia, severe matcrnal hypertension and tachycardia without severe adverse effects. It crosses fetal s~~praventricular placenta and in chronic therapy for hyperlension with verapamil, lower birth weight in infants have been reported. Maternal second degree atrioventricular block can occur. It is also excreted in milk and although some studies have shown no adverse effects in breast fed infants, others have reported high concentration in milk and cautioned against breastfeeding while on verapamil therapy.
- Diltiazem: The electrophysiological aclion $ similar to verapamil. No adverse effect is reported for its use in pregnancy. It is also excreted in milk.
- Nifedipine: It is a lipophylic dihydropyridine derivative. It has a potent vasodilating effect on vascular smooth muscle and minimal effect on cardiac conduction system. It reduces systemic arterial and pulmonary arterial pressures, its use as an anti-hypertensive agent is effective and safe. It has also been used in primary dysrnenoirhea, bladder instability and Raynaud's phenomenon. 11 can cross the placenta, fetus can metabolize the drug. It is no1 teratogenic. It has also been used as a tocolytic agent to delay labour, It is excreted in milk but breastfeeding is safe.
- Amlodipine: This is less lipid soluble, has a slow, smooth onset and ultra-long duration of action (plasma half life of 36 hrs), it is a vasodilator and may be used as once daily antihypertensive agent and also in angina pectoris. It is effective and well tolerated. It has little if any negative inotropic action and inay be used in angina or hypertension with left ventricular dysfunction. The Prospective Randornised Amlodepine Survival Evalualion (PRASE) Study with class 11 to IV (New York Heart Association Class) in patients with ischemic cardiornyopathy,showed that arnlodipine can be safely used to control hypertension or angina without adverse effect on survival. Side efrects include edema of the legs. In the treatment of hypertension in pregnancy calcium channel antagonists are also acceptable on the basis of limited data.
- Nicardipine: It is dihydropyl-idine calcium antagonist used in treatment of angina and hypertension. It is similar to nifedipine and also used as a tocolytic agent,more potent, but slow in action compared to other drugs.
Adenosine
It is a purine nucleoside and is effective in treating paroxysmal supraventricular tachycardias. It is a natural compound and has a very short half-life of seven seconds and hence an attractive drug to use in pregnancy. However the data on its use in pregnancy is limited. Several case reports of its use in pregnancy with supraventricular tachycardias have shown good results showing efficacy and lack of adverse or teratogenic effects on the fetus. Though data is not available of its secretion in milk, because of its short action it may be safe to use in lactating mothers.
Diuretics
By definition diuretics are drugs that increase urine flow. They are mainly used to treat medical conditions where there is excess accumulation of fluid and salt in the body, as in patients with heart failure, liver disease and kidney disease. These drugs act on the kidneys to increase urine output. Diuretics are also used in the treatment of hypertension. All diuretics initially lower the blood pressure by increasing urinary sodium excretion and by reducing plasma volume, extra cellular fluid voluine and cardiac output. In later stages (6-8 weeks) diuretics acl by reducing the peripheral resistance which may involve potassium channel activation. Diuretics are generally classified as
1 ) Loop Diuretics: Such as bumetanide, filrosemide and torsemide act on the loop of Henle and inhibit sodium, potassium and chloride co-transporter.
2)Thiazide and Thiazide: Thiazide and Thiazide like diuretics which inhibit sodium and chloride cotransporter. They act on the distal convoluted tubules. The drugs include hydrochlorothiazide, chlorothiazide and chlorthalidone.
3) Potassium Sparing Diuretics: They prevent the loss of potassium. Amiloride and triarnterene belong to this group. Inhibitors of mineralocorticoids, like spionolactone is also included in this group, together called 'potassium sparing diuretics'.Use of Diuretics in Pregnancy
1)Hydrochlorothiade: Not commonly used drug in the treatment of hypertension in pregnancy. Usual dose is 25 to lOOmg orally. Prevents nolmal physiologic volume expansion that occurs in pregnancy and may reduce uterine blood flow. It should be restricted in its use in women with volume overload states.
2 ) Furosemide: It is used to treat pulmonary edema associated wilh pre-eclampsia.The usual dose is 10 mg IV initial dose. 20-80 mg per day orally.
3) Spironolactone: Anti aldosterone agent, used to treat hypertension and congestive cardiac failure. Recently, it has been shown to reduce mortality in severe heart failure patients. However its use in pregnancy and safety has not been documented.ACE1 (Angiotensin Converting Enzyme Inhibitors)This group of drugs are inclicated in non-pregnant patients in the management of hypertension, congestive cardiac failure, left ventricular dysfunction, and in ischemic heart diseases and particularly indicated in diabetics to prevent proteinuria. However they are contraindicated in pregnancy because of fetal toxicity and cleath.
Antibiotics
Antibiotics are used to treat concurrent infections during pregnancy. In general every medication is assigned to a category based on whether it is safe or risky to use duiing pregnancy.
Category A
Only a few medications fall in category A, which means that human studies have shown no evidence of fetal harm in the first trimester or later in the pregnancy. Very few medications fall in this categoly. Example Nystatin vaginal prepswations(Mycostatin).
Category B
Most antibiotics are category B, which means that there is no known association with birth defects or other pregnancy related conlplications and the dlvg is probably safe.These include Amoxycillin, Anlpicillin, Amoxycillin-clavulinate, Dicloxacillin, nitrofurantoin, metronidazole. (Controversial over oral use in first tiimester).Cephalosporins, clindamycin, erythromycin, azithromycin, sulfa-drugs (until near term) acyclovir, valacyclovir.
Category C
No enough information about their use in pregnancy or there are concerns arising from animal studies, but no confirlnation of problems like birth defects in humans,These include trimethoprim, clarithroinycin, ciprofloxacin, tluconazole, terconazole,isoniazid, rifampicin, mebendazole, tetanus toxoid, vaccines- hepatitis A, hepatitis B,influenza, polio, measeles, mumps and rubella.
Category D
Medications have clear cut problems in pregnancy and should not be used unless there are no better alternatives. The category D includes, tetracycline derivatives, which can cause discoloration of teeth, tetracycline, doxycycline, sulfa dn~gs. If near delivery, because they can increase the chance of serious newboil1 jaundice.
-
Nifedipine: It is a lipophylic dihydropyridine derivative. It has a potent vasodilating effect on vascular smooth muscle and minimal effect on cardiac conduction system. It reduces systemic arterial and pulmonary arterial pressures, its use as an anti-hypertensive agent is effective and safe. It has also been used in primary dysmenorrhea, bladder instability and Raynaud's phenomenon. It can cross the placenta, fetus can metabolize the drug. It is not teratogenic. It has also been used as a tocolytic agent to delay labour. It is excreted in Inilk but breastfeeding is safe.
- Amlodipine: This is less lipid soluble, has a slow, smooth onset and ultra-long duration of action (plasma half life of 36 hrs), it is a vasodilator and may be used as once daily antihypertensive agent and also in angina pectoris. It is effective and well tolerated. It has little if any negative inotropic action and may be used in angina or hypertension with left ventricular dysfunction. The Prospective Randornised Amlodepine Survival Evaluation (PRASE) Study with class I1 to IV (New York Heart Association Class) in patients with ischemic cardiomyopathy,showed that arnlodipine can be safely used to control hypertension or angina without adverse effect on survival. Side effects include edema of the legs. In the treatment of hypertension in pregnancy calcium channel antagonists are also acceptable o n the basis of limited data.
-
Nicardipine: It is dihydropyridine calcium antagonist used in treatment of angina and hypertension. It is similar to nifedipine and also used as a tocolytic agent, more potent, but slow in action compared to other drugs.
Adenosine
It is a purine nucleoside and is effective in treating paroxysmal supraventricular tachycardias. It is a natural compound and has a very short half-life of seven seconds and hence an attractive di-ug to use in pregnancy. However the data on its use in pregnancy is limited. Several case reports of its use in pregnancy with supraventricular tachycardias have shown good results showing efficacy and lack of adverse or teratogenic effects on the fetus. Though data is not available of its secretion in milk, because of its short action it may be safe to use in lactating mothers.
Diuretics
By definition diuretics are drugs that increase urine flow. They are mainly used to treat medical conditions where there is excess accumulation of fluid and salt in the body, as in patients with heart failure, liver disease and kidney disease. These drugs act on the kidneys to increase urine output. Diuretics are also used in the treatment of hypertension. All diuretics initially lower the blood pressure by increasing urinmy sodium excretion and by reducing plasma volume, extra cellular fluid volume and cardiac output. Ln later stages (6-8 weeks) diuretics act by red~zcing the peripheral resistance which may involve potassium channel activation.Diuretics are generally classified as
1) Loop Diuretics: Such as bumetanide, furosemide and torsemide act on the loop of Henle and inhibit sodium, potassium and chloride co-transporter.
2)Thiuzide and Thiazide: Thiazide and Thiazide like diuretics which inhibit sodium and chloride cotransportera They act on the distal convoluted tubules. The drugs include hydrochlorothiazide, chlorothiazide and chlorthalidone.
3 ) Potassium Sparing Diuretics: They prevent the loss of potassium. Alniloride and triamterene belong to this group. Inhibitors of mineralocorticoids, like spionolactone is also included in this group, together called 'potassium sparing diuretics'.Use of Diuretics in Pregnancy
1) Hydrochlorotltiade: Not commonly used drug in the treatment of hypertension in pregnancy. Usual dose is 25 to l0Omg orally. Prevents normal physiologic volume expansion that occurs in pregnancy and may reduce uterine blood flow. It should be restricted in its use in women with volume overload states.
2 ) Furosemi.de: It is used to treat pulmonary edema associated with pre-eclampsia.The usual dose is 10 mg IV initial dose. 20-80 mg per day orally.
3) Spironolactone: Anti aldosterone agent, used to treat hypertension and congestive cardiac failure. Recently, it has been shown to reduce mortality in severe heart failure patients. However its use in pregnancy and safety has not been documented.
ACE1 (Angiotensin Converting Enzyme Inhibitors)
This group of drugs are indicated in non-pregnant patients in the management of hypertension, congestive cardiac failure, left venlricular dysfunction, and in ischemic heart diseases and particularly indicated in diabetics to prevent proteinuiia. However ;hey are contraindicated in pregnancy because of fetal toxicity and death.
Antibiotics
Antibiotics are used to treat concurrent infections during pregnancy. In general every medication is assigned to a category based on whether it is safe or risky to use during pregnancy.
Category A
Only a few medications fall in category A, which means that human studies have shown no evidence of fetal harin in the first trimester or later in the pregnancy. Veiy few medications fall in this catcgoiy. Example Nystatin vagii~al preparations(Mycostatin).
Category B
Most antibiotics are category B, which means that thcre is no known association with birth defects or other pregnancy related co~nplications and the drug is probably safe.These include Amoxycillin, Ampicillin, Ainoxycillin-clavulinate, Dicloxacillin, nitrofurantoin, metronidazole. (Controversial over oral use in first trimester). Cephalosporins, clindaniycin, erythromycin, azithromycin, sulfa-diugs (until near term) acyclovir, valacyclovir.
Category C
No enough infomation about their use in pregnancy or there are concerns arising from animal studies, but no confirmation of problems like birth defects in humans,These include trimethoprim, clarithromycin, ciprofloxacin, fluconazole, terconazole,isoniazid, iifampicin, mebendazole, tetanus toxoid, vaccines- hepatitis A, hepatitis B,influenza, polio, measeles, mumps and rubella.
Category D
Medications have clear cut problems in pregnancy and should not be used unless there are no better alternatives. The category D includes, tetracycline derivatives, which can cause discoloration of teeth, tetracycline, doxycycline, sulfa drugs. If near delivery,because they can increase the chance of serious newborn jaundice,
Aspirin
Aspirin is an antiplatelet d u g that has used over 100 years in various conditions. It acts by inhibiting cyclooxygenase, inhibiting the production of thromboxane A2 which is a powerful vasoconstrictor: The dose recommended is 75 325 mg daily and is used in ischemic heart disease as a primary prophylaxis in stable angina, in unstable angina, in acute myocardial infarction and as a secondary prophylaxis after myocardial infarction. It is also used before and after percutaneous coronary interventions, after coronary artery bypass surgery, in coronary ectasia and aneurysms, Kawasaki disease and in prevention of rectal cancer.
Aspiiin can cause gastric erosion particularly in high doses. At term of pregnancy aspirin need to be avoided because of its risk of bleeding. Other side effects include allergic phenomenon, precipitation of bronchial asthma, aspirin resistance can occur in some individuals.
Warfarin
Warfarin is a coumariii derivative, produces an anticoagulation effect by interfering with cyclic interconversion of vitamin K and its 2, 3 epoxide (Vitamin K epoxide) Vitamin K is a cofactor for the carboxylation of glutamate residues to gamma-carboxy glutamates (Gla) on the N terminal regions of vitamin K dependent proteins. Warfarin also interferes with the carboxylalion of G l a proteins synthesized in the bone. This can cause fetal bone abnormalities when mothers are treated with warfarin during pregnancy but do not affect bone metabolism in children or adults. When administered orally, it is rapidly absorbed from gastrointestinal tract and reaches peak concentration in 90 minutes and has a half life of 36 to 42 hrs, circulates bound to plasma proteins, mainly albumin and accumulates in the liver. Genetic factors, drugs, diet and various disease states interfere with the response to warfarin. Warfarin is a racernic mixture of two optically active isomers R and S forms in equal proportion.Certain drugs like phenylbutazone, sulphinpyrazone, metronidazole inhibit clearance of S isomer and potentiate the effect of warfarin on the Prothrombin Timc (PT). Drugs like cimetidine, inhibit clearance of R isomer and only modestly affects the PT in patients treated with warfain. Amiodarone inhibits clearance of botli R and S isomers and hence potentiates warfarin anticoagulation. Patients receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary Vitamin K derived froin plant material. Aspirin and nonsteroidal anti-inflammatory agents can increase the risk of warfarin associated bleeding. Eiythromycin can also potentiate anticoagulant effect of warfarin. The practice of giving loading dose initially is not necessary. The usual maintenance dose of 5 mg daily is started and prothrombin time is measured International Normalized Ratio (INR) is calculated and dose of warfarin is adjusted to maintain INR between 2 and 3. Frequent checking is needed. The larget INR also varies depending on the clinical usage of warfarin e.g., for preventing deep vein thrombosis, or for mechanical heart valves.
Inotropes
Inotropic drugs slimulate the myocardium, particularly used ik treating pal'ients with congestive cardiac failure. The cornillonly used inotropic drugs are:
1) Digitalis Glycosides.
2) Adrenergic Agonists: Dopamine, ~obut'arnine, Epinephrine, Isoproterenol, nor Epinephrine.
3) Phospho-diesterase Inhibitors: ~nwinone, Milrenone, Enoximone, Vestarenone.
4) Phospho-diesterase Inhibitors with Calci~lm Sensiliser Activity: pimobendon,levosemindon.
1) Digitalis Glycosides
Digitalis has been used as an inotropic agent in treatment of heart failure for more than 200 years. It stimulates the n~yocardium while depressing sinoahial and ahioventricular nodal functions and this action is pat-licularly useful in treating patients with heart l'ailure and ahial fibrillation. Digitalis inhibits sodium and potassium ATPase in the sarcoleminal membrane of cardiac myocytes, which result in Pregnancy arm increase of calcium available for contractile proteins causing increased force of contracGon. Digitalis preparations are used in pregnancy to treat ml~ythmias and also in congestive heart failure. It belongs to Category C for use in pregnancy (Details already discussed).
2) Adrenergic Agonists
In the failing human heart beta-adrenergic pathways undergo desensitization regulato~y changes that occur in receptors, G proteins and adenylcyclase. All beta-adrenergic agonist are given intravenously for short term support in decompensated heart failure. However they are also arrhythmogenic.
a) Dobutamine: It is an extremely useful agent for moderately decompeilsated heart failure. It increases cardiac output, decreases systemic vascular resistance, and is also a vasodilator. At higher dose it exhibits alpha1 adrenergic agonist action causing vasodilatation, with minimal change in after load and preload. Another advantage is that it does not produce much increase in heart rate at doses of 10 rnicrogm/kg/min. Dobutamine infusions are initiated at 2-3 microgm/kg/min and dose is tiitrated. The limitations of Dobutamine are:
1) It is a weak beta agonist.
2) Only moderately lowers elevated pulmonary artery pressure.
3) May produce desensitizing phenomenon when used chronical1y:In
pregnancy it is usually safe and belongs to Category B.
b) Dopamine: Doparnine is a catecholamine which is the~recursor of nor epinephrine in the catecholamine synthesis pathway. It stimulates both adrenergic and dopamine receptors. Haemodynarnic effect is dose dependent. Low dose is associated with renal and spl$chnic vasodilatation resulting in enhanced diuresis. Moderate doses enhance cardiac contractility and heart rate. High doses .cause increased peripheral vasoconstriction. Used in severe heart failure particularly with hypo-tension. Usual dose is 5 rnicrogm/kg/min by continuous infusion arid titration of dosage which should not exceed 20 rnicrogm/kg/min. Its safety in pregnancy has not been established and belongs to category C.
c) Nor Epinephrine: Naturally occurring catecholamine, potent alpha-receptor and mild beta receptor activity, causes increase in myocardial contractility, heart rate and &soconstriction, increase pressure and after load. Generally reserved for patients with severe hypotension. Dose is 0.5 to 1 microgm/kg/min IV infusion. It belongs to category C, Safety in pregnancy not established.
3) Phospho-diesterase Inhibitors
The ~hoi~ho-diesterase
type III enzyme is associated with the sarcoplasrnic reticulum in the cardiac myocytes and vascular smooth muscles where L
i breaks down cyclic AMP (Adenosine Monophosphate) in to AMP. The phosphodiesterase inhibitors(PDEI) inhibit this enzyme and increase systolic calcium in+the myocyte. They are also vasodilators. and inhibit platelet aggregation.
a) Amrinone: It produces vasodilatation and also tachycardia. It produces thromboyictopenia and may be associated with subsensitivity in subjects with advanced heart failure, it is not widely used. It belongs to category C use in pregnancy and safety not established.
b) Milrenone: It does not cause thrombocytopenia commonly, incidence being 0.4 per' cent, it produces sustained inoko~ic and vasodilator effects whenadministered intravenously. The PROMISE trial, Prospective Randomized Milreiione Survival Evalulation, showed increase in mortality in patients with lieart failure receiving oral milrenone and hence development of oral milrenone was abandoned. However the dosage used in this trial was high. IV milrenone is used for short-term circulatory support in patients with heart failure.
C) Vesnwinone is an oral form of inotropic agent but this also has dose related increase in mortality.Use of milrenone and arnrinone in pregnancy, safety has not been established and belollgs to category C.
4) Phospho-diesternse Inhibitors with Calcium Sensitizer Drugs belonging to this group are Pimobendan and Levosemendan, Pimobendan
is a weak inotropic agent and oral form is available. Levosemindan is available both oral and intravenous forms. Data on safety of their use in pregnancy is not available.
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