Cardiovascular drugs and diuretics

4.6.1

β-Receptor blockers

Circulatory symptoms and hypoglycemia have been cited in connection with the intake of β-receptor blockers via mother’s milk. However, by contrast to prenatal exposure, such effects are less likely during breastfeeding, due essentially to the relatively low concentrations of these drugs in infant blood.

Bradycardia, hypotension and tachypnea have been seen in connection with acebutolol , which has a half-life of 3–4 hours and 26% plasma protein binding (PPB). Therefore, mathematically, the baby has received about 5–10% of the maternal dose per kg of bodyweight ( ). In particular, the active metabolite, diacetolol (half-life 8 to 13 hours), accumulates in the mother’s milk with an unusually high milk/plasma (M/P) ratio of up to 24.7.

Atenolol has a half-life of 6 to 7 hours, a minimal PPB, and is hydrophilic. A recent study ( ) examines the influence of atenolol on breastfed babies at 2 to 4 weeks of age ( n = 32), 3 to 4 months ( n = 22) and 6 to 8 months ( n = 17). The maternal dose was between 25 and 200 mg/day. The M/P ratio was, on average, greater than 4.9, whereby the average relative infant dose was less than 15%. Infant doses of 34.8% (after 2 to 4 weeks) or 17.8% after 3 to 4 months were noted. Atenolol was not detected in the serum of any of the babies at 3 to 4 months. Further, whether maternal atenolol had a depressive effect on the heart rate in crying infants has been examined and no effect has been noted in this single study. However, describes a breastfed infant who had toxic concentrations of atenolol acquired from her mother (dose 50 mg twice daily). This full-term infant at the age of 5 days had been transferred to the neonatal intensive care unit because of cyanosis and two episodes of bradycardia (80 beats/min). Forty-eight hours after discontinuing breastfeeding, the atenolol concentration in the baby’s serum was 2010 ng/mL and 24 hours later it was 140 ng/mL. The possible accumulation of atenolol in human milk and infant serum should be considered before prescribing, because safer β-blockers can be used during breastfeeding.

Betaxolol has a half-life of 14 to 22 hours and a PPB of 50%. The relative dose transmitted by the milk reaches a maximum of 4.3% shortly after birth ( ).

Labetalol , which is widely used in the USA, works as an α- and β-receptor blocker, has a half-life of 6 to 8 hours, and a PPB of 50%. With long-term treatment with 300 to 1,200 mg/day, a mother’s maximum milk concentration of 0.7 mg/L and an M/P ratio between 0.2 and 1.5 are reported. Thus, an infant would receive, at most, 0.1 mg/kg daily. This represents 0.3% of the maternal dose per kg bodyweight (survey by ).

There is substantial experience available for metoprolol (half-life 3 to 4 hours, PPB 12%). With long-term therapy with 100 and 200 mg, a maximum of 0.7 mg/L is detected in the milk. The M/P ratio is 3. The daily dose for the infant is, nevertheless, 0.1 mg/kg at most. This represents 3.2% of the maternal weight-related dose. About 10% of the northern European population is thought to metabolize metoprolol slowly. This could be the reason why a plasma concentration of 45 μg/L is measured in one (symptom-free) infant. Among other breastfed infants, it is 0.5–3 μg/L (survey in ). The therapeutic concentration for adults is given as 93–881 μg/L.

With oxprenolol, up to 1.5% of the maternal weight-related dose is transmitted to the baby ( ). Also, the low transfer of oxprenolol via the mother’s milk (half-life 1 to 2 hours, PPB 80%) is confirmed in another study ( ).

Shortly after birth, 3.1 μg/L of S-enantiomers of pindolol and 1.9 μg/L of its R-enantiomers are found in the milk of three breastfeeding mothers who took 20 mg pindolol (half-life 3–4 hours, PPB 40–60%) daily. This represents 0.36% of a maternal weight-related dose ( ). The transfer of mepindolol can be 5% of the maternal weight-related dose (survey in ).

Among β-blockers propranolol is the most frequent studied and used drug.

Propranolol has a PPB of 90% and a half-life of 3 to 6 hours. The maximum transfer of 0.4% into the mother’s milk is quite low (survey in ).

With oral use of timolol , the portion of the maternal weight-related dose that is transmitted is 3.3% ( ). Timolol is used primarily in eye drops for glaucoma treatment ( Chapter 4.12.8 ). This leads to limited concentrations in the milk. calculated a relative dose of 0.024% if the mother puts drops in both eyes twice daily.

There are insufficient data on bisoprolol (half-life 10–12 hours PPB 30%), carvedilol (half-life 6–10 hours PPB >98%), celiprolol half-life 5–6 hours, PPB 25%), nebivolol (half-life of 10–24 hours with slow metabolization, PPB of 98%), penbutolol (half-life of 20 hours PPB 80–98%), and talinolol to make a judgment. This also applies to esmolol (half-life 9 minutes, PPB 55%), which is indicated for i.v. injection with supraventricular tachycardias.

Sotalol has a high risk for accumulation in infants (see also Section 4.6.10 ).

4.6.2

Hydralazine

With 150 mg/day of hydralazine in the breast-feeding mother, a maximum of 130 μg/L is measured in the milk – which is 20 μg/kg per day or 1% of the therapeutic dose for an infant ( ). Following parenteral administration of 10–40 mg, an average of 47 μg/L, including the hydralazine metabolites, was measured in mother’s milk. The M/P ratio was 0.5. With this therapy, up to 108 μg/L of hydralazine was found in the plasma of breastfed infants ( ). By comparison, the plasma concentration in an infant being treated with 2 mg/kg was given as 1,700 μg/L. No toxic symptoms have been observed while breastfeeding. Dihydralazine can be evaluated as if hydralazine.

4.6.3

α-Methyldopa

With daily treatment with 250–2,000 mg of α-methyldopa , up to 1.14 mg/L is measured in the milk. The M/P ratio is 0.2– 0.5. For the infant, a daily dose of 0.17 mg/kg can be calculated, which represents 3.2% of the maternal dose per kg (survey in ). Only in one of three infants could the medication be detected in plasma (90 μg/L). For the mother, it is 4,250 μg/L. No toxic symptoms are observed in the infant. α-methyldopa can promote milk production as a result of increased prolactin secretion ( ).

4.6.4

Calcium antagonists

There is no information on the transfer of amlodipine into the mother’s milk. Two case reports describe age-appropriate development with a maternal dose of 5 and 10 mg/day ( , ).

In 11 mothers, only limited amounts of nicardipine are detected in mother’s milk under steady-state conditions ( ). For a few days postpartum, seven mothers have received nicardipine in an hourly dose of 1–6.5 mg for treating preeclampsia. Less than 0.3 μg/day nicardipine in the mother’s milk, or between 0.015 and 0.004% of a therapeutic infant dose, is calculated for these mother–child pairs ( ).

With nifedipine and its active pyridine metabolites, a maximum of 2–10 μg/kg/day is transmitted to the infant when the mother has taken 30–90 mg/day. That is less than 5% of a weight-related child’s dose ( ). Average values of 2% and less are probably even more realistic ( , ). Nifedipine is also used successfully to treat Raynaud phenomenon of the breast nipple. reports on 12 breastfeeding women complaining of pain in the nipple, which was finally diagnosed as Raynaud phenomenon. Those mothers, who chose nifedipine therapy, had rapid relief from the symptoms. Interestingly, eight of the 12 women and their children had previously been treated with antimycotics because of a suspected Candida albicans infection. A further case report describes good tolerance of nifedipine for vasospasms of the nipple ( ). In a retrospective review of 22 cases of breastfeeding mothers diagnosed with Raynaud phenomenon of the nipple, previous treatment for Candida mastitis with oral or topical antifungals was ineffective in 20 cases (91%). Of the 12 patients who tolerated a trial with nifedipine, 10 (83%) report a decrease or resolved nipple pain during lactation. Thus, nifedipine and not the antifungal, appears to be an effective treatment of Raynaud phenomenon of the nipple ( ).

With 6 × 60 mg of nimodipine , maximum concentrations of 3.5 μg/L in the mother’s milk have been described ( ). Mathematically, this would be only 0.01% of the weight-related maternal dose. A further case confirms this limited transfer of nimodipine ( ).

With nitrendipine , a maximum relative dose of 0.6%, including its metabolites, can reach the infant ( ).

During therapy with the calcium antagonists mentioned, no intolerance in the breastfed infant has been described. By contrast felodipine , gallopamil , isradipine , lercanidipine , manidipine , nilvadipine and nisoldipine have been insufficiently studied.

For verapamil and diltiazem , see Section 4.6.10 . Both have been considered as appropriate during breastfeeding by the .

The relative infant dose was 0.2% for verapamil and 0.9% for diltiazem and thus, the relative amount of these drugs transferred to the breastfed infant is quite small. In some cases no verapamil is detected in infant’s plasma.

4.6.5

ACE inhibitors

In nine mother–baby pairs with a daily dosage of 20 mg of benazepril, a maximum of 0.003 μg, including the active metabolite, benazeprilate , is measured per liter of milk. For an exclusively breastfed baby, this represents 0.00014% of the maternal weight-related dose ( ).

With 300 mg captopril daily, 4.7 μg/L milk is reported. The M/P ratio is 0.03. The infant receives up to 0.7 μg/kg/day. This represents about 0.014% of the maternal weight-related dose ( ).

Enalapril can be similarly evaluated. The relative dose for the infant is about 0.1% ( , , ). By contrast to the maternal serum, there is no lowering of the angiotensin-converting enzyme found in milk samples ( ). No undesirable effects on the infant have been described.

Quinapril concentrations are reported for six mother-child pairs. The drug could not be detected in any of the milk samples. Based on the detection limit, the maximum estimated relative infant dose is 1.6% ( ).

There are insufficient data to evaluate cilazapril , fosinopril , lisinopril , moexipril , perindopril , ramipril , spirapril , trandolapril and zofenopril .

Following the use of ACE inhibitors in late pregnancy, kidney function disturbances as extreme as anuria requiring dialysis have been noted in the newborn ( Chapter 2.8 ), but not during breastfeeding. For this reason, the considers the use of those ACE inhibitors that have been tested extensively to be acceptable during breastfeeding.

4.6.6