ACE inhibitors

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Pharmacology and toxicology

Benazepril, Captopril, Cilazapril, enalapril, fosinopril, Imidapril, Lisinopril, moexipril, perindopril, quinapril, ramipril, Spirapril, and trandolapril are angiotensin-converting enzyme inhibitors (ACE inhibitors) that inhibit the conversion of angiotensin I to angiotensin II. They are effective and generally well-tolerated, and in recent years there has been increasing use of these drugs. However, in genera! there is no clear advantage with respcct to a lowering of mortality in comparison to the classic antihypertensives such as (i-reccptor blockers and thiazide diuretics.

There are conflicting results concerning teratogenicity. More than 600 evaluated pregnancies in case reports and case series indi cate that exposure to ACE inhibitors in the first trimester do not appear to be associated with any increase in the incidence of mal formations (Schaefer 2006, Burrows 1998, Gilstrap 1998, Barr 1997, de Moura 1995). Most of the data available refer to the use of Captopril and enalapril.

Data from a prospective study indicate that there was no increase in any pattern of developmental anomalies in 86 newborns whose mothers had been treated with captopril in the first trimester. Similarly, in 4 of 40 children with a birth defect who had been exposed to enalapril, no specific pattern of malformations was observed (Rosa, cited by Briggs 2005). A recently published epidemiologic cohort study analyzed births and medical records and reported finding statistical indications of increased risk of cardiovascular and CNS malformations in infants whose mothers received a prescription for an ACE inhibitor during first trimester (209 mothers) (Cooper 2006). The cardiovascular defects consisted of 7 cases (atrial and/or septal defects and/or patent ductus arteriosus); the three cases classified as having CNS defects were spina bifida (1), microcephaly, undefined "eye anomaly" (1), and coloboma, which is not a true CNS defect. Adverse outcomes were found in a total of 18 infants. This study used prescription records as a surrogate for exposure, and did not exclude the possible confounding effects of diabetes mellitus, The results of this study provide a signal which has not been confirmed by other data. A large, prospective cohort study should be enrolled, to test especially whether there is an increased risk for heart or CNS malformations.

Lisinopril, a long-acting ACE inhibitor has been used to treat malignant hypertension in pregnancy (Tomlinson 2000). Tabacova (2003B) analyzed 110 pregnancies with abnormal outcome after exposure to enalapril, which have been reported to the FDA. Mainly when medication was taken beyond the first trimester, complications were noted as follows: oligohydramnios and resulting contractures, ossification defects, pulmonary hypoplasia, and renal insufficiency up to anuria.

The following reports of fetal and neonatal toxicity after exposure in the second half of pregnancy are typical: hypoxia, hypotension, renal tubular dysgenesis, oligohydramnios, and anuria requiring dialysis following the use of ACE inhibitors in late pregnancy (Murki 2005, Filler 2003, Gilstrap 1998, Lavoratti 1997). Hypoplasia of the skull bones (calvarial hypoplasia) has also been observed in six infants, which could be a consequence of limited perfusion and increased pressure on the skull caused by oligohydramnios (Barr 1994). If oligohydramnios is diagnosed in pregnancy while taking an ACE inhibitor, and medication is stopped, there is a chance that amniotic fluids will regenerate (Muller 2002).

The mechanism of toxicity is as follows. Fetal urine production and kidney function start at the end of the first trimester. Angiotensin-converting enzymes appear at about 26 weeks' gestation. ACE inhibitors reduce the tonus of kidney vessels, and as a consequence urine production is reduced, followed by an oligohydramnios, because beyond the sixteenth gestational week the fetal urine production is the main sourcc for the amniotic fluid. Prasad (2003) describes a dysgenesia of renal tubules caused by hypoxia.

Similar developmental disturbances have also been observed in experimental animal studies with higher doses of ACE inhibitors.

Spontaneous abortions, intrauterine fetal deaths and premature births with hyaline membrane syndrome have also been reported following administration of ACE inhibitors, hut it is not clear to what degree these adverse events can be attributed to the medication, or to the severe hypertension. This is also true in the ease of persistent ductus arteriosus, which could theoretically be explained by drug-induced elevation of bradykinin.

No specific data were found on the use of benazepril, cilazapril, fosinopril, imidapril, perindopril, quinapril, ramipril, and trandolapril in pregnancy. Theoretically, these drugs have a similar potential for inducing adverse fetal and neonatal effects to other ACE inhibitors.

Recommendation. ACE inhibitors are contraindicated throughout pregnancy, except in cases of severe illness that cannot be treated in any other way. Where clinically appropriate, medication should be changed to one of the antihypertensive drugs of choice. If exposure has occurred in the first trimester, a detailed ultrasound diagnosis is advisable. Whether fetal echocardiography should be recommended in any case of first-trimester exposure is a question of debate. Overall, exposure to an ACE inhibitor during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy. However, in cases involving long-term prenatal therapy in the second and/or third trimesters, the fetus should be monitored for the potential development of oligohydramnios, and fetal growth should be assessed with detailed ultrasound scans.

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