Benzodiazepines

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Pharmacology

Benzodiazepines are used as AEDs, tranquilizers, and hypnotics. In the following pages, only those representatives of this group which are currently used for antiepileptic therapy will be discussed (for details on benzodiazepines, sec also Chapter 2.11). Diazepam and clonazepam have proven themselves as AEDs. They inhibit the spread of pathological excitation, but not focal activities. Following oral administration, diazepam is quickly absorbed and is primarily bound to plasma proteins. It is hydroxylated in the liver and metabolized to the still active desmethyldiazepam, which is excreted through the kidneys after glucuronidation. The half-life is between 1 and 2 days; in newborns it is considerably longer bccause of the diminished clearance. Diazepam crosses the placenta easily. During birth, the concentration in the cord blood is up to three times the level in the maternal blood (Bakke 1982).

Clonazepam and clobazam are similar to diazepam, chemically and structurally.

Toxicology

Earlier publications have described an increased risk of cleft lip and cleft palate with diazepam treatment (Saxen 1975). This could not be substantiated in a later trial (Rosenberg 1983). In view of one case report describing an oblique facial cleft in a newborn of a mother who attempted suicide in early pregnancy with 50 tablets of diazepam (Rivas 1984), and given the rarity of this malformation, an increased risk with extremely high dosages can be suspected. Other birth defects, i.e. inguinal hernia, were described but could not be confirmed. The question was reviewed in a meta-analysis (Dolovitch 1998): pooled data from cohort studies demonstrated no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft, Case-control studies, however, indicated increased rates of major birth defects, in particular isolated oral clefts.

Laegreid (1989) reported on eight children whose mothers had abused prescription drugs during their pregnancies, taking at least 30 mg of diazepam and 75 mg of oxazepam per day. All the children had facial anomalies; in addition, some of them were microcephalic, had toxic symptoms (apnea), and showed signs of withdrawal postpartum. Later, mental retardation, attention deficits, and hyperkinetic disorders were observed to varying degrees. However, these case descriptions have been criticized on the grounds that the kind of exposure and its scope are not adequately documented and, in one case, that Zellweger syndrome was not ruled out. In follow-up studies on the children at about 18 months, an improvement in the symptoms was established (Laegreid 1992).

In a number of animal studies (Kellogg 1985, Simmons 1984), it is has been demonstrated that diazepam at low dosages can modify selected behaviors based upon permanent modification of the downstream responses to the benzodiazepine receptors. The results of these studies support the hypothesis that in utero exposure to drugs targeted for action on the central nervous system, including diazepam, can induce long-lasting alterations to the neural substrates of behavior of the offspring, with resulting functional consequences.

Benzodiazepine therapy does not seem, according to the current state of knowledge, to have as high a teratogenic risk as the other anticonvulsants. However, the risk of functional disturbances in newborns is to be considered when benzodiazepines are used in high doses during the birth process, or when 15-20 mg is taken regularly over a prolonged period, including during the last trimester. On the one hand, respiratory depression must be expected after high doses prc-partum - for example, for treatment of seizures during eclampsia. On the other hand, after continuous exposure, withdrawal symptoms like restlessness, tremors, muscular hypertonia, vomiting, diarrhea, and convulsions can occur in the neonatal period. A "floppy infant syndrome", with muscle flacidity, lethargy, disturbances of temperature regulation, and weak sucking, lasting from a week to many months, has been described. A dose-response relationship is likely, because the frequency of newborn complications rises when doses cxcecd 30-40 mg or when diazepam is taken for extended periods, allowing accumulation to occur (Gillberg 1977, Haram 1977, Scanlon 1975). However, because it accumulates in the fetus, daily doses of even 6mg of diazepam may lead to symptoms in neonates.

In the newborn, diazepam can dislodge bilirubin from its binding with albumin and - at least theoretically - at high dosages can intensify the neonatal icterus.

There are about 175 documented pregnancies with exposure to clonazepam in pregnancy {Lin 2004, Vajda 2003, Weinstock 2001, Omoy 1998). Although tetralogy of Fallot, microcephaly, and dysmorphic features were observed, no particular pattern of anomalies can be defined, and data do not show a significant increase in major birth defects.

There is insufficient information on clobazam in pregnancy with respect to fetal outcome. Structural teratogenic effects are just as unlikely as they are with other benzodiazepines, In the neonatal period, the same complications as with diazepam would seem to be possible.

Recommendation. Should there be an indication for low doses of diazepam or clonazepam, treatment is permitted even during the first trimester. After long-term treatment, especially during the third trimester, withdrawal effects in the newborn must be expected, and the child should be observed closely during the first days of life. This applies also to those cases where high dosages were used shortly before or during delivery, when neonatal respiratory depression is possible.

Exposure to benzodiazepines is not an Indication for a termination of the pregnancy. In cases of abuse or long-term treatment with high dosages during organogenesis, a detailed fetal anatomical ultrasound examination should be offered. If such exposure has occurred during later pregnancy, observations of fetal motor patterns can be performed by ultrasound.

2.10.3 Carbamazepine

Pharmacology

Carbamazepine has structural similarities to tricyclic antidepressants, and is used for grand-mal epilepsy, focal and psychomotor seizures, and trigeminal neuralgia. The anticonvulsive action of carbamazepine, similar to that of other AEDs, can be explained as a membrane-stabilizing action. Carbamazepine is well-absorbed when given orally, binds strongly to proteins, and has a plasma half-life of 1-2 days. In the fetus, carbamazepine reaches 50-80% of the maternal concentration.

Toxicology

Carbamazepine is teratogenic in human beings. Monotherapy was found to increase the malformation rate about a two-fold by several authors (Matalon 2002, Ornoy 2000, Canger 1999, Kaneko 1999, Samrén 1999, 1997), while others do not find increased rates of birth defects (Morrow 2006, Artama 2005, Kaaja 2003). A single group of investigators described a fetal carbamazepine syndrome, with dysmorphic features - e.g. upslanting palpebral fissures, epicanthal folds, short nose, long philtrum, distal digit hypoplasia, and microcephaly (Jones 1989). Carbamazepine increases the risk of spina bifida, microcephaly, and hypospadias. The risk of spina bifida is increased about ten-fold - i.e. it occurs in about 1% of exposed newborns. Apart from spina bifida, there have been additional reports of hypospadias, microcephaly, some facial dysmorphic features, and the absence of hypoplastic distal phalanges (Kallén 1994, Robert 1994, Little 1993, Rosa 1991, Jones 1989). Dean (2002) observed cases of facial dysmor-phology and developmental delay.

After an association between carbamazepine and congenital eye malformations (i.e. anophthalmia, microphthalmia, and coloboma) in children was proposed by Sutcliffe (1998), who reported four cases, a Dutch group from EUROCAT (Kroes 2002) checked all of their cases with eye malformations for carbamazepine use by the mother, and also reviewed 13 studies in the literature. The analysis did not support Sutcliffe's hypothesis.

Kaaja (2003) prospectively followed up 970 pregnancies in women with epilepsy at a single maternity clinic. The occurrence of major malformations was associated with various anticonvulsants, but not with carbamazepine monotherapy.

The teratogenic effect of carbamazcpine seems to be associated with noticeably reduced activity of the enzyme, epoxide hydrolase. This enzyme defect - apparently attributable to a genetic predisposition - may be measured in the fetal amniocytes, but a test for routine clinical use is as yet not available,

Postnatal development

The risk of cognitive disturbances with carbamazepine monotherapy was reported in subsequent studies (Ornoy 1996), and observed especially in children who also have facial dysmorphia. On the contrary, in a study by Gaily (2004), the intelligence of 182 children of mothers with epilepsy (study group) and 141 control children was tested in a blinded setting at preschool or school age. Data on maternal antiepileptic treatment and seizures during pregnancy were gathered prospectively. Of these children, 107 were exposed to antiepileptic monotherapy, among them 86 to carbamazepine. Thirty children were exposed to polytherapy; 23 cases included carbamazepine. The median maternal doses and blood levels of carbamazepine during the second half of pregnancy were 600 mg and 26pmol/l. The mean verbal and non-verbal IQ scores in the children exposed in utero to carbamazepine monotherapy did not differ from those in the control subjects. The authors concluded that carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in prenatally exposed offspring. Exposures to polytherapy and to another drug (valproate) during pregnancy were associated with significantly reduced verbal intelligence.

Carbamazepine can induce vitamin K deficiency, resulting in coagulation disturbances in the neonate (Howe 1999), like all enzyme-inducing AEDs (see also section 2.10.6).

Recommendation. Carbamazepine may be used in pregnancy to treat epilepsy, keeping in mind the risks mentioned. Monotherapy is desirable, The drug concentration should be monitored regularly, and the daily dose kept as low as can be justified therapeutically. Liver and kidney function, as well as hematological parameters, should be checked regularly.

Exposure to carbamazepine does not require termination of pregnancy. However, as an additional preventive measure, a detailed ultrasound diagnosis should be conducted in the second trimester as well as an a-fetopro-tein determination in the maternal serum around week 16, especially to detect neural tube defects.

To decrease the risk of coagulation disturbances in the fetus and newborn, the newborn should receive 1 mg of vitamin K (preferably intramuscularly) at birth and 1 mg orally every 3 days in the first 2 weeks of life (see also section 2.10.6).

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Free Yourself from Panic Attacks

Free Yourself from Panic Attacks

With all the stresses and strains of modern living, panic attacks are become a common problem for many people. Panic attacks occur when the pressure we are living under starts to creep up and overwhelm us. Often it's a result of running on the treadmill of life and forgetting to watch the signs and symptoms of the effects of excessive stress on our bodies. Thankfully panic attacks are very treatable. Often it is just a matter of learning to recognize the symptoms and learn simple but effective techniques that help you release yourself from the crippling effects a panic attack can bring.

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