21710 Retinoids for acne and psoriasis therapy Pharmacology

Isotretinoin (13-cis-retinoic acid) and tretinoin (all-trans-retinoic acid) arc natural derivatives of vitamin A (rctinol). In synthetic derĂ­vate form, they have been used with great success for over 20 years, both externally and systemicaliy, to treat cystic acne. Tretinoin is also licensed as a systemic preparation for treating promyelocyte leukemia. As far as we know today, tretinoin is identical to the body's own growth factor, which is in all cells and is bound to specific retinoid receptors (Committee on Developmental Toxicology 2000). Retinoic acid has a very important role during the embryonic phase because it controls, among other things, the development of the brain, face, thymus, heart, and spinal cord.

Retinoids also stimulate the proliferation of epidermal cells. In the skin, they loosen the keratin layer and in this way ease the scaling process. Isotretinoin also causes the sebaceous glands to atrophy. This explains its effectiveness in acne therapy. The half-lives of isotretinoin and of its metabolite. 4-oxo-isotretinoin, are, on average, 29 hours and 22 hours respectively. In extreme cases the half-lives can be up to a week (Nulman 1998).

Acitretin and etretinate (which is now no longer sold) have proved themselves in the treatment of psoriasis. Both lead to prolonged high concentrations of retinoids in the body. Acitretin is metabolized to etretinate, which has a half-life of 80-175 days. A correlation has been established between alcohol consumption and increasing etretinate serum levels (Larsen 2000).

Adapalene belongs to the synthetic, polyaromatic, receptor-selective retinoids. These are indicated for the treatment of severe acne vulgaris, and tazarotine is indicated for the treatment of psoriasis. Topical treatment of AIDS-associated Kaposi sarcoma can be carried out using the 0.1% gel alitretinoine. By activating retinoid receptors, tumor growth will be blocked.

Toxicology

The marked teratogenic properties of retinoids have long been known from experimental animal embryo/fetotoxicology. Today, retinoids should be considered to be (he most teratogenic medications since thalidomide. Their use in pregnancy increases the risk for spontaneous abortion, and leads to the characteristic retinoid embryopathy: anomalies of the ears (including agenesis or stenosis of the auditory canal), facial and palatine defects, micrognathia, cardiovascular (conotruncal) defects, and developmental defects of the thymus (with possible immunological consequences) and the central nervous system (ranging from neurological damage to the eyes and inner ear, to hydrocephalus) (Lammer 1988, 1985). Intelligence deficits have also been described to some extent in children without recognizable birth defects (Adams 1991).

Prospective epidemiological studies on maternal intake of isotretinoin showed 40% spontaneous abortions, an increased rate of premature births, and up to 35% major birth defects. Follow-up studies with intrauterine retinoid-exposed children at the age of 5-10 years showed high rates of mental retardation and, specifically, weaknesses in visual-spatial orientation and in behavior. In 25% of the children, no major malformations were diagnosed (Adams 2004).

Even though the scientific community - for example, the Teratology Society (1991) in the USA - has given forceful warnings of the teratogenic risk, children with birth defects due to isotretinoin have continued to be bom in North America. Apparently, in many cases the required explanation of the risks is still not effective today (Robertson 2005, Honein 2000). The pharmaceutical companies and the U.S. FDA have received notification of more than 150 cases of children with developmental disorders after intrauterine exposure to Isotretinoin.

In a retrospective study in California, 5 of 14 pregnancies where the mothers had isotretinoin therapy were voluntarily terminated, 4 aborted spontaneously, and there were 5 live births, of which only one showed the characteristic malformations (Honein 2001). The fetopathological results from two voluntarily aborted fetuses did not show gross malformations, but there were middle and internal ear anomalies (Moerike 2002), Three casuistic publications (Barbero 2004, de Die-Smulders 1995, Geiger 1994) have described the classical acitretin embryopathy (microcephaly, facial dysmorphology, atrioseptal defect, and bilateral sensorineural deafness). At 18 months, this child showed a persistent microcephaly and retarded neurological development. The mother had taken 10 mg of acitretin daily till the tenth gestational week (Barbero 2004).

From post-marketing studies, 13 acitretin-treated fathers were found (9 retrospective and 4 prospective); 11 fathers had been treated with acitretin until conception, and 2 stopped the therapy between 6 months and 4 weeks before conception. Of the latter, the pregnancy from the last-mentioned treated father ended in a spontaneous abortion, and the other with termination of pregnancy because of unspecified developmental disorders. The outcomes for the 11 fathers treated at least up until conception were 5 healthy children, 5 spontaneous abortions, and 1 termination of pregnancy (Geiger 2002). Furthermore, Geiger (1994) describes 75 pregnancies where the mother was exposed to acitretin either during (8 cases) or before (67 cases) pregnancy. In the group of 8 cases exposed during pregnancy, 4 aborted spontaneously and 2 were electively terminated. There was one typical malformation in a fetus after induced abortion (microtia, and malformations of the face and extremities); the mother had received 50 mg of acitretin daily for the first 19 weeks of pregnancy. In one of the 2 live-born infants, a high-frequency hearing disorder was diagnosed. Of the group of 67 women exposed to acitretin before pregnancy (mean, 5 months before conception), no typical malformations were found where information on the fetus was available.

In the same publication, Geiger (1994) reports on 75 women who underwent etretinate treatment during pregnancy. Of 29 neonates, 6 had typical malformations and 3 had non-typical abnormalities. There were 5 spontaneous abortions, and of the 41 induced abortions for which there was information, 5 fetuses had the typical malformations. Another group of 173 women who underwent etren-itate therapy before pregnancy delivered 88 newborns, of which 5 showed typical malformations and 13 showed non-typical abnormalities (not specified). Thirteen pregnancies ended in induced abortions for which fetal information is available; this shows that three of these fetuses had typical malformations and one had non-typical malformations. The rate of spontaneous abortions was lower when exposure was only before pregnancy. It was concluded that no threshold dose could be established in human therapy, based on these data.

External use

Five case descriptions in the last few years have raised the suspicion that typical retinoid birth defects cannot be absolutely ruled out after topical use of tretinoin (Selcen 2000, Colley 1998, Navarrc-Bclhasscn 1998, Lipson 1993, Camera 1992). Two controlled studies involving a total of 300 pregnant women gave no indication of a teratogenic effect (Shapiro 1997, Jick 1993). However, the larger of these studies was based on prescription protocols from which it cannot be definitively determined that the medication was, in fact, used. In addition, the design and number of cases in this study do not allow the assumption that tretinoin is harmless (Martfnez-Frias 1999). A prospective study of 106 tretinoin topically-treated women during the first trimester did not indicate either a higher spontaneous abortion rate or an increased risk of malformations (Loureiro 2005).

Pharmacologically, an average absorption rate of 2% with a maximum of about 6% (van Hoogdalem 1998), the usual concentration of 0.05% in topical retinoid preparations, and evidence that a noteworthy rise in endogenous retinoid concentration in the plasma (2-5|ig/l) does not occur after external use indicate that a teratogenic effect is unlikely if the treated area and thus the resorption is not very large. Normal circulating levels in women are within that range, while teratogenic levels are much higher (Miller 1998).

The usual daily dosage is a maximum of 2g of ointment with 1 mg of the active ingredient (0.05%). However, it must be kept in mind that with severely inflamed skin or additional (disinfectant) use (i.e. benzoyl peroxide - see section 2.17.3), the absorption rate may be increased. External use of isotretinoin has to be judged in a similar way to that of tretinoin.

A case report on adapalene used until week 13 of pregnancy mentions a terminated pregnancy based upon ultrasonographic diagnosis of cerebral and ocular disorders that are not judged to be typical for retinoids (Autret 1997). A prospective epidemiological study included 94 pregnancies exposed to topical retinoid (tretinoin, isotretinoid or adapalene); no indications for increased spontaneous abortion or higher risk of developmental disorders were found (Carlier 1998). The publication is, however, rather poor in details regarding the time and type of treatment, and dysmorphological criteria.

Topical use of tazarotene gives 6% resorption of the application. It has been found to have a half-life of 18 hours. The hydrophilic properties of the metabolites prevent fat storage. General remarks (without details) refer to healthy children being born to mothers who had local application of tazarotene during pregnancy (Menter 2000).

There is no experience with topical treatment with alitretinoin during pregnancy.

Recommendation. Systemic therapy with the retinoids, acltretin, etretinate, Isotretinoin, and tretinoin, is absolutely contraindicated during pregnancy. For women of childbearing age, treatment is only permitted when other therapeutic measures have not been effective, when there is sufficient contraceptive protection with two separate effective forms of birth control at the same time (Food and Drug Administration 2004), and after ruling out a pregnancy. Reliable contraception must be used for 2 years after stopping acitretin and etretinate, and for a month after ending treatment with isotretinoin. When considerably less time has passed, especially when there has been treatment in early pregnancy, severe damage to embryonic development, including spontaneous abortion, is possible. Diagnostic ultrasonography is indicated in such cases. Hence, In some instances, interruption of the pregnancy must be discussed. For additional information about pregnancy prevention, see www.ipledgeprogram.com.

Topical use of retinoids is also contraindicated during pregnancy. In cases of such therapy in early pregnancy, Interruption of pregnancy is unnecessary because of the apparently limited teratogenic risk - if, indeed, there exists any risk at all. However, a detailed fetal ultrasound diagnosis should be planned. There is insufficient experience available concerning the synthetic, polyaro-matic receptor selective retinoids adapalene, tzarotine, and alitretinoin.

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A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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