Ortho Tri-Cyclen (Ethinyl Estradiol; Norgestimate)
Ethinyl Estradiol; Norgestimate
Brand Names: Ortho-Cyclen®, Ortho-Tri-Cyclen®, Previfem™, Sprintec™, TriNessa™, Tri-Previfem™, Tri-Sprintec™ | MonoNessa™ | Ortho TriCyclen® Lo | Sprintec-28™
Classification:
Hormones and Hormone Modifiers
Hormones and Hormone Modifiers
Description: Ethinyl estradiol and norgestimate are used together as an oral contraceptive agent. At this time, norgestimate containing products have not been evaluated for postcoital contraception. Ethinyl estradiol is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. Norgestimate is a progestin of high progestational, slight estrogenic, and low androgenic activity. Norgestimate has little effect on serum lipoproteins and has very little negative effect on carbohydrate metabolism. The low androgenicity of norgestimate has shown to be efficacious in the treatment of acne vulgaris, and the norgestimate containing combination oral contraceptives are the only group to obtain FDA approval for this indication in women at this time. Ethinyl estradiol; norgestimate containing contraceptives were first approved by the FDA in 1989. Ortho TriCyclen® tablets received FDA approval for the treatment of acne vulgaris in December 1996. Ortho TriCyclen Lo® tablets were approved in August 2002 for routine contraception; the formulation offers a mid-level dosage of estrogen (i.e., 25 mcg/tablet) that may lessen the incidence of side effects such as nausea and vomiting without causing an increased incidence of breakthrough bleeding associated with low-estrogen oral contraceptives.
Mechanism of Action: The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, preventing penetration of sperm. Alteration in endometrial tissues also occurs. When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology.
Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is now recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate sebaceous gland hyperresponsiveness to androgens and lead to acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies.
 Mononessa Tablets (Tab 0.035;0.25 mg;mg)
Pharmacokinetics: Following oral administration in the third cycle of use, approximately 60% of norgestimate and 83% of ethinyl estradiol survive absorption and first pass through the liver. Both hormones are widely distributed. Ethinyl estradiol is highly but non-specifically protein-bound to albumin. Ethinyl estradiol induces an increase in the serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin (CBG). Norgestimate is strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG).
Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate. Ethinyl estradiol is primarily metabolized in the liver via CYP3A4 to 2-hydroxy-ethinylestradiol. Both ethinyl estradiol and its hydroxylated and methylated metabolites undergo glucuronide and sulfate conjugation. Estrogen conjugates can be hydrolyzed back to the active drug in the GI tract and then undergo entero-hepatic recycling.
Norgestimate is considered a pro-drug and is metabolized by hydrolysis, reduction, and hydroxylation to 17-deacetyl norgestimate, 3-keto-norgestimate and levonorgestrel. It is believed that only 17-deacetyl norgestimate significantly contributes to norgestimate’s pharmacologic activity. All three metabolites may subsequently undergo glucuronide and sulfate conjugation.
Excretion of the oral contraceptive steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 12 - 30 hours for 17-deacetyl norgestimate and 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormones that allows for once-daily administration.
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[ Revised 5/1/2006 4:41:00 PM ]
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