Drugs and pregnancy


RETINOL AND RETINOIC ACIDS



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RETINOL AND RETINOIC ACIDS

  • These are identical to the natural physiological agents.

  • TRETINOIN (Retin-A®, 1971; Renova®, 1995)

    • Topical application for treatment of acne

    • In acne treatment, Retin-A® is comedolytic and inhibits keratinization - promotes expulsion of open comedones (promotes expulsion of sebum from the follicle)

      • Decreases cohesiveness of epithelial cells in follicle

      • Decreases thickness of stratum corneum

    • Other Effects – diminishes fine lines and wrinkles (Renova®)

      • Promotes dermal collagen synthesis

        • Glucocorticoids tend to  collagen synthesis

      • Promotes new blood vessel formation

      • Promotes thickening of epidermis

    • ADVERSE EFFECTS

      • No systemic effects as only 10% is absorbed into circulation

      • Increases susceptibility to sunburn, use sunscreen (15SPF) and protective clothing

      • Not usually prescribed to pregnant patients (see below)

  • ISOTRETINOIN (Accutane®, 1982)

    • Systemic/oral therapy reserved for treatment of severe nodular acne in patients who are unresponsive to conventional therapy, including systemic antibiotics




        • MECHANISM:

          • Decreases sebum production

          • Decreases sebaceous gland size

          • Decreases keratinization

          • Decreases inflammation 


        • SIDE EFFECTS

          • Similar to those of hypervitaminosis A 


          • SIDE EFFECTS ON EPITHELIA

            • Dryness of skin and mucous membranes - results in

              • Most common:

                • Dry itchy eyes, nose, mouth

                • Nose bleeds

                • Inflammation of lips (cheilitis)

            • Hair loss, peeling of skin from palms and soles when we have excess amounts

            • Sensitivity to UV light, use protection against sun

            • Inflammatory bowel disease—probably due to maintenance of normal epithelium in the gut

          • HYPERLIPIDEMIA – 25%

          • EFFECTS ON BONE FORMATION

            • Long-term therapy- calcification of ligaments and tendons surrounding joint

            • Decreased bone mineral density

            • Pain in joints muscles

          • SUDDEN REDUCTION IN NIGHT VISION

            • Seems paradoxical—not enough vit A can go blind and if you have too much you can loose your ability to see at night at least temporarily

          • PSEUDOTUMOR CEREBRI - RARE

            • Benign cerebral hypertension, can be mistaken for a tumor

              • Might have headaches

            • This HTN can leads to edema of optic disk (papilledema), which can lead to permanent blindness

            • More likely if tetracycline co-administered

          • DEPRESSION - RARE, BUT...

            • Depression and suicidal ideation may be associated with retinoids. Since 1989, 12 patients have committed suicide

            • Must be discussed with patient, so that any signs or symptoms are reported to physician and therapy stopped 


        • CONTRAINDICATION: PREGNANCY

          • Isotretinoin is a pregnancy category X drug and should not be taken during pregnancy. There is a very high risk of birth defects, e.g.

            • Skull abnormalities

            • External ear malformation

            • Facial malformation

            • Cleft palate

            • CNS abnormalities

            • CV abnormalities 


          • IMPORTANT: To prevent birth defects isotretinoin must be prescribed under the iPLEDGE program, which was introduced march 1, 2006 and replaced the S.M.A.R.T.

            • LOTS OF THINGS have to be done to make sure the woman is aware of the side effects and is not at risk of becoming pregnant

    • ACITRETIN AND ETRETINATE - SYNTHETIC ANALOGS

      • These contain an aromatic ring, but retain the flexible side chain and therefore interact with most RARs. They are approved for systemic treatment of psoriasis. Their side effects and contraindications are similar to isotretinoin.

        • ACITRETIN (Soriatane®, 1996) is the active metabolite of etretinate (Tegison®, 1986-2003). Etretinate accumulates in adipose tissue and has a very long half-life (120 days) compared with acitretin (49 hours). Because this increases risk of birth defects etretinate has been removed from market (2003).

        • However, if ethanol is consumed by patients taking acitretin, etretinate is synthesized, consequently, alcohol should be avoided during therapy up to 2 months after the last dose.

        • Also, patients should not become pregnant for at least 3 years after the last dose

        • Also patients should not donate blood during therapy or for 3 years after therapy

        • MECHANISM in PSORIASIS:

          • Inhibits proliferation of epithelial cells

          • Inhibits keratinization of epithelial cells

          • Inhibits differentiation of epithelial cells

    • TAZAROTENE (Tazorac®, 2000; Avage®, 2002)

      • Tazarotene is a synthetic retinoid with an aromatic ring in the side chain, which restricts the flexibility of the structure. Thus, although it binds to all three retinoic acid receptors RAR,  , and γ, it has some selectivity for  and γ.

      • It is a prodrug, which is hydrolyzed to produce a carboxylic acid – tazarotenic acid – the active drug. It is used topically for the treatment of both acne and psoriasis and wrinkles. First topical retinoid approved for psoriasis

      • Avage® is the same preparation approved for (-quote from drug label-) “mitigation of facial fine wrinkling, facial mottled hyper- and hypo-pigmentation, and benign facial lentigines in patients who use comprehensive skin care and sunlight avoidance programs”...it “DOES NOT ELIMINATE or PREVENT WRINKLES, REPAIR SUN-DAMAGED SKIN, REVERSE PHOTOAGING, or RESTORE MORE YOUTHFUL OR YOUNGER SKIN.” In one study, after 24 weeks treatment 16% of patients treated with vehicle had improvement, while 40% treated with tazarotene had improvement.

        • Use is contraindicated in women who are or may become pregnant

        • Most common side effects are limited to the skin

          • Peeling, red skin, dry skin, burning, itching

          • Avoid exposure to sun, or UV lamps

    • BEXAROTENE (Targretin®, 1999)

      • Bexarotene is a drug that is a selective agonist for retinoid X receptors (, , γ), and does not activate RAR receptors.

      • EFFECTS

        • Inhibits growth of tumor cell lines of hematopoietic and squamous cell origin

      • INDICATION

        • Treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients resistant to one prior systemic therapy

      • CONTRAINDICATED in pregnancy – precautions similar to isotretinoin

      • SIDE EFFECTS

        • Elevation of TGs, LDL cholesterol

        • Hypothyroidism


REGULATION, DEVELOPMENT AND SELLING OF DRUGS


  • To prescribe drugs responsibly requires some understanding of the processes of drug development and marketing, and the roles and interests of industry, government, organized medicine, and individual physicians in these processes.

  • Drugs are available as prescription and non-prescription (over-the-counter, OTC) drugs. Human use, regulation of the sale and distribution of the drug, content of the package insert, and the content of marketing and “educational” materials for both medical professionals and for the public all must receive approval. That is the role of the U.S. Food and Drug Administration.

  • DRUG DISCOVERY AND DEVELOPMENT

    • Potentially useful drugs are identified by (a) chemical modification of a known drug, (b) screening of synthetic and natural products for desirable effects; and (c) design of new drugs based on advances in biology and in the understanding of the nature of the disease. Very few of these reach the stage of human trials, and even fewer become marketed drugs. Almost all of this work is performed by, or supported by the pharmaceutical industry.

    • These chemicals are screened by a variety of in vitro and in vivo methods to detect biological activity (both potentially beneficial and adverse). At some point in this process, a patent is obtained. This protects the patent holder and provides exclusive rights to market the drug, but also starts the clock for patent protection. After the patent expires, others may manufacturer and sell the drug under their own name, or under the generic name.

  • LAWS REGULATING DRUG DEVELOPMENT, MARKETING, PRESCRIPTION AND USE

    • Federal laws regulate the manufacture and sale of drugs in interstate commerce. These laws empower the FDA (Food and Drug Administration) to approve each drug for sale and advertising when the FDA is satisfied about its purity, safety, and effectiveness. Note that there is no requirement that the drug be shown to as effective as already-approved dugs, or to provide new or unique benefits.

    • An approved prescription drug may be dispensed only by the order of a licensed practitioner. [State laws determine who may prescribe drugs]. After a prescription drug has been in use long enough to establish a safe record, the drug may be evaluated by the FDA for sale as a non-prescription, or “over-the-counter” (OTC) drug. A different agency, the Drug Enforcement Agency (DEA), has additional authority over "Controlled Substances"; i.e., drugs that are likely to be abused, and be associated with addiction or dependence.

  • DRUG APPROVAL PROCESS

    • FDA regulations mandate the following steps for any candidate drug:

      • Preclinical evaluation of safety and efficacy in animals. Typically 3-4 years, and using multiple species. Goals are to provide evidence of effectiveness, data on appropriate human dose for initial testing, information about mechanism of action and pharmacokinetic characteristics, acute and chronic toxicity, carcinogenesis and mutagenesis.

    • IND (Investigational New Drug). With results of the preclinical studies, an IND application is filed to get permission for the following clinical studies.

      • Phase I clinical trial. Done with a small number of healthy volunteers, typically 20-100. Goals are to determine the safe dose range in man and to provide pharmacokinetic data.

      • Phase II clinical trial. Conducted on a limited number of patients to determine safety and probable efficacy. Typically 100-200 patients, often single-blind design, typically in specialized clinical testing centers.

      • Phase III clinical trial. If the drug gets through Phase II, the studies are repeated with a large population of patients (1,000 - 6,000). Usually 2-4 years, double-blind, controlled trials, usually at multiple sites.

    • NDA (New Drug Application). With all of the above data, the sponsor may file a NDA for approval by the FDA. This review is usually about ó to 3 years, and the FDA may require additional testing. Approval of the NDA marks the appearance of the drug in the marketplace. Though it is approved for a specific use, except under very unusual circumstances, the physician is under no legal obligation to limit the use of the drug to this specific use. With approval for manufacturing and sale, FDA must also approve the claims (advertisements) of the sponsor regarding safety and efficacy.

      • Phase IV - monitoring. FDA also requires post-marketing monitoring by the manufacturer to detect "unexpected" toxic reactions. All physicians can (should) report unexpected problems. Based on these, approval may be withdrawn, or other changes made.

    • On average, it takes about 10 years for a drug to go from preclinical testing to market. About 5 of 4,000 drugs subjected to preclinical testing make it to human testing; only one of these 5 is approved by FDA, at an average cost of more than $800 million/drug.

  • INTERACTIONS BETWEEN PRACTITIONERS AND THE PHARMACEUTICAL INDUSTRY

    • The pharmaceutical industry needs physicians (and their patients) for Phase II and III studies, and is willing to pay. There have been a few notable instances made public of physicians who have gotten involved in practices that are, or which give the appearance of misconduct. The pharmaceutical industry has the goal of making a profit. They need to persuade you to prescribe their drug. The mechanisms used, and the ethics of some practices, are topics of much discussion. Many physicians do not feel that they, personally, are influenced by gifts, free lunches for their office staff, continuing education programs at golf resorts, free samples for patients, etc. Published evidence shows they are mistaken (see Brennan et al, JAMA, 295:429-433, 2006; this source can point you to several useful publications). Moreover, there is concern that physicians are unduly influenced to the detriment of the public.

    • The industry spends a huge amount on “education”, including interactions between the physician and educational representative (“sales rep”). Many are of the opinion that the main objective is not education, but to get the doctor to prescribe the particular drug, regardless of its relative benefits and risks as compared to alternate treatments.

    • Several physicians and groups of physicians have advocated taking NO gifts, samples, or other materials from the pharmaceutical industry, and not to meet with their “educational representatives”




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