Drugs and pregnancy



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L-NORGESTREL—now a days this is becoming more popular

  • NORGESTIMATE

    ANTI-PROGESTINS

    • RU486 (MIFEPRISTONE)

      • Controversial abortifacient (used to induce abortions)

      • Binds both progesterone and glucocorticoid receptors - preventing gene transcription

        • Also very good antagonist at glucocorticoid receptor but its typical used to block progesterone receptor

      • Other potential therapeutic uses:

        • Inhibition of progesterone- and glucocorticoid-dependent tumors

        • Effective in treatment of fibroid tumors


        • Cushing’s disease


        • Post-coital birth control—better ways of achieving this now

    CONTRACEPTION

    • CONTROL OF IMPLANTATION BY PROGESTERONE AND HCG


    RU486 causes breakdown of the endometrial layer because the progesterone cannot be stimulated to maintain it and once that endometrial layer starts to break down you get partial detachment of the embryo and viability of the embryonic cells starts to  and its ability to produce hCG also  which leads to  maintenance of the CL (which is producing endogenous progesterone) so this also acts to  progesterone. With  P you also get  breakdown of endometrial layer and enhanced uterine contractility b/c now PG can be secreted and these contraction combined w/ the partial detachment due to atrophy of the endometrium leads to complete detachment and expulsion of the embryo. You also get a softening and dilation of the cervix Most serious side effect of this treatment is BLEEDING which can be sufficient enough to cause death.

    Early stages of implantation and development. Trophoblasts cells that go on to form the placenta are growing very rapidly and producing hCG to signal to the CL to continue to making progesterone so the endometrial layer is maintained for development. Progesterone supports the secretory endometrium, it also inhibits the contractility of the uterine muscle by inhibiting the production and secretion of PG’s, and it firms the cervix and inhibits the dilation of it.
    macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 5.15.50 pm.png

    • ABORTIFACIENT ACTIONS OF RU486

    macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 5.16.38 pm.png

        • RU486 alone: 400-600 mg/day (oral) for 4 days = 85% effective –no longer used these days

        • RU486 (600 mg) + Prostaglandin E1 (to  contractions) = 95% effective preferred use of this

    • DIVERSE THERAPEUTIC APPROACHES TO CONTRACEPTION

      • COMBINED ORAL CONTRACEPTIVES (COCS)


      • TRANSDERMAL CONTRACEPTION (THE “PATCH”)—estrogens on patch that get slowly absorbed

      • INTRADERMAL CONTRACEPTION (NORPLANT®)
--capsule inserted under the skin giving very long acting effects

      • POST-COITAL BIRTH CONTROL (“MORNING AFTER PILL”, OR PLAN B®)

      • CONTRACEPTIVE RINGS (NUVARING®)—estrogen (and progestin) in a ring that is inserted by the uterus

        • There is also P-only vaginal rings

      • INJECTABLE (DEPO-PROVERA®)

    • TRANSDERMAL CONTRACEPTION

      • ORTHO EVRA® – The “Patch”

      • Transdermal administration of NORELGESTROMIN AND ETHINYL ESTRADIOL

      • Norelgestromin = active metabolite of norgestimate (so cant use this in the patch b/c to be active it must be converted to norelgestromin in the liver)

      • Patch applied weekly

      • Advantages:

        • Bypasses hepatic metabolism


        • Lower peak plasma concentrations of drug than COCs

        • Presumed lower rates of side effects


        • Better compliance

        • Comparable failure rates to COCs in typical usage

      • Disadvantages:

        • Skin allergies
--but can rotate patch placement to get around this

        • Higher steady state concentrations of drug than COCs

    • INTRADERMAL CONTRACEPTION

      • NORPLANT II® (Jadelle®)

      • Two flexible capsules containing NORGESTREL (3rd generation progestin)

      • Inserted under skin on upper arm or thigh

      • Insertion and removal require minor surgery with local anesthetic

      • Effective for up to 5 years

      • Approved in 1990 in USA

      • Many millions of users worldwide

      • Serum steroid levels are 1/5 to 1/3 of oral contraceptives

      • Fewer side effects

      • Effectiveness:


        • After One Year: 0.2 failures per 100 women years

        • After Five Years: 0.8 failures per 100 women years—same as COC

    • POST-COITAL BIRTH CONTROL

      • High doses of estrogens historically taken at high doses for 5-6 days following intercourse

      • Effective when begun by 72 hours post-coitum

      • Estrogens typically used: CONJUGATED ESTROGENS, ETHINYL ESTRADIOL

      • New studies suggest that 3rd generation progestins are more effective.

      • Plan B” drug (L-NORGESTREL) approved by FDA in 1999; as over-the-counter drug to adults in 2009.

        • Effectiveness: 89% (72 hours), 95% (24 hours) 


      • Mechanism – Delays ovulation and sperm migration, found not to disrupt implantation

        • Remember these are not true progestational agents—they don't support the secretory phase of the endometrium so now the sperm have a hard time migrating up the uterus and fallopian tubes to get to the egg

        • In women who have ovulated Plan B has no protective effect b/c it doesn't block implantation or fertilization of egg

      • Strong side effects –these are minimized w/ Plan B though

        • Nausea

        • Vomiting


        • Severe cramps

    • COMBINED ORAL CONTRACEPTIVES (COCS)

      • Monophasic

        • Constant dose of estrogen + progestin over 21 days

      • Diphasic and triphasic—these were developed to deal with the problem of irregular spotting associated with the monophasic approach

        • Constant low dose of estrogen + variable dose of progestin

        • Diphasic: progestin dose increased once at approx. day 10, higher dose maintained to day 21.

          • Somewhere in the middle you  the dose of progestin 


        • Most common is Triphasic - Progestin increased in 2nd and 3rd week of 21 day dosing regimen

          • Progestin is  twice (at end of 1st week and end of 2nd week)

      • Progestin-Only (“Mini-Pill”)

        • Low dose of progestin

        • Taken every day—fairly effective

      • Most commonly used drugs:

        • ✶Estrogen: ETHINYL ESTRADIOL (Estinyl®)


        • ✶ Progestin: NORETHINDRONE (Norlutin®), L-NORGESTREL (Ovrette®)

    • FAILURE RATES OF ORAL CONTRACEPTIVES

      • Monophasic: 0.7 per 100 women years

      • Phasic: 1.0 per 100 women years

      • Progestin Only: 3.0 per 100 women years

      • Combination and phasic types are the safest

      • Why use “mini-pill”? B/c there are a lot of side effects associated with estrogen therapies of all sorts.

        • If you have patient w/ a history of one of the side effects from the estrogens (like migraines) maybe you’ll try the mini pill instead

    • ADVERSE SIDE EFFECTS OF COC

      • GENERAL CONSIDERATIONS

        • Incidence of serious side effects is low

          • You have 3-4x’s greater risk of dying from this drug than those who don't take the drug

        • Many reversible changes to intermediary metabolism occur but long-term consequences not well understood

        • Minor side effects are frequent but transient (tend to occur w/in the first month or two of usage and then your body acclimates)

        • 33% of COC users stop therapy for reasons other than planned pregnancy


          • Is it because

            • Do minor side effects add up?

            • Is dosing regimen too cumbersome?

            • Are serious side effects too scary for them?

          • We don't know.

      • MILD SIDE EFFECTS

        COMPLAINT

        SOLUTION

        Nausea

        Breast discomfort

        Fluid retention


        Decrease estrogen (b/c usually do to overstimulation by estrogen component)

        Weight gain

        Depression



        Hair growth

        Decrease progestin (b/c these things are usually caused by the progestin)
or switch to 3rd generation drug (e.g. NORGESTREL)

        • Headache


        • Amenorrhea


          • Short to prolonged period of non-ovulation after cessation of treatment

      • SERIOUS SIDE EFFECTS—remember the relative risk for these things is pretty low

        • Thrombotic Disorders

          • Thromboembolism and thrombophlebitis (first serious side effect discovered)

          • Pulmonary embolism

          • Thrombotic and hemorrhagic strokes

          • Risk of thromboembolism: 


            • Non-users - 1 per 1000 women years


            • Users - 3 per 1000 women years


            • Risk rises within first month; remains constant –no cumulative risk

            • Risk returns to normal within one month of discontinuance

          • Underlying physiological cause:


            • Decrease in Anti-thrombin III (major inhibitor of blot clotting so more likely to clot)

        • Cardiovascular Disorders

          • Myocardial Infarction
(heart attack)

            • Risk of MI increased slightly for all COC users
(like 2-3 fold )

            • Risk much greater in women with predisposing conditions

              • Diabetes or smokers

            • Underlying physiological cause:

              • Decreased levels of HDL and increased levels of LDL cholesterols

          • Hypertension


            • 3-6 fold increase in the incidence of overt hypertension


            • Contributing factor to increased thrombolic and coronary risk

        • Cancer Complicated and Controversial

          • Liver Cell Adenoma—benign growths on the liver

            • Prolonged use (>3 years) leads to increase risk of benign hepatic adenomas

            • Usually not life-threatening - unless adenoma ruptures

          • Cervical and Vaginal Cancer

            • Clear risk due to use of diethylstilbestrol (DES)

            • Risk only for daughters of women who used DES during 1st trimester of pregnancy—this is a historical problem—doctors prescribed it for women who wanted to get pregnant which is not what it does!

          • Breast Cancer


            • Controversial. Most studies show increased risk.

        • Endometrial and Ovarian Cancers

          • Several studies show 2-15X risk of endometrial cancer for estrogen-alone therapies

          • Clear evidence that risks of endometrial and ovarian cancers decrease in women taking COCs

          • COCs resulted in 2-fold protection against endometrial (12 vs 23 per 100,000) and ovarian cancer (18 vs 30 per 100,000)

          • Magnitude of protection constant with age (35+ years)

          • “Hormonal Chemoprevention of Cancer in Women” Henderson et al, Science 259: 633 (1993)

          • macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 5.16.14 pm.png

            • showed that it is the Progestin that is protective against these cancers b/c remember P stimulates rapidly growing endometrial cells to stop rapidly growing and differentiating cause the endometrium to go into the secretory phase. P blocks E growth properties on the endometrium.

    SIDE EFFECTS OF ESTROGEN REPLACEMENT THERAPY (ERT)

    • Conventional Wisdom

      • ERT alleviated symptoms of menopause

      • ERT protected against bone loss

      • ERT in combination with progestin protected against endometrial and ovarian cancers

      • **ERT protective against heart disease**--THIS IS NOT TRUE

        • Early studies really were poorly done

      • Therefore, ERT for life encouraged in women over 50.

    • Recent results of the NIH Women’s Health Initiative study:


      • 16,000 healthy women 50 to 79 years old


      • Estrogen plus progestin (Prempro® - Wyeth) compared to placebo group

      • Small decrease in bone fractures


      • Small decrease in colorectal cancer—not sure why

      • 26% increase in breast cancer


      • 29% increase in heart attacks

      • 41% increase in strokes


      • 22% overall increase in cardiovascular disease—opposite of what used to be thought

    • Bottom Line? ERT only for moderate to severe symptoms of menopause (hot flashes and night sweats) and as second-line drug for prevention of osteoporosis (when bisphosphonates don't work)

    • Side Effects of the WHI Study

      • “What happened is that medical practice, as it often does, got ahead of medical science. We made observations and developed hypotheses – and forgot to prove them.”
Susan M. Love, NY Times, July 16, 2002macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 5.28.11 pm.png

    ANDROGENIC STEROIDS

    • Produced in testis, ovary and adrenals

    • Testosterone


      • Produced in Leydig cells of testis


      • Converted to Dihydroxytestosterone (DHT) by Sertoli cells and other target tissues

      • DHT is more potent agonist

    • Physiological processes stimulated

      • Androgenic effects

        • Development of male sex organs

        • Spermatogenesis


        • Larynx enlargement

        • Hair growth


      • Anabolic Effects

        • Bone growth


        • Muscle development

        • Erythropoiesis

    ANDROGEN DRUGS

    • TESTOSTERONE

      • Clinically ineffective

    • ESTERIFIED TESTOSTERONES

      • Examples: TESTOSTERONE CYPIONATE, TESTOSTERONE PROPIONATE

    • SYNTHETIC TESTOSTERONES

      • Examples: METHYLTESTOSTERONE, FLUOXYMESTERONE

      • Orally effective

    • FINASTERIDE

      • Blocks the enzyme that converts testosterone to DHT in target cells

      • Subject of curious pricing

        • PROSCAR® - Benign prostatic hyperplasia - 5 mg/day = $0.47/mg –CHEAPER

        • PROPECIA® - Male-pattern baldness - 1 mg/day = $1.67/mg

    ANABOLIC STEROIDS

    • Can develop compounds that are more anabolic than androgenic (reflected in the ratios of the table bleow)

    • Anabolic effects include


      • Trophic effects on muscle, bone and blood cells

      • Reduction in nitrogen excretion

    • Testing in animals has uncovered steroids in which androgenic and anabolic effects can be separated

      DRUG

      ANDROGENIC : ANABOLIC ACTIVITY

      TESTOSTERONE

      1:1

      FLUOXYMESTERONE

      1:2

      ETHYLESTRENOL

      1:8

      OXANDROLONE

      1:13

    • Separation of anabolic and androgenic effects not as effective in humans

    • In female athletes


      • Marked increase in muscle mass, strength and aggressiveness (highly anabolic in women)

      • Acute “masculinization” - hirsutism, deep voice, depressed menses

    • In male athletes: questionable efficacy? The level of training these athletes undergo probably has more to do with the  in muscle mass they see than the anabolic steroids themselves

    • In both sexes: danger of liver disease (jaundice) etc.

    MALE CONTRACEPTION?

      • Many early studies “failed” to find effective male contraceptive

        • Due in part to over-emphasis on azoospermia

        • Notion was only takes one sperm to fertilize an egg and the male produces millions and millions of sperm the only way to achieve effective contraception in men is to get them down to producing NO SPERM but that's not necessarily true

      • New studies suggest that critical threshold is 3 X 106 sperm per ejaculation—below that is considered infertile

        • WHO Study


          • Testosterone injections

          • 98.6% effective

        • Anzac Research Institute (Australia) Study

          • Progestin (NORGESTREL) injection @ 3 months + testosterone implants or patches

            • B/c testosterone production is controlled by the same HP axis as women

            • 100% effective in small trial


    NSAIDS AND OTHER ANTI-INFLAMMATORY DRUGS

    SIMPLIFIED MODEL OF RHEUMATOID ARTHRITISmacintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 3.56.03 pm.png

    • Bone is covered in cartilage to  wear and tear on the bone and to  the wear and tear on the cartilage the joint itself is encased in synovial membrane which secretes synovial fluid which acts like an oil to  wear and tear on cartilage.

    • RA is an autoimmune disease in which antibodies against self-proteins are generated

    • Macrophages (M) engulf antigens that pass to lymph nodes and present peptides to T-cells leading to T-cell activation and proliferation. Requires interleukin-1 (IL-1) produced by macrophage and induction of IL-2 production by T-cells—IL-2 is important for T cell proliferation

    • Activated, type 1 helper TH1-cells pass through blood to inflamed tissue, where they activate M that present the appropriate antigen - a process involving release of IFN γ

    • Activated M release TNF and IL-1, cause expression of adhesions proteins which attract other cells to the site which activate other M, fibroblasts and osteoclasts, and growth factors that promote angiogenesis (supply growing pannus)

      • Fibroblasts and osteoclasts especially start to secrete collagenases which start to break down cartilage and osteoclasts break down bone

    • Prostaglandins, leukotrienes and NO released by M lead to vasodilation, and increased vascular permeability

    • TNF promote entry of WBCs from blood, e.g. by inducing expression of VCAM-1. “Pannus” –is swelling of synovial membrane thickened by infiltration of T cells, macrophages, fibroblasts- develops at junction of synovial membrane and cartilage

    • Matrix metalloproteinases (MMPs) released from activated macrophages and fibroblasts break down cartilage

    • Activated osteoclasts promote breakdown of bone

    • Net result joint damage and deformation


    Sites of Action of Anti-inflammatory Drugs. TNFbinds to its receptor and activates a kinase (IBK) which phosphorylates the inhibitory protein IB, which is then degraded. NFB is then free to enter the nucleus and activate expression of various genes.

    -Zileuton was an important drug for asthma and now RA because it inhibits 5’-LO which makes LT’s. Zafirlukast is an antagonist of LT so it also is important in asthma and allergies but not indicated for RA. Most important anti-inflamm drugs are glucocorticoids (stim production of IkB as well as other things)


    macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 3.58.09 pm.png

      • TNF plays a key role in propagating inflammation. TNF is a protein produced by macrophages following stimulation by various agents, e.g. lipopolysaccharide (LPS, or endotoxin) produced by gram-negative bacteria. TNF binds to specific receptors on a variety of cell types and activates a transcription factor called nuclear factor B (NF-B), which enters the nucleus and switches on the synthesis of many proinflammatory proteins.

        • These include:

          • Cyclooxygenase 2 (Cox-2))

          • 5’-Lipoxygenase (5’LO) and its activator protein-FLAP

          •  Inducible nitric oxide synthetase (iNOS)

          • Phospholipase A2

          • Adhesion molecules in leukocytes and endothelial cells, which promote binding of leukocytes at the site of inflammation

          • TNF and interleukin-1 (IL-1) to amplify and propagate the process

      • Activation of NF-B occurs when its inhibitor, a protein called I-B, is phosphorylated by a specific protein kinase (I-B kinase, IKK) and degraded. The net effect is an increased synthesis of prostaglandins and leukotrienes

        • TNF binds to its receptors and will activate a kinase which will phosphorylate IkB which inactivates it and released NFkB to go into the nucleus and turn on synthesis of proteins which drive inflammation—this causes more cytokines to be released and these inflammatory processes will result in the synthesis of PLA2 which releases arachadonic acid causing the synthesis of COX2 that generates the prostaglandins. Also induces the synthesis of 5’-Lipoxygenase which leads to leukotriene production. Inducible NOS gets activated and you get NO. To keep the inflammatory processes in control we have other actions like these cells produce IL-1 receptor antagonists so that will moderate effects on IL-1. Also produce other receptors for TNF, which gets cleaved from the membrane making them soluble receptors and these are receptors obviously for TNF and if its bound to a soluble receptor it is not activating the cell so this will  TNF effects. Most importantly It induced IkB inhibitory protein which will block NFkB effects in the nucleus.

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