Drugs and pregnancy



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Me-NE is an a2 agonist in the brain (like Clonidine), inhibits sympathetic output to vascular SM and heart

  • this is good because if you peripherally vasodilate the SNS will reflex stimulate the heart and if you inhibit the 1 receptors (like w/  blockers) the SNS will reflex constrict the arterioles. If you inhibit the output of the SNS from the brain you inhibit both of those things at the same time and maintain the normal regulatory mechanisms for the baroreceptor reflex and you can still cause vasoconstriction (its not like using an  blocker) so you can still regulate your BP well

  • Me-NE is also an a1 agonist in vascular SM so does not block vasoconstriction or baroreflex completely

  • Similar result to clonidine, but less bradycardia

  • Renal blood flow and function not affected

  • SIDE EFFECTS: (brain 2) sedation, dry mouth, prolactin­

    • Minimal side effects

  • Other ANTIHYPERTENSIVE DRUGS used in PREGNANCY

    • LABETALOL

    • Atenolol

    • Nifedipine-- Ca channel blocker

    • Thiazides

    • HYDRALAZINE

  • SEVERE PRE-ECLAMPSIA (>180/110)

    • LIFE-THREATENING condition that requires treatment, if immediate delivery not chosen

      • Goals: 1) lower BP, and 2) prevent seizures

    • HYDRALAZINE (Apresoline®) (IV or IM) and/or LABETALOL (IV) – lower BP

      • Hydralazine and labetalol often used in combination

        • Hydralazine is a vasodilator that works on the arterial side of circulation and to tx moderate to severe HTN it is used with a -blocker and a diuretic

      • For hypertension, when diastolic BP > 110 mmHg

    • NIFEDIPINE (Oral)

    • SODIUM NITROPRUSSIDE (IV)

    • MAGNESIUM SULFATE – to tx seizures if they do develop

      • Prevents seizures in severe pre-eclampsia and patients with CNS manifestations, (headache, visual problems)

        • Reduces risk of eclampsia by 58%, death by 45%

      • Treats seizures of eclampsia

        • We know from the GI lecture that if its give orally it stays in the gut and works as a laxative

      • Prophylaxis postpartum for women with CNS manifest.

      • ADMINISTRATION

        • Maintain plasma MgSO4 at 4-7 mM

          • 4 g IV over 20-30 min, then infusion of 1-3 g/hr

      • MONITORING

        • Monitor reflexes, respiration, Ca gluconate to reverse


    PHARMACOLOGY OF THE REPRODUCTIVE HORMONES

    ENDOCRINE CONTROL OF OVULATION AND IMPLANTATION

    The Hypothalamus secretes a master hormone called GnRH (secreted in a pulsatile nature) which has actions on the pituitary gland and will stimulate the pituitary gland and gonadotropin proteins hormones are released. The first gonadotropin that is released is FSH and it travels to ovaries and stimulates the follicle and the main effect that FSH has is that is causes it to secrete estrogen (17  estradiol is the most important estrogen in humans). Estradiol in the uterus is a trophic hormone and tends to cause proliferation of target tissues and it will stimulate the endometrial cells of the uterus to grow (must have growth of endometrial layer for implantation). Estrogen also has a positive effect on hypothalamus pituitary axis especially on GnRH secretion—causes another round of GnRH release. This second surge of GnRH causes the release of LH. LH goes to the follicle cell and stimulates it to ovulate and release eggs into the fallopian tube. LH also cause the follicle to differentiate into the structure called the corpus luteum. (CL). CL produces progesterone. Progesterone does 3 important things: 1. Goes to rapidly growing endometrial layer of the uterus and causes them to stop growing and differentiate into their secretory phase. This allows the endometrium to now be able to support a fertilized egg. 2. Progesterone along with prolactin goes to the breast and aids in milk production. 3. It also effects the hypothalamus-pituitary axis Both high levels of E and P have a negative effect on GnRH secretion. So if an egg does not implant into the uterus, the high levels of E and P  GnRH and the LH stimulation of the CL  and the CL atrophies and P  and the endometrial layer can no longer be maintained and you have shedding of the endometrial layer and menstruation. However (not illustrated) if the egg is fertilized and implants there is problem—the uterus still need continuous P for early stages of egg and fetal development to proceed. But by this cycle the uterus cannot keep getting its P so the way we get around this is that the fetus takes matters into its own hands and the placental tissues which are derived from tissues in fertilized eggs. And these placental tissues secrete a gonadotropin that essentially has LH activity called hCG and it goes to the CL and doesn't allow it to atrophy so P is still released by the CL.


    GNRH AND GONADOTROPINS

    • GONADOTROPIN-RELEASING HORMONE (GNRH)

      • Decapeptide secreted by the hypothalamus

      • Serum half-life = 4 min
(needs a rapid turn over rate to be able to work in a pulsatile fashion)

      • Secretion occurs in pulses

        • Pulsatile IV or subcutaneous administration @ 60 - 120 min ➙ FSH and LH secretion

          • Physiological pulsatile nature is essential for stimulating the pituitary but if the pituitary is exposed to continuous chronic GnRH then it actually has a inhibitory effect on pituitary

        • Continuous administration ➙ gonadotropin suppression

      • Synthetic analogs now available

        • Longer half-lives

        • Higher receptor-binding affinities –more potent drugs

        • Synthetic GnRH = GONADORELIN


    Gly at position 6 is very important for binding at the GnRH receptor so substitutions at this point can allow for tighter binding of compounds leading to hyper potency. Substitution at Gly at position 10 give an ethylamide group which gives compounds longer half lives. LEUPROLIDE was one of the first synthetic high potency analog to be made.
    STRUCTURE AND POTENCY OF GNRH AND ANALOGS

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    • GONADOTROPINS

      • Historically have been known as MENOTROPINS

        • From urine of postmenopausal women
they have higher levels of LH and FSH

          • FSH and LH are large protein hormones ( and  chain on each) and you can make these from scratch but they are difficult and expensive to make from scratch.

        • Contain naturally-modified FSH and LH activity of low potency

      • UROFOLLITROPIN ✶


        • Menotropin containing only FSH activity

        • Used more commonly than recombinant FSH because its cheaper to use.

      • RECOMBINANT FSH (rFSH)


        • Follitropin alpha and beta

          • Identical except for carbohydrate side-chains

          • Identical activities / more expensive

      • HUMAN CHORIONIC GONADOTROPIN (hCG) ✶

        • Isolated from urine of pregnant women

        • Secreted by placenta goes into the maternal blood stream gets secreted by the kidneys in the moms urine

        • LH activity (ovulation and progesterone secretion)

      • RECOMBINANT hCG (rhCG)


        • Choriogonadotropin alpha

        • Most expensive

    • THERAPEUTIC USES OF GNRH & ANALOGS

      • Induction of ovulation in amenorrheic women (cant produce enough GnRH)

        • Gonadorelin 5 ug @ 90 min

          • Use this b/c you want it to have rapid turn over so you can release it in a pulsatile fashion to stimulate the pituitary

        • One cycle of treatment often enough to induce ovulation

      • In vitro fertilization—used when you have blocked fallopian tubes

        • Continuous LEUPROLIDE to suppress LH & FSH


          • High potency long acting GnRH

        • Use Controlled gonadotropin doses (UROFOLLITROPIN & hCG)  until you see follicle development and ovulation which mostly likely will lead to an egg in the fallopian tube

          • You can then retrieve the egg and fertilize it in the petri dish and implant it in the uterus

      • Delayed puberty - pulsatile (GONADORELIN)

      • Precocious purberty - continuous (LEUPROLIDE) to suppress the menses

      • Endometriosis (usually due to overstimulationg by estrogens)- LEUPROLIDE to inhibit the ovulatory cycle

      • Prostate cancer - LEUPROLIDE, HISTRELIN, GOSERELIN

        • Testosterone stimulates the growth of prostate tissue and in older men you can have BPH or prostate cancer and you use high potency analogs to inhibit testosterone secretion.

    ESTROGENS

    • ESTROGEN PREPARATIONS

      • NATURAL ESTROGENS

    macintosh hd:users:elisafuray:desktop:screen shot 2013-04-20 at 5.03.17 pm.png

          • *KNOW ESTRADIOLsecreted by the ovaries and adrenal glands. They all pretty equal in their potency at the receptor but estradiol is the one that is secreted at much higher concentrations by the ovaries. Dominant estrogen that is controlling the female reproductive cycle. Pharmacologically 17  estradiol is hardly ever used.

        • Structurally similar compounds with similar potencies

        • Quickly inactivated by liver by conjugation (sulfation and glucoronation). Rapid elimination by kidneys

        • Not orally effective. Administration ➙ transdermal or intramuscular

      • CONJUGATED ESTROGENS

        • Obtained from pregnant mare’s urine or stallion

        • Circa 60% SULFATED ESTRONE—even thought they’ve been sulfated they still bind to the estrogen receptor and still work but you have to use them at higher doses. Nice thing about these is they have already passed metabolism by the liver (where they were sulfated) making them orally effective.

        • Orally effective at high concentrations


        • Common drug: PREMARIN® (Wyeth)

        • PREMARIN + PROGESTIN = PREMPRO® (Wyeth)

      • SYNTHETIC, STEROIDAL ESTROGENS (MOST IMPORTANT CLASS)

        • ETHINYL ESTRADIOL, QUINESTROL, MESTRANOL

          • Dominant synthetic estrogen in oral contraceptive pills

        • Potent agonists
at the estrogen receptor

        • Less-rapidly metabolized by liver  Longer duration of action

        • Orally effective

      • SYNTHETIC, NON-STEROIDAL ESTROGENS

        • DIETHYLSTILBESTROL (DES)

          • Moderately potent agonist, slowly inactivated by liver, orally effective, common in past usage

          • The structure of this compound doesn't look like it’d be an agonist at the E receptor but the two ethers actually form a benzene ring in space and the structure begins to look like a steroid

        • CHLOROTRIANISENE

          • Very fat soluble, stored in adipose tissue and slowly released

    • THERAPEUTIC USES OF ESTROGENS

      • Dysmenorrhea

        • Difficult or painful menstruation

        • Contractions caused by overstimulation of uterus by prostaglandins—this is occurring is response to the ovulatory cycle. So rx an OC pill and you can inhibit the ovulatory cycle (progestins in OC pills also inhibit the secretion of prostaglandins too)

        • Usual therapy: NSAIDs

        • For intractable dysmenorrhea: Inhibit ovulatory cycle by chronic administration of estrogens and progestins

      • Hirsutism

        • Masculinization due to excess androgen production by ovary or adrenals

        • Deeping of voice, facial hair, etc

        • Estrogens can combat the over production of androgens

      • Contraception

      • Menopause

        • Most of symptoms of menopause are caused by cessation of ovulatory cycle and estrogen withdrawal

        • Symptoms attributable to lack of estrogen stimulation

          • Hot flashes, sweating, atrophic vaginitis

        • Estrogen replacement therapy (ERT), usually in conjunction with 
progestin

          • First they just gave ethinyl estradiol but they found that it was associated with  risk of endometrial cancer so the progestins were added to protect against this.

      • Postmenopausal Osteoporosis

        • Dramatic loss of bone matrix due to estrogen deficiency it can lead to fractures, etc

          • Estrogen is trophic at bone tissue—it promotes growth so loss of it will lead to bone matrix loss

        • Greatest bone loss occurs within five years of menopause and then declines gradually after that

        • Therapy: chronic or cyclic administration of estrogen + progestin (same reason that progestin was added to tx menopause) immediately after menopause or at onset of bone loss (it was previous prescribed for life after this but that has changed and will be discussed later).
Withdrawal of therapy may result in accelerated bone loss

      • Conventional “Wisdom”  ERT for life.

        • New risk evidence has undermined this practice

    • NON-STEROIDAL DRUGS FOR OSTEOPOROSIS

      • BISPHOSPHONATES

        • MOA:

          • Retard dissolution of hydroxyapatite crystals

          • These compounds go into bone and replace the pyrophosphate with this structure and it becomes part of the bone crystal structure. Considered permanent components of bone structure one they are administered. The reason they prevent bone loss is b/c these compounds stabilize the bone mineral, they are less likely to be cleaved, etc leading to much slower turn over rate of bone mineral

        • Examples

          • Pyrophosphate

            • Pyrophosphate crystals are an important component of bone mineral

          • ALENDRONATE ✶ (Fosomax®)

          • ETIDRONATE (Didronel®)

          • PAMIDRONATE (Aredia®)—3rd generation drug w/ the best efficacy

        • Pharmacodynamics:


          • 1-10% oral dose is absorbed –so 90% is wasted

          • Of that 10% that gets absorbed 50% accumulates in bone
and 50% excreted in urine so really doesn't do much of anything to other parts of the body which is good—specific for targeting bone tissue

        • Used in Paget’s disease (degenerative loss of bone due to a genetic mutation) as well as post menopausal osteoporosis

        • Recently approved for treating hypercalcemia that arises from certain kind of Malignancies/cancer


        • ALENDRONATE:


          • Now commonly used for post-menopausal osteoporosis

          • Also shown useful in preventing male vertebral fractures (so women and men can benefit from this drug)

    ANTI-ESTROGENS


    • Antagonize Action of Estrogen at the Receptor

      • TAMOXIFEN

      • Clomiphene

      • Historically thought to be global competitive antagonists at the E receptor— which bind but do not activate the estrogen receptor blocking estradiol mediated responses

        • but as its been studied this view is changing because competitive antagonist should have a global action (block all estrogen mediated responses) and shouldn't have agonist activity anywhere.

      • Now better viewed as SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)

      • CLOMIPHENE (Clomid®)

        • Used in the treatment of anovulatory infertility

        • Acts by inhibiting estrogen-mediated repression of GnRH release by hypothalamus

          • If you have too much estrogen being produced by the adrenals and ovaries you will suppress the hypothalamus-pituitary axis (just like having an endogenous OC pill) so you wont ovulate.

          • Antagonist at the hypothalamus but doesn't work as an antagonist at the breast like tamoxifen.

        • Not effective in patients with pituitary or ovarian dysfunction 


        • Dosing regimen causes rise in plasma LH and FSH levels by 5th day

          • Single dosing regimen results in single ovulation

          • Repeated dosing required for subsequent ovulations

        • Normal ovulatory cycle not usually resumed 


        • Effectiveness


          • 80% of patients ovulate


            • of the 80% 40 to 50% of these become pregnant

      • TAMOXIFEN (Nolvadex®)

        • Orally effective

        • Used to treat steroid-dependent breast cancer

          • 2 types of breast cancers

            • Estrogen receptor positive—these are not the best kind b/c they grow slower (still can be dangerous though) and they are stimulated to grow by estrogens so you can slow down the growth by txing with an E receptor antagonist.

            • Estrogen receptor negative—these are the worst kind b/c they are faster growing and more likely to mets and kill you

        • Inhibits estrogen stimulation of cancer growth

        • Can be used on pre- and post-menopausal women with ER- positive tumors 


        • Shown to be just as effective as cytotoxic anti-neoplastics 
(chemotherapy)

          • Many fewer serious or unpleasant side effects

          • Becoming drug of choice 





        • Side effects:

          • Hypercalcemia—b/c you antagonizing E receptors at the bone

          • Bone pain-- b/c you antagonizing E receptors at the bone

          • Increased risk of endometrial cancer—this is an agonist effect which is weird b/c we call this drug an antagonist. It is acting like an estrogen in the uterus

    • ANTI-ESTROGENS (SERMS)


      • RALOXIFENE (Evista®)

        • Approved as agonist for postmenopausal osteoporosis—stimulates bone density

        • Antagonist at uterus


        • Early evidence of antagonism at breast

        • Some physicians are starting to use this as HRT in postmenopausal women

    • ANTI-ESTROGENS (INHIBITORS OF BIOSYNTHESIS)

      • Used to treat E Receptor positive Breast Cancer Resistant to Tamoxifen

        • Want to make sure there is no estradiol present (synthesized in the ovaries, adrenal glands, and to a lesser extent the liver) to stimulate the growth of these cancers because blocking the receptor no longer works



      • AMINOGLUTETHIMIDE (Cytadren®)

        • Blocks conversion of cholesterol to pregnenolone in adrenals and other tissues
(blocks the first step in the synthesis of all steroids)

        • Given at high concentrations this drug can blocks aromatase which converts androstenedione and testosterone to estradiol—but b/c it blocks all steroid synthesis you would not use this very commonly

        • Reduces all steroid synthesis, including estradiol


          • So also will need replacement therapy especially for glucocorticoids Hydrocortisone replacement required




    • ANTI-ESTROGENS (INHIBITORS OF BIOSYNTHESIS) AROMATASE INHIBITORS

      • ✶
ANASTROZOLE (Arimidex®) and LETROZOLE (Femara®)

        • Anastrozole is the most commonly prescribed

        • Binds reversibly and is a competitive non-steroidal inhibitors of aromatase responsible for conversion of androgens to estrogens

          • Aromatase is responsible for conversion of androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) so if you block this enzyme this conversion does not take place so you don't make estrogens.

      • EXEMESTANE (Aromasin®)—2nd generation

        • Non-reversible steroidal inhibitor of aromatase—so much longer duration of action in inhibiting the enzyme



    PROGESTINS
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