Reproductive System DrugsOB will cover cover uterine relaxants, drugs to

induce labor & fertility drugs

Marylou V. Robinson PhD FNP

Drugs Affecting the Female Reproductive System

1. Contraceptives2. Estrogen (Premarin)3. Estrogen-progestin combos (EPT)4. HRT5. Medroxyprogesterone (Depro-Provera)6. SERMs7. IUDs

Cycle Overview (pg. 768)Progesterone

•Increases mostly during luteal phase while being made by corpeus luteum•fertilized ovum implant doesn’t occur corpeus luteum atrophy progesterone & estrogen production•menses (approx. days 1-5 of 28-day cycle)• secretions but makes them more viscous and difficult for sperm to travel thru

Estrogen•Negative-feedback on ant. Pituitary hormones luteinizing hormone (LH) & follicle-stimulating hormone (FSH)

• Rapid peak in LH causes ovulation in middle of cycle (between follicular & luteal phases) quick LH to nl post-ovulation• Makes ruptured follicle

(corpus luteum) make progesterone

• FSH makes follicles produce estrogen in follicular phase estrogen causes FSH

Estrogens (pg. 769), KNOW• Premenopausal women: most estrogen (also progesterone)

production occurs in ovaries (post-menopausal, decline then production cessation in ovaries)– Small amounts made in peripheral tissues: liver, fat, bone (also

placenta w/ progesterone during pregnancy)– Also affects bone, blood vessels, liver, heart & CNS– Main endogenous estrogen = estradiol (others include estrone &

estriol)– Synthetic estrogens identical to endogenous ones

• Function: female maturation, female reproductive organs, metabolic actions

• Action: synthesis of DNA, RNA & protein in estrogen-sensitive tissues– Na and water retention, cholesterol

Approved Estrogen Uses (pg. 776)1. OCPs: estrogen thickens cervical mucus barrier & vaginal acidity to block

fertilization, also exerts negative feedback on LH & FSH (prevents follicular maturation & ovulation)

2. Menopause HRT (estrogen deficiency, Turner’s): manage vasomotor symptoms (hot flush, night-sweat) that don’t go away w/in first few months– most common non-contraceptive use– Short-term safe, long-term use discouraged D/T risks

3. Urogenital atrophy: urethra/vagina have highest concentration of estrogen receptors – Degenerate post-menopause when estrogen – Urethra: incontinence, urinary frequency– Vagina: dryness, pain w/ intercourse topicals preferred (lower estrogen blood

concentrations4. Osteoporosis (secondary) PPX: risk after ovarian removal or menopause, when

estrogen accelerates bone reabsorption 12% bone loss shortly after menopause – Estrogen can moderately slow bone reabsorption & osteoporosis, doesn’t really reverse

bone loss & stopping estrogen HT will just cause the 12% bone loss to happen anyway– Osteoporosis drugs work better and are generally safer– NEVER GIVE THESE FOR BONE HEALTH ALONE (TOO MANY SE)

Estrogen SE

• Stomach cramps or gas• HA, n/v (less with non-PO routes and/or taken w/ food

or HS)• Some women: migraines somewhat during ovulation D/T

estrogen

• decreased libido • Fluid retention: edema of LE (lower extremity), breast

pain & enlargement also WEIGHT GAIN (5 lbs) • Estrogens activate RAAS possible bloating, weight gain, HTN

Cautions with Estrogen• Risk of endometrial CA with prolonged use: estrogens cause

endometrial proliferation/hyperplasia when used alone (in women w/ uterus) may become CA (esp. post-menopausal women)• Hormone combos greatly risk: progesterone opposes estrogen-caused

hyperplasia & decreases endometrial proliferation• Admin: assess for endometrial carcinoma if “benign” bleeding persists pasts

first 6 months of TX or begins after prolonged use• Somewhat-similar to breast cancer: they’re both estrogen-sensitive tissues

• Should not be given to lactating women ( milk production)• Could also feminize male babies or cause severe acne & development of

secondary sex characteristics in female babies• Preg Cat X: not dangerous but useless during pregnancy• Baseline liver labs before therapy: benign hepatic adenoma risk w/ OCPs

(can still rupture & cause fatal bleeding)• Also drug use or Hepatitis concerns

• Increases lipid levels: LDL• Increases heartburn/GERD: relaxes cardiac sphincter• Increases gallbladder stones: risk of cholecystitis D/T chronic gallstones

greatest in postmenopausal women on HRT > 5 years• Estrogen & OCPs precipitate gallstones & gallbladder disease already present

Estrogen & CV Risk• CV risk: R/T MI, CVA, DVT & pulmonary embolism– Not PPX: doesn’t slow atherosclerosis or prevent recurrent CVA– Pt Edu: avoid smoking, exercise regularly, avoid saturated fats,

follow treatments for maintenance of HTN/DM/hypercholesterolemia

• Coagulation tendencies: estrogen coagulation-suppressing factor antithrombin & levels of clotting factors II, VII, IX, X & XII– Only somewhat levels of factors that break down fibrin in clots– Combos venous thromboembolism (VTE) risk in pre/post-

menopausal women– Estrogen alone risk of MI or CHD in women > age 60

• Tobacco: smoking risk of serious cardiac events (CVA, TIAs, thromboembolism, pulmonary embolism)– Absolute contraindication: risk is higher in women > 35 years of

age– Estrogen is #1 cause of strokes in women < age 35

Estrogen Contraindications• Known or suspected BCA: estrogen hasn’t been shown

to cause BCA but promotes estrogen-receptor BCA cancer growth – more dose-dependent & R/T older age– R/O ER-BCA before RX, annual breast exam, annual

mammogram > age 40• Abnormal vaginal bleeding, endometriosis, uterine

fibroids• Hypercalcemia (estrogens may mineral deposits)• Thrombophlebitis or hx of VTE or pulmonary embolism

Estrogen Preparations• Estradiol and estrone are natural occurring steroidal

estrogens• Conjugated estrogen (Premarin): natural formulation

but processed (most common)• Diethylstilbesterol (DES): synthetic estrogen

– Preg Cat X: causes clear cell carcinoma (rare vaginal cancer) in women who had fetal exposure, off-market

– Male children have risk of testicular cancer• Transdermal estrogen (Estraderm)• Vaginal creams• Compounded mixtures: made by hand into

individualized estrogen mixture (typically topical, also PO) not standardized tho

• Synthetic estrogens typically identical, but natural estrogen may have fewer SE (recent research)

Progesterone and Progestin

• Prototype: progestin• Action– Pro-gestational: produce biochemical

changes in the endometrium to prepare for implantation of embryo (also maintain uterus during pregnancy)

– Opposes estrogen-mediated endometrium stimulation

– Suppresses ovulation during pregnancy– Can increase appetite

Progestin• Indication– Female hormonal imbalance– Amenorrhea, dysmenorrhea, endometriosis – Combined with estrogen to lower risk of

endometrial Ca– Prevent pregnancy in lactating women (can’t

give them estrogen)

Oral Contraceptives• Newer, low-dose OCPs have:– Lower risk for adverse CV effects

(stroke, thromboembolus)– Decreased risk for ectopic pregnancy

• Low dose formulations are for the thin teenager.–Most older and heavier folks they are not

as effective (possibly D/T blood levels, sequestration in adipose, altered metabolism)

OCPs

• Estrogens and progestins (various manufacturers)

• Action– Inhibit secretion of FSH and LH– Changes in endometrium that impair

ova implantation– Increased vaginal mucus to impede

passage of sperm

OCPs

• SE– Wt Gain, – Stomach cramps,

Swelling of Face and LE

– HA (esp. aural migraines)

– Mood alteration– Gall stones– Increased clotting

– Amenorrhea, – Breakthrough

Bleeding, – Menorrhagia, – Acne (androgens)– Insomnia, – Breast Pain, – Increased risk STD

(behavior & more viscosity can trap STDs

– Hyperglycemia

Benefits• protection against pregnancy

– 98% best use– 70% in many women– Less than 50% in teens

• ovarian cysts suppression (PCOS): very painful condition

• iron deficiency anemia resolution ( OCs heavy menstrual bleeding blood loss)

• reduced rheumatoid arthritis (D/T immune system?): women feel better w/ RA when pregnant (same as OCPs)

• higher bone density ?

Estrogen-progestin Combos

–Monophasics: fixed ratio of estrogen and progestin that is taken for 21 days• Alesse-28, Ortho-Cyclen, Lo-Ovral

– Biphasic: supplies 2 different amounts of progestin during the first (follicular) and second (luteal) phases of the menstrual cycle• Ortho-Novum

– Triphasic: dose of estrogen is constant while progestin is progressively increased (three times) for 21 days• Ortho-Novum 777, Triphasil, Ortho-Tri-Cyclen

Extended Cycle (Seasonale meds)

• Take for 3 months/withdraw for period (only 3 days off meds)

• Lots of break through bleeding most don’t get to 3 months without sudden onset menses

• Best suggestion is when have bleeding, do withdraw and then start on own schedule.

Something about those pills• What is different about YAZ (pg. 788)?–What diuretic drug is it similar to?

• Yaz = drosperinone + ethinyl estradiol• Drosperinone: 4th gen progestine & structural analog of

spirolactone (blocks aldosterone), added to OC fluid retention

–What are the risks?• Drosperinone also K-sparing (hyerkalemia) caution

using w/ other hyperkalemia-associated drugs (ARBs, ACE inhibitors)

• Greater risk of VTE than other progestins

• What is the link between OCP and glaucoma?– Raise blood pressure, sodium & water retention

(greater risk for life, along with cataracts)

Rings and Things• Rings (NuvaRing)– Insert for 3 weeks remove for menses– Clear to the eye– If fall out, rinse and re-insert (need back-up

contraception for 7 days if ring is out > 3 hours during weeks 1-3)

– Better for “discrete” birth control over OCPs• Patches– Changed weekly. Three in a box– Can’t place on breasts (adipose tissue or breast

tissue stimulation): higher BCA risk– Need back-up contraception for 7 days if patch is off

> 24 hours during weeks 1-3)• Both have higher risk for clotting than pills

( higher estrogen exposure needed for other routes)

Other Contraceptives• Low-dose progestogens (mini-pill): do not

contain estrogen- less effective/forgiving (don’t inhibit ovulation as

well), most when just starting these– Breastfeeding AOK (progestin don’t milk

production)

• Long-acting: progestin-only– Implanon (capsule implanted in arm)– Depo-Provera (IM injection q 3 mo)– IUD (with and without med), pg. 796

– SE: vag bleeding, muscle pain, GI distress, wt gain, vaginitis, breast discharge

Medroxyprogesterone (Depro-Provera), pg. 796

• Long-acting OC (progestin-only): protects against pregnancy for ≥ 3 months

• Admin: IM (also SQ) q 3 months– Discontinuing TX delays fertility by ≈ 9 months (up to 2-3

years)– Starting TX: give during first 5 days nl menses or w/in first 5

days post-partum (if not breastfeeding)/ w/in first 6 weeks post-partum if breastfeeding

• Mechanism: inhibits gonadotropin secretion– Inhibits follicular maturation & ovulation– Thickens cervical mucus– Thins endometrium egg implantation less likely

• SE: similar to other progestin-only TX (bloating, HA, depression, libido)– No significant cervical/breast/ovarian CA risk– Highly bone-bleaching: may cause reversible bone loss, but

regular bone marrow density scans (BMDs) aren’t recommended need more dairy & calcium supplements (this is less mitigated as age increases)

Education• Compliance is important: choosing the right

birth control depends on effectiveness, safety & personal preference- Patient: life may begin at conception instead of

implantation

• Take tablets at the same time every day– Miss 1 dose: take ASAP– Miss 2 doses: take 2 tabs/day for the next 2 days– Miss 3 doses: stop taking, use another form until

menses occurs or pregnancy R/O– Last 7 tablets are placebo in traditional packs– Newer branded are only 3-4 days placebo

IUDs (pg. 796)• Long-term OC

– Copper T380A (Paraguard): doesn’t release meds– Levonorgestrel-releasing (Mirena): used esp. for menorrhagia

(heavy menstrual bleeding)– Potentially good option for at-risk teens (less issues of

compliance)• Mechanism: harmless local inflammatory response

(spermicidal), does not prevent ovulation– Paraguard copper may also prevent implantation (also EC when

placed w/in 5 days unprotected sex)– Mirena endometrial involution & thickening of mucus

• Placed w/in 7 days menses onset: lidocaine & ibuprofen can prevent cramping

• SE: abd cramping, altered menses (more local, less systemic [lower bone loss?])– Paraguard: monthly bleeding– Mirena: commonly amenorrhea or light spotting– PID secondary to STD: only use in women at low risk of STIs

(monogamous couples)– Greater risk ectopic pregnancy

Mifepristone (RU-486) [Mifeprex] pg. 799• Progesterone Antagonist (abortifacient): given with

misoprostol to stimulate uterine contraction and aid in expulsion of the tissue dislodged (fetus or excessive lining) – Used w/in first 7 weeks of conception– Safe alternative to surgical abortion– Also the most effective known emergency contraceptive EC

when taken w/in 5 days after sex, but not approved for EC– MD giving Mifeprex has to be able to perform surgical abortion

or curettage (surgical tissue removal from uterus) if abortion fails

• Abortion requires 3 visits to MD: – Day 1: get pill– Day 3: ultrasound to determine if abortion occurred (re-admin

Mifeprex if it didn’t)– Day 14: ultrasound to confirm pregnancy’s termination (surgical

abortion if it didn’t)• Bleeding can be severe and require transfusions

– Cannot be used in patients w/ tubal (ectopic) pregnancy, hemorrhagic disorders or anticoagulant drugs

– Bleeding caused by Mifeprex could mask symptoms of these serious conditions

Levonorgestrel (Plan B), pg. 797

most commonly used ECP• Levonorgestrel: progestin• Separate RX or use of pills on hand (formula by

pharmacist)• Large dose impairs implantation of fertilized

egg– Must be taken w/in 5 days after unprotected sex– Successful if menstrual bleeding occurs w/in 21 days– “large dose” still for “avg woman” ≤ 120 lbs

• Doesn’t abort implanted eggs – Pregnancy = implantation of fertilized egg

• Spike in clotting risks: not recommended for routine use

• No Rx in most states for women ≥ age 17

Why don’t we use indomethacin (Indocin) in later pregnancy?

• Closes ductus arteriosis in fetus (inhibits prostaglandin synthesis)• Normally blood goes around fetus’ lungs during

pregnancy• Infants with patent ductus arteriosus (PDA) didn’t

have valve close between aorta & pulmonary artery indomethacin is used on them to fix PDA

• NL use: NSAID & antirheumatic• NSAIDS BAD 4 PREGNANCY

Post-Menopause (pg. 771)• Estrogen can be used for hot flashes & bone

health – MUST have progestin if have uterus

• SSRI & SNRI have hot flash indication (paroxetine or venlafaxine): vasomotor S/S in post-menopause by CNS serotonin

• Herbals have no evidence of helping• Selective estrogen receptor modulator (SERM)

[covered with MSK]: can help with bones (activates estrogen receptors) & lipids– Tamoxifen (Nolvadex): can inhibit (cancerous)

breast growth by blocking estrogen receptors– Blocking estrogen receptors leads to hot flashes – Also has risk of endometrial cancer & VTE

Clomiphene (Clomid)• Ovulation Inducer: Preg Cat X• Use: Induces ovulation in anovulatory

women who desire pregnancy. Requires intact anterior pituitary, thyroid, and adrenal function.

• Mechanism: Stimulates release of pituitary gonadotropins, follicle-stimulating hormone, and luteinizing hormone, resulting in ovulation and the development of the corpus luteum.

ospemifene (Osphena)• SERM-like medication (not actually

SERM): hormone, estrogen agonist/antagonist

• Same estrogen issues: – potential uterine cancer– Cannot take with hx of blood clots, CA– risk HD: cigarette smoking, high BP, high

cholesterol, diabetes, and being overweight during estrogen therapy• DM patients esp. as risk for clots!

Male Hormonal Meds

1. 5-Alpha reductase inhibitors (Proscar)2. Phosphodiesterase inhibitors (Viagra)3. Testosterone (Ch. 65)

Androgens

• Male sex hormones necessary for development of male sex characteristics

• Primarily testosterone• Can be given to women with low

levels to help with libido issues– Bad acne

Testosterone

• Naturally occurring, produced in testes• Synthetic testosterone in various forms• Action– Stimulates synthesis and activity of RNA– Potent anabolic agents that increase

muscular and skeletal proteins– Enhanced storage of phosphorus, sulfate,

sodium and potassium

Testosterone• Indication– Main: Androgen deficiency, hypogonadism

• Androgen deficiency: S/S & testosterone blood levels < 220 ng/dL adjust to mid-normal range (300-450 ng/dL)

• Might reverse ED

– Delayed male puberty– Treatment of anemia (stimulates erythropoiesis),

no strong impact

• NOT used for infertility, prostate cancer or nodules, HF

• Abuse potential: illegal use for wt gain, muscle development and strength– Most androgens Schedule III

Testosterone• Administration: PO, IM, patches

• SE: Abd pain, insomnia, dizziness, red skin, HA, N/V/D, depression, pruritus, jaundice (hepatotoxic), libido – Females

• Acne, deepening of the voice, increase hair growth or alopecia, enlarged clitoris, irregular menses

• Androgens can injure female fetus (masculinization)

– Males• Urinary urgency, gynecomastia, frequent erections• Salt & water retention may lead to edema

– Children: premature epiphyseal closure (radiograph hands/wrists biannually)

Testosterone Therapy• Caution– Causes fluid retention and hypercholesterolemia

use carefully w/ cardiac issues or renal disease• HDL & LDL

– DDI: anticoagulants ( warfarin levels)–May cause prostate enlargement and worsen BPH–Makes hypercalcemia secondary to metastatic Ca

worse• Testosterone can promote PCA growth that’s started

Testosterone Therapy

• Baseline ht, wt, and sexual develop. in children, bone age determination q6mo

• Monitor serum calcium, cholesterol levels, LFTs, H & H for polycythemia

• Monitor tumor growth• Older men, monitor for signs of BPH

BPH (pg. 839)• Prototype: finasteride (Proscar), a 5-Alpha-Reductase Inhibitor

• Action: blocks enzyme that converts testosterone into potent androgen (DHT) by 70% causes shrinkage of prostate epithelial tissue mechanical obstruction of urethra (results in 6-12 months)– Doesn’t blood testosterone levels– Goal: urinary symptoms & slow disease progression– Taken for life

• Use: preferred for men w/ very large BPH (mechanical obstruction, more epithelial tissue)– alpha blockers (antihypertensives) for smaller BPH, relax bladder

smooth muscle to dynamic obstruction (no effect on BPH size)– Saw palmetto ineffective for BPH– Finasteride also made as Propecia, used for male-pattern baldness

Finasteride (Proscar) SE• SE: libido, impotency, decreased amount of

ejaculate, gynecomastia• Proscar PSA (prostate-specific androgen) levels, get

baseline test– Consider possible prostate cancer if PSA doesn’t after 6

months of therapy• Preg Cat X: alters fetal development of male genitalia

(hypospadias), smaller prostate & seminal vesicles– Women pregnant with male fetus should not handle the

drug– Manufacturer recommends women who might get

pregnant not handle drug without gloves (can be absorbed thru the skin)

Drugs That Impair Libido and Sexual Gratification

• Antihistamines• Anticholinergics• Antihypertensives

(BB, CCB, diltiazem)

• Antianxiety and psychotropic drugs

• Antidepressants• Antifungals • Opioids

• Thiazide diuretics• ETOH• Barbiturates• H2 receptor

antagonists (cimetidine, ranitidine)

• Hormones

Drugs That Enhance Libido & Sexual Gratification

• None specifically approved but there are substances that temporarily modify physiologic responses and perception of enjoyment

• Numerous aphrodisiacs have been tried:– Cantharis (Spanish fly)– Yohimbine (from West African tree)– Opioids: morphine, heroin, cocaine, marijuana, LSD– Amyl nitrite– Alprostadil (prostaglandin): injectable into corpus cavernosus

ED Drugs (pg. 834)• Prototype: sildenafil (Viagra)

– Phosphodiesterase Type 5 (PDE5) inhibitor– 1st approved PO drug for ED, 1st-line ED TX– Not an aphrodisiac

• NL: arousal PNS local nitric oxide nitric oxide activates cyclic guanosine monophosphate (cGMP) relaxed arterial/trabecular smooth muscle arterial dilation local blood flow & BP expanded corpus cavernosum venous occlusion & venous outflow erection– Goes away when cGMP is removed by PDE5 (enzyme

converts cGMP guanosine monophosphate)• Action: levels of cGMP, a smooth muscle relaxant

inflow of blood & erection• Indication: impotence (ED)

– Also pulmonary arterial HTN (PAH)• Administration: 1 hr before sexual activity (t ½ 4

hours)

Viagra• SE: HA, nausea, facial flushing, nasal congestion, back pain, flu

syndrome, arthralgia, allergic rxn, priaprism – Cardiovascular sx (angina, tachycardia, hypotension): could be Viagra

(huge vascular shifting) or sex activity– Visual changes at higher doses (blurring, blue tint, photosensitivity),

nonarteritic Ischemia Optic Neuropathy (NAION) also possible when blood flow to optic nerve’s blocked (esp. in men w/ anatomic or vascular risk factors)

• Contraindication: concomitant use of organic nitrates, alpha blockers, CYP3A4 inhibitors– Nitrates (NTG, nitroprusside): also promote vasodilation via cGMP

(nitrates synthesis & Viagra slows breakdown), could cause fatal hypotension must wait 24 hours between Viagra & nitrate, more if Viagra was taken w/ a CYP3A4 inhibitor that slows elimination

– α-andrenergic blockers: dilate arterioles & BP combined effect causes significant postural hypotension

– CYP3A4 inhibitors (also hepatic/renal impairment): ketoconazole, erythromycin, cimetidine, grapefruit suppress metabolism & levels

• Education– Delayed response if taken with high-fat meal (slows liver metabolism,

absorption)– Increase fluids to 2000 mL per day can prevent UTI– Seek immediate TX for chest pain, palpitations, sudden sharp HA – Report visual changes “blue”– Seek immediate TX if erection > 4 hours

Other ED meds• Varendafil (Levitra), pg. 837: similar to Viagra– Also requires no alpha blocker meds– DDIs w/ CYP3A4 meds (grapefruit)

• Taldalafil (Cialis), pg. 838: lasts much longer than Viagra or Levitra– Provides coverage for 36 hours, therapeutic levels

in 2 hours–Most men use it within 4 hours– Now available in daily dosing for more spontaneous

lifestyle (only if “get lucky” ≥ 2x/week

Drugs Used in Renal Disease

kidneys = major organ for drug elimination• Renal dose adjustments: made w/ CCr

(creatinine clearance) or measuring certain drugs’ blood levels

Multiple Drugs• Epogen (ethrythropioetin): anemia reversal• Bind excess phosphates (PO4

3-) that accumulate in renal disease

– Aluminum hydroxide (also antiulcer, antacid): binds to phosphate in GI tract, but has aluminum absorption over time

– Calcium Acetate: binds to excess phosphate & excreted• Vitamin D supplementation: Calcitriol (Rocaltrol), CKD

patients can’t convert Vitamin D to active form– Helps body absorb phosphates & calcium from blood instead

of dissolving it from bone or over-compensating PTH• Diuretics (loop & osmotic): help with fluid balance• Sodium bicarbonate for acid-base imbalance

(metabolic acidosis): will make basically all drugs inert cement (not work)

– Given IV: binds most other drugs and cannot be mingled in the line

– Encourages severe salt and water retention– sodium overload (CV workload), gastric acid hypersecretion

Hyperkalemia Issues*

• Serious cardiac risks of rhythm issues

• Spiked T waves on EKGs, possible cardiac arrest

• Confusion, anxiety, paresthesias

Cation-Exchange Resin• Prototype: sodium polystyrene (Kayexalate) – Proven to not work!!!!!!

• Indication: elevated serum potassium levels• Action: given as enema– Exchanges sodium ions for potassium ions– K+ binds to the substrate eliminated via feces

• What can happen to the VS of a patient with vagal issues (enema)? HR will drop. – Vagus nerve innervates PNS below neck, i.e., lung,

heart, abd viscera– Stimulation: bradycardia & arrhythmia

Hyperkalemia Interventions

• Stop K sources of any drugs: K-sparing diuretics & KCL supplements

• Infuse insulin + glucose to promote uptake into cells

• If acidotic might use NaHCO3 (sodium bicarb.)

• Dialysis• New drug just approved 11/2014