Chapter 50: Estrogens and Progestins: Basic Pharmacology and

Noncontraceptive Applications
This chapter provides a comprehensive overview of estrogens and progestins, focusing on their
basic pharmacology and noncontraceptive applications, including hormone therapy (HT) for
menopause and other conditions.

I. Endogenous Hormones: Estrogens and Progestins

●​ Definition: Estrogens and progestins (also known as progestogens) are hormones with
multiple actions, primarily promoting female maturation and regulating reproductive
organ activity. They also affect bone mineralization and lipid metabolism.
●​ Principal Endogenous Hormones:
○​ Estrogen: Estradiol.
○​ Progestin: Progesterone.
●​ Production Sites: Primarily produced by the ovaries. Large amounts are produced by the
placenta during pregnancy. Small amounts are also produced in peripheral tissues.

II. The Menstrual Cycle

●​ Overview: A coordinated series of ovarian and uterine events, typically lasting about 28
days.
○​ Follicular Phase (Days 1-14): First half of the cycle.
○​ Luteal Phase: Second half of the cycle.
●​ Ovarian Events:
○​ Several ovarian follicles ripen.
○​ One ripe follicle ruptures (ovulation).
○​ The ruptured follicle evolves into a corpus luteum.
○​ If fertilization does not occur, the corpus luteum atrophies.
●​ Uterine Events:
○​ During follicular ripening, the endometrium thickens and increases in vascularity
(prepares for nidation).
○​ After ovulation, the uterus continues preparation by increasing secretory activity.
○​ If implantation fails, the thickened endometrium breaks down, causing
menstruation.
●​ Roles of Estrogens and Progesterone:
○​ Estrogens: Secreted by maturing ovarian follicles during the first half of the
cycle, causing endometrial proliferation.
 ○​ Estrogens and Progesterone: Produced by the corpus luteum during the second
half of the cycle, maintaining the hypertrophied endometrium. Decline in these
hormones at cycle end causes endometrial breakdown and menstruation.
●​ Role of Pituitary Hormones:
○​ Follicle-Stimulating Hormone (FSH): Acts on developing ovarian follicles in
the first half of the cycle, causing them to mature and secrete estrogens. Rising
estrogen levels then suppress further FSH release (negative feedback).
○​ Luteinizing Hormone (LH): Midcycle LH surge causes dominant follicle to
rupture and release ovum. After ovulation, LH influences the ruptured follicle to
become a corpus luteum and secrete progesterone.

III. Estrogens

●​ Biosynthesis and Elimination

○​ Females:
■​ Premenopausal: Ovary is the principal source. Ovarian follicles
synthesize estrogens during the follicular phase; corpus luteum synthesizes
them during the luteal phase. Estradiol is the major ovarian estrogen.
■​ Periphery: Estradiol converted to less potent estrone and estriol.
■​ Elimination: Hepatic metabolism and urinary excretion.
■​ Pregnancy: Placenta produces large quantities, leading to high urinary
estrogen levels.
○​ Males: Testes convert small amounts of testosterone to estradiol and estrone.
Additional estrogen production occurs in peripheral tissues (e.g., liver, fat,
skeletal muscle) via enzymatic conversion of testosterone.
●​ Mechanism of Action: Primarily through receptors in the cell nucleus (ERa and ERẞ).
Some ERs are on cell membranes, producing a rapid response.
○​ ERa Expression: Vagina, uterus, ovaries, mammary glands, vascular epithelium,
hypothalamus.
○​ ERẞ Expression: Ovary, prostate, and to a lesser extent, lungs, brain, bones,
blood vessels.
●​ Physiologic and Pharmacologic Effects
○​ Primary and Secondary Sex Characteristics in Females: Support development
and maintenance of female reproductive tract and secondary sex characteristics
(uterus, vagina, fallopian tubes, breasts, nipple/genitalia pigmentation).
○​ Reproduction-Related Processes:
■​ Follicular phase: Promote ductal growth in breast, thickening of
vaginal/uterine epithelium, copious endocervical mucus.
■​ Increase vaginal acidity.
■​ Decline in estrogen at cycle end can trigger menstruation (though fall in
progesterone primarily causes endometrial breakdown).
 ■​ After menstruation, promote endometrial restoration.
■​ During pregnancy: Stimulate uterine blood flow, uterine muscle growth,
and ductal proliferation in breast.
○​ Metabolic Actions: Affect bone, cardiovascular, blood, and neural tissue, and
glucose homeostasis.
■​ Bone: Positive effect on bone mass by blocking bone resorption and
possibly promoting mineral deposition. Promote epiphyseal closure during
puberty, stopping linear growth.
■​ Cardiovascular: Reduce cardiovascular disease risk in premenopausal
women. Decrease vasoconstriction, promote vasodilation via nitric oxide
production. Favorably affect cholesterol (reduce LDL, elevate HDL).
■​ Blood Coagulation: Both promote (increase coagulation factors, decrease
coagulation suppressors) and suppress (increase fibrin breakdown factors).
Net effect depends on hereditary factors.
■​ Central Nervous System (CNS): Neuroprotective effect (defend neurons
from oxidative stress/injury). Role in neuronal growth/repair via nerve
growth factors. Preserve cognitive function, enhance short-term memory,
regulate mood (via synaptic changes, serotonin, dopamine,
norepinephrine). Enhance cerebral perfusion.
■​ Glucose Homeostasis: Increase insulin sensitivity, promote glucose
uptake, protect pancreatic islet beta cells.
●​ Physiologic Alterations Accompanying Menopause
○​ Onset: Typically around 51-52 years (95% of women 45-55 years). Menstrual
cycle becomes irregular, anovulatory cycles, amenorrhea, then cessation of
ovulation and menstruation. Ovarian estrogen production gradually ceases.
○​ Symptoms/Changes: Vasomotor symptoms, sleep disturbances, urogenital
atrophy, bone loss, altered lipid metabolism, cognitive changes, altered sexual
response.
■​ Vasomotor Symptoms (Hot Flashes, Night Sweats): Occur in ~70% of
postmenopausal women. Sudden skin flushing, sweating, warmth. Can
cause sleep disturbances, fatigue, irritability. May persist for years or
decades.
■​ Genitourinary Syndrome of Menopause (GSM): Due to decline in
estrogen and loss of ERs in urethra and vagina.
■​ Urethral atrophy: Urge incontinence, urinary frequency, urethritis,
UTIs.
■​ Vaginal atrophy: Dryness, dyspareunia (pain with intercourse),
decreased acidity, increased risk of vaginal infections.
 ■​ Female Sexual Interest-Arousal Disorder (FSIAD): More common
during menopause. Presents as decreased libido or arousal, often
independent of dyspareunia. Can cause personal distress.
■​ Mental Changes: Difficulty in problem-solving, short-term memory loss,
depression, increased anxiety. Compounded by sleep disturbances.
■​ Bone Loss: Accelerated bone resorption, ~12% loss of bone density
shortly after menopause. Can lead to osteoporosis (demineralization,
altered architecture, reduced strength), compression fractures, hip/wrist
fractures.
■​ Altered Lipid Metabolism: Slight increases in LDL cholesterol,
concomitant decreases in HDL cholesterol. Contributes to increased
cardiovascular disease risk post-menopause.
●​ Clinical Pharmacology: Therapeutic Uses (Noncontraceptive)
○​ Menopausal Hormone Therapy (HT): Most common noncontraceptive use,
usually with progestins. (Discussed after progestins).
○​ Female Hypogonadism: Exogenous estrogens induce puberty in girls with
estrogen deficiency (primary ovarian failure, hypopituitarism, bilateral
oophorectomy, Turner syndrome). Promotes breast development, reproductive
organ maturation, pubic/axillary hair. Regimen: continuous low-dose for ~1 year,
then cyclic higher doses. Managed by specialists.
○​ Acne: Oral contraceptives (estrogen in combination) can help, limited to patients
14-15+ years old who desire contraception.
○​ Cancer Palliation: Palliative therapy for advanced prostate cancer in men and
select metastatic breast cancer in men/women. Directed by oncologist.
○​ Gender-Affirmation Therapy for Transgender Women: Prescribed off-label to
promote female characteristics (with testosterone-decreasing meds). Highly
individualized, considering fertility maintenance. Monitoring includes serum
estrogen, testosterone, prolactin, triglycerides, and potassium (if spironolactone
used). Risks are similar to nontransgender patients; thromboembolic events are
greatest risk (unless other risk factors like smoking). Continued screening for
prostate and breast cancer is necessary. Managed by endocrinologists/specialists.
●​ Adverse Effects
○​ Major Concerns: Endometrial hyperplasia, endometrial cancer, breast cancer,
and cardiovascular thromboembolic events. Endometrial risks resolved by
co-prescribing progestin.
○​ Other Effects: Gallbladder disease, jaundice (preexisting liver dysfunction),
headache (especially migraine), fluid retention/edema. Nausea is most frequent
but diminishes with use. Chloasma (patchy brown facial discoloration).
●​ Contraindications: History of DVT, pulmonary embolus, stroke, MI due to
thromboembolic event. Pregnancy, undiagnosed vaginal bleeding. History of liver
disease, estrogen-dependent tumors, breast cancer (except specific palliation uses).
●​ Interactions:
○​ CYP1A2 and CYP3A4 Substrates: Inducers of these isoenzymes lower estrogen
levels; inhibitors raise them.
○​ Decrease effectiveness of some antidiabetic drugs and thyroid preparations.
○​ Interact with anticoagulants and other clotting-affecting drugs.
●​ Preparations and Routes of Administration
○​ Preparations: Conjugated (pregnant horses' urine) and esterified (plant-based)
forms. Synthetic conjugated estrogens (Cenestin, Enjuvia) withdrawn.
○​ Routes:
■​ Oral: Most convenient. Estradiol alone or with progestins.
■​ Transdermal: Emulsion, spray, gels, patches. Application specific to body
regions (e.g., thighs/calves for emulsion, forearm for spray, arm/thigh for
gels, trunk for patches).
■​ Advantages over Oral: Reduced total estrogen dose (bypasses
liver), less nausea/vomiting, less blood level fluctuation, lower risk
for DVT, PE, stroke.
■​ Intravaginal: Inserts, creams, vaginal rings.
■​ Local Effects: Inserts (Imvexxy, Vagifem, Yuvafem), creams
(Estrace Vaginal, Premarin Vaginal), one ring (Estring) for
vulval/vaginal atrophy.
■​ Systemic Effects: Other ring (Femring) for hot flashes/night
sweats, and local effects. Femring releases enough estrogen for
systemic effects.
■​ Parenteral: IV and IM rare. IV limited to acute, emergency control of
heavy uterine bleeding.
●​ Patient Education (Estrogen Administration)
○​ Transdermal Patch: Apply to clean, dry skin on abdomen/trunk (not
breasts/waistline), press firmly for 10s. Reapply if falls off. Remove old, apply
new 1-2 times weekly as directed. Rotate site, no same site more than once
weekly.
○​ Transdermal Emulsion: Apply each morning to top of both thighs and back of
both calves.
○​ Transdermal Gel: Apply once daily after showering to one arm (shoulder to
wrist).
○​ Transdermal Spray: 1-3 sprays once daily to inner forearm, dry at least 2 min
before dressing, 30 min before washing.
○​ Intravaginal Cream: Apply high into vagina, usually at bedtime, with applicator.
 ○​ Intravaginal Ring: Insert as deeply as possible, leave 3 months, then
remove/replace.
○​ Intravaginal Insert: 1 insert daily for 2 weeks, then twice weekly. Place as deep
as comfortable with applicator.
●​ Summary of Key Prescribing Considerations (Estrogens)
○​ Therapeutic Goal: Manage symptoms/structural changes from decreased
endogenous estrogen. Palliation of metastatic breast cancer in selected cases.
○​ Baseline Data: Heart rate, blood pressure, weight. Pregnancy test, TSH, serum
triglyceride (or full lipid panel). Screening for breast cancer and cardiovascular
disease. Gynecologic exam if indicated.
○​ Monitoring: Blood pressure, weight, serum triglycerides, TSH (if on thyroid
replacement). Regular breast/pelvic exams. Schedule endometrial biopsy for
unscheduled bleeding >6 months.
○​ High-Risk Patients (Contraindications): Abnormal vaginal bleeding (unknown
cause), estrogen-dependent cancer/breast cancer (unless indicated as treatment),
history of DVT/PE, stroke/MI/arterial thromboembolism within past year,
abnormal liver function/disease, pregnancy.
○​ Evaluating Therapeutic Effects: Relief of symptoms, pink/moist vagina on
exam (for menopausal HT).
○​ Minimizing Adverse Effects:
■​ Nausea: Common early, diminishes over time. Advise avoiding cooking
odors, stuffy environments; suggest dry foods, raw fruits/vegetables.
Guided imagery, relaxation, yoga, music therapy may help.
■​ Endometrial carcinoma: Estrogen alone increases risk. Adding progestin
lowers risk to pretreatment levels.
■​ Other effects: Abnormal vaginal bleeding, hypertension, benign hepatic
adenoma, reduced glucose tolerance (similar to OCs).

IV. Phytoestrogens

●​ Definition: Plant-based compounds with weak estrogenic activity (isoflavones, lignins,

coumestans). Isoflavones from soy/red clover are most studied.
●​ Use: Commonly used "natural" way to manage menopausal symptoms.
●​ Evidence: Strong anecdotal support, but inconsistent findings from randomized
controlled trials. Not recommended due to inadequate evidence, but not necessarily
discouraged.
●​ Risks: Less potent than estradiol but carry some same risks (thromboembolic events,
breast/uterine/ovarian cancer history are contraindications).
●​ Recommendations: Obtain from whole food sources to avoid overdosage. Typical
supplemental dose: 40-80 mg daily (may take weeks for effects).
V. Selective Estrogen Receptor Modulators (SERMs)

●​ Definition: Drugs that activate ERs in some tissues and block them in others. Aim to
provide estrogen benefits while avoiding drawbacks (e.g., bone protection vs. cancer
promotion).
●​ Available in US: Tamoxifen, toremifene, raloxifene, bazedoxifene. None offers all
benefits or avoids all drawbacks.
●​ Tamoxifen (Nolvadex-D):
○​ First widely used SERM.
○​ Mechanism: Blocks ERs in breast (inhibits cell growth), used for breast cancer
prevention/treatment. Activates ERs for osteoporosis protection and favorable
lipid effects.
○​ Adverse Effects: Hot flashes (due to ER blockade). Increased risk for
endometrial cancer and thromboembolism (due to ER activation).
●​ Raloxifene (Evista):
○​ Similar to tamoxifen.
○​ Key Difference: Does not activate ERs in endometrium, so no risk for uterine
cancer.
○​ Effects: Protects against breast cancer and osteoporosis, increases risk for
thromboembolism, induces hot flashes.
○​ Approved Uses: Prevention/treatment of osteoporosis, prevention of breast
cancer in high-risk women.
●​ Bazedoxifene (Duavee):
○​ Approved in 2013 in combination with conjugated estrogens (Duavee) for
vasomotor symptoms and osteoporosis prevention in postmenopausal women with
a uterus.
○​ Mechanism: Bazedoxifene component reduces risk of excessive uterine lining
growth caused by estrogen.
○​ Contraindications: Same as other estrogen-containing products.

VI. Progestins

●​ Definition: Progesterone is the principal endogenous progestational hormone. Acts to

prepare uterus for implantation and maintain pregnancy.
●​ Biosynthesis: Produced by ovaries (corpus luteum in second half of menstrual cycle,
stimulated by LH) and placenta (large amounts during pregnancy).
○​ Corpus luteum production ceases if no implantation. If implantation, hCG
stimulates corpus luteum to continue production for ~7 weeks until placenta takes
over.
●​ Mechanism of Action: Through receptors in the cell nucleus (PR-A and PR-B). PR-B
mediates stimulatory actions, PR-A mediates inhibitory actions.
●​ Physiologic Effects
○​ During Menstrual Cycle: Secreted in second half, transform endometrium to
secretory state. Fall in progesterone levels is principal stimulus for menstruation
onset.
○​ Other Effects (Menstrual Cycle): Endocervical secretions become scant/viscous
(vs. profuse/watery with estrogen). Breast epithelium divides and grows. CNS
actions may cause depression/sleepiness. Increases body temperature by​
0.6∘C (1∘F) at midcycle/ovulation.
○​ During Pregnancy: High levels suppress uterine smooth muscle contraction
(sustain pregnancy). Suppresses GI smooth muscle (constipation). Promotes
growth/proliferation of alveolar tubules (milk production structures) in breast.
Metabolic effects: suppression of arterial PCO2, altered serum bicarbonate,
elevated serum pH. May help suppress maternal immune system to prevent fetal
attack.
●​ Clinical Pharmacology: Therapeutic Uses (Noncontraceptive)
○​ Menopausal Hormone Therapy (HT): Primary noncontraceptive use is to
counteract adverse effects of estrogen on endometrium. (Discussed further
below).
○​ Dysfunctional Uterine Bleeding: Characterized by heavy irregular bleeding due
to insufficient progesterone to balance estrogen's stimulatory effect on
endometrium.
■​ Goals: Stop hemorrhage and establish regular monthly cycle.
■​ Acute: Progestin for 10-14 days (withdrawal bleeding occurs when
stopped). Oral contraceptive twice daily for 5-7 days can stabilize
endometrium.
■​ Long-Term: Cyclic therapy to promote regular endometrial
breakdown/menstruation (e.g., 10-14 days after menses onset for 10 days,
or first 10 days of each month).
○​ Amenorrhea: Induce menstrual flow in selected women. Progestin for 5-10 days
followed by withdrawal bleeding (if adequate endogenous estrogen). If low
estrogen, estrogen may be needed first to induce proliferation.
○​ Endometrial Hyperplasia and Carcinoma:
■​ Carcinoma: Palliative in metastatic endometrial carcinoma (do not
prolong life). Managed by specialists.
■​ Hyperplasia: Suppressed by progestins (counteract estrogen's
proliferative effects). Options: oral megestrol acetate,
medroxyprogesterone acetate; local levonorgestrel (Mirena IUD).
○​ Other Uses: Support early pregnancy (corpus luteum deficiency, IVF).
Hydroxyprogesterone acetate (Makena) approved for preventing preterm birth in
singleton pregnancies with history of preterm delivery.
 ●​ Adverse Effects: Breast tenderness, headache, abdominal discomfort, arthralgias,
depression (up to 20% of patients). When used continuously for birth control: greatly
decreased cervical mucus, endometrial layer involution, spotting, breakthrough bleeding,
irregular menses. Increased breast cancer risk in postmenopausal women when combined
with estrogen.
●​ Preparations and Routes of Administration: Oral, IM, subcutaneous (subQ),
intravaginal, intrauterine, transdermal.
○​ Oral: Medroxyprogesterone acetate (Provera), norethindrone (Micronor,
Nor-QD), norethindrone acetate (Aygestin), megestrol acetate (Megace),
levonorgestrel (Plan B One-Step, Next Choice), micronized progesterone
(Prometrium). Newer oral: norgestimate and drospirenone (Prefest, Angeliq with
estradiol).
○​ IM: Medroxyprogesterone acetate (Depo-Provera), progesterone (in oil).
○​ SubQ: Medroxyprogesterone acetate (Depo-SubQ Provera 104).
○​ Intravaginal: Progesterone gel (Crinone), vaginal insert (Endometrin).
○​ Transdermal: Norethindrone (CombiPatch with estradiol), levonorgestrel
(Climara Pro with estradiol).
○​ SubQ Implant: Etonogestrel (Nexplanon).
○​ Vaginal Ring: Etonogestrel with estradiol (NuvaRing).
●​ Summary of Key Prescribing Considerations (Progestins)
○​ Therapeutic Goal (Noncontraceptive): Counteract endometrial hyperplasia from
unopposed estrogen in HT; manage dysfunctional uterine bleeding, amenorrhea,
endometriosis; support pregnancy in corpus luteum deficiency, IVF, prevent
prematurity.
○​ Baseline Data: Heart rate, blood pressure, weight. Pregnancy test. Screening for
breast/cardiovascular disease. Pelvic exam if indicated.
○​ Monitoring: Blood pressure, fluid retention/weight. Consider transvaginal
ultrasound/hysteroscopy for undiagnosed bleeding >6 months.
○​ High-Risk Patients (Contraindications): Undiagnosed abnormal vaginal
bleeding. Relative contraindications: active thrombophlebitis/history of
thromboembolic disorders, active liver disease, breast carcinoma.
○​ Minimizing Adverse Effects: Breakthrough bleeding, spotting, amenorrhea are
common. Warn patients, instruct to report abnormal/prolonged vaginal bleeding.

VII. Menopausal Hormone Therapy (HT)

●​ Definition: Low doses of estrogen (with or without progestin) to compensate for estrogen
loss during menopause.
●​ Regimens:
○​ Estrogen Alone (ET): For women who have had a hysterectomy.
 ○​ Estrogen Plus Progestin (EPT): For women with an intact uterus (progestin
counterbalances estrogen-mediated endometrial stimulation, preventing
hyperplasia/cancer).
●​ Primary Indications: Control vasomotor symptoms. Hot flashes and night sweats can
significantly impact quality of life.
●​ Patient-Reported Benefits: Improved sleep, restored libido, improved cognition,
enhanced mood. (Anecdotal evidence supports quality-of-life benefits).
●​ Medical Benefits: Suppression of vasomotor symptoms, prevention of urogenital
atrophy, prevention of osteoporosis and related fractures. Highly effective, but urogenital
atrophy and osteoporosis prevention benefits decline after HT withdrawal.
●​ Historical Context (WHI and HERS Studies):
○​ Early 2000s studies (WHI, HERS/HERS II) showed HT could​
increase cardiovascular events, DVT, stroke. EPT (but not ET) significantly
increased breast cancer incidence. Led to sharp decline in HT use.
○​ Re-examination of Studies: Subjects tended to be older; doses higher and
duration longer than current recommendations.
○​ Newer Findings (WHI, ages 50-59, <10 years HT):
■​ Increased venous thromboembolic episodes: ET (1.1-5/1000 women), EPT
(5.1-10/1000 women).
■​ No increase in CHD for ET. CHD increase for EPT (1.1-5/1000 women).
■​ Overall mortality reduction for both ET and EPT (5.1-10 fewer
deaths/1000 women) compared to non-HT users.
○​ Current View: More reasoned approach, considering dosage, initiation time,
length of use, and patient age. Benefits often outweigh risks for younger, recently
menopausal women. Risk for complications increases with age. HT use in women
>65 years may increase dementia risk.
●​ Benefits and Risks (Table 50.1, ages 50-59 over 5 years):
○​ Benefits (fewer cases/1000 women):
■​ Coronary heart disease: EPT 0.9, ET 3.8.
■​ Osteoporotic fractures: EPT 4.9, ET 5.9.
■​ Breast cancer: EPT 1.5 (fewer cases, not increased risk as noted in earlier
studies where general population was looked at).
■​ Colorectal cancer: EPT 1.2.
■​ Type 2 diabetes mellitus: EPT 11, ET 11.
■​ Mortality for all causes: EPT 5.3 fewer deaths, ET 5 fewer deaths.
○​ Risks (increased cases/1000 women):
■​ Thromboembolism: EPT 5, ET 2.
■​ Stroke: EPT 1.0, ET 1.2.
■​ Breast cancer: EPT 6.8.
■​ Cholecystitis: EPT 9.6, ET 14.2.
●​ Recommendations on Hormone Therapy Use (Composite from NAMS, Endocrine
Society, FDA, USPSTF):
○​ General: Individual risk profile. Inform of known risks. Women with multiple
risk factors consider alternatives.
○​ Long-term HT: Benefits for disease prevention generally do not outweigh risks;
should generally be avoided.
○​ Short-term HT (<5 years): Benefits for menopausal symptoms often justify
risks.
○​ Dosage/Duration: Lowest dosage, shortest time needed for goals.
○​ Approved Indications: Only three:
■​ Moderate to severe vasomotor symptoms.
■​ Genitourinary syndrome of menopause.
■​ Prevention of postmenopausal osteoporosis.
○​ Duration/Risk: First two indications are relatively short-term (3-4 years), low
risk (except for established heart disease). Osteoporosis prevention requires
lifelong HT, higher risk.
○​ Progestin in EPT: Only approved for endometrial cancer protection from
unopposed estrogen. EPT for women with intact uterus. ET for women with
hysterectomy.
●​ Treatment of Vasomotor Symptoms:
○​ HT is most effective. Use lowest effective dose. Reassess need regularly.
○​ Alternatives (for high-risk women): Less effective than estrogen.
■​ Antidepressants (SSRIs: escitalopram, paroxetine; SNRIs: desvenlafaxine)
can modestly reduce hot flashes.
■​ Clonidine (alpha2 agonist), pregabalin (GABA analog) show some
success.
■​ Ineffective/Discouraged: Soy isoflavones (may worsen symptoms), black
cohosh (risk without substantial benefit).
●​ Treatment of Genitourinary Syndrome of Menopause (GSM):
○​ Estrogen is most effective.
○​ FDA Recommendation: If HT solely for vulvar/vaginal symptoms, topical
estrogen is preferred due to lower systemic risks.
○​ Options: Vaginal creams, inserts, vaginal rings (Table 50.2).
■​ Local-only: Imvexxy, Vagifem, Yuvafem inserts; Estrace Vaginal,
Premarin Vaginal creams; Estring vaginal ring. Imvexxy specifically for
dyspareunia.
■​ Systemic/Local: Femring vaginal ring (releases enough estrogen for
systemic effects).
●​ Prevention of Osteoporosis:
 ○​ HT reduces bone loss and fracture risk. However, bone mass rapidly decreases
when HT stops (~12% loss). Requires lifelong HT to maintain bone health,
increasing harm risk.
○​ Alternatives Preferred: Raloxifene, bisphosphonates (alendronate), calcitonin,
teriparatide.
○​ HT Labeling: "When prescribed solely to prevent postmenopausal osteoporosis,
approved nonestrogen treatments should be carefully considered." HT only for
significant osteoporosis risk when benefits outweigh risks.
○​ Primary Prevention: Adequate calcium/vitamin D, weight-bearing exercise, no
smoking/excessive alcohol.
●​ Inappropriate Uses for HT:
○​ Heart Disease: Should not be prescribed to prevent CHD. Confers no protection
for most, may increase CHD/MI risk in some. Counsel on alternative
cardiovascular health measures (no smoking, exercise, diet, meds for
hypertension/diabetes/hypercholesterolemia).
○​ Dementia: Should not be used to prevent dementia (including Alzheimer's). No
evidence of protection; EPT may cause dementia, ET can increase risk for
dementia/mild cognitive impairment.
●​ Discontinuing Hormone Therapy:
○​ Vasomotor symptoms may return, typically within 4 days.
○​ No firm guidelines for stopping. Two methods:​
immediate cessation or tapering slowly (dose tapering or day tapering).
○​ Dose Tapering: Gradually reduce daily dose; delay further reductions if intense
symptoms return.
○​ Day Tapering: Daily dose unchanged, increase days between doses (e.g., every
other day).
○​ Important: Only estrogen dosage should be lowered. Progestin dosage in EPT
should remain unchanged to prevent endometrial hyperplasia.
●​ Drug Products for Hormone Therapy: Oral, transdermal, intravaginal.
○​ Oral Estrogens: Conjugated equine estrogens (Premarin), estradiol (Estrace),
estropipate.
○​ Transdermal Estrogens: Estradiol (patches, gels, spray, emulsion).
○​ Oral Estrogen/Progestin Combinations: Conjugated equine
estrogens/medroxyprogesterone acetate (Prempro, Premphase),
estradiol/norethindrone acetate (Activella), ethinyl estradiol/norethindrone
(Femhrt).
○​ Combination Estrogen/Progestin Patches: Estradiol/norethindrone
(CombiPatch), estradiol/levonorgestrel (Climara Pro).
○​ Intravaginal Products: Inserts, creams, rings (primarily for urogenital atrophy).
●​ Dosing Schedules:
 ○​ Systemic HT: Estrogen daily. Women with uterus also receive progestin to
counteract estrogen's stimulant effects on endometrium.
○​ Commonly Administered: Estrogen and progestin continuously.
○​ Alternative: Estrogen continuously, progestin cyclically (e.g., calendar days
15-28). Cyclic progestin promotes monthly bleeding, so continuous preferred by
most.
○​ Vaginal Estrogens: Continuously for 1-2 weeks, then 1-3 times/week, titrating to
symptoms. Estring remains for 3 months.
●​ Black Box Warning (Estrogen Therapy):
○​ Increased endometrial cancer risk in women with uterus taking unopposed
estrogen.
○​ May increase risk for DVT and stroke.
○​ Not indicated for cardiovascular disease or dementia; may increase dementia risk
in women 65+.
●​ Black Box Warning (Estrogen and Progestin Therapy):
○​ May increase risk for thromboembolic events (DVT, stroke, MI, PE).
○​ Not indicated for cardiovascular disease or dementia; may increase dementia risk
in women 65+.
○​ May increase breast cancer risk.
●​ Patient Education (Estrogens):
○​ Nausea: Reduce by taking with food, dosing at night; diminishes over time. Avoid
cooking odors, stuffy environments; dry foods, raw fruits/vegetables may help.
○​ Cancer risk: Small risk of breast/endometrial cancer. Periodic mammograms
needed. Report persistent/recurrent vaginal bleeding for endometrial carcinoma
evaluation.
○​ Cardiovascular risk: Avoid smoking, regular exercise, decrease saturated fats, take
meds for hypertension/diabetes/high cholesterol.
●​ Patient-Centered Care Across the Life Span (Estrogens):
○​ Children: Not indicated for prepubertal children.
○​ Pregnant Women: Contraindicated.
○​ Breastfeeding Women: May affect infant development, decrease milk
quantity/quality.
○​ Older Adults: Beers Criteria lists estrogens as potentially inappropriate.
●​ Patient-Centered Care Across the Life Span (Progestins):
○​ Children: Not indicated for prepubertal children.
○​ Pregnant Women: High-dose therapy in first 4 months associated with increased
birth defects (limb reductions, heart defects, masculinization of female fetus).
○​ Breastfeeding Women: May contribute to neonatal jaundice.
○​ Older Adults: Only indicated if taking estrogen and has a uterus.
Chapter 51: Birth Control
This chapter covers pharmacologic methods of contraception, with a primary focus on
combination oral contraceptive pills, their mechanisms, effectiveness, adverse effects, and
special considerations.

I. Introduction to Birth Control

●​ Definition: Interfering with the reproductive process from gametogenesis to nidation.

●​ Pharmacologic Methods: Oral contraceptives (OCs), etonogestrel implants, injectable
medroxyprogesterone acetate, intrauterine devices (IUDs), vaginal rings, transdermal
patches.
●​ Focus of Chapter: Combination oral contraceptive pills (most widely used reversible
form). Sterilization is used more often but is irreversible.

II. Effectiveness of Birth Control Methods

●​ Expressed As: Percentage of unplanned pregnancies during first year of use.

●​ Theoretical Use: Pregnancy rates when method is used exactly as it should be
(consistently, properly).
●​ Actual Use: Pregnancy rates observed in practice (higher due to inconsistent/improper
use).
●​ Most Effective (Failure Rate 0.05-0.8%):
○​ Etonogestrel subdermal implant (Nexplanon).
○​ Intrauterine devices (IUDs): Copper T 380A (ParaGard), Levonorgestrel T
(Mirena).
○​ Surgical sterilization (female: tubal ligation, male: vasectomy).
●​ Very Effective (Failure Rate 0.3-8%):
○​ Oral contraceptives (combination, progestin-only).
○​ Intramuscular medroxyprogesterone acetate (Depo-Provera).
○​ Vaginal contraceptive ring (NuvaRing).
○​ Contraceptive patch (Ortho Evra).
●​ Effective (Failure Rate 2-21%):
○​ Condoms (male, female).
○​ Diaphragm with spermicide.
●​ Least Effective (Failure Rate 16-32%):
○​ Contraceptive sponge.
○​ Spermicide alone.
○​ Periodic abstinence.
○​ Withdrawal.
III. Selecting a Birth Control Method

●​ Key Factors: Effectiveness, safety, personal preference.

●​ Effectiveness: Most effective methods listed above. Barrier
methods/spermicides/periodic abstinence need near-perfect use for reasonable protection.
●​ Safety:
○​ Combination OCs: Avoid in women with certain cardiovascular disorders or
smokers >35 years. Alternative methods preferred (diaphragm, progestin-only
pill, IUD).
○​ OCs can cause significant side effects, but risks are low compared to
pregnancy/childbirth.
●​ Personal Preference: Major factor for consistent adherence. Practitioners should educate
patients.
●​ Additional Factors: Family planning goals, age, frequency of intercourse, adherence
capacity.
○​ Sterilization if family planning goals met.
○​ Frequent coitus: OCs or long-term methods (Nexplanon, Depo-Provera, IUD).
○​ Limited sexual activity: Spermicide, condom, diaphragm.
○​ Multiple partners: Barrier methods + spermicides (STD protection).
○​ Adherence issues: Long-term methods (vaginal ring, IUD, Nexplanon,
Depo-Provera) for reliable protection.
●​ Online Tool: Planned Parenthood's computerized selection tool.

IV. Oral Contraceptives (OCs)

●​ Categories:
1.​ Combination OCs: Estrogen + progestin (most widely used).
2.​ Progestin-Only OCs: "Minipills" (just progestin).

A. Combination Oral Contraceptives

●​ Overall Safety: Safe and effective, though minor side effects are common. Newer OCs are
considerably safer than older, high-dose versions. Risk of mortality associated with OCs
is much smaller than with pregnancy/delivery.
●​ Mechanism of Action: Primarily inhibit ovulation.
○​ Estrogen: Suppresses FSH release from pituitary (inhibits follicular maturation).
○​ Progestin: Acts in hypothalamus/pituitary to suppress midcycle LH surge
(triggers ovulation).
○​ Secondary Mechanisms: Thicken cervical mucus (sperm barrier), alter
endometrium (less hospitable for implantation).
●​ Components:
 ○​ Estrogens: Ethinyl estradiol (most common), mestranol (converted to ethinyl
estradiol), estradiol valerate (converted to estradiol).
○​ Progestins: Eight different types, grouped into four generations. All equally
effective. Differences in side effects (thrombotic events, androgenic effects,
hyperkalemia).
■​ First Generation (e.g., Norethindrone): Lower thrombosis risk, mildly
androgenic.
■​ Second Generation (e.g., Levonorgestrel): Greater thrombosis risk than
FGPs, more androgenic.
■​ Third Generation (e.g., Desogestrel): Greater thrombosis risk than FGPs
(especially desogestrel), less androgenic.
■​ Fourth Generation (e.g., Drospirenone): Greater thrombosis risk than
other progestins (especially drospirenone), less androgenic, low risk for
acne/hirsutism. Drospirenone carries hyperkalemia risk.
●​ Effectiveness: Very effective with perfect use (0.3% failure rate). Typical use failure rate
is 8%. Reduced efficacy in higher-weight women, but still more reliable than most
alternatives.
●​ Adverse Effects (Severe effects are rare, but full medical history needed):
○​ Thromboembolic Disorders: Increased risk for VTE, arterial thromboembolism,
PE, MI, thrombotic stroke (2-3 times non-users, but absolute risk is small: 8-10
events/10,000 woman-years). Risk is lower than with pregnancy/delivery. OCs
promote thrombosis by raising clotting factors.
■​ Progestins can contribute; drospirenone and desogestrel carry greatest risk.
■​ Risk much lower with today's low-estrogen OCs (<50 µg ethinyl
estradiol).
■​ Major Risk Factors: Heavy smoking, history of thromboembolism,
thrombophilias. Also diabetes, hypertension, cerebrovascular disease,
CAD, surgery with immobilization.
■​ MI Risk: Reanalysis shows risk limited to older women who smoked.
Nonsmokers >35 can continue low-estrogen OCs until menopause without
increased MI risk.
■​ Minimizing Risk: Estrogen dose no greater than needed. Avoid
drospirenone/desogestrel OCs. Do not prescribe for heavy smokers,
history of thromboembolism, or other risk factors. Discontinue 4 weeks
before surgery with expected postoperative thrombosis.
■​ Patient Education: Inform about symptoms (leg tenderness/pain, chest
pain, SOB, severe headache, visual disturbance); seek prescriber if occur.
■​ Former OC Users: May be protected against cardiovascular disease (8%
decrease in overall CVD incidence).
 ■​ History of Thrombosis: Avoid estrogen/progestin products. Can use
progestin-only methods (levonorgestrel IUD, medroxyprogesterone
acetate injection, etonogestrel implant, minipill).
○​ Black Box Warning (OC Pills): Cigarette smoking increases risk of serious
cardiovascular side effects from combination OCPs.
○​ Cancer: No known risk, except promoting (not causing) existing breast cancer
growth.
■​ Protection: OCs protect against ovarian and endometrial cancer.
■​ Cervical Cancer: No effect, caused by HPV.
■​ Breast Cancer: Recent studies show a small increased risk with hormonal
contraceptive use, higher with longer duration. Risk affected by age,
personal cancer risk, overall health. Increased risk in women with BRCA1
mutation (not BRCA2). Contraindicated in women with breast cancer.
○​ Hypertension: Can cause, but very low risk with low-estrogen preparations.
Raise BP by increasing angiotensin/aldosterone. Options: discontinue OC or
manage HT with drugs.
○​ Abnormal Uterine Bleeding: May decrease/eliminate menstrual flow.
Breakthrough bleeding/spotting common (especially with extended-cycle OCs or
low-estrogen OCs in first 3 months). Assess for pregnancy if period missed on
monthly cycle OCs. Normal menstruation usually resumes after discontinuation;
irregular menses will return to previous pattern.
○​ Use in Pregnancy/Lactation:
■​ Pregnancy: No therapeutic role, contraindicated. Rule out pregnancy
before starting. Stop immediately if pregnancy occurs (no fetal harm risk
with inadvertent early use).
■​ Lactation: Enter breast milk, reduce milk production (especially early
lactation). Progestin-only OCs preferred during lactation (little/no effect
on milk production).
○​ Stroke in Women with Migraine: May increase risk for thrombotic stroke
(absolute increase low). Generally safe for women <35, nonsmokers, healthy,
without aura.
○​ Effects Related to Estrogen or Progestin Imbalance: Mild side effects due to
excess/deficiency.
■​ Estrogen Excess: Nausea, breast tenderness, edema, bloating,
hypertension, migraine, cervical mucorrhea, polyposis.
■​ Estrogen Deficiency: Early/midcycle breakthrough bleeding, increased
spotting, hypomenorrhea.
■​ Progestin Excess: Increased appetite, weight gain, depression, tiredness,
fatigue, hypomenorrhea, breast regression, monilial vaginitis, acne, oily
scalp, hair loss, hirsutism.
 ■​ Progestin Deficiency: Late breakthrough bleeding, amenorrhea,
hypermenorrhea.
■​ Management: Adjust estrogen/progestin balance. Start with 30-35 µg
ethinyl estradiol. Nausea: dose at bedtime, less estrogen OC.
Spotting/bleeding (first 3 months): resolve on own; if not, increase
estrogen or different progestin. Androgenic effects (acne, hirsutism):
switch to drospirenone/dienogest OC. Change OCs at beginning of new
cycle.
○​ Glucose Intolerance: OCs can elevate blood glucose (due to progestin). More
likely in diabetics/gestational diabetes history. Hypoglycemic agents can control
elevations. Monitor prediabetics for hyperglycemia. Less likely with desogestrel
or norgestimate OCs.
●​ Noncontraceptive Benefits: Decrease risk for ovarian/endometrial cancer, ovarian cysts,
PID, benign breast disease, iron deficiency anemia, acne. Reduce menstrual cramps, flow
volume/duration, more predictable menses. Reduce symptom intensity in PMS/PMDD.
Reduce migraine frequency in some with menstrual migraine. May benefit rheumatoid
arthritis.
●​ Drug Interactions:
○​ Drugs/Herbs Reducing OC Effects: CYP3A4 inducers (e.g., rifampin, St. John's
wort) accelerate OC metabolism, reduce effects. Look for breakthrough
bleeding/spotting; may need increased estrogen, backup contraception, or
alternative method.
○​ Drugs Whose Effects are Reduced by OCs: Warfarin (OCs increase clotting
factors), hypoglycemic agents (OCs increase glucose). May need increased
dosages of these drugs.
○​ Drugs Whose Effects are Increased by OCs: Theophylline, tricyclic
antidepressants, diazepam, chlordiazepoxide (OCs impair hepatic metabolism).
May accumulate to toxic levels; reduce dosages.
●​ Preparations: Nearly all combination OCs contain ethinyl estradiol (same estrogen) but
different progestins. Low-estrogen OCs are safer. High-estrogen OCs reserved for women
taking P450-inducing drugs.
○​ Levomefolate-containing OCs (e.g., Beyaz, Safyral, Tydemy, YAZ Plus):
Contain folic acid metabolite to reduce risk of fetal neural tube defects if
pregnancy occurs.
○​ Natazia: Unique components (estradiol valerate, dienogest), four-phase dosing,
shorter/lighter withdrawal bleeding. Dienogest does not cause potassium
retention. Can reduce blood loss in heavy/prolonged menstrual bleeding.
●​ Dosing Schedules:
 ○​ 28-day-cycle schedules: Most OCs. Monophasic (constant estrogen/progestin),
biphasic, triphasic, quadriphasic (varying levels). No significant advantage of
multi-phasic over monophasic.
■​ Typical: 21 days active pill, 7 days no pill/inert pill/iron pill.
■​ Start: Day 1 of menstrual cycle (immediate protection, no backup needed)
or first Sunday after menses onset (backup needed for first 7 days).
■​ Take at same time daily. Successive cycles every 28 days, even with
breakthrough bleeding.
○​ Extended-cycle and continuous schedules: Decrease withdrawal bleeding
episodes, menstrual pain, PMS, headaches. Prolonged use possible because OCs
suppress endometrial thickening. No special combo needed; can use monophasic
28-day products for extended use.
●​ What to Do If Doses Are Missed:
○​ Risk of pregnancy increases with each successive omission.
○​ 28-Day Cycle Products (CDC Guidelines):
■​ 1+ pill missed in Week 1: Take 1 pill ASAP, continue pack. Use backup
for 7 days.
■​ 1-2 pills missed in Week 2 or 3: Take 1 pill ASAP, continue active pills,
skip placebo, go straight to new pack.
■​ 3+ pills missed in Week 2 or 3: Same as above, but use backup for 7
days.
○​ Extended/Continuous Cycle OCs: Up to 7 days missed with little/no increased
pregnancy risk if pills taken continuously for prior 3 weeks.
○​ Note: Guidelines may differ by product; refer to package insert.

B. Progestin-Only Oral Contraceptives ("Minipills")

●​ Components: Progestin only, no estrogen.

●​ Advantages: Do not cause thromboembolic disorders, headaches, nausea, or most other
combination OC adverse effects. Slightly safer than combination OCs.
●​ Disadvantages: Less effective, more likely to cause irregular bleeding (breakthrough
bleeding, spotting, amenorrhea, inconsistent cycle length, variations in flow). Irregular
bleeding is major drawback and reason for discontinuation.
●​ Mechanism of Action: Largely by altering cervical secretions (thick, sticky mucus acts
as sperm barrier). Modify endometrium (less favorable for implantation). Weak inhibitors
of ovulation.
●​ Dosing: Take at same time every day for effectiveness. Taking even 3 hours late reduces
efficacy; use backup/EC if unprotected intercourse. Taken continuously, initiated on day
1 of menstrual cycle. Backup needed for first 7 days.
●​ Missed Doses:
 ○​ 1 pill missed: Take ASAP, use backup for at least 2 days. Resume as scheduled
next day.
○​ 2+ pills missed: Restart regimen, use backup for at least 2 days. If no menstrual
bleeding, perform pregnancy test.

V. Combination Contraceptives with Novel Delivery Systems

●​ Mechanism: Same as combination OCs (estrogen/progestin, systemic absorption,

suppress ovulation).
●​ Difference: How hormones are delivered (skin for patch, vaginal mucosa for ring).
Pharmacology essentially identical to OCs.

A. Transdermal Contraceptive Patch (Xulane)

●​ Mechanism: Same as combination OCs.

●​ Efficacy/Side Effects: Same contraceptive efficacy, incidence of breakthrough
bleeding/spotting.
●​ Dosing: Applied once a week (more convenient, better adherence than daily OCs).
●​ Components: 0.53 mg ethinyl estradiol, 4.86 mg norelgestromin (active metabolite of
norgestimate). Releases 35 µg ethinyl estradiol, 150 µg norelgestromin daily.
●​ Application: First patch on first 24 hours of menstrual period (for new users) or first day
of withdrawal bleeding (switching from OCs).
●​ Detachment: 4.6% partially/completely detached in trials. Reattach/replace. If off <24
hours, no backup needed. If off >24 hours, start new cycle, use backup for 7 days.
●​ Adverse Effects: Breast discomfort, headache, local irritation, nausea, menstrual cramps.
Higher incidence of breast discomfort and dysmenorrhea vs. Triphasil (OC).
●​ Contraindications/Drug Interactions: Same as combination OCs.
●​ VTE Risk: Possibly higher than OCs. Patch users exposed to 60% more estrogen than 35
µg estrogen OC users, potentially increasing VTE risk.

B. Vaginal Contraceptive Ring (NuvaRing)

●​ Mechanism: Estrogen/progestin combo, prevents pregnancy by suppressing ovulation.

●​ Adverse Effects/Interactions/Warnings/Contraindications: Same as combination OCs.
●​ Description: Transparent, flexible ring, 2.1 in diameter. User inserts.
●​ Components: 2.7 mg ethinyl estradiol, 11.7 mg etonogestrel (active metabolite of
desogestrel). Releases 15 µg ethinyl estradiol, 120 µg etonogestrel daily. Hormones
absorbed through vaginal mucosa for systemic effects.
●​ Dosing: Insert once monthly, leave for 3 weeks, remove for 1 week (withdrawal
bleeding). Insert new ring on schedule even if bleeding ongoing.
 ●​ Expulsion: If expelled before 3 weeks, wash with warm water and reinsert. If cannot
reuse, insert new one. If >3 hours elapse before reinsertion, contraception may be
diminished; use backup for 7 days.
●​ Adverse Effects: Vaginitis, headaches, upper respiratory infection, leukorrhea, sinusitis,
weight gain, nausea. Reasons for discontinuation: foreign body sensation, coital
problems, expulsion, vaginal symptoms, headache, emotional lability. Serious adverse
effects (thrombosis, embolism, hypertension) same risk as combination OCs.

VI. Long-Acting Contraceptives

A. Subdermal Etonogestrel Implants (Nexplanon)

●​ Description: Single 4-cm rod with 68 mg etonogestrel (synthetic progestin). Implanted

subdermally in nondominant arm. Provides contraception for 3 years (studies show up to
5 years effectiveness).
●​ Mechanism of Action: Suppresses ovulation, thickens cervical mucus, causes
endometrium to become involuted (hostile to implantation).
●​ Pharmacokinetics: Daily release 60-70 µg initially, declines to 25-30 µg over 3 years.
Metabolized by liver. Undetectable 5-7 days after removal.
●​ Drug Interactions: Hepatic enzyme inducers (barbiturates, phenytoin, rifampin,
carbamazepine, topiramate, HIV protease inhibitors, St. John's wort) may reduce
efficacy; do not use with these drugs.
●​ Adverse Effect: Irregular Bleeding: Common and unpredictable. Amenorrhea in 22%,
infrequent bleeding in 34%, frequent bleeding in 7%, prolonged bleeding in 18%.
Hemoglobin unaffected. Leading reason for discontinuation.
●​ Use During Breastfeeding: Safe after 21st postpartum day. Very little etonogestrel in
breast milk. No significant effects on infant physical/psychomotor development or milk
production/quality, even if implanted few days postpartum.

B. Depot Medroxyprogesterone Acetate (DMPA) (Depo-Provera)

●​ Administration: IM or subQ injection.

●​ Protection: Against pregnancy for 3 months or longer.
●​ Mechanism of Action: Inhibits gonadotropin secretion, thereby: (1) inhibiting follicular
maturation and ovulation, (2) thickening cervical mucus, (3) causing endometrial
thinning (unlikely implantation).
●​ Return of Fertility: Delayed by average of 9 months after discontinuation.
●​ Adverse Effects:
○​ Menstrual disturbances (irregular at first, then may cease after 6-12 months).
○​ Mild weight gain (~3.5 lb in first year).
○​ Abdominal bloating, headache, depression, decreased libido (unclear if DMPA is
cause).
 ○​ Cancer: No increase in cervical, ovarian, or breast cancer risk in women. Reduced
endometrial cancer risk.
○​ Reversible Bone Loss: Risk for BMD decline (1-2% per year in first 1-2 years).
BMD returns to pretreatment levels within ~30 months after discontinuation.
Unclear if increases fracture risk.
■​ FDA Black Box Warning (2018): Recommends against use >2 years.
■​ ACOG Recommendation (2008): Warning appears unwarranted.
Practitioners should not let bone loss concerns deter prescribing or limit to
2 years. No routine BMD testing recommended. Counsel patients that
fracture risk is theoretical, pregnancy risks are real.

VII. Intrauterine Devices (IUDs)

●​ Reliability: Among most reliable forms of reversible birth control.

●​ Safety: Very safe when used by appropriate patients.
●​ PID Risk: Historically a concern. Recent studies/reviews do not support increased PID
risk with current IUDs. Risk highest during first 20 days after insertion (9.7 cases/1000
woman-years), then declines. Screen for gonorrhea/chlamydia before or at insertion.
●​ Adverse Effects: Cramping and altered menses. Cramping most intense at insertion
(minimize with topical anesthetic or ibuprofen).
●​ Classes:
1.​ Hormone-Free Copper IUD (TCu380A / ParaGard):
■​ Mechanism: Foreign body reaction and chemical changes toxic to sperm,
interfering with fertilization.
■​ Benefits: Highly effective, good option for hormone-sensitive women.
■​ Side Effects: Heavier menstrual bleeding and cramping.
■​ Duration: Can be used for up to 10 years (likely longer).
2.​ Levonorgestrel-Containing IUDs (various dosages, e.g., Mirena):
■​ Mechanism: Thicken cervical mucus, inhibit ovulation, alter
endometrium (prevents implantation).
■​ Side Effects: Bleeding irregularities (spotting, irregular cycles,
oligomenorrhea/amenorrhea).
■​ Duration: 3 to 7 years depending on dose form.

VIII. Spermicides

●​ Definition: Chemical surfactants that kill sperm by destroying cell membranes.

●​ Available Forms: Foam, gel, jelly, suppository, vaginal film, contraceptive sponge. OTC
purchase.
●​ Effectiveness: Moderately effective alone. Increased efficacy with diaphragm or condom.
Contain nonoxynol 9 or octoxynol 9.
 ●​ Side Effects: Generally devoid of serious effects. No relationship with birth defects.
Some evidence nonoxynol 9 may increase HIV transmission (promotes lesions
facilitating HIV penetration). Allergic reactions occur in some.
●​ Correct Use: Apply before intercourse (no more than 1 hour in advance if used alone).
Shake foam containers. Insert suppositories 10-15 minutes before intercourse for
dissolution. Reapply for each act of intercourse. Postpone douching for at least 6 hours
after coitus.
●​ Contraceptive Sponge (Today Sponge): Soft, porous polyurethane disk with 1000 mg
nonoxynol 9. Protects by releasing spermicide, absorbing seminal fluid, blocking sperm
penetration. Single sponge effective for 24 hours regardless of coital frequency. Remove
after 24 hours. High unintended pregnancy rates (16% nulliparous, 32% parous). Most
common adverse effects: vaginal irritation/dryness.

IX. Emergency Contraception (EC)

●​ Definition: Contraception implemented after intercourse (unprotected sex, contraceptive

failure, sexual assault).
●​ Methods: Emergency contraceptive pill (ECP/morning-after pill) or copper-T IUD
insertion. ECPs most common.
●​ Types of ECPs: Progestin-only, ulipristal-containing, estrogen/progestin. Progestin-only
most widely used.

A. Progestin-Only Emergency Contraception Pills

●​ Products: Plan B One-Step, Next Choice One Dose, Next Choice (all contain
levonorgestrel). Marketed specifically for EC.
●​ Plan B One-Step and Next Choice One Dose: Single high-dose (1.5 mg) levonorgestrel
tablet.
○​ Timing: Take within 72 hours of unprotected intercourse (earlier is best), but can
be effective up to 5 days. Success indicated by menstrual bleeding in ~21 days.
○​ Effectiveness: Reduce odds of pregnancy by 89% and 84% respectively (from
~8% to 1-1.3%).
○​ Mechanism: Primarily by delaying/stopping ovulation. Inhibition of fertilization
may contribute.​
Not effective after fertilization; not abortifacients.
○​ Side Effects: Heavier menstrual bleeding, nausea, abdominal pain, headache,
dizziness. Nausea reduced by antiemetic 1 hour before dosing. No increased risk
for major congenital malformations/pregnancy complications if pregnancy occurs.
○​ Availability: Over-the-counter, no prescription needed.
●​ Next Choice: Two 0.75 mg levonorgestrel tablets.
 ○​ Dosing: 1 tablet within 72 hours, second 12 hours later (taking both at same time
is equally effective). Effective up to 5 days, most effective earlier.
○​ Side Effects: Similar to Plan B One-Step. Repeat dose if vomiting within 2 hours.
○​ Availability: Without prescription.

B. Ulipristal Acetate Emergency Contraception Pill (ella)

●​ Mechanism: Agonist-antagonist at progestin receptors, primarily suppresses ovulation.

●​ Key Differences from Levonorgestrel ECPs:
1.​ Highly effective up to 5 days (120 hours) after intercourse (vs. 3 days for
levonorgestrel).
2.​ Requires a prescription for all women regardless of age.
●​ Dosage: 1 tablet (30 mg) up to 5 days after unprotected intercourse.
●​ Side Effects: Headache, nausea, dysmenorrhea, abdominal pain. Repeat dose if vomiting
within 3 hours.

C. Estrogen/Progestin Emergency Contraception Pills (Yuzpe Regimen)

●​ Regimen: Two doses of an OC with estrogen (ethinyl estradiol) + progestin

(levonorgestrel or norgestrel). First dose within 72 hours, second 12 hours later.
●​ Mechanism: Interferes with ovulation, fertilization, implantation.​
Will not cause abortion.
●​ Effectiveness/Side Effects: Less effective (75% vs 89% for Plan B One-Step) and causes
more nausea (50% vs 13.3%) and vomiting (19% vs 6%).
●​ Current Use: Infrequently used due to better, better-tolerated, and readily available
ECPs.

D. Mifepristone as an Emergency Contraception Pill

●​ Mechanism: Blocks progesterone/glucocorticoid receptors.

●​ Timing: If taken within 5 days of unprotected intercourse, it prevents pregnancy (ECP).
If taken after this time, it may terminate an existing pregnancy (abortifacient).
●​ Effectiveness (ECP): 100% effective when used as ECP.
●​ Approval: Available in US but not approved as EC.

E. The Copper Intrauterine Device (IUD) for EC

●​ Effectiveness: Insertion within 5 days of unprotected intercourse can prevent pregnancy in

most women (>99.9% effective).
●​ Benefits: Provides ongoing contraception for up to 10 years.
●​ Drawbacks: Expensive, not all women are candidates, may be difficult to obtain quickly.

X. Drugs for Medical Abortion

A. Mifepristone (RU 486) with Misoprostol

●​ Mifepristone (Mifeprex): Synthetic steroid, blocks progesterone/glucocorticoid receptors.

Approved indication: termination of early intrauterine pregnancy (cotreatment with
misoprostol usually required).
●​ Mechanism of Action (Mifepristone): Blockade of progesterone receptors leads to
decidual breakdown and detachment of conceptus. Promotes cervical softening/dilation.
Increases uterine prostaglandin production and myometrial responsiveness to
prostaglandins. All lead to expulsion of conceptus.
●​ Misoprostol: Synthetic prostaglandin, reinforces uterine contractions.
●​ Effectiveness: Together, terminate pregnancy in ~95% of women. Performed early
(within 7 weeks of conception).
●​ Adverse Effects:
○​ Common: Abdominal pain (cramping) and vaginal bleeding are unavoidable.
Cramping in ~80% of patients after misoprostol (may need opioid analgesic).
Bleeding/spotting lasts 9-16 days (some >30 days).
○​ Serious: Severe bleeding (~1%, may need curettage, uterotonic drugs,
fluids/blood). Sepsis (rare, fatal cases). Alert for signs of sepsis (fever, severe
abdominal pain, pelvic tenderness). Atypical sepsis presentation: nausea,
vomiting, diarrhea without fever/pain.
○​ Ectopic Pregnancy: Bleeding could mask ruptured ectopic pregnancy; must be
ruled out by ultrasound before use.
○​ Teratogenic Risk: Misoprostol (not mifepristone) is a proven teratogen (can
cause Möbius syndrome). If abortion fails, surgical abortion should be considered.
●​ Contraindications: Ectopic pregnancy, hemorrhagic disorders, use of anticoagulant
drugs. Adrenal insufficiency, long-term glucocorticoid therapy (mifepristone blocks
glucocorticoid receptors).

XI. Summary of Key Prescribing Considerations (Combination Oral

Contraceptives)

●​ Therapeutic Goal: Prevention of unwanted pregnancy.

●​ Baseline Data: History of hypertension, diabetes, thromboembolism,
cerebrovascular/cardiovascular disease, breast cancer. Urine pregnancy test.
●​ Monitoring: No routine monitoring required.
●​ High-Risk Patients (Contraindications): Current pregnancy, history of
thromboembolus, breast cancer, women >35 who smoke tobacco. Use with caution in
diabetes, hypertension, cardiac disease.
●​ Evaluating Therapeutic Effects: For menstrual symptoms, assess decrease in cramping,
flow, or duration of menses.
 ●​ Minimizing Adverse Effects: Educate on missed dose protocol (medication type, cycle).
Effectiveness can be reduced by some medications (e.g., certain antibiotics).

Chapter 52: Androgens

This chapter focuses on androgens, particularly testosterone, their biosynthesis, physiological
and pharmacological effects, therapeutic uses, adverse effects, and abuse potential.

I. Introduction to Androgens

●​ Definition: Hormones that promote expression of male secondary sex characteristics.

●​ Primary Endogenous Androgen: Testosterone.
●​ Production Sites: Testes, ovaries, adrenal cortex.
●​ Other Effects: Influence female sexuality, significant non-sexual
physiologic/pharmacologic effects.
●​ Primary Clinical Application: Management of androgen deficiency in males.
●​ Principal Adverse Effects: Virilization (development of male secondary sex
characteristics) and hepatotoxicity.
●​ FDA Approval: Only for testosterone deficiency due to hypogonadism (used off-label
for other purposes, often illicitly). Close monitoring needed.

II. Testosterone

●​ Prototype: Testosterone is the prototype androgen.

●​ Biosynthesis and Secretion:
○​ Males: Made by Leydig cells of testes. Daily production 2.5-10 mg. Synthesis
promoted by FSH and LH (interstitial cell-stimulating hormone) from anterior
pituitary. Regulated by negative feedback (rising testosterone suppresses FSH/LH
release). Small amounts from adrenal glands (minimal functional significance).
Peak production ~age 17, steady until 30-40, then slow decline.
○​ Females: Preandrogens (testosterone precursors) secreted by adrenal cortex and
ovaries. Conversion to testosterone in peripheral tissues. Adrenal preandrogen
synthesis regulated by ACTH; ovarian by LH. Daily production ~300 µg (150 µg
from each ovary/adrenal). Total 10-40 times less than men. Excessive androgen
secretion from ovarian/adrenocortical pathology can cause virilization. Production
decreases at menopause.
●​ Mechanism of Action: Through specific receptors in cell cytoplasm. Hormone-receptor
complex migrates to nucleus, acts on DNA to promote mRNA synthesis, leading to
 specific protein production. In some tissues (prostate, seminal vesicles, hair follicles),
receptors interact with dihydrotestosterone (DHT), a testosterone metabolite.
●​ Physiologic and Pharmacologic Effects:
○​ Sex Characteristics in Males:
■​ Pubertal transformation: Increased testosterone promotes enlargement
of testes, penis, scrotum. Pubic/axillary hair, adult male body hair patterns.
Stimulates bone/skeletal muscle growth (increased height/weight).
Accelerates epiphyseal closure (stops linear growth). Larynx enlargement
(deepens voice). Increased sebaceous glands (oily skin, acne). Beard
development. Takes several years.
■​ Spermatogenesis: Necessary for sperm production and maturation.
Deficiency causes sterility.
○​ Sex Characteristics in Females: Moderate effects physiologically (clitoral
growth, possibly libido maintenance). Excessive androgen production (e.g.,
congenital adrenal hyperplasia) or therapeutic/abused androgens can cause
virilization.
○​ Anabolic Effects: Promotes skeletal muscle growth. Dramatic effects in young
males/females. Modest effects in healthy adult males (testes already produce
near-maximal stimulation).
○​ Erythropoietic Effects: Promotes erythropoietin synthesis, increasing
erythrocyte production. Explains higher male hematocrit. Women given
testosterone have increased hematocrit/hemoglobin (~4.3 g/dL). Men have
smaller increase (~1 g/dL).

III. Clinical Pharmacology of Androgens

●​ Classification:
○​ Testosterone and Testosterone Esters: Testosterone, testosterone cypionate,
testosterone enanthate.
○​ 17-α-Alkylated Compounds: Fluoxymesterone, methyltestosterone, oxandrolone
(noted for hepatotoxicity).
●​ Distinction: Androgenic and anabolic actions are mediated by the same receptor. All
anabolic hormones are also androgenic. Therefore, all testosterone-like drugs are referred
to as androgens.
●​ Therapeutic Uses (Individual androgens differ in application).
○​ Male Hypogonadism: Testes fail to produce adequate testosterone (hereditary,
pituitary/hypothalamic failure, primary testicular dysfunction).
■​ Replacement Therapy: Beneficial when testicular failure in adult males.
Restores libido, increases ejaculate volume, supports secondary sex
characteristics.​
Will not restore fertility. Drugs: testosterone, testosterone enanthate,
 testosterone cypionate. (See Table 52.2 for preparations/dosages). FDA
(2018) only approves testosterone for​
confirmed testosterone deficiency due to hypogonadism, not age-related
decline.
○​ Delayed Puberty (Males): Most often familial, spontaneous later puberty.
Limited course of androgen therapy (fluoxymesterone, methyltestosterone)
off-label if psychological distress. Long-term replacement if true hypogonadism.
○​ Testosterone Therapy in Menopausal Women: Can alleviate fatigue, reduced
libido, reduced genital sensitivity. NAMS: positive effect on sexual function,
candidates if no other cause of decreased desire and estrogen taken.​
Not FDA approved in US (approved in UK). Prescribed off-label at lower doses
to mimic premenopausal production (~300 µg/day).
○​ Cachexia: Wasting from severe illnesses (AIDS, trauma, chronic infections)
where testosterone levels decline. Testosterone therapy decreases muscle wasting
risk. Oxandrolone (Oxandrin) is FDA-approved for this purpose (synthetic
testosterone derivative).
○​ Anemias: Sometimes used for anemias refractory to other therapy (aplastic
anemia, renal failure anemia, Fanconi anemia, cancer chemotherapy anemia).
Promote erythropoietin synthesis. Less favored with emergence of other therapies
like erythropoietin-stimulating agents.
○​ Drug Therapy for Transgender Men: Prescribed off-label as gender-affirmation
therapy. Goal: stop menstruation, stimulate male secondary sex characteristics.
Similar to hypogonadism treatment. Monitor serum testosterone, hematocrit,
hemoglobin, cholesterol. Successful outcomes: voice deepens, male-pattern hair
growth, decreased glandular breast tissue, clitoral enlargement, improved quality
of life/mental health. Adverse effects same as other testosterone therapy (acne,
hair loss, polycythemia, hypercholesterolemia, liver impairment, thromboembolic
disorders). Theoretical increased endometrial cancer risk if no hysterectomy (not
demonstrated in practice). Continued screening for breast, cervical, uterine cancer
needed if no gender-affirming surgery. Initiated/managed by
endocrinologists/specialists.
●​ Black Box Warning (Oxandrolone): Peliosis hepatitis (blood-filled liver cysts, liver
failure, intra-abdominal hemorrhage), highly vascular liver tumors. Increased
atherosclerosis risk from elevated LDL, decreased HDL.

IV. Adverse Effects

●​ Virilization in Women, Girls, and Boys: Most common complication.

○​ Women (high doses): Acne, deepening voice, facial/body hair proliferation,
male-pattern baldness, increased libido, clitoral enlargement, menstrual
irregularities. Clitoral growth, hair loss, voice lowering may be irreversible.
 ○​ Children: Pubic hair growth, penile enlargement, increased erections, priapism in
boys. Pubic hair growth, clitoral enlargement in girls. Discontinue androgens at
first virilizing effects to prevent irreversible masculinization.
●​ Premature Epiphyseal Closure: In children, can decrease adult height. Monitor with
hand/wrist radiographs every 6 months.
●​ Hepatotoxicity: Cholestatic hepatitis, other liver disorders (clinical jaundice rare).
Periodic liver function tests. Reversible after discontinuation. Rarely, hepatocellular
carcinoma with prolonged use. Associated primarily with​
17-α-alkylated androgens (e.g., fluoxymesterone, methyltestosterone); these should not
be used long-term. Testosterone and testosterone esters are​
not associated with liver disease.
●​ Effects on Cholesterol Levels: Lower HDL, elevate LDL. May increase atherosclerosis
risk.
●​ Prostate Cancer: Androgens do not cause, but can promote growth of existing prostate
cancer. Contraindicated in men with diagnosed prostate cancer. Monitor men without
diagnosed cancer for covert cancer.
●​ Edema: From androgen-induced salt/water retention. Concern for heart failure patients or
those predisposed to edema. Treatment: discontinue androgen, give diuretic if needed.
●​ Abuse Potential: Frequently misused by athletes for performance enhancement
("anabolic steroids"). Regulated as Schedule III controlled substances.
○​ Athletic Use: Can significantly increase muscle mass/strength, even without
exercise.
○​ Adverse Effects (high doses): Salt/water retention (hypertension). Suppress
LH/FSH (testicular shrinkage, sterility, gynecomastia). Acne common. Reduced
HDL, elevated LDL (theoretical atherosclerosis risk). Hepatotoxicity (cholestatic
hepatitis, jaundice, hepatocellular carcinoma) from 17-α-alkylated compounds.
Kidney damage. Menstrual irregularities, virilization in females. Reduced adult
height in boys/girls.
○​ Psychologic Effects: Reputed to cause depression, manic episodes,
aggressiveness. Surveys link abuse with risky behavior/aggression.
○​ Abuse Syndrome: Preoccupation with use, difficulty stopping. Abstinence
syndrome similar to alcohol/opioid/cocaine withdrawal upon discontinuation.
●​ Risk for Thromboembolic Events: Postmarketing reports of stroke, MI, DVT, PE.
Believed due to testosterone's erythropoietic effects. FDA issued Testosterone Product
Safety Alert (2018) requiring labeling changes.

V. Androgen Preparations for Male Hypogonadism

●​ Treatment Options: Expanded beyond IM testosterone esters. Now include nasal gel,
transdermal patch, transdermal gel, topical solution, buccal tablet, implantable
subcutaneous pellets. All Schedule III controlled substances.
●​ Oral Androgens: Fluoxymesterone, methyltestosterone. Not first-line due to erratic
androgenic effects and hepatotoxicity (17-α-alkylated); should not be used long-term.
●​ Transdermal Testosterone: Patch, gel, liquid. Absorbed through skin, slowly into blood.
○​ Patches (Androderm): 2 or 4 mg testosterone/24 hrs. Applied once daily to
upper arm, thigh, back, or abdomen. Principal AE: rash at site.
○​ Gels (AndroGel, Testim, Fortesta, Vogelxo):
■​ Black Box Warning: Secondary exposure to testosterone gel (uncovered
skin, unwashed clothing) caused virilization in children.
■​ Advantages over patches: Less local irritation, cannot fall off, more
consistent testosterone levels.
■​ Disadvantage: Can be transferred to others by skin-to-skin contact (only
10% absorbed, 90% remains on skin). Can cause virilization in female
partners, fetal harm, genital enlargement, premature pubic hair, advanced
bone age, increased libido, aggressive behavior in children. Effects regress
after exposure stops.
■​ Guidelines to reduce transfer: Wash hands after application, cover site
with clothing once dry, wash site before skin contact with others.
Women/children avoid contact, wash contaminated skin immediately.
■​ Application (AndroGel): Metered-dose pump or unit-dose foil packets.
Applied once daily (morning) to clean, dry skin of shoulders, upper arms,
or abdomen (not genitalia). Wash hands, cover treated area. Wait 5-6 hours
before showering/swimming. Measure testosterone levels 14 days after
initiation, then periodically.
■​ Application (Testim): 5-g tubes (50 mg testosterone, 10% absorbed).
Applied once daily to shoulders/upper arms (not abdomen/scrotum). Wash
hands, cover area immediately. Avoid showering for at least 2 hours.
Check testosterone after 14 days, periodically.
■​ Application (Fortesta): Metered-dose pump (10 mg/actuation). Applied
to front/inner thigh. Wash hands, cover area. Avoid swimming/showering
for 2 hours. Flammable (alcohol-based), avoid flames/smoking until dry.
Check testosterone after days 14 and 35, periodically.
■​ Application (Vogelxo): Tube formulation like Testim; pump like Fortesta.
Same advice/precautions.
○​ Topical Solution (Axiron): For underarm application. Testosterone absorbed
rapidly into skin, then slowly into blood. Steady-state in 14 days. Decline to
baseline 7-10 days after stopping.
■​ Application: Metered-dose pump (30 mg/actuation). Pump onto
applicator, apply to clean, dry, intact underarm skin (nowhere else). Do not
swim/bathe for 2 hours. Apply deodorant/antiperspirant​
 before testosterone. Flammable. Apply to each axilla same time every
morning. Measure testosterone after 14 days, then adjust dosage.
■​ Transfer Risk: Can be transferred through skin-to-skin contact (same
guidelines as gels).
○​ Nasal Gel (Natesto): Newest formulation. Metered-dose pump (5.5
mg/actuation).
■​ Contraindications: Nasal disorders/abnormalities (chronic sinusitis,
deviated septum). Inadequate testing for interactions with other nasally
administered drugs; only adrenergic agonists approved for
co-administration.
■​ Local AEs: Rhinorrhea, epistaxis, nasopharyngitis (modest effects).
■​ Administration: Prime pump, blow nose, insert pump into nostril (tip
toward lateral wall), depress slowly until stops, wipe tip on lateral wall
while withdrawing. Massage nose below bridge after both nostrils. Avoid
blowing/sniffing for at least 1 hour.
○​ Implantable Testosterone Pellets (Testopel): Long-acting. Implanted
subdermally in hip or abdominal wall. Each pellet 75 mg testosterone. Usual
dosage 150-450 mg (2-6 pellets) every 3-6 months. Provides steady levels but
requires invasive procedure.
○​ Testosterone Buccal Tablets (Striant): Produce steady blood levels. Applied to
gum area above incisor, held for 30 seconds. Recommended dosage: 1 tablet
every 12 hours, alternating sides. Replace if falls out <8 hours (new one for rest of
interval); if >8 hours, new one and skip next scheduled dose (remains 16 hours).
Not affected by eating, drinking, gum, brushing.
■​ Adverse Effects: Local irritation, bitter taste, taste distortion (usually
transient). No serious gum changes up to 1 year. Hypothesized transfer via
saliva during kissing.
○​ Intramuscular Testosterone Esters (Testosterone cypionate, testosterone
enanthate): Formulated in oil, long-acting. Slowly absorbed, then hydrolyzed to
free testosterone. Produce widely varying blood levels (high after dosing, low
before next dose). Can cause significant variations in libido, energy, mood.

VI. Summary of Key Prescribing Considerations (Androgens)

●​ Therapeutic Goal: Manage hypogonadism and testosterone deficiency via

supplementation.
●​ Baseline Data: Serum testosterone concentration, CBC, lipid panel, liver function, PSA.
●​ Monitoring: Serum testosterone, lipids, liver function, PSA after 1 year (refer to
urologist if PSA >4.0 ng/mL or >1.4 ng/mL above baseline).
●​ High-Risk Patients (Contraindications): Pregnant women, men with prostate cancer or
breast cancer, for enhancing athletic performance.
 ●​ Evaluating Therapeutic Effects: Development of secondary sex characteristics,
restoration of energy, libido, other testosterone deficiency symptoms.
●​ Minimizing Adverse Effects:
○​ Virilization (females): Deepening voice, chest/facial hair, acne, menstrual
irregularities. Assess at each encounter. Withdraw early to avoid irreversible
changes.
○​ Accelerated bone maturation (children): Decrease adult height. Monitor
epiphyses with hand/wrist radiographs twice yearly.
○​ Hepatotoxicity (17-α-alkylated androgens): Cholestatic hepatitis, jaundice, liver
disorders (rarely cancer). Monitor for signs (jaundice, fatigue, malaise). Obtain
periodic liver function tests. Liver function normalizes after cessation. Avoid
long-term use.
○​ Edema: Salt/water retention. Assess for edema/weight gain at each encounter.
Withdraw androgen or use diuretic if indicated.
○​ Masculinization of female fetus: Rule out pregnancy before use. Ensure female
patients of child-bearing age use adequate, consistent contraception.
●​ Patient Education (Topical Testosterone): Wash hands after application, cover site with
clothing once dry, wash site before contact with others. Warn women/children to avoid
contact with user's skin where applied; wash contaminated skin if accidental contact.
●​ Patient Education (Androgens - General):
○​ Female patients: signs of virilization (deepening voice, acne, hair changes,
menstrual irregularities); report if occur.
○​ Signs of liver dysfunction (yellow skin/eyes, fatigue, appetite loss, dark urine,
light stools); report changes.
○​ Swelling/unusual weight gain (salt/water retention); report events.
○​ Fetal malformations risk. If pregnant-capable, emphasize consistent use of
reliable contraception.

Chapter 53: Male Sexual Dysfunction and Benign Prostatic

Hyperplasia
This chapter delves into male sexual dysfunction, primarily erectile dysfunction (ED) and
premature ejaculation (PE), and benign prostatic hyperplasia (BPH), including their
pathophysiology and pharmacological management.

I. Male Sexual Dysfunction

A. Erectile Dysfunction (ED)

 ●​ Definition: Persistent inability to achieve or sustain an erection suitable for satisfactory
sexual performance.
●​ Prevalence: Affects up to 30 million men in the United States.
●​ Associations: Commonly associated with chronic illness (diabetes, hypertension,
depression). Incidence 35-75% in men with diabetes.
●​ Medication-Induced ED: Approximately one-fourth of ED cases due to medications.
(See Table 53.1 for common drugs, e.g., digoxin, clonidine, propranolol,
hydrochlorothiazide, spironolactone, fluoxetine, alcohol, finasteride).
●​ Age-Related Risk: Increases with advancing age (4% of men in 50s, 17% in 60s, 47% of
men >75 unable to achieve any erection).
●​ First-line Treatments: Lifestyle measures (exercise, smoking cessation), changing drug
regimens (removing ED-causing drugs), and drug therapy with sildenafil (Viagra) or
other PDE-5 inhibitors.
●​ Other Interventions: Psychotherapy, surgical penile prosthesis implantation.
●​ Physiology of Erection:
○​ Begins with sexual arousal, increased parasympathetic nerve traffic to penis, local
release of nitric oxide (NO).
○​ NO activates guanylyl cyclase, producing cyclic guanosine monophosphate
(cGMP).
○​ cGMP promotes relaxation of arterial and trabecular smooth muscle.
○​ Resultant arterial dilation increases local blood flow/pressure; combined with
trabecular smooth muscle relaxation, causes expansion/engorgement of sinusoidal
spaces in corpus cavernosum.
○​ This causes venous occlusion, reducing venous outflow.
○​ Increased arterial pressure/inflow + reduced venous outflow leads to sufficient
engorgement for erection.
○​ Erection subsides when cGMP is removed by phosphodiesterase type 5 (PDE-5),
which converts cGMP to guanosine monophosphate.

B. Oral Drugs for ED: Phosphodiesterase-5 (PDE-5) Inhibitors

●​ Four Available: Sildenafil (Viagra), Tadalafil (Cialis), Vardenafil (Levitra, Staxyn),

Avanafil (Stendra).
●​ First-line Therapy: All are considered first-line for ED.
●​ Selection: Based on patient preference and prescriber judgment due to insufficient
head-to-head comparisons.
●​ Patient Education (PDE-5 Inhibitors):
○​ Dosing: With or without food (high-fat meals delay absorption for avanafil,
sildenafil, vardenafil, but not tadalafil).
○​ Avoid grapefruit juice (elevates drug levels).
○​ Timing: Avanafil ~15-30 min before sexual activity. Others ~1 hour before.
 ○​ Cardiovascular risk: Counsel men with preexisting cardiovascular disease on
cardiac risk of sexual activity. If symptoms (anginal pain, lightheadedness) during
sex, stop activity and discuss with prescriber.
○​ Priapism: Seek immediate medical attention if erection >4 hours (can cause
permanent damage).
○​ Vision/Hearing loss: Stop PDE-5 inhibitor and seek immediate medical attention
if sudden loss of vision (one/both eyes) or hearing loss.
○​ Nitrates: Avoid for at least 12h (avanafil), 24h (sildenafil/vardenafil), 48h
(tadalafil) after taking PDE-5 inhibitor.

1. Sildenafil (Viagra)

●​ First Oral Treatment: Introduced 1998. Enhances natural response to sexual stimuli;
doesn't cause erection directly.
●​ Other Approved Use: Pulmonary arterial hypertension (PAH), sold as Revatio.
●​ Mechanism: Selective inhibition of PDE-5. Increases/preserves cGMP levels in penis,
making erection harder/longer lasting. No effect without sexual stimuli.
●​ Benefits: 70% of men with ED (organic, psychogenic, mixed cause) saw improvement.
Dose-related, lasts up to 4 hours (fades after 2 hours). Helps ED from diabetes, spinal
cord injury, prostate resection, or unknown cause.
●​ In Men Without ED: Little/no effect on erection quality/duration.
●​ In Women: Not approved, studies showed little enhancement of sexual arousal.
●​ Adverse Effects:
○​ Hypotension: Small reduction in BP at recommended doses. Severe hypotension
with nitrates or alpha blockers.
○​ Priapism: Few cases reported (painful erection >6 hours). Immediate medical
intervention if >4 hours (permanent damage risk). Can be relieved by aspiration,
vasoconstrictor irrigation, or surgery.
○​ Nonarteritic Ischemic Optic Neuropathy (NAION): Very rare, irreversible
blurring/loss of vision (optic nerve blood flow blockage). Usually underlying risk
factors. No direct causal link, but avoid sildenafil if NAION in one eye.
○​ Sudden Hearing Loss: Very rare, usually unilateral, sometimes with
dizziness/vertigo/tinnitus. Partial/complete loss. No direct causal link, but
suspected. Discontinue for ED; continue for PAH.
○​ Other: Headache, flushing, dyspepsia (most common). Nasal congestion,
diarrhea, rash, dizziness. Mild transient visual disturbances (blue tinge, light
sensitivity, blurring) in ~3%. May intensify obstructive sleep apnea.
●​ Drug Interactions:
○​ Nitrates (e.g., nitroglycerin): Absolute contraindication due to life-threatening
hypotension. At least 24 hours between last sildenafil dose and nitrate
administration (longer if sildenafil elimination slowed).
 ○​ Alpha Blockers (e.g., doxazosin): Can cause symptomatic postural hypotension.
Use with caution.
○​ CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, grapefruit juice): Suppress
sildenafil metabolism, increase levels. Use with caution.
●​ Safety for Men with Coronary Heart Disease (CHD):
○​ Sildenafil itself appears safe for men with stable CHD at rest or during exercise
(no harmful effects on coronary blood flow, hemodynamic parameters, CHD
symptoms, exercise tolerance, ischemia).
○​ Sexual activity, not sildenafil, is likely cause of ischemic events in men with
CHD.
○​ Use with caution in men with: MI, stroke, life-threatening dysrhythmia within 6
months; resting hypotension (<90/50 mmHg); resting hypertension (>170/110
mmHg); heart failure; unstable angina.
○​ Absolute contraindication if taking nitroglycerin or other nitrates.
○​ Careful cardiovascular evaluation recommended before prescribing.

2. Vardenafil (Levitra, Staxyn)

●​ Actions/Use: Second selective PDE-5 inhibitor for ED. Relaxes arterial/trabecular

smooth muscle. Effects begin ~60 min, persist ~4 hours. No evidence of
faster/longer/better than sildenafil.
●​ Adverse Effects: Headache, flushing, rhinitis (most common). Can lower BP. Can cause
visual changes, sudden hearing/vision loss (NAION).​
Prolongs cardiac QT interval (risk for serious dysrhythmias, but none reported). Use
with caution with other QT-prolonging drugs.
●​ Drug Interactions:
○​ Contraindicated with alpha blockers and nitrates.
○​ Plasma levels increased by CYP3A4 inhibitors (ketoconazole, ritonavir); use with
caution.
○​ Caution with QT-prolonging drugs.

3. Tadalafil (Cialis)

●​ Actions/Use: Approved shortly after vardenafil for ED. Relaxation of penile smooth
muscle via cGMP accumulation.
●​ Unique Feature: Effects last ~36 hours (much longer than sildenafil/vardenafil). Dosing
not tightly coupled to sexual activity. Approved for as-needed and daily dosing (for men
anticipating sex at least twice weekly).
●​ Other Uses: Benign prostatic hyperplasia (BPH) , PAH (sold as Adcirca).
●​ Adverse Effects: Headache, dyspepsia, back pain, myalgia, limb pain, flushing, nasal
congestion (most common). Can lower BP. Rarely alters color vision. Few cases of
 NAION/sudden hearing loss (causal link not established). Long duration of action means
AEs may persist for hours.
●​ Drug Interactions:
○​ Contraindicated with nitrates or alpha blockers (except tamsulosin).
○​ CYP3A4 inhibitors increase levels. Max dose 10 mg every 72 hours for men on
CYP3A4 inhibitors.
●​ Dosing:
○​ "As needed": No minimum time identified by manufacturer; 1 hour reasonable
for absorption. Reduce dose in moderate renal/hepatic insufficiency. Avoid in
severe hepatic insufficiency.
○​ Daily: Recommended for men anticipating sex at least twice weekly. Take at same
time each day.

4. Avanafil (Stendra)

●​ Actions/Use: Latest selective PDE-5 inhibitor for ED (approved 2012). Same actions as
others.
●​ Unique Feature: Fastest onset of action (effects begin ~15 min). Lasts ~2 hours.
●​ Adverse Effects: Headache (at least 10%). Flushing, nasal congestion, nasopharyngitis in
some. Can lower BP.
●​ Drug Interactions:
○​ Contraindicated with nitroglycerin/other nitrates.
○​ Increases hypotensive effects of alcohol and antihypertensives (especially
alpha-adrenergic antagonists). Start at 50 mg if taking antihypertensives.
○​ Plasma levels increased by CYP3A4 inhibitors (ketoconazole, ritonavir,
erythromycin). Dosing should not exceed 50 mg in 24 hours for patients on
CYP3A4 inhibitors.

C. Nonoral Drugs for Erectile Dysfunction

●​ Second-line agents due to inconvenient dosing (injection into penis or urethral insertion).

1. Alprostadil (Prostaglandin E1)

●​ Mechanism: Active ingredient is PGE1, a vasodilator. Relaxes smooth muscle (arterial,

venous, trabecular), causing rapid arterial blood inflow, filling sinusoidal spaces for
erection. Pressure from engorged penis helps block venous outflow.
●​ Adverse Effects: Dull ache in penis (32% users). Urethral burning (12%). Minor
bleeding/spotting, testicular pain (~5%). Systemic symptoms rare.
●​ Routes:
 ○​ Transurethral (Muse): Pellets inserted into urethra. Only ED drug approved for
twice-daily use. Erection 5-10 min after insertion, lasts 30-60 min. Dosage
individualized in office.
○​ Intracavernosal Injection (Caverject, Caverject Impulse, Edex): Direct
injection into corpus cavernosum. Rapid response, relatively painless. Optimal
dose in office for erection sufficient for intercourse, lasting <1 hour. Max 3
times/week, no more than once in 24 hours.
■​ Acute AEs: Burning, prolonged erection, priapism.
■​ Chronic AEs: Penile fibrosis may develop with continued injections (not
reported with pellets).

2. Papaverine Plus Phentolamine

●​ Mechanism: Papaverine (vasodilator) + phentolamine (alpha-adrenergic blocker).

Injected directly into corpus cavernosum. Increases arterial inflow (alpha-blockade, direct
papaverine action) and decreases venous outflow. Erection within 10 min, lasts 2-4 hours.
●​ Adverse Effects: Priapism (~10%). Painless fibrotic nodules in corpus cavernosum
common. Orthostatic hypotension with dizziness, transient paresthesias, ecchymosis,
difficulty achieving orgasm/ejaculation.
●​ Approval/Recommendation: Not FDA approved for ED. Many experts do not
recommend due to significant AEs and concerns about compounding pharmacies.

D. Nonpharmacological Interventions for Erectile Dysfunction

●​ For patients not benefiting from drug therapy.

●​ Options: Vacuum-assisted devices (increase arterial blood flow, constrictive ring
maintains engorgement). Penile prostheses (inserted rods for permanent erection,
inflatable prostheses). Revascularization surgery (less frequently used, low good
outcomes). Psychotherapy (for psychological concerns like trauma, anxiety, relationship
issues, depression).
●​ Clinical Guidelines: American Urological Association (2018) guidelines offer all
options as first-line, including surgery. Canadian Urologic Association guidelines offer
step-by-step management. Both evidence-based.

E. Summary of Key Prescribing Considerations (PDE-5 Inhibitors for ED)

●​ Therapeutic Goal: Enhance hardness and duration of erection in men with ED.
●​ Baseline Data: Heart rate, blood pressure. Thorough eye examination. Assess hearing.
Evaluate for cardiovascular disorders (stroke, hypotension, hypertension, heart failure,
unstable angina, MI, recent severe dysrhythmia).
 ●​ Monitoring: Heart rate, blood pressure. Eye exam (visual acuity, color vision, pupillary
response, fundoscopic). Assess for tinnitus, vertigo, hearing loss. Assess for
signs/symptoms of pulmonary edema.
●​ High-Risk Patients (Contraindications): Men taking nitrates. Generally avoid in men
taking alpha blockers. Avoid vardenafil (not sildenafil/tadalafil) in men taking class I or
III antidysrhythmic drugs. Carefully consider cardiac risk of sexual activity in men with
preexisting cardiovascular disease. Use with caution in men taking CYP3A4 inhibitors,
with NAION, CHD, other cardiovascular disorders.
●​ Evaluating Therapeutic Effects: Patient satisfaction with therapy.
●​ Minimizing Adverse Effects:
○​ Diet/timing: High-fat meals delay absorption for avanafil, sildenafil, vardenafil
(not tadalafil), delaying onset.
○​ Timing: Avanafil ~15-30 min before sex. Other PDE-5 inhibitors ~1 hour before.
Only tadalafil approved for daily dosing.
○​ Vision/hearing changes: Emphasize examination for these changes.
○​ Priapism: Surgical emergency if >4 hours; go to ED.

F. Premature Ejaculation (PE)

●​ Definition:
○​ Lay: Ejaculation occurs earlier than man or partner desires (~30% of male
population).
○​ International Society of Sexual Medicine (ISSM): More restrictive, generally
accepted definition.
■​ Ejaculation before or within 1 minute of vaginal penetration (lifelong PE)
or 2-3 minutes (acquired PE).
■​ Inability to delay ejaculation in all (or almost all) vaginal penetrations.
■​ Psychological distress due to inability to delay ejaculation.
■​ Using ISSM criteria: ~4% of male population has PE.
●​ Pathophysiology: Several proposed causes.
○​ Genetic variations, glans penis hypersensitivity, overexcitement.
○​ Psychological factors: performance anxiety, body image concerns, interpersonal
relationship issues.
○​ Neurotransmitter dysregulation: Serotonin delays ejaculation; dopamine and
oxytocin stimulate it. Alterations in synthesis/release or receptor sensitivity may
play a role.
○​ Each cause likely accounts for small percentage; more research needed.
●​ Drug Therapy (Off-label, no FDA-approved drugs).
○​ First-line: Selective Serotonin Reuptake Inhibitors (SSRIs) or topical anesthetics.
○​ SSRIs: Recommended first-line. Prevent serotonin reuptake, increasing serotonin
in synapses, enhancing neurotransmission. Paroxetine most effective.
 ■​ Dosing: Lower doses than for depression. Typical daily dosing: citalopram
20-40 mg, fluoxetine 20-40 mg, paroxetine 10-40 mg, sertraline 50-200
mg. Maximal response in 2-3 weeks with daily dosing.
○​ Topical Anesthetics (e.g., lidocaine, prilocaine): Decrease glans penis
sensitivity.
■​ Problem: May be transferred to partner, causing vaginal numbness and
delayed orgasm. Use with a condom.
○​ Other Drugs (if first-line ineffective):
■​ Clomipramine (Anafranil): Tricyclic antidepressant affecting serotonin
uptake. Second-line. Dosage: 12.5-50 mg daily.
■​ Tramadol: Opioid analgesic. Positive results in studies, but
addiction/harmful AE risk makes it less attractive.
■​ PDE-5 Inhibitors: Show success if PE accompanies ED.
■​ Oxytocin receptor antagonists: No significant improvement demonstrated.
●​ Nonpharmacological Treatments:
○​ Radiofrequency ablation: Disrupts nerve signals, promising but needs RCTs.
○​ Acupuncture: Almost doubled ejaculation time (to 65.7 seconds vs 33.1 seconds).
●​ Clinical Guidelines: ISSM clinical guidelines for PE management.

II. Benign Prostatic Hyperplasia (BPH)

●​ Definition: Common condition, nonmalignant prostate enlargement. Affects >50% of

men by 60, 90% by 85. No evidence of predisposition to prostate cancer.
●​ Pathophysiology: Prostate gland surrounds male urethra. Normal weight 4-20g, BPH
prostate can reach 50-80g.
1.​ Excessive growth of epithelial (glandular) cells and smooth muscle cells.
2.​ Epithelial overgrowth: Mechanical obstruction of urethra.
3.​ Smooth muscle overgrowth: Dynamic obstruction of urethra.
4.​ Ratio of epithelium to smooth muscle varies; larger prostates have higher
epithelial percentage.
●​ Signs and Symptoms: Urinary hesitancy, urgency, increased frequency, dysuria,
nocturia, straining to void, postvoid dribbling, decreased force/caliber of urinary stream,
incomplete bladder emptying sensation. No direct correlation between symptoms and
prostate size.
●​ Long-term Complications: Obstructive nephropathy, bladder stones, recurrent UTIs.
●​ Treatment Modalities:
1.​ Invasive Treatments: Transurethral resection of prostate, laser prostatectomy,
transurethral electrovaporization, transurethral microwave therapy. For severe
symptoms/complications.
2.​ Drug Therapy: For moderate symptoms.
3.​ "Watchful Waiting": Annual reevaluation, for minimal symptoms.
A. Drug Therapy for Benign Prostatic Hyperplasia

●​ Goals: Relieve bothersome urinary symptoms, delay disease progression.

●​ Classes:
1.​ 5-α-Reductase Inhibitors: For very large prostates (mechanical obstruction).
2.​ α1-Adrenergic Antagonists (Alpha Blockers): Preferred for relatively small
prostates (dynamic obstruction).
3.​ PDE-5 Inhibitor (Tadalafil): Also approved for BPH.
4.​ Combination Products: Alpha blocker + 5-α-reductase inhibitor.

1. 5-α-Reductase Inhibitors

●​ Available: Finasteride (Proscar), Dutasteride (Avodart). Both reduce prostate size over
several months. No proof one is better.
●​ Finasteride (Proscar):
○​ Mechanism: Inhibits 5-α-reductase (converts testosterone to DHT in reproductive
tissue). Reduces blood DHT by 70% (no effect on testosterone). Decreased DHT
promotes prostate epithelial tissue regression, reducing mechanical obstruction.
Most effective in very large prostates. Shrinkage occurs slowly (6-12 months).
○​ Adverse Effects:
■​ Prostate Cancer: Reduces low-grade prostate cancer risk but increases
likelihood of high-grade tumor. FDA recommends against labeling for
prostate cancer prevention.
■​ Generally well tolerated.
■​ Decreased ejaculate volume and libido (5-10% of patients).
■​ Gynecomastia in some men.
■​ Teratogenic to male fetus: Contraindicated in pregnant women or those
who may become pregnant. Pregnant women should not handle
broken/crushed tablets (can be absorbed through skin). Men should not
donate blood while on finasteride or for 1 month after stopping (to avoid
exposing pregnant recipient).
■​ PSA Levels: Decreases serum PSA (marker for prostate cancer) by
30-50%. Determine before treatment and 6 months later. If PSA doesn't
fall as expected, evaluate for prostate cancer.
○​ Dosing: 5 mg once daily, lifelong. Also 1-mg tablets (Propecia) for male-pattern
baldness.
●​ Dutasteride (Avodart):
○​ Similarities to Finasteride: Reduces ejaculate volume/libido, causes PSA
decline, teratogenic, increases high-grade prostate tumor risk, not for cancer
prevention.
 ○​ Key Differences: More complete reduction in circulating DHT (93% vs 70%).
Inhibits 5-α-reductase in skin/liver as well as reproductive tissue.
○​ Pharmacokinetics: Extremely long half-life (~5 weeks); takes months to clear
after stopping.
○​ Handling: Can be absorbed through skin; pregnant women should not handle.
Men should not donate blood while on dutasteride or for at least 6 months after
stopping.
○​ Administration: Capsule must be swallowed whole with water (contents
irritating to oropharyngeal mucosa).
●​ Summary of Key Prescribing Considerations (5-α Reductase-Inhibitors):
○​ Therapeutic Goal: Reduce prostate size, relieve bladder outlet obstruction
symptoms.
○​ Baseline Data: PSA.
○​ Monitoring: Repeat PSA at 6 months (evaluate for prostate cancer if no
decrease). Repeat PSA periodically.
○​ High-Risk Patients: Do not prescribe for suspected prostate cancer.
○​ Evaluating Therapeutic Effects: Anticipate symptom improvement after 6-12
months.
○​ Minimizing Adverse Effects: Sexual dysfunction common, can be permanent.
Patient should return for possible dosage adjustment/medication change if
concerned.

2. α1-Adrenergic Antagonists (Alpha Blockers)

●​ Approved for BPH: Alfuzosin (Uroxatral, Xatral), Terazosin (Hytrin), Doxazosin

(Cardura), Silodosin (Rapaflo), Tamsulosin (Flomax). No direct comparisons in trials, so
no definitive recommendation on superior efficacy. Silodosin and tamsulosin may be
better tolerated.
●​ Mechanism of Action: Block α1 receptors (bladder neck, prostate capsule, prostatic
urethra), relaxing smooth muscle and decreasing dynamic obstruction. Rapid
symptomatic improvement and increased urinary flow. Preferred for mild prostatic
enlargement (dynamic obstruction is major contributor). Must be taken lifelong. Do not
reduce prostate size.
●​ Receptor Specificity and Blood Pressure Impact:
○​ Selective α1a Blockers (Silodosin, Tamsulosin): Selective for α1a receptors in
prostate. Little/no effect on blood pressure. No benefit for hypertension.
○​ Nonselective α1 Blockers (Alfuzosin, Terazosin, Doxazosin): Block α1
receptors in blood vessels as well as prostate. Promote vasodilation, lower blood
pressure. Doxazosin and terazosin developed as antihypertensives. Useful for
patients with BPH + hypertension. May be dangerous for men with reduced BP.
●​ Adverse Effects: Generally well tolerated.
 ○​ Nonselective Agents: Hypotension, fainting, dizziness, somnolence, nasal
congestion.
○​ Selective Agents (Silodosin, Tamsulosin): Less likely to cause
hypotension/related effects. Can cause abnormal ejaculation (failure, reduced
volume, retrograde ejaculation).
○​ Do not reduce PSA levels (unlike 5-α-reductase inhibitors).
○​ Intraoperative Floppy-Iris Syndrome (IFIS): Increased risk during cataract
surgery (can increase postoperative pain, delay recovery, reduce vision
improvement, cause iris defects, blindness in severe cases). Postpone alpha
blocker therapy until after surgery. Inform ophthalmologist if currently taking.
●​ Drug Interactions:
○​ Nonselective alpha blockers: Caution with other BP-lowering drugs (organic
nitrates, antihypertensives, PDE-5 inhibitors) due to excessive hypotension risk.
○​ CYP3A4 inhibitors: Strong inhibitors (erythromycin, itraconazole, nefazodone,
HIV protease inhibitors) can dramatically increase alfuzosin and silodosin levels.
Do not combine.
●​ Use in Women: Tamsulosin and other alpha blockers used off-label for urinary
hesitancy/retention associated with bladder outlet obstruction or insufficient detrusor
muscle contraction. Benefits from relaxing smooth muscle in bladder neck and urethra.
Max improvement may take weeks.

3. α1 Blocker/5-α-Reductase Inhibitor Combination

●​ Effectiveness: Superior to either agent alone in clinical trials.

●​ Rationale: Alpha blocker provides rapid symptomatic relief (smooth muscle relaxation);
5-α-reductase inhibitor provides additional relief over time (shrinks prostate) and may
delay disease progression.
●​ Examples: Tamsulosin + dutasteride (Jalyn), doxazosin + finasteride.

4. Tadalafil, a PDE-5 Inhibitor

●​ Approved Use: Men with BPH alone or BPH combined with ED.
●​ Effects in BPH: Modest decrease in symptoms (urinary frequency, urgency, straining)
but no improvement in urinary flow rate. Only 1 in 6 men benefit. Initial improvement in
2 weeks.
●​ Mechanism (Proposed): Relaxes smooth muscle in prostate, bladder, urethra. Other
PDE-5 inhibitors can also reduce BPH symptoms.
●​ Risks: Risk for hypotension. Use with caution in men taking alpha blockers; avoid in
men taking nitrates.

B. Other Drugs for Benign Prostatic Hyperplasia

 ●​ Anticholinergics: For OAB symptoms (urgency, frequency) often experienced by men
with BPH. Examples: darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine,
trospium. Can be used alone or with alpha blocker (e.g., tamsulosin).
●​ Botulinum Toxin (Botox): Single injection into prostate can relieve urinary symptoms
for up to 1 year. Benefits from blocking acetylcholine release, reducing prostate size, and
reducing PSA levels.

C. Complementary and Alternative Medication for Benign Prostatic Hyperplasia

●​ Saw Palmetto: Widely used, but numerous RCTs refute benefits. Cochrane review (32
RCTs, 5666 men) found no significant difference from placebo, even at 2-3x usual dose.
●​ Clinical Guidelines: American Urological Association does not recommend any dietary
supplement or herbal treatment until sufficient evidence from rigorous trials.

Chapter 82: Drug Therapy for Sexually Transmitted Diseases

This chapter provides an overview of common sexually transmitted diseases (STDs) and their
pharmacological treatments, guided by CDC clinical guidelines.

I. Introduction to Sexually Transmitted Diseases (STDs)

●​ Definition: Infectious diseases primarily transmitted through sexual contact. Also known
as sexually transmitted infections (STIs).
●​ Prevalence: Very common in the US, major public health problem.
●​ Recent Trends (2018 CDC Report): Sharp increases in reported STDs.
○​ Chlamydia: 1.7 million new cases in 2017 (up 22% since 2013).
○​ Gonorrhea: 555,608 new cases in 2017 (up 67%).
○​ Syphilis: 30,644 new cases in 2017 (up 76%).
●​ Actual numbers likely higher due to underreporting.
●​ Treatment Recommendations: Based on CDC Sexually Transmitted Diseases Treatment
Guidelines, 2015.

II. Chlamydia Trachomatis Infections

●​ Causative Organism: Chlamydia trachomatis. Most frequently reported bacterial STD.

●​ Manifestations: Genital tract infections, proctitis, conjunctivitis, lymphogranuloma
venereum (LGV), ophthalmia and pneumonia in infants.
●​ Symptoms: Frequently asymptomatic in women, may also be asymptomatic in men.
 ●​ Untreated in Women: Can cause pelvic inflammatory disease (PID), ectopic pregnancy,
infertility (sterility in up to 50,000 women/year from fallopian tube scarring).
●​ Screening: CDC recommends annual screening for all sexually active adolescent girls
and women through age 25.
●​ Treatment:
○​ Adults and Adolescents:
■​ Azithromycin, 1 g PO once.
■​ Doxycycline, 100 mg PO twice daily x 7 days.
○​ Children:
■​ <45 kg: Erythromycin base/ethylsuccinate,​
12.5 mg/kg PO 4 times/day x 14 days.
■​ ≥45 kg but <8 years: Azithromycin, 1 g PO once.
■​ ≥8 years: Azithromycin, 1 g PO once or Doxycycline, 100 mg PO twice
daily x 7 days.
■​ Note: In preadolescent children, sexual abuse is more likely cause than
perinatal transmission, especially >2 years old. Diagnosis must be
definitive.
○​ Pregnant Women: Azithromycin, 1 g PO once.
○​ Newborns (Ophthalmia or Pneumonia): Erythromycin base/ethylsuccinate,
12.5 mg/kg PO 4 times/day x 14 days.

III. Lymphogranuloma Venereum (LGV)

●​ Causative Organism: Unique strain of C. trachomatis. Strictly sexually transmitted.

●​ Prevalence: Most common in tropical countries, occurs in US (especially South).
●​ Manifestation: Begins as small erosion/papule in genital region, then migrates to
regional lymph nodes causing swelling.
●​ Treatment: Doxycycline, 100 mg PO twice daily x 21 days.

IV. Gonococcal Infections (Gonorrhea)

●​ Causative Organism: Neisseria gonorrhoeae.

●​ Antimicrobial Resistance: Increasingly resistant to oral cephalosporins, leading to
revised recommendations.
●​ Treatment (Urethral, Cervical, and Rectal Infection):
○​ Preferred: Ceftriaxone, 250 mg IM once, plus Azithromycin, 1 g PO once.
○​ If patient refuses IM: PO cefixime (Suprax) can substitute for IM ceftriaxone,
but CDC recommends not routine substitution due to documented/anticipated
resistance.
○​ If allergic to Azithromycin: 7-day course of doxycycline may be substituted.
 ○​ Cephalosporin Allergies: Options not as clear. Double azithromycin dose as
monotherapy will cure most but​
not recommended due to treatment failures and rapid resistance.
●​ Pharyngitis: Same as urethral/cervical/rectal infection.
●​ Disseminated Gonococcal Infection (DGI) in Adults: Ceftriaxone, 1 g IM or IV every
24 h, plus Azithromycin, 1 g PO once.
○​ DGI with Meningitis: Ceftriaxone, 1-2 g IV every 12 h x 10-14 days, plus
Azithromycin, 1 g PO once.
○​ DGI with Endocarditis: Ceftriaxone, 1-2 g IV every 12 h x 28 days or more,
plus Azithromycin, 1 g PO once.
●​ Conjunctivitis: Ceftriaxone, 1 g IM once, plus Azithromycin, 1 g PO once.
●​ Newborns:
○​ Ophthalmia Neonatorum Prophylaxis: Erythromycin 0.5% ophthalmic
ointment in each eye at birth (required by law in most states). If not available,
parenteral ceftriaxone.
○​ Ophthalmia Neonatorum (serious infection, can cause blindness): Ceftriaxone
25−50 mg/kg (not to exceed 125 mg) IM or IV once.
○​ Disseminated Infection or Scalp Abscess: Ceftriaxone, 25−50 mg/kg IM or IV
once daily x 7 days (or Cefotaxime, 25 mg/kg IM or IV every 12 h x 7 days).
Dosing increased to 10-14 days if meningitis.
●​ Preadolescent Children: Sexual abuse is most common cause. Vaginal, anorectal,
pharyngeal infections most common.
○​ Arthritis, Bacteremia: If ≤45 kg, ceftriaxone 50 mg/kg IM or IV once daily x 7
days (max 1 g). If >45 kg, ceftriaxone 1 g IM or IV once daily x 7 days.
○​ Vulvovaginitis, Cervicitis, Proctitis, Pharyngitis, Urethritis: If ≤45 kg,
ceftriaxone 25−50 mg/kg (not to exceed 125 mg) IM or IV once. If >45 kg, same
as adult.

V. Nongonococcal Urethritis (NGU)

●​ Definition: Urethritis caused by any organism other than N. gonorrhoeae.

●​ Common Agents: C. trachomatis (most common), Ureaplasma urealyticum,
Trichomonas vaginalis, Mycoplasma genitalium.
●​ Diagnosis: Polymorphonuclear leukocytes + negative culture for N. gonorrhoeae.
Prevalent in sexually active adolescent girls.
●​ Treatment:
○​ Acute Infection: Azithromycin, 1 g PO once OR Doxycycline, 100 mg PO twice
daily x 7 days.
○​ Recurrent/Persistent: Azithromycin, 1 g PO once (if original treatment was
doxycycline) OR Moxifloxacin 400 mg PO daily x 7 days (if original treatment
was azithromycin).
 ○​ If Trichomonas outbreaks common: Metronidazole (2 g PO once) or Tinidazole
(2 g PO once).

VI. Pelvic Inflammatory Disease (PID)

●​ Causative Organisms: N. gonorrhoeae, C. trachomatis, others. Consequences of failure

can be severe (e.g., sterility).
●​ Treatment:
○​ Inpatients: Doxycycline (100 mg IV or PO every 12 h) plus either cefoxitin (2 g
IV every 6 h) or cefotetan (2 g IV every 12 h). OR Clindamycin (900 mg IV every
8 h) plus gentamicin (​
3−5 mg/kg IM or IV once or 2 mg/kg IM or IV once then 1.5 mg/kg every 8 h).
Many experts recommend IV antibiotics in hospital.
○​ Outpatients: Doxycycline (100 mg PO twice daily x 14 days) plus either
cefoxitin (2 g IM once, boosted with probenecid 1 g PO once) or ceftriaxone (250
mg IM once), with or without metronidazole (500 mg PO twice daily x 14 days).

VII. Sexually Acquired Epididymitis

●​ Causative Organisms: C. trachomatis, N. gonorrhoeae, enteric organisms.

●​ Characteristics: Occurs primarily in young adults (<35 years old). May be associated
with urethritis. Primary symptoms: fever + pain in back of testicles developing over
hours.
●​ Treatment:
○​ Without history of insertive anal sex: Ceftriaxone (250 mg IM once) plus
Doxycycline (100 mg PO twice daily x 10 days).
○​ With history of insertive anal sex: Ceftriaxone (250 mg IM once) plus either
Levofloxacin (500 mg PO daily x 10 days) or Ofloxacin (300 mg PO twice daily
x 10 days).
○​ Testicular pain management: analgesics, bed rest, ice packs.

VIII. Syphilis

●​ Causative Organism: Treponema pallidum. Can occur in skin, bones, joints, eyes.
Neurosyphilis risk increased in HIV-infected individuals. Congenital syphilis possible if
infant exposed in utero (sores, rhinitis, bone tenderness).
●​ Treatment: Penicillin G is drug of choice for all stages. Form and dosage depend on
disease stage.
○​ Primary Syphilis, Secondary Syphilis, and Early Latent Syphilis (<1 year
duration):
■​ Adults: Benzathine penicillin G, 2.4 million units IM once.
 ■​ Children: Benzathine penicillin G,​
50,000 units/kg IM once (max 2.4 million units).
○​ Late Latent Syphilis (>1 year duration) or Latent Syphilis of Unknown
Duration:
■​ Adults: Benzathine penicillin G, 2.4 million units IM once/week for 3
weeks.
■​ Children: Benzathine penicillin G,​
50,000 units/kg IM once/week for 3 weeks (max 7.2 million units over
treatment course).
○​ Tertiary Syphilis: Benzathine penicillin G, 2.4 million units IM once/week for 3
weeks (must rule out CNS involvement).
○​ Neurosyphilis: Aqueous crystalline penicillin G, 18-24 million units IV daily for
10-14 days (continuous infusion or 3-4 million units every 4 h).
○​ Congenital Syphilis: Aqueous crystalline penicillin G, 50,000 units/kg IV every
12 h for first 7 days, then 50,000 units/kg every 8 h for next 3 days. OR Procaine
penicillin G,​
50,000 units/kg IM once daily for 10 days.

IX. Bacterial Vaginosis

●​ Causative Organisms: Gardnerella vaginalis, Mycoplasma hominis, various anaerobes.

●​ Treatment:
○​ Metronidazole, 500 mg PO twice daily x 7 days.
○​ Metronidazole gel (0.75%), 1 full applicator (5g) intravaginally once daily x 5
days.
○​ Clindamycin cream (2%), 1 full applicator (5 g) intravaginally at bedtime x 7
days.

X. Trichomoniasis

●​ Causative Organism: Trichomonas vaginalis. Most common nonviral STD in US.

●​ Symptoms: Men usually asymptomatic. Women may be asymptomatic or have diffuse,
malodorous, yellow-green vaginal discharge, burning, itching. Rapid movement of
protozoa notable on microscopic exam.
●​ Treatment:
○​ Single oral dose of Metronidazole, 2 g PO once OR Tinidazole, 2 g PO once.
○​ Dosing can be repeated for treatment failure.
○​ Male partners of infected women should​
always be treated.
○​ Metronidazole: No evidence of birth defects in humans (despite some clinician
concerns during pregnancy).
 ○​ Tinidazole: Should​
not be prescribed for pregnant women.

XI. Chancroid

●​ Causative Organism: Haemophilus ducreyi. Also known as soft chancre.

●​ Treatment:
○​ Azithromycin, 1 g PO once.
○​ Ceftriaxone, 250 mg IM once.
○​ Ciprofloxacin, 500 mg PO twice daily x 3 days.
○​ Erythromycin base, 500 mg PO 3 times/day x 7 days.

XII. Genital Herpes Simplex Virus Infections

●​ Causative Organism: Herpes simplex virus (HSV). May recur for life, but subsequent
episodes may become shorter/less severe, rarely cease.
●​ Neonatal Infection: Can be transmitted in utero (rare, can cause spontaneous
abortion/fetal malformation) or during delivery (can cause blindness, severe neurologic
damage, death).
○​ Protection during delivery: Cesarean delivery if mother has active infection.
○​ Treatment for infected infants: Acyclovir.
●​ Treatment: Three drugs: Acyclovir (Zovirax), Famciclovir (Famvir), Valacyclovir
(Valtrex).
○​ Goal: Cannot eliminate virus, but reduce symptoms and shorten duration of
pain/viral shedding.
○​ First Episode, Genital Herpes:
■​ Acyclovir, 400 mg PO 3 times/day x 7-10 days (or longer). OR Acyclovir,
200 mg PO 5 times/day x 7-10 days (or longer).
■​ Famciclovir, 250 mg PO 3 times/day x 7-10 days (or longer).
■​ Valacyclovir, 1 g PO twice daily x 7-10 days (or longer).
○​ Severe Infection: Acyclovir, 5−10 mg/kg IV every 8 h for 2-7 days or until
clinical improvement, then PO acyclovir to complete at least 10 days.
○​ Recurrent Episodes:
■​ Acyclovir, 800 mg PO twice daily x 5 days OR 800 mg PO 3 times/day x
2 days OR 400 mg PO 3 times/day x 5 days.
■​ Famciclovir, 125 mg PO twice daily x 5 days OR 1 g twice daily x 1 day
OR 500 mg once, then 200 mg twice daily for 2 days.
■​ Valacyclovir, 500 mg PO twice daily x 3 days OR 1 g PO once daily x 5
days.
○​ Daily Suppressive Therapy:
■​ Acyclovir, 400 mg PO twice daily.
 ■​ Famciclovir, 250 mg PO twice daily.
■​ Valacyclovir, 500 mg PO once daily OR 1 g PO once daily.
○​ Neonatal Herpes: Acyclovir, 20 mg/kg IV every 8 h x 14 days (skin/mucous
membrane) or x 21 days (disseminated/CNS infection).

XIII. Proctitis

●​ Causative Organisms: Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema

pallidum, herpes simplex virus.
●​ Treatment: Ceftriaxone (250 mg IM once) plus Doxycycline (100 mg PO twice daily x 7
days).

XIV. Venereal Warts

●​ Causative Organism: Human papillomavirus (HPV). (Treatment discussed in Chapter

88).

XV. Drug Categories Used in Treatment of Sexually Transmitted Infections (Box

82.1)

●​ Amebicide, Antiprotozoal, Miscellaneous Antibiotic: Metronidazole, Tinidazole.

●​ Aminoglycoside: Gentamicin.
●​ Antivirals: Acyclovir, Famicyclovir, Valacyclovir.
●​ Cephalosporins: Cefotetan, Cefoxitin, Ceftriaxone, Cefotaxime.
●​ Lincosamide: Clindamycin.
●​ Macrolides: Azithromycin, Erythromycin.
●​ Penicillins: Penicillin G (Benzathine, Aqueous crystalline, Procaine).
●​ Quinolone: Ciprofloxacin, Moxifloxacin, Levofloxacin, Ofloxacin.
●​ Tetracycline: Doxycycline.

Chapter 87: Drugs for the Eye

This chapter focuses on pharmacological management of glaucoma, allergic conjunctivitis, and
other common eye conditions.

I. Introduction

●​ Vision Importance: Majority of people would miss vision most if one sense was lost.
 ●​ Glaucoma: Leading cause of irreversible blindness, but preventable with proper
management.
●​ Focus: Primarily glaucoma; also allergic conjunctivitis and other common eye
conditions. Discussion limited to ophthalmologic applications of drugs.

II. Glaucoma

●​ Definition: Group of diseases characterized by decreased peripheral vision secondary to

optic nerve damage.
●​ Most Common Forms: Primary open-angle glaucoma (POAG) and angle-closure
glaucoma.

A. Primary Open-Angle Glaucoma (POAG)

●​ Pathophysiology: Angle between iris and cornea is open, allowing unimpeded aqueous
humor outflow. IOP is often elevated but can be normal. Painless, insidious disease;
injury develops over years. Symptoms absent until extensive optic nerve damage.
●​ Management: Directed at reducing elevated IOP (only modifiable risk factor). IOP
reduction can slow/stop disease progression. Managed by specialists, but primary care
providers monitor/follow-up.
●​ Mechanism of IOP Reduction: Chronic drug therapy. Drugs either:
1.​ Facilitate aqueous humor outflow.
2.​ Reduce aqueous humor production.
●​ First-line Drugs:
1.​ β-adrenergic blocking agents (β blockers).
2.​ α2-adrenergic agonists.
3.​ Prostaglandin analogs.
●​ Second-Line/Other Options: Cholinergic drugs, carbonic anhydrase inhibitors, Rho
kinase inhibitors.
●​ Surgical Intervention: If drugs cannot reduce IOP to acceptable level.

B. Angle-Closure Glaucoma

●​ Pathophysiology: Angle between iris and cornea is constricted, blocking aqueous humor
outflow. Develops suddenly, extremely painful. Irreversible vision loss in 1-2 days
without treatment. Much less common than POAG.
●​ Treatment: Drug therapy (to control acute attack) followed by corrective surgery.
○​ Drugs for acute attack: Combination of osmotic agents, short-acting miotics,
carbonic anhydrase inhibitors, topical β-adrenergic blocking agents.
○​ Definitive treatment: Laser iridotomy or surgical Peripheral Iridectomy after IOP
reduced by drugs.
C. Specific Drug Classes for Glaucoma

1. β-Adrenergic Blocking Agents (Beta Blockers)

●​ Mechanism: Lower IOP by decreasing production of aqueous humor. Both nonselective

(block β1 and β2) and cardioselective (block β1 only) are effective.
●​ Use: Primarily for open-angle glaucoma (initial & maintenance therapy). Used in
combination for emergency management of acute angle-closure glaucoma.
●​ Adverse Effects:
○​ Local: Minimal. Transient ocular stinging common. Occasionally conjunctivitis,
blurred vision, photophobia, dry eyes.
○​ Systemic: Can be absorbed sufficiently to cause systemic effects.
■​ Bradycardia, AV heart block, bronchospasm: Can occur due to
systemic absorption, especially in susceptible patients (e.g., those with
asthma/COPD from β2 blockade, heart disease from β1 blockade).
●​ Patient-Centered Care Across the Life Span (Beta Blockers):
○​ Children: Levobunolol and metipranolol not recommended for children.
Pilocarpine may cause paradoxical IOP increases; indicated for primary
congenital glaucoma, not secondary.
○​ Pregnant Women: IOP usually decreased during pregnancy, allowing lower drug
doses. Adverse events in animal studies for all beta-blocker preparations except
betaxolol.
○​ Older Adults: Beers Criteria lists beta blockers as potentially inappropriate.
Cholinesterase inhibitors may cause bradycardia/hypotension leading to fall risk.

2. Prostaglandin Analogs

●​ Approved: Latanoprost (Xalatan), Travoprost (Travatan), Bimatoprost (Lumigan),

Tafluprost (Zioptan), Latanoprostene bunod (Vyzulta).
●​ Effectiveness: As effective as β blockers, fewer side effects. Considered first-line.
●​ Mechanism: Increased aqueous humor outflow.
●​ Latanoprost (Xalatan):
○​ Significant Side Effect: Harmless heightened brown pigmentation of the iris,
most noticeable in green-brown, yellow-brown, or blue/gray-brown irides. Rare in
blue, green, or blue-green irides. Stops progressing if discontinued, but usually
does not regress.
○​ Other Side Effects: Increased pigmentation of eyelid/eyelashes (length,
thickness). Blurred vision, burning, stinging, conjunctival hyperemia, conjunctival
edema, punctate keratopathy. Rarely macular edema.
○​ Systemic Reactions: Rare.
●​ Other Prostaglandin Analogs: Travoprost, bimatoprost, tafluprost, latanoprostene
bunod similar to latanoprost.
 ●​ Children: Latanoprost and tafluprost not recommended for children. Manufacturers of
travoprost and latanoprostene bunod don't recommend for children <16 due to possible
long-term pigmentary changes.

3. α2-Adrenergic Agonists

●​ Mechanism: Decrease aqueous humor formation.

●​ Brimonidine (Alphagan P, Lumify): Common.
●​ Apraclonidine (Iopidine): Lowers IOP by reducing aqueous humor production and
possibly increasing outflow.
○​ Indication: Short-term therapy of open-angle glaucoma (if not responding to
maximal doses of other drugs) and preoperative medication before laser
procedures.
○​ Side Effects: Headache, dry mouth, dry nose, altered taste, conjunctivitis, lid
reactions, pruritus, tearing, blurred vision. Does not cross blood-brain barrier, so
no hypotension.
●​ Children: Apraclonidine not recommended for children. Brimonidine not recommended
for children <2 years old.
●​ Combination: Fixed-dose combination of brimonidine (α2 agonist) and timolol
(nonselective β blocker) available. Benefits/adverse effects similar to separate use.

4. Cholinergic Drugs

●​ Types: Muscarinic agonists (Pilocarpine) and Cholinesterase inhibitors (Echothiophate).

●​ Pilocarpine:
○​ Mechanism: Stimulates cholinergic receptors, producing miosis (pupil
constriction) and ciliary muscle contraction (focuses lens for near vision). Lowers
IOP indirectly.
■​ Open-angle: Ciliary muscle contraction widens trabecular meshwork
spaces, facilitating aqueous humor outflow.
■​ Angle-closure: Iris sphincter contraction pulls iris away from trabecular
meshwork pores, removing outflow impediment.
○​ Major Side Effects (Eye): Ciliary muscle contraction focuses lens for near vision
(corrective lenses can help). Rarely, sustained ciliary muscle contraction causes
retinal detachment. Pupil constriction.
●​ Echothiophate: Cholinesterase inhibitor (inhibits acetylcholine breakdown, promotes
acetylcholine accumulation at muscarinic receptors). Produces same ocular effects as
pilocarpine (miosis, near vision focus, IOP reduction).
○​ Side Effects: Myopia, excessive pupillary constriction.​
Major Concern: Association with long-acting cholinesterase inhibitors and
cataract development.
 ○​ Systemic Effects: Absorbed into systemic circulation can cause
parasympathomimetic responses: bradycardia, bronchospasm, sweating,
salivation, urinary urgency, diarrhea.
●​ Children: Pilocarpine may cause paradoxical IOP increases; indicated for primary
congenital glaucoma, not secondary.

5. Carbonic Anhydrase Inhibitors (CAIs)

●​ Mechanism: Decrease aqueous humor formation.

●​ Examples: Acetazolamide (Diamox), Methazolamide (Neptazane), Dorzolamide
(Trusopt), Brinzolamide (Azopt).
●​ Brinzolamide (Azopt): Topical. As effective as dorzolamide, better tolerated.
○​ Most common AEs: Bitter aftertaste, transient blurred vision. Less ocular
stinging/burning than dorzolamide.
○​ Preservative: Contains benzalkonium chloride, absorbed by soft contact lenses.
Patients should wait 15 min after administration before inserting soft contact
lenses.
●​ Contraindication: Patients with marked renal impairment should not take CAIs (applies
to topical and systemic formulations).
●​ Children: Brinzolamide and methazolamide not recommended for children.

6. Rho Kinase Inhibitor

●​ Netarsudil (Rhopressa): Newest glaucoma drug (approved 2017).

●​ Mechanism: Decreases IOP by increasing aqueous humor outflow through trabecular
meshwork (exact mechanism unknown).
●​ Dosing: 1 drop daily of 0.02% solution.
●​ Adverse Effects: Few known other than eye discomfort (in part from benzalkonium
chloride). Subconjunctival hemorrhage may occur (visually disturbing, not serious).
●​ Children: Not recommended for children.

D. Patient Education (Glaucoma)

●​ Adherence: Take prescribed medications on schedule; skipping/not refilling can lead to

vision loss.
●​ Report Symptoms: Notify provider immediately for vision loss, severe eye pain,
headache, nausea/vomiting (could indicate angle-closure glaucoma).
●​ Photophobia: Sunglasses, wide-brimmed hat outdoors.
●​ Miotics: May cause blurred vision, poor night vision, difficulty focusing for near vision.
Assess for cholinergic effects (wheezing, slowed HR, decreased BP, urinary urgency,
diarrhea, excessive salivation/perspiration).
 ●​ Minimizing Eye Discomfort: Artificial tears (not within 30 min of drug admin), warm
compresses.

E. Summary of Key Prescribing Considerations (Glaucoma)

●​ Therapeutic Goal: Reduce IOP to prevent optic nerve damage and preserve vision.
●​ Baseline Data: Visual acuity, IOP, visual fields, optic disc appearance. Thorough history
for risk factors and contraindications.
●​ Monitoring: IOP, visual fields, optic disc changes. Adverse effects.
●​ Identifying High-Risk Patients: History of medication nonadherence (risk for
permanent visual deficits). History of heart failure, bradycardia, heart block, asthma,
obstructive pulmonary disease (poor candidates for β-blocker therapy).
●​ Evaluating Therapeutic Effects: Periodic evaluations compared with baseline data. May
refer for specialty evaluation.
●​ Minimizing Adverse Effects: All agents can cause eye discomfort/itching. Artificial
tears (not within 30 min of drug admin) may help. Warm compresses.

III. Allergic Conjunctivitis (AC)

●​ Pathophysiology: Inflammation of conjunctiva from allergen exposure. Symptoms:

itching, burning, thin watery discharge, occasionally red eyes.
●​ Treatment Modalities:
○​ Mild Symptoms (intermittent/short-lived pruritus): OTC artificial tears,
topical ophthalmic decongestants/antihistamines.
○​ Moderate Symptoms (mild-severe pruritus, few days-2 weeks, no redness):
H1-receptor blockers with mast-cell stabilizing properties, NSAIDs,
glucocorticoids.
○​ Severe Symptoms (moderate-severe pruritus, chronic, with redness):
Prescribed H1-receptor blockers with mast-cell stabilizing properties, oral
antihistamines.
●​ Topical Ophthalmic Decongestants: Constrict dilated conjunctival blood vessels, reduce
redness. Prolonged use (>2 weeks) can cause rebound congestion.
●​ Mast-Cell Stabilizers: Take several days for symptom relief, several weeks for maximal
benefit. Should not be abandoned prematurely.
●​ H1-Receptor Blockers with Mast-Cell Stabilizing Properties: Examples: Alcaftadine,
Azelastine, Epinastine, Ketotifen, Olopatadine, Bepotastine.
●​ NSAIDs: Ketorolac tromethamine.
●​ Glucocorticoids: Loteprednol etabonate, Dexamethasone sodium phosphate,
Fluorometholone, Prednisolone acetate/sodium phosphate.
●​ Patient Education (Topical Drugs for Allergic Conjunctivitis):
 ○​ Mast-cell stabilizers: Don't abandon prematurely; take days for relief, weeks for
max benefit.
○​ Oral antihistamines: May cause eye dryness; artificial tears/lubricants help.
○​ Artificial tears: Help flush allergens, available OTC.
○​ Cold compresses: For severe discomfort.
○​ Avoid rubbing eyes and wearing contact lenses (worsens symptoms).
○​ Notify provider if symptoms worsen or no relief after 2 weeks (may indicate other
problem).
○​ Benzalkonium chloride (common preservative): Absorbed by soft contact lenses.
Wait 15 min between drops and lens insertion.

IV. Topical Drugs for Eye Infections

●​ Use: Treating viral/bacterial eye infections, preventing infection after ocular surgery. Not
needed for most minor ocular irritations.
●​ Antivirals: Trifluridine, Ganciclovir (pharmacology in Chapter 80).
●​ Antibacterial Drugs: Fluoroquinolones (Ciprofloxacin, Gatifloxacin, Levofloxacin,
Moxifloxacin, Ofloxacin), Macrolides (Azithromycin, Erythromycin), Aminoglycosides
(Gentamicin, Tobramycin).
●​ Glucocorticoids: Increased risk for infection due to immunosuppression. Symptoms
similar to inflammatory disorders; consult ophthalmologist to verify no underlying
viral/fungal infection (can cause permanent vision loss).

V. Dyes for Evaluation of Eye Problems

●​ Fluorescein: Water-soluble dye, produces intense green color.

○​ Topical: Detects corneal epithelial lesions (abrasions/defects turn bright green).
Assesses aqueous humor flow.
○​ Intravenous: Facilitates visualization of retinal blood vessels (evaluates diabetic
retinopathy, retinal vascular abnormalities). Assesses aqueous humor flow.
○​ Adverse Effects (systemic): Nausea, vomiting, paresthesias, pruritus. Severe
reactions (anaphylaxis, pulmonary edema, cardiac arrest) rare.
●​ Rose Bengal: Topical, visualizes corneal and conjunctival epithelium abrasions (injured
tissue appears rose colored with slit lamp). Used for diagnosis of dry eyes.

Chapter 88: Drugs for the Skin

This chapter covers the pharmacology of topical glucocorticoids, keratolytic agents, drugs for
acne, sunscreens, drugs for atopic dermatitis, wart removal agents, and other miscellaneous skin
conditions.

I. Skin Anatomy and Function

●​ Epidermis: Outer layer of skin.

○​ Basal Layer: Contains germinal cells (produce new cells) and melanocytes
(produce melanin, determines skin color, protects against UV radiation).
○​ Stratum Corneum (Cornified Layer): Outermost layer. Older cells pushed
outward, die, cytoplasm converted to keratin (hard, proteinaceous material).
Rough, horny texture. Undergoes continuous exfoliation (shedding).

II. Drug Vehicles

●​ Lotions: Water-based, may contain alcohol/acids (can cause burning). Little/no oil,
lighter feel than creams, nongreasy (promotes patient satisfaction). Easy to spread (good
for large/hairy areas, intertriginous areas). Suitable for oily skin, may decrease oiliness.
●​ Gels: Transparent, water or alcohol base, usually contain cellulose. Liquefy on skin
contact, often cooling effect as they dry. Nongreasy, drying effects (good for oily skin).
Spread easily (good for large/hairy areas). Dry clear/invisible (more acceptable for facial
regions). May cause burning.

III. Topical Glucocorticoids

●​ Relative Potency: Classified from super-high to least potency (see Table 88.1).
●​ Factors Affecting Response: Concentration, inherent activity, vehicle, method of
application.
●​ Occlusive Dressings: Enhance percutaneous absorption by as much as 10-fold, greatly
increasing pharmacologic effects.
●​ Systemic Absorption: Can be absorbed into systemic circulation.
●​ Application: Apply in thin film, gently rub into skin. Do not use occlusive dressings
unless instructed by prescriber. Avoid tight-fitting diapers/plastic pants when applying to
diaper region of infants/adults.

IV. Keratolytic Agents

●​ Definition: Drugs that promote shedding of the stratum corneum. Used for conditions
with overgrowth or abnormal thickening of skin.
●​ Effects: Range from peeling to extensive desquamation.
●​ Compounds: Salicylic acid and sulfur. Other keratolytic drugs discussed under "Topical
Drugs for Acne".
 ●​ Salicylic Acid: Promotes desquamation by dissolving intracellular cement binding scales
to stratum corneum.

V. Drugs for Acne

●​ Pathophysiology: Chronic skin disorder, usually begins in puberty, more common/severe

in males. Lesions typically on face, neck, chest, shoulders, back.
○​ Mild Acne: Open comedones (blackheads) most common (sebum + keratin plug,
exposed surface black from oxidation). Closed comedones (whiteheads) when
pores blocked below skin surface.
○​ Severe Acne: Abscesses, inflammatory cysts.
○​ Improvement after puberty, clears in early 20s for some, persists for decades in
others.
○​ Initiated by increased androgen production during adolescence, leading to
increased sebum production and follicular turnover.
●​ Management:
○​ Mild Acne: Topical antibiotics, topical retinoids.
○​ Moderate Acne: Oral antibiotics (doxycycline, minocycline), comedolytics
(retinoids, azelaic acid). Hormonal agents (combination OCs, spironolactone) for
young women unresponsive to other drugs.
○​ Severe Acne: Isotretinoin.

A. Topical Drugs for Acne

1. Antibiotics

●​ Benzoyl Peroxide: First-line for mild-moderate acne. Antibiotic and keratolytic.

○​ Mechanism: Suppresses P. acnes (via active oxygen release), reduces
inflammation, promotes keratolysis. Does not promote resistance.
○​ Adverse Effects: Drying, peeling skin. Reduce frequency for severe local
irritation (burning, blistering, scaling, swelling). Potentially serious
hypersensitivity reactions (especially in asthma patients). Health Canada warning
issued 2015.
●​ Clindamycin and Erythromycin: Suppress P. acnes, decrease inflammation.
Monotherapy leads to resistance.
●​ Dapsone (Aczone): Thin film once or twice daily. Use with benzoyl peroxide can
discolor skin yellow-orange. Slight risk of hematologic effects with topical use in patients
with glucose 6-phosphate dehydrogenase (G6PD) deficiency.

2. Retinoids (Derivatives of Vitamin A)

 ●​ Role: Cornerstone of acne therapy. Unplug existing comedones, prevent new ones.
Reduce inflammation, improve penetration of other topical agents.
●​ Approved for Acne: Tretinoin, adapalene, tazarotene. Alone or with other
antimicrobials. Adapalene first OTC topical retinoid for acne (12+ years).
●​ Tretinoin (Atralin, Avita, Retin-A, Retin-A Micro): Also for fine wrinkles. Not to be
confused with isotretinoin.
○​ Adverse Effects: Increases susceptibility to sunburn. Warn patients to use SPF
15+ sunscreen and wear protective clothing. Do not apply to existing sunburn.
●​ Adapalene (Differin): Modulates inflammation, epithelial keratinization, follicular cell
differentiation. Reduces comedone/inflammatory lesion formation. Benefits in 8-12
weeks. May exacerbate acne initially by affecting invisible lesions.
●​ Tazarotene (Avage, Fabior, Tazorac): For topical therapy.

3. Keratolytics (Other than Salicylic Acid)

●​ Azelaic Acid (Azelex, Finacea): 20% cream (approved for acne). 15% gel/foam
approved for rosacea. Apply twice daily, decrease to once for excessive irritation.
Improvement within 4 weeks.

B. Oral Drugs for Acne

1. Antibiotics

●​ Used for moderate to severe acne. Suppress growth of​

P. acnes and reduce inflammation.
●​ Examples: Doxycycline, minocycline, erythromycin, tetracycline,
trimethoprim/sulfamethoxazole, azithromycin.
●​ Adverse Effects: Most common: GI upset, candidal vaginitis. Doxycycline can cause
esophageal ulceration (take with full glass of water, remain upright for 20-30 min).
●​ Resistance: Widespread development of resistance. Should be combined with topical
benzoyl peroxide to minimize resistance development. Use for shortest duration possible.

2. Isotretinoin (Absorica, Amnesteem, Claravis, Myorisan, Zenatane)

●​ Severe Acne: Principal agent for severe nodulocystic acne. Highly effective, produces
prolonged remission.
●​ Black Box Warning: High risk of severe structural/cognitive defects in developing fetus.
Increased risk for spontaneous abortion.
●​ Mechanism: Reduces sebum production, sebaceous gland size, inflammation, and
keratinization.
●​ Adverse Effects:
○​ Physical: Nosebleeds (80%), lip inflammation (90%), eye inflammation (40%),
dry/itchy skin/nose/mouth (80%). Muscle/bone/joint pain/stiffness (15%). Back
 pain in ~30% pediatric patients. Premature epiphyseal closure (for those still
growing). Skin rash, headache, hair loss, peeling of palms/soles. Reduced night
vision (sometimes sudden onset). Skin sensitized to UV light (increased sunburn
risk).
○​ CNS/Psychiatric: May cause depression, suicidal ideation. Rarely psychosis,
aggression, violent behavior. Monitor for mood changes.
○​ GI: Inflammatory bowel disease (IBD) rare. Monitor for new/worsened
abdominal pain, diarrhea, rectal bleeding.
○​ Other: Elevated triglycerides (up to 45% of patients); monitor lipid levels. Liver
dysfunction (rare, monitor liver enzymes).
●​ Drug Interactions: Effects increased by tetracyclines and vitamin A. Tetracyclines
increase intracranial pressure.
●​ iPLEDGE Program: Risk Management Program required by FDA due to teratogenicity.
Strict requirements for prescribers, patients, pharmacies.
○​ Patients (females of child-bearing potential):
■​ Must use​
two effective forms of birth control (even if one is tubal ligation or male
vasectomy).
■​ Review educational material on contraception, failure reasons, importance
of effective contraception.
■​ Contraception 1 month before, during, and 1 month after treatment.
■​ Sign Patient Information/Informed Consent document.
■​ Register with iPLEDGE, contact monthly during treatment, 1 month after
stopping.
■​ Pregnancy test (at least 2 negative before starting, monthly during, 1
month after).
■​ Can't donate blood while taking or for 1 month after stopping.
■​ Avoid vitamin A supplements, alcohol.
■​ Avoid cosmetic skin procedures (waxing, laser, dermabrasion) during
treatment and up to 6 months after (scarring risk).
■​ Report severe headaches, vision changes (other than decreased night
vision), vomiting, weakness, seizures (signs of increased brain pressure).
■​ Report depression symptoms or thoughts of harming self/others.
■​ Report problems with erection.
●​ Minimizing Adverse Effects: Avoid prolonged sun exposure. If night vision decreased,
increase ambient light, avoid night driving. Discontinue if: pregnancy occurs,
depression/aggression/mood disturbance, papilledema/pseudotumor cerebri signs (refer to
neurologist), hepatitis/elevated liver enzymes not normalizing, significant uncontrolled
hyperlipidemia.

3. Hormonal Agents (for acne in young women)

 ●​ Mechanism: Decrease androgen activity, leading to decreased sebum production.
●​ Combination OCs: Four approved for acne: Estrostep, Ortho Tri-Cyclen, Beyaz, YAZ.
Limited to females 15+ who want contraception.
●​ Spironolactone: Also reduces androgen activity.

C. Patient-Centered Care Across The Life Span (Antiacne Drugs)

●​ Children: Retinoids not recommended <12 years (except Atralin for 10+). Benzoyl
peroxide, sulfacetamide, dapsone, azelaic acid, salicylic acid recommended for 12+.
Hormone therapy not for prepubertal children.
●​ Pregnant Women: Benzoyl peroxide and topical salicylic acid preferred (OTC).
Retinoids are teratogens (verify absence of pregnancy). Oral/topical dapsone associated
with neonatal complications (hyperbilirubinemia, methemoglobinemia, hemolysis).
Animal studies suggest azelaic acid may have adverse effects, but systemic absorption is
minimal.

VI. Sunscreens

●​ Solar UV Radiation: UVA (95%, penetrates epidermis/dermis, primary cause of

immunosuppression, photosensitive drug reactions, photoaging) and UVB (penetrates
epidermis, primary cause of tanning/sunburn). Both promote DNA damage, can cause
pre-malignant/malignant skin cancers.
●​ Benefits: Impede UV penetration to skin cells, protect against harmful effects.
●​ Sun Protection Factor (SPF): Indicates protection against UVB. SPF 15 (93% block),
SPF 30 (96.7%), SPF 40 (97.5%). FDA no longer allows advertising high SPF values
(>50 labeled as SPF 50+) due to diminishing returns.
●​ Range of UV Protection:
○​ All sunscreens protect against UVB; some protect against UVA.
○​ Broad spectrum: Protects against UVA and UVB.
■​ Highly protective: Broad-spectrum with SPF 15+ (protects against
sunburn, skin cancer, photoaging).
■​ Moderately protective: Broad-spectrum with SPF 2-14 (protects against
sunburn, not skin cancer/photoaging).
●​ Other Sun Protection Actions: Wear sunglasses, protective clothing, wide-brimmed hat.
Avoid sun exposure midday (10 AM - 4 PM). Stay in shade when outdoors.

VII. Drugs for Atopic Dermatitis (Eczema)

●​ Characteristics: Chronic inflammatory skin disease. Dry, scaly skin, intense pruritus
(leads to scratching/rubbing, erythema, abrasions, rash, erosions with exudate, increased
infection susceptibility). Continued scratching leads to lichenification. Underlying cause:
abnormal T lymphocyte activity.
 ●​ First-line Therapy: Moisturizers (e.g., Cetaphil Moisturizing Cream).
●​ Topical Immunosuppressants:
○​ Tacrolimus ointment (Protopic):
■​ Cancer Risk Concern: Increases skin cancer in animals exposed to UV
light, increases lymphoma in mice. Human cases of skin cancer/lymphoma
reported, but causal link not established.
■​ Minimize Risk: Protect treated areas from direct sunlight, avoid
sunlamps/tanning beds.
■​ Concentrations: 0.03% and 0.1%. Adults can use either. Children 2-16
years use 0.03%. Not for children <2 years.
■​ Application: Thin layer twice daily. Avoid occlusive dressings.
Intermittent or short-term treatment.
○​ Pimecrolimus cream (Elidel): 1% cream, for mild-moderate atopic dermatitis.
Very similar to tacrolimus.
○​ Crisaborole ointment (Eucrisa): Novel agent. Inhibits phosphodiesterase type 4
(PDE4), reduces cytokines and skin inflammation. Apply thin layer twice daily.
■​ Adverse Effects: Generally well tolerated. Most common: burning,
stinging at application site. Hypersensitivity reactions (contact urticaria)
occurred.

VIII. Agents for Wart Removal

●​ Warts: Small, benign growths on skin/mucous membranes, caused by Human

Papillomavirus (HPV) infection (~100 types). Most resolve spontaneously, some last
years.
●​ Venereal Warts (Condyloma acuminatum): Form around cervix, vulva, urethra, glans
penis, anus.
●​ Treatment Approaches: Drugs (provider-administered or home-applied), cryotherapy,
surgical excision. Repeated application until warts disappear.
●​ Prevention: Gardasil 9 vaccine (protects against HPV-6, -11 causing 90% venereal warts;
and HPV-16, -18 causing 70% cervical cancers).

A. Provider-Applied Drugs

●​ Podophyllin (podophyllum resin): For perianal and venereal warts (not effective for
common warts). Active ingredient podophyllotoxin (inhibits DNA synthesis/mitosis,
leads to cell death/wart erosion).
○​ Preparation: 25% podophyllum resin. Highly caustic, apply only by trained
clinician.
 ○​ Toxicity Prevention: Wash off with alcohol/soap and water a few hours after
application (to minimize systemic absorption). Limit to small surface area/few
warts.
○​ Systemic Toxicity: Can be absorbed sufficiently to cause CNS/peripheral
neurotoxicity, bone marrow suppression, kidney damage, liver damage, paralytic
ileus. Avoid in pregnancy.

B. Patient-Applied Drugs (Home Use)

●​ Imiquimod cream (Zyclara, Aldara):

○​ Formulations: 3.75% (Zyclara) applied once daily for up to 8 weeks; 5%
(Aldara) applied 3 times/week for up to 16 weeks.
○​ Application: At bedtime, washed off in morning.
●​ Podofilox (Condylox): Inhibits mitosis.
○​ Preparation: 0.5% gel or solution.
○​ Application: Twice daily for 3 consecutive days, followed by 4 days off. Repeat 4
times or until warts gone. Wash hands before/after.​
Does not need to be washed off application site.
○​ Adverse Effects: Local inflammation, burning, erosion, pain, itching, bleeding
common. Minimize by limiting application area/number of warts.

IX. Drugs for Miscellaneous Skin Conditions

A. OnabotulinumtoxinA (Botox) for Nonsurgical Cosmetic Procedures

●​ Mechanism: Acetylcholine release inhibitor, neuromuscular blocking agent. Protein from​

Clostridium botulinum. Doses for cosmetic use are too small to cause botulism toxicity.
●​ Products: Botox (approved for various uses), Botox Cosmetic (approved only for frown
lines).
●​ Application (frown lines): Five injections into specific muscles (corrugator, procerus).
Procedure takes minutes.
●​ Results: Not instantaneous or permanent. Muscle paralysis develops slowly (3-10 days),
fades in 3-6 months. Injections can be repeated to maintain benefits (at least 3 months
between treatments). No data on long-term effects.
●​ Adverse Effects:
○​ Black Box Warning: Spread of toxin from injection site leading to
life-threatening injuries (not observed with small cosmetic doses).
○​ Cosmetic Treatment AEs: Headache, facial pain, swelling, bruising (most
common). Swelling/bruising reduced by applying ice.

B. Seborrheic Dermatitis
 ●​ Characteristics: Chronic inflammatory skin condition (face, scalp, trunk). Symptoms
from inflammatory reaction to​
Malassezia (yeast) infection.
●​ Treatment:
○​ Acute: Topical ketoconazole (antifungal active against yeast). Available as 2%
cream, foam, gel, 1-2% shampoos. Cream/foam twice daily for 4 weeks. Gel once
daily for 2 weeks. Concurrent topical glucocorticoids can accelerate initial
response.
○​ Maintenance: Periodic use of yeast-suppressing shampoo (ketoconazole,
pyrithione zinc, selenium sulfide).

C. Drugs for Hair Loss

1. Minoxidil (Rogaine)

●​ Use: Promotes hair growth, delays hair loss (topical).

●​ Adverse Effects: Generally devoid of AEs. Few report pruritus, local allergic responses
(rash, swelling, burning). Systemic reactions (hypotension, headache, flushing) rare due
to low absorption.

2. Finasteride (Propecia)

●​ Use: Androgenic alopecia (male-pattern baldness). Also for BPH (Proscar, 5-mg tablets).
●​ Mechanism: Male-pattern baldness caused by DHT (dihydrotestosterone) in scalp.
Finasteride inhibits enzyme converting testosterone to DHT, promoting hair growth.
1-mg dose reduces serum DHT by 65% in 24 hours.
●​ Response: Benefits develop slowly (4-8 weeks or more), fade within 8 weeks of
stopping.

D. Eflornithine (Vaniqa)

●​ Use: Topical treatment for unwanted facial hair in women.

●​ Effects: Slows hair growth, causes hair to be finer/lighter, decreases need for shaving
(does not remove hair entirely). Requires continuous treatment.
●​ Absorption: Very little systemic absorption (~1%). Eliminated intact in urine, no
metabolism.
●​ Adverse Effects: Generally well tolerated. Transient stinging, burning, tingling, or rash
at application site (most common). Some concern about possible fetal harm.

X. Local Anesthetics

●​ Examples: Benzocaine, lidocaine, pramoxine.

 ●​ Use: Applied topically to relieve pain and itching associated with various skin disorders
(sunburn, plant poisoning, fungal infection).

Chapter 89: Drugs for the Ear

This chapter discusses drugs used to treat disorders of the middle and external ear, focusing on
otitis media (OM) and otitis externa (OE).

I. Otitis Media (OM) and Its Management

●​ Definition: Inflammation of the middle ear.

●​ Prevalence: Most prevalent disorder of childhood. Affects >75% of children by 3 years,
~95% by 12 years. Most common reason antibiotics are prescribed for children.
●​ Causes: Bacterial or viral infection, or noninfectious causes. Only bacterial OM responds
to antibiotics. Most cases resolve spontaneously.

A. Acute Otitis Media (AOM)

●​ Definition: Infection of the middle ear.

●​ Microbiology:
○​ Streptococcus pneumoniae (33%).
○​ Haemophilus influenzae (27%).
○​ Moraxella catarrhalis (22%).
○​ Others (e.g.,​
Streptococcus pyogenes, Staphylococcus aureus).
○​ No bacteria found in 10-30%.
○​ Both bacteria and viruses in 66%; viruses alone in 4%.
●​ Diagnosis: Three elements must be present:
○​ Acute onset of signs/symptoms.
○​ Middle ear effusion (MEE) or purulent otorrhea if TM ruptured. MEE indicated
by bulging TM with limited mobility, best predictor of AOM.
○​ Middle ear inflammation (distinct TM erythema or distinct otalgia). TM erythema
alone is unreliable as indicator.
●​ Distinguish from Otitis Media with Effusion (OME): OME has MEE but no
signs/symptoms of acute infection.
●​ Treatment Approach:
○​ Observation vs. Antibiotics: Most AOM episodes resolve spontaneously.
Immediate antibacterial therapy is only marginally superior for resolution and no
 better for pain relief. Observation approach is acceptable to parents. Delaying
antibiotics does not significantly increase mastoiditis risk.
○​ Criteria for Antibiotics (Table 89.2):
■​ Children <6 months: All receive antibiotics, regardless of
certainty/severity.
■​ Children 6 months - 2 years: Antibiotics indicated if diagnosis is certain.
■​ Children 2+ years: Antibacterial therapy only if diagnosis certain and
symptoms severe.
■​ In all other cases, observation.
○​ First-Line Antibiotics (Nonsevere Illness):
■​ Amoxicillin, 90 mg/kg per day in two divided doses.
■​ Alternative if penicillin allergy (non-type I): Cefdinir, Cefuroxime,
Cefpodoxime.
■​ Alternative if type I penicillin allergy: Azithromycin or Clarithromycin.
○​ First-Line Antibiotics (Severe Illness): Amoxicillin (45 mg/kg bid) +
clavulanate (3.2 mg/kg bid), OR Ceftriaxone 50 mg/kg IM for 1 or 3 days.
○​ Persistent Symptoms After Observation (48-72h): Same as for immediate
antibiotic therapy.
○​ Persistent Symptoms After Antibiotic Therapy (48-72h, indicates resistance):
■​ Nonsevere illness: Amoxicillin + clavulanate.
■​ Non-type I allergy: Ceftriaxone IM or IV for 3 days.
■​ Type I allergy: Clindamycin (plus third-generation cephalosporin if
non-type I allergy) and tympanocentesis.
●​ Pain Management: Must be included.
○​ Mild-moderate pain: Acetaminophen or ibuprofen.
○​ Moderate-severe pain: Codeine or similar drugs may be needed.
○​ Topical Anesthetic (for children >5 years): Procaine or lidocaine drops (fill EAC,
use solution-soaked cotton pledget). Repeated every 1-2 hours.​
Contraindicated if TM is perforated.
●​ Prevention:
○​ Breastfeeding for at least 6 months.
○​ Avoid child care centers when respiratory infections prevalent (if possible).
○​ Eliminate exposure to tobacco smoke.
○​ Reduce pacifier use in second 6 months of life.
○​ Avoid supine bottle feeding.
○​ Prevention and treatment of influenza.
○​ Vaccination against pneumococcal infection.
○​ Tympanostomy tubes: Permit drainage/aeration of middle ear. Reduce AOM
episodes in children with recurrent AOM. Complications: obstruction, secondary
infection, premature extrusion.
 ●​ Otic Preparations (vs. Oral): Advantages: go directly to infection source (high local
concentration), decreased systemic absorption (less adverse effects), less likely to
contribute to resistance. Most contraindicated if TM is perforated.

II. Otitis Externa (OE) and Its Management

●​ Definition: Also known as "swimmer's ear". Bacterial infection of the external auditory
canal (EAC).
●​ Most Common Pathogens: Pseudomonas aeruginosa, Staphylococcus aureus. Others:​
Staphylococcus epidermidis, Microbacterium otitidis.
●​ Symptoms: Rapid-onset ear pain, pruritus, ear fullness sensation, tenderness on
manipulation of external ear, edema/erythema of EAC. Impaired hearing, purulent
discharge may occur.
●​ Predisposing Factors: Abrasion and excessive moisture. Abrasion from
cleaning/scratching EAC (cotton-tipped swab, foreign object, hearing aids, earplugs).
Moisture washes away protective cerumen.
●​ Treatment:
○​ Mild Cases: 2% acetic acid solution (safe, effective, inexpensive). Alcohol +
acetic acid promotes tissue drying. Acidification and drying may be sufficient.
○​ More Extensive Infection: Topical antibiotic.
■​ Past Standard: Hydrocortisone + neomycin + polymyxin B
(hydrocortisone reduces inflammation/edema, neomycin/polymyxin kill
bacteria). Drawbacks: neomycin is ototoxic, causes local
swelling/erythema in ~15%.
■​ Preferred Today: Quinolones (e.g., ciprofloxacin) are highly effective
and safe for perforated TMs.
○​ Prevention:
■​ Dry EAC after swimming/showering by toweling, tipping head, pulling
auricle.
■​ Don't remove cerumen (earwax).
■​ Don't use earplugs (except when swimming).

B. Necrotizing Otitis Externa (NOE)

●​ Definition: Rare but potentially fatal complication of AOE. Bacteria invade mastoid or
temporal bone.
●​ Spread: To skull base (cranial nerves affected), dura mater (meningitis, lateral sinus
thrombosis).
●​ Usual Pathogen: P. aeruginosa.
●​ Symptoms: Progressive severe otic pain, purulent discharge from ear, granulation of
tissue in EAC.
 ●​ High-Risk Groups: Older people with diabetes, immunocompromised individuals
(especially HIV infection).
●​ Treatment: All patients receive antipseudomonal ear drops. Systemic therapy or referral
indicated if infection spread beyond EAC. Systemic therapy or combination
systemic/topical therapy for patients with diabetes or immune deficiencies.

III. General Prescribing Considerations for Ear Drugs

●​ Recurrent AOM: Consider referral to otolaryngologist if 3+ episodes in 6 months or 4+

in past year. Tympanostomy tubes may be indicated, especially if hearing loss is a
concern.
●​ TM Status: If TM not intact, avoid ototoxic drops (e.g., aminoglycoside preparations).
Prescribe quinolone or quinolone/glucocorticoid combination (safe for perforated TMs).
●​ AOE with swollen canal: Insert a wick to ensure medication reaches affected tissues.
●​ Evaluating Therapeutic Effects: Patients with both AOM and AOE should have
improvement in 48-72 hours. Instruct them to return if no improvement