Reproductive System Module

Reproductive System Module
By: Tadesse B. (PhD)

Contents
• Pharmacology of androgens and other anabolic steroids (1 hr)
• Pharmacology of agents used for treatment of sexual and

reproductive tract infections (2 hrs)
• Pharmacology of uterotonics, abortifacients, uterine relaxants,

and drug used in pregnancy (2 hrs)
• Pharmacology of contraceptives (2 hrs)
Tadesse B. (PhD) 2
Pharmacology of Androgens And
Other Anabolic Steroids
Tadesse B. (PhD) 3
Introduction
• Androgen hormones are produced by the testes, ovaries, and
adrenal cortex.
• The major endogenous androgen is testosterone.
– The testosterone precursors androstenedione & dehydroepiandrosterone
(DHEA) are weak androgens that can be converted peripherally to
testosterone
• Other androgens include: Dihydrotestosterone (DHT), and DHEA
sulfate (DHEA-S)
• Testosterone are present in much higher levels in men and play an
important role in male traits and reproductive activity.
• Androgens are noted most for their ability to promote expression
of male sex characteristics.
– However, androgens also influence sexuality in females.
– In addition, androgens have significant physiologic and pharmacologic
effects unrelated to sexual expression or function.
Tadesse B. (PhD) 4
Introduction…
• The primary clinical application of the androgens is
management of androgen deficiency in males
• Androgens are a class of drugs used to treat symptoms of
low testosterone in adult men who have
– Hypogonadism (a condition in which the body does not
produce enough natural testosterone) in males and
– Metastatic breast cancer in females
• Leydig cells synthesize the majority of testosterone by the
pathways shown in Figure 1.
• In women, testosterone also is the principal androgen and is
synthesized in the corpus luteum & the adrenal cortex by
similar pathways.
Tadesse B. (PhD) 5
Fig 1. Pathway of synthesis of testosterone in the Leydig cells of the testes. In Leydig cells, the 11 and 21
hydroxylases (present in adrenal cortex) are absent, but CYP17 (17α-hydroxylase) is present. Thus,
androgens and estrogens are synthesized; corticosterone and cortisol are not formed. Bold arrows
indicate favoured pathways.
Tadesse B. (PhD) 6
Metabolism of Testosterone
• Testosterone has many different effects in
tissues, both directly and through its
metabolism to dihydrotestosterone and
estradiol (Figure 2).
– 5α-reductase catalyzes the conversion of
Testosterone to dihydrotestosterone.
• Dihydrotestosterone binds to the androgen
receptor with higher affinity than testosterone
and activates gene expression more efficiently.
– Aromatase catalyzes the conversion of
testosterone to estradiol.
• Hepatic metabolism converts testosterone to

the biologically inactive compounds
androsterone & etiocholanolone (Figure 2).
• Dihydrotestosterone is metabolized to
androsterone, androstanedione, and
androstanediol.
Fig 2 Metabolism of testosterone to its
major active and inactive metabolites
Tadesse B. (PhD) 7
Classification of Androgens
• Substances which cause secondary sex characteristics in male
• Natural Androgens:
– From Testes:
• Testosterone (secretes 5-12 mg daily that is synthesized from cholesterol)
• Dihydrotestosterone (more active): converted from Testosterone by 5 -
reductase
– From Adrenal Cortex: (Weak Androgens)
• Dihydroepiandrosterone
• Androstenedione
• Female Testosterone: 0.25-0.5 mg/day (Ovary + adrenals)
• Androsterone- metabolite of testosterone
• Synthetic Androgens:
– Methyltestosterone & Fluoxymesterone are 17-alkyl derivatives of
Testosterone
• Orally active, have submaximal efficacy and potential to cause cholestatic
jaundice
– Propionate and enanthate
– Testosterone undecanoate and Mesterolone (orally active)
Tadesse B. (PhD) 8
Physiological and Pharmacological Effects of Androgens
• Testosterone is the
principal circulating
androgen in men.
• At least three mechanisms
contribute to the varied
effects of testosterone:
– Direct binding to the
Androgen receptor (AR);
– Conversion to
dihydrotestosterone,
which also binds to the
AR; and
– Conversion to estradiol, Fig 3. Direct effects of testosterone & effects
which binds to the mediated indirectly via dihydrotestosterone or
estrogen receptor (Figure estradiol
3).
Tadesse B. (PhD) 9
Physiological and Pharmacological Effects of Androgens…
Actions and Effects

• Sex organs and secondary sex characters:
• Testosterone is responsible for all the changes that
occur in a boy at puberty:
• Growth of genitals
• Growth of hair
• Larynx grows and voice deepens
• Behavioural effects like increased physical vigour,
aggressiveness, etc.
Tadesse B. (PhD) 10
• Testes: Testosterone is responsible for spermatogenesis and

maturation of spermatozoa
• Skeleton and skeletal muscle (Anabolic)
• Testosterone is responsible for pubertal growth in boys and to a smaller
extent in girls
• Testosterone also promotes muscle building if aided by exercise
• Erythropoiesis: Testosterone accelerates erythropoiesis by
increasing erythropoietin level
• CNS: Feedback control of follicle stimulating hormone
(FSH) and Luteinizing hormone (LH) with inhibin-B and
activin; increase in libido; aggressiveness
• In Females: suppression of ovulation, irregular menstruation,
Hirsutism, deepening of voice, frontal baldness, enlargement of
clitoris and prominent musculature
Tadesse B. (PhD) 11
Consequences of Androgen Deficiency

• The consequences of androgen deficiency depend on the
stage of life during which the deficiency first occurs and
on the degree of the deficiency.
During Fetal Development
• Testosterone deficiency:
– In a male fetus during the first trimester in utero causes
incomplete sexual differentiation.
– Complete deficiency of testosterone secretion results in
entirely female external genitalia.
– It also leads to failure of the Wolffian ducts or
mesonephric ducts to differentiate into the male internal
genitalia
Tadesse B. (PhD) 12
Consequences of Androgen Deficiency
During Fetal Development…
• Similar changes occur if testosterone is secreted normally, but its action
is diminished due to an abnormality of the AR or of the 5α-reductase
• Abnormalities of the AR can have quite varied effects.
– Most severe form: results in complete absence of androgen action and a
female phenotype;
– Moderately severe forms: result in partial virilization of the external genitalia;
&
– Mildest forms: permit normal virilization in utero and result only in impaired
spermatogenesis in adulthood
• Abnormal 5α-reductase
– Results in incomplete virilization of the external genitalia in utero but normal
development of the male internal genitalia, which requires only testosterone
• Testosterone deficiency during the third trimester impairs phallus growth.
– The result, microphallus, is a common occurrence in boys later discovered to be
unable to secrete LH due to abnormalities of GnRH secretion or action.
– In addition, the testes fail to descend into the scrotum; this condition,
cryptorchidism, occurs commonly in boys whose LH secretion is subnormal
Tadesse B. (PhD) 13
Consequences of Androgen Deficiency…
Before Completion of Puberty
• When a boy can secrete testosterone normally in utero but
loses the capacity to do so before the anticipated age of
puberty, the result is failure to complete puberty.
• All of the pubertal changes including those of the external
genitalia, sexual hair, muscle mass, voice, and behaviour, are
impaired .
• In addition, if growth hormone secretion is normal when
testosterone secretion is subnormal during the years of
expected puberty,
– The long bones continue to lengthen because the epiphyses
do not close.
• The result is longer arms and legs relative to the trunk.
– Enlargement of glandular breast tissue, called gynecomastia.
Tadesse B. (PhD) 14
After Completion of Puberty
• When testosterone secretion becomes impaired after puberty
(e.g., castration or antiandrogen treatment), regression of the
pubertal effects of testosterone depends on both the degree and
the duration of testosterone deficiency.
• When the degree of testosterone deficiency is substantial,
– Libido and energy decrease within a week or two, but other
testosterone-dependent characteristics decline more slowly.
• A clinically detectable decrease in muscle mass in an individual
does not occur for several years.
• ↓ in hematocrit & hemoglobin will occur within several months
• ↓ in bone mineral density probably can be detected within 2
years, but an  in fracture incidence would not be likely to occur
for many years.
• A loss of sexual hair takes many years.
Tadesse B. (PhD) 15

In Women
• Loss of androgen secretion in women:
– Results in a ↓ in sexual hair, but not for many years.
– May also result in the loss of effects associated with
libido, energy, muscle mass and strength, and bone
mineral density (when the loss of androgens is
especially with the severe loss of ovarian and adrenal
androgens that occurs in panhypopituitarism)
• Panhypopituitarism: A rare condition in which the pituitary
gland stops making most or all hormones.
Tadesse B. (PhD) 16
Therapeutic Androgens & Other Anabolic Steroids
Preparations
• Ingestion of testosterone is not an effective means of replacing
testosterone deficiency due to the rapid hepatic catabolism.
• Most pharmaceutical preparations of androgens, therefore, are
designed to bypass hepatic catabolism of testosterone.
• Androgens Available for Therapeutic Use
– Testosterone
– Testosterone Esters
• Testosterone enanthate/undecanoate/cypionate
– 17α-Alkylated Androgens
• Methyltestosterone, oxandrolone, stanozolol,
Fluoxymesterone, danazol
– Other
• 7α-Methyl-19-nortestosterone, tetrahydrogestrinone
Tadesse B. (PhD) 17
Therapeutic Androgens & Other Anabolic Steroids…
Medication Route Dosage
Testosterone undecanoate Oral 40-80 mg up to three times/day
Buccal 30mg twice daily
Nasal spray 11mg three times daily
Transdermal (TD) gel 25-100mg/day
Testosterone TD patch 2.5-10mg/day
TD liquid 30-120mg/day
SC 150-600mg every 3-6 months
50-100mg once/week or
Testosterone enanthate IM, SC
100-250mg every 2-4 wks
50-100mg once/week or
Testosterone cypionate IM, SC
100-250mg every 2-4 wks
Testosterone isobutyrate IM, SC 50-100mg once/week
250mg every 2-3 wks or
Mixed testosterone esters IM, SC
500mg every 3-6 wks
Testosterone undecanoate IM, SC 750-1,000mg every 10-14 wks
Tadesse B. (PhD) 18
Fig 4. Pharmacokinetic profiles of testosterone preparations during chronic administration to
hypogonadal men. Doses of each were given at time 0. Shaded areas indicate range of normal
levels. Tadesse B. (PhD) 19
Mechanism of Action of Testosterone
• After binding of testosterone to its receptor, the
hormone-receptor complex migrates to the cell nucleus and
then acts on DNA to promote synthesis of specific
messenger RNA molecules.
• These, in turn, serve as templates for production of
specific proteins, which then mediate testosterone effects.
• It should be noted that in some tissues— prostate,
seminal vesicles, and hair follicles —androgen receptors
do not interact with testosterone itself.
– Rather, they interact with dihydrotestosterone, a
testosterone metabolite
Tadesse B. (PhD) 20
Pharmacokinetics
• Testosterone
– Inactive orally due to high first-pass metabolism
– Given as IM and has short duration of action
– 98% is bound to sex hormone binding-globulin and
to albumin
• Plasma t1/2 is 10-20 min.
• Methyltestosterone and fluoxytestosterone
– Metabolized slowly and have longer duration
Tadesse B. (PhD) 21
Therapeutic Uses of Androgens
• Hypogonadism (Male, Female):
– Primary or secondary respond to androgen treatment
• Hypopituitarism
• Improve libido:
– At low doses only
• Hereditary Angioneurotic Edema:
– Increase synthesis of complement esterase inhibitors
• AIDS related muscle wasting
• Aging:
– Improve bone mineralization
• Stimulate Erythrocyte Production-
– But replaced by recombinant erythropoietin
• For Osteoporosis-
– But replaced by bisphosphonates
Tadesse B. (PhD) 22
Therapeutic Uses of Androgens…
Tadesse B. (PhD) 23
Androgens …
Side Effects and Toxic Effects
• All androgens suppress gonadotropin secretion when taken in
high doses and thereby suppress endogenous testicular
function
• High doses of androgens also cause erythrocytosis
• Principal adverse effects are virilization and hepatotoxicity.
• Virilisation, menstrual irregularities in women
• Acne in males and females
• Oligozoospermia (A low sperm count), precocious puberty
with shortening of stature
• Cholestatic jaundice, hepatic carcinoma
• Lowering of HDL and rise in LDL is observed
• Anabolic steroid abuse (26-30 times more)
Tadesse B. (PhD) 24
Androgens …
Contraindication
• Lactating mother, Carcinoma of prostrate, Dysfunctional breast,
liver disease, kidney disease, CHF, Elder people, Migraine and
diabetes
• Use in Pregnancy
– Because of their ability to induce masculinization of the
female fetus, androgens are contraindicated during pregnancy.
– Potential fetal changes include vaginal malformation, clitoral
enlargement, and formation of a structure resembling the male
scrotum.
– Virilization is most likely when androgens are taken during the
first trimester.
– Women who become pregnant while using androgens should be
informed about the possible impact on the fetus.
• The ability to cause fetal harm outweighs any possible therapeutic benefit.
Tadesse B. (PhD) 25
Other Anabolic Steroids
• These are synthetic androgens with high anabolic and low androgenic
activity
• Anabolic steroids, also known more properly as anabolic–androgenic
steroids are steroidal androgens that include natural androgens like
testosterone as well as synthetic androgens that are structurally related
and have similar effects to testosterone.
• They  protein within cells, especially in skeletal muscles, and also have
varying degrees of virilizing effects, including induction of the
development and maintenance of masculine secondary sexual
characteristics such as the growth of facial and body hair.
• Androgens are one of three types of sex hormone agonists, the others
being estrogens like estradiol and progestogens like progesterone.
• Drugs included:
– Androstenedione, Stanozolol (Winstrol), Nandrolone also
known as 19-nortestosterone (Deca Durabolin),
Metandienone, also known as methandienone or
methandrostenolone (Dianabol)
Tadesse B. (PhD) 26
Other Anabolic Steroids…
Uses
• Catabolic states:
– Acute illness, severe trauma, major surgery etc.
• Only useful for short-term treatment
• Renal insufficiency
• Osteoporosis
• Sub-optimal growth in boys
• Enhance physical activity in athletes (dope test)
Tadesse B. (PhD) 27
Testosterone Esters (Anabolic steroids)
• Esterifying a fatty acid to the 17α-hydroxyl group of testosterone creates a
compound that is even more lipophilic than testosterone itself.
• It includes testosterone enanthate (heptanoate) or cypionate
(cyclopentylpropionate), administered IM every 1-2 weeks to hypogonadal men
• Attempts to ↓ the frequency of injections by ing the amount of each
injection result in wider fluctuations and poorer therapeutic outcomes.
• Testosterone undecanoate:
– Used mainly in the treatment of low testosterone levels in men, including
hormone therapy for transgender men.
– It is taken by mouth or given by injection into muscle (IM).
– Produces stable serum testosterone concentrations for 2 months
• Testosterone cypionate & Testosterone enanthate:
– Used mainly in the treatment of low testosterone levels in men.
– It is also used in hormone therapy for transgender men.
• Testosterone propionate:
– Used mainly in the treatment of low testosterone levels in men.
– It is also used to treat breast cancer in women.
Tadesse B. (PhD) 28
Alkylated Androgens
• Adding an alkyl group (methyl or ethyl group) to the
17α position of testosterone retards its hepatic
catabolism, allowing for oral administration.
• Consequently, 17α-alkylated androgens are androgenic
when administered orally
– However, they are less androgenic than testosterone and
cause hepatotoxicity, whereas native testosterone does not.
• Examples: methyltestosterone, metandienone, norethan
drolone, mestanolone.
Tadesse B. (PhD) 29
Alkylated Androgens…
• Methyltestosterone
– Used in the treatment of low testosterone levels in men, delayed
puberty in boys, at low doses as a component of menopausal hormone
therapy for menopausal symptoms like hot flashes, osteoporosis, and low
sexual desire in women, and to treat breast cancer in women
– It is taken by mouth or held in the cheek or under the tongue
• Side effects of methyltestosterone
– It include symptoms of masculinization like acne, increased hair growth,
voice changes, and increased sexual desire.
• Fluoxymesterone
– Used in the treatment of low testosterone levels in men, delayed puberty in
boys, breast cancer in women, and anemia.
– It is taken by mouth
• Side effects of fluoxymesterone
– Similar to methyltestosterone
– It can also cause liver damage and cardiovascular side effects like high
blood pressure
Tadesse B. (PhD) 30
Why Abuse Anabolic Androgenic Steroid?
• Most common reason:

– Improve athletic performance
– Also to gain rapid and substantial muscle size
and/or reduce body fat in an effort to attain a
desired physical appearance
• Reinforcement issues:
– In addition to initial physical gains, androgen
receptors in the brain stimulate feelings of
euphoria and ed aggressiveness
Tadesse B. (PhD) 31
Other Anabolic Steroids…
Side Effects
• The 17α-alkylated androgens are the only androgens that cause
hepatotoxicity
• When administered in high doses, affect serum lipid concentrations
– ↓HDL cholesterol and  LDL cholesterol.
• Women and children experience virilization, including facial and body
hirsutism, temporal hair recession in a male pattern, and acne.
• Boys experience phallic enlargement, and women experience clitoral
enlargement.
• Common problems due to chronic abuse also include hypertension,
blood clotting, atherosclerosis, jaundice, hepatic carcinoma, tendon
damage, and reduced fertility in males
• Mild: ed sexual drive, acne, ed body hair and baldness, aggressive
behaviour
• Severe life threatening side effects include heart attacks and liver
cancer
Tadesse B. (PhD) 32
Key Points
• Testosterone is the principal endogenous androgen.
• Important physiologic effects of androgens are pubertal transformation
in males, maintenance of adult male sexual characteristics, promotion of
muscle growth, and stimulation of erythropoiesis.
• The major indication (and only FDA-approved indication) for androgens
is male hypogonadism.
• The major side effects of androgens are edema, virilization in females,
premature epiphyseal closure in children, and liver toxicity (in people
taking 17-alpha-alkylated androgens).
• Androgens are contraindicated during pregnancy, owing to a risk for
injury to the female fetus.
• Large doses of androgens can increase muscle mass and strength in
athletes.
– However, athletic use of androgens is illegal & can cause significant harm.
Tadesse B. (PhD) 33
Summary
Tadesse B. (PhD) 34
Pharmacology of agents used for treatment of
Sexual and Reproductive Tract Infections
Tadesse B. (PhD) 35
Introduction
• Sexually transmitted infections (STIs), also known as
sexually transmitted diseases (STDs), are infectious
diseases transmitted primarily through sexual contact.
• For the top three reportable STIs in 2015 there were:
– 1,526,658 new cases of chlamydia (an increase of 5.9%),
– 395,216 new cases of gonorrhea (up 12.8%), and
– 23,872 new cases of primary & secondary syphilis (up 19%)
Tadesse B. (PhD) 36
Sexually Transmitted Infections (STI): Etiological Classification
Disease Causative Organism

Syphilis Treponema pallidum
Chancroid Hemophilus ducreyi
Donovanosis Klebsiella granulomatis
Lymphogranuloma venerum Chlamydia trachomatis
Gonococcal genital infection Neisseria gonorrhoeae
Chlamydia trachomatis
Mycoplasma genitalium
Non gonococcal genital infection Ureoplasma urealyticum
Gardenella vaginalis
Candida albicans
Herpes genitalis Herpes simplex virus
AIDS Human immunodeficiency virus
Tadesse B. (PhD) 37
Sexually Transmitted Infections (STIs)
Chlamydia trachomatis Infections: Characteristics
• Chlamydia trachomatis is the most frequently reported bacterial STI
• The various strains of Chlamydia can cause genital tract infections,
proctitis, conjunctivitis, and lymphogranuloma venereum (LGV),
as well as ophthalmia and pneumonia in infants.
• Infection is frequently asymptomatic in women, and may also be
asymptomatic in men.
• In women, untreated infection can cause pelvic inflammatory
disease (PID), ectopic pregnancy, and infertility.
• Because infection is often asymptomatic in women and because
sequelae can be serious, the CDC now recommends annual screening
for all sexually active women 25 years or younger.
• Screening is also recommended for women older than 25 years who
have a new sex partner, multiple partners, or a partner with a history
of an STI
Tadesse B. (PhD) 38
Sexually Transmitted Infections (STIs)…
Chlamydia trachomatis Infections: Treatment
Adults and Adolescents
• For uncomplicated urethral, cervical, or rectal infections in adults or
adolescents, treatment with either azithromycin or doxycycline is
recommended.
• Patients who are unable to take these medications may take
erythromycin, levofloxacin, or ofloxacin.
Infection in Pregnancy
• Azithromycin is the preferred treatment for C. trachomatis infection
during pregnancy.
• Although doxycycline and other tetracyclines are active against C.
trachomatis,
– These drugs are contraindicated as they can damage fetal teeth & bones.
• If the patient cannot take azithromycin, the approved alternatives are
amoxicillin, erythromycin base, or erythromycin ethylsuccinate
Tadesse B. (PhD) 39
Infants
• About half the infants born to women with cervical C. trachomatis acquire
the infection during delivery, putting them at risk for pneumonia and
conjunctivitis (ophthalmia neonatorum).
– Pneumonia is generally not severe and lasts about 6 weeks.
– Conjunctivitis does not result in blindness & spontaneously resolves in 6
months.
• The preferred treatment for both infections is oral erythromycin base
or erythromycin ethylsuccinate.
• Azithromycin suspension may be given as an alternative.
• Although topical erythromycin, tetracycline, or silver nitrate may be
given to prevent conjunctivitis
– These drugs are not completely effective and they have no effect on
neonatal pneumonia caused by C. trachomatis
Tadesse B. (PhD) 40
Preadolescent Children
• Although infection in preadolescent children can result from
perinatal transmission, sexual abuse is the more likely cause,
especially in children older than 2 years.
– Because of the legal implications, diagnosis must be definitive.
• Treatment depends on the age and weight of the child.
• For children who weigh:
– < 45 kg, the preferred treatment is oral erythromycin base or
erythromycin ethylsuccinate.
– 45 kg or more, but are < 8 years of age, the preferred treatment is
azithromycin.
• For children at least 8 years of age, the preferred treatments are
azithromycin or doxycycline
Tadesse B. (PhD) 41
Lymphogranuloma Venereum (LGV)
• LGV is caused by a unique strain of C. trachomatis.
• Transmission is strictly by sexual contact.
– Most common in tropical countries.
• Infection begins as a small erosion or papule in the genital region.
– From this site, the organism migrates to regional lymph nodes, causing
swelling, tenderness, and blockage of lymphatic flow.
– Tremendous enlargement of the genitalia may result.
– The enlarged nodes, called buboes, may break open and drain.
• Doxycycline is the drug of choice for genital, inguinal, &
anorectal LGV
• Alternative for those who cannot take tetracycline antibiotics:
Erythromycin base
Tadesse B. (PhD) 42
Gonococcal Infections: Characteristics
• Gonorrhea is caused by Neisseria gonorrhoeae, a gram-negative
diplococcus often referred to as the gonococcus.
• Gonorrhea is second only to chlamydia as the most common STI &
transmitted almost exclusively by sexual contact
• The intensity of symptoms differs between men and women.
– In men, the main symptoms are a burning sensation during urination
and a pus-like discharge from the penis.
– In contrast, gonorrhea in women is often asymptomatic or may present as
mild cervicitis.
• Serious infection of female reproductive structures (vagina, urethra,
cervix, ovaries, fallopian tubes) can occur, ultimately resulting in
sterility.
• Among people who engage in oral sex, the mouth and throat can
become infected, causing sore throat and tonsillitis.
• Among people who engage in receptive anal sex, the rectum can
become infected, causing a purulent discharge and tenesmus, a constant
urge to defecate even when the bowels are empty.
• Bacteremia can develop in males and females, causing cutaneous
lesions, arthritis, and, rarely, meningitis and endocarditis.
Tadesse B. (PhD) 43
Gonococcal Infections: Treatment
• Owing to antibiotic resistance, treatment of gonorrhea has changed
over the years—and undoubtedly will continue to evolve.
• In the 1930s, virtually all strains of the gonococcus were sensitive to
sulfonamides.
– Within a decade, sulfonamide resistance had become common.
• Penicillin was active against all gonococcal strains during that time
– However, in 1976, organisms resistant to penicillin began to emerge.
• More recently, resistance to fluoroquinolones has become common.
• As a result, in 2007 the CDC recommended against using fluoroquinolones
for gonorrhea, leaving cephalosporins as the preferred treatments.
– This recommendation was changed yet again in 2012, also triggered by
antimicrobial resistance.
• The CDC currently recommends dual treatment with ceftriaxone and
azithromycin as the preferred treatment for gonorrhea
Tadesse B. (PhD) 44
Gonococcal Infections: Treatment…
Urethral, Cervical, and Rectal Infection
• Because of increasing resistance to cephalosporins, preferred treatment now
consists of a combination of two drugs:
– Ceftriaxone given intramuscularly (IM) plus oral (PO) azithromycin.
• If a patient refuses IM therapy, PO cefixime (400 mg once) can be
substituted for IM ceftriaxone;
– However the CDC recommends not routinely substituting this drug because
resistance to cefixime has been documented and is anticipated to increase.
• If a patient is allergic to azithromycin, a 7-day course of doxycycline
may be substituted.
• For patients with cephalosporin allergies, the options are not as clear.
– Although prescribing double the azithromycin dose as monotherapy will
cure gonorrhea in most cases, the CDC does not recommend this because of
treatment failures and rapid development of resistance.
• The CDC suggests substituting gemifloxacin for the cephalosporin
component, despite having recommended against using quinolones to treat
gonorrhea.
• Spectinomycin, an aminoglycoside, has also been suggested
Tadesse B. (PhD) 45
Pharyngeal Infection
• Gonococcal infection of the pharynx is more difficult to treat than infection of the
urethra, cervix, or rectum; therefore, parenteral therapy is recommended for all
patients.
– The preferred treatment is ceftriaxone combined with azithromycin.
Conjunctivitis
• Gonococcal conjunctivitis can be reliably eradicated with ceftriaxone plus
azithromycin.
• Treatment also includes washing the infected eye with saline solution once.
Disseminated Gonococcal Infection (DGI)
• DGI occurs secondary to gonococcal bacteremia.
• Symptoms include petechial or pustular skin lesions, arthritis, arthralgia, and
tenosynovitis (inflammation of the tendon sheath).
• Endocarditis and meningitis occur rarely.
• In the absence of endocarditis or meningitis, treatment consists of IM or
intravenous (IV) ceftriaxone plus azithromycin.
• For patients with endocarditis or meningitis, the preferred treatment is IV
ceftriaxone plus azithromycin
Tadesse B. (PhD) 46
Neonatal Infection
• Neonatal gonococcal infection is acquired through contact with infected cervical
exudates during delivery.
• Infection can be limited to the eyes, or it may be disseminated.
• Gonococcal neonatal ophthalmia is a serious infection.
• The initial symptom is conjunctivitis.
• Over time, other structures of the eye become involved.
• Blindness can result.
• The recommended therapy is a single dose of ceftriaxone given by either IM
injection or IV infusion.
• To protect against neonatal ophthalmia, a topical antibiotic should be instilled into
both eyes immediately postpartum.
– According to the 2015 CDC guidelines, the only approved topical agent is 0.5%
erythromycin ophthalmic ointment.
– If this antimicrobial is not available, parenteral therapy with ceftriaxone should be used.
• In neonates, DGI is rare.
– Possible manifestations include sepsis, arthritis, meningitis, and scalp abscesses.
– Either of two antibiotics is recommended for treatment: ceftriaxone or cefotaxime
Tadesse B. (PhD) 47
Preadolescent Children
• The most common cause of gonococcal infection is sexual abuse.
• Vaginal, anorectal, and pharyngeal infections are most common.
• Because of legal implications, diagnosis must be definitive.
• Growing a specimen in culture is the preferred technique.
• Treatment depends on the type of infection and the weight of the
child.
• For children who have localized infection (vulvovaginitis, cervicitis,
urethritis, pharyngitis, proctitis) and who weigh
– ≤ 45 kg, the preferred treatment is a single IM or IV dose of ceftriaxone
– > 45 kg, treatment is the same as for adults.
• For children of any weight who have systemic infection (bacteremia,
arthritis):
– The preferred treatment is ceftriaxone (IM or IV) daily for 7
days
Tadesse B. (PhD) 48
Nongonococcal urethritis (NGU)
• NGU is a urethritis caused by any organism other than Neisseria gonorrhoeae,
the gonococcus.
• The most common infectious agent is C. trachomatis (15% to 55%).
• Other likely agents are Ureaplasma urealyticum, Trichomonas vaginalis, and
Mycoplasma genitalium.
• NGU is diagnosed by the presence of polymorphonuclear leukocytes and a negative
culture for N. gonorrhoeae.
• The infection is especially prevalent among sexually active adolescent girls.
• The recommended treatment is either azithromycin or doxycycline.
• Alternative regimens are erythromycin base, erythromycin ethylsuccinate,
levofloxacin, or ofloxacin.
• For persistent or recurrent NGU, one of two drugs:
– Metronidazole or Tinidazole is recommended if T. vaginalis transmission is a suspected
cause.
– Tinidazole is contraindicated in breast-feeding women
• Azithromycin should be added to the regimen if it was not used during initial
therapy.
– If the infection still fails to respond, the cause may be M. genitalium.
• When M. genitalium is suspected, a trial with moxifloxacin may be warranted
Tadesse B. (PhD) 49
Pelvic Inflammatory Disease (PID)
• Acute PID is a syndrome that includes endometritis, pelvic peritonitis,
tubo-ovarian abscess, and inflammation of the fallopian tubes.
• Infertility can result.
• Prominent symptoms are abdominal pain, vaginal discharge, and fever.
• Most frequently, PID is caused by N. gonorrhoeae, C. trachomatis, or both.
– However, Mycoplasma hominis, as well as assorted anaerobic &
facultative bacteria, may also be present.
• Multiple organisms are likely to be involved, drug therapy must provide
broad coverage.
• Since no single drug can do this, combination therapy is required.
• For the hospitalized patient: treatment can be initiated with either IV
cefoxitin or IV cefotetan combined with IV doxycycline.
– After symptoms resolve, IV therapy can be discontinued—but must be
followed by oral doxycycline (for 14-days)
– An alternative recommended regimen:
• Consists of IV clindamycin plus IV or IM gentamicin.
Tadesse B. (PhD) 50
Pelvic Inflammatory Disease (PID)…
• Outpatients:
– Can be treated with either IM ceftriaxone or IM cefoxitin as a
single dose boosted with oral probenecid.
– Treatment should also include doxycycline with or without
metronidazole.
• Because PID can be difficult to treat and because the
consequences of failure can be severe (e.g., sterility), many
experts recommend that all patients receive IV antibiotics
in a hospital
Tadesse B. (PhD) 51
Acute Epididymitis
• Epididymitis may be acquired by sexual contact or non-sexually.
• Sexually acquired epididymitis is usually caused by N. gonorrhoeae, C.
trachomatis, or both.
– The syndrome occurs primarily in young adults (younger 35 years of age) and
may be associated with urethritis.
– Primary symptoms are fever accompanied by pain in the back of the testicles
that develops over the course of several hours.
• For patients with gonococcal or chlamydial infection:
– The recommended treatment is ceftriaxone plus doxycycline.
• For patients who engage in insertive anal sex:
– The addition of levofloxacin or ofloxacin is recommended to target enteric
bacteria.
• Testicular pain can be managed with analgesics, bed rest, and ice packs.
• Non–sexually transmitted epididymitis:
– Generally occurs in older men & in men who have had UT instrumentation.
– Causative organisms are gram-negative enteric bacilli & Pseudomonas species
– Ofloxacin can be used for treatment.
Tadesse B. (PhD) 52
Syphilis
• It is caused by the spirochete Treponema pallidum.
• T. pallidum has remained highly responsive to penicillin, the
treatment of choice.
Characteristics
• Syphilis develops in three stages: termed primary, secondary, and
tertiary.
• T. pallidum enters the body by penetrating the mucous
membranes of the mouth, vagina, or urethra of the penis.
– After an incubation period of 1 to 4 weeks, a primary lesion, called a
chancre, develops at the site of entry.
– The chancre is a hard, red, protruding, painless sore.
– Nearby lymph nodes may become swollen.
– Within a few weeks the chancre heals spontaneously, although T.
pallidum is still present
• In clinical practice, chancres are rarely seen, especially in females.
Tadesse B. (PhD) 53
Syphilis: Characteristics…
• Secondary syphilis develops 2 to 6 weeks after the chancre heals.
– Symptoms result from the spread of T. pallidum through the bloodstream.
– Skin lesions and flu-like symptoms (fever, headache, reduced appetite,
general malaise) are typical.
– Enlarged lymph nodes and joint pain may also be present.
– The symptoms of secondary syphilis resolve in 4 to 8 weeks, but may
recur episodically over the next 3 to 4 years.
• Tertiary syphilis develops 5 to 40 years after the initial infection.
– Almost any organ can be involved.
– Infection of the brain—neurosyphilis—is common, and can cause senility,
paralysis, and severe psychiatric symptoms.
– The heart valves and aorta can be damaged.
– Lesions can also occur in the skin, bones, joints, and eyes.
– The risk for neurosyphilis is ↑ed in individuals with HIV infection.
• Infants exposed to T. pallidum in utero can be born with syphilis.
• Early signs of congenital syphilis include sores, rhinitis, and severe tenderness
over bones.
Tadesse B. (PhD) 54
Syphilis: Treatment
• Penicillin G is the drug of choice for all stages of syphilis.
– The form and dosage of penicillin G depend on the disease stage.
• Early syphilis (primary, secondary, or latent syphilis of less than 1
year’s duration)
– Treated with a single IM dose of benzathine penicillin G.
• Late latent syphilis (more than 1 year’s duration) and tertiary
syphilis :
– Also treated with IM benzathine penicillin G.
– However, instead of receiving a single dose, adults and children receive three doses 1
week apart.
• Neurosyphilis requires more aggressive therapy.
– The recommended treatment is IV penicillin G daily for 10 to 14 days, administered
either by continuous infusion or by intermittent therapy every 4 hours.
• For congenital syphilis:
– Treatment options are either IV penicillin G or IM procaine penicillin G.
Tadesse B. (PhD) 55
Syphilis: Treatment
• Syphilis in pregnancy:
– Should be treated with penicillin G, using a dosage appropriate
to the stage of the disease.
How should patients with penicillin allergy be treated?
• For non-pregnant patients with early or late syphilis:
– Either doxycycline or tetracycline may be used.
• For patients with neurosyphilis:
– Ceftriaxone can be effective but possible cross-reactivity with penicillin is
a concern.
• If the patient is a child or pregnant woman:
– The CDC recommends a penicillin-allergy desensitization protocol to permit
penicillin use, rather than substituting another drug for penicillin.
Tadesse B. (PhD) 56
• Acquired Immunodeficiency Syndrome

(AIDS)
– AIDS is caused by the human immunodeficiency
virus (HIV)
Tadesse B. (PhD) 57
Herpes Simplex Virus (HSV) Infections: Characteristics
• Most genital herpes infections are caused by herpes simplex virus type 2 (HSV-2).
– However, an ↑ing number of anogenital infections are caused by HSV-1, the herpes
virus that causes cold sores.
• Symptoms of primary infection develop 6 to 8 days after contact.
• Some people with HSV infection are asymptomatic or have relatively mild symptoms;
however, for others there is a common presentation.
• In females: blisters or vesicles can appear on the perianal skin, labia, vagina, cervix, and
foreskin of the clitoris.
• In males: vesicles develop on the penis and occasionally on the testicles.
• Painful urination and a watery discharge can occur in both sexes.
• Also, the patient may experience systemic symptoms: fever, headache, myalgia, and tender,
swollen lymph nodes in the affected region.
• Within days, the original blisters can evolve into large, painful, ulcer-like sores.
• Over the next 2 to 3 weeks, all symptoms resolve spontaneously.
– However, this does not indicate cure.
• The virus remains present in a latent state and can cause recurrence.
• Because available drugs can’t eliminate the virus, there is no cure.
• Symptoms may recur for life; however, for some patients, subsequent episodes become
progressively shorter and less severe, and in rare cases they may cease entirely
Tadesse B. (PhD) 58
• Herpes Simplex Virus (HSV) Infections
Neonatal Infection
• Genital herpes in pregnant women can be transmitted to
the infant.
• Transmission can occur in utero, which is very rare, or
during delivery.
– Infection acquired in utero:
• Can result in spontaneous abortion or fetal malformation.
– Infection acquired during delivery:
• Can cause blindness, severe neurologic damage, and even death.
• To protect the infant during delivery, birth should be
accomplished by cesarean delivery if the mother has an
active infection.
• Infants who acquire the infection should be treated with
acyclovir.
Tadesse B. (PhD) 59
Herpes Simplex Virus (HSV) Infections:
Treatment
• Genital herpes can be treated with three drugs: acyclovir,
famciclovir, & valacyclovir
– They can reduce symptoms and shorten the duration of pain and
viral shedding but they cannot eliminate the virus
• Patients with recurrent infections may take the drugs:
– Every day (suppressive therapy)- reduces the frequency and
intensity of episodes or
– Just when symptoms appear (episodic therapy)- reduces
symptom intensity after an episode has begun
Reduction of Transmission
• Transmission of HSV can occur when symptoms are absent as well as when
symptoms are present.
• Valacyclovir can decrease transmission of genital herpes by 50%, but it
doesn’t stop it entirely
– Accordingly, patients must continue to use condoms
• Because viral shedding is ↑ed when the infection is active, it is advisable to
abstain from sex during breakouts
Tadesse B. (PhD) 60
Proctitis
• Sexually acquired proctitis (inflammation of the rectum)
results primarily from receptive anal intercourse.
• Symptoms include anorectal pain, tenesmus (the sensation
of needing to defecate even when the bowel is empty), and
rectal discharge.
• Usual causative organisms are N. gonorrhoeae, C. trachomatis,
T. pallidum, and HSV.
• The preferred treatment is ceftriaxone plus doxycycline
Tadesse B. (PhD) 61
Summary: Drug Therapy Recommendations for STIs
Chlamydia trachomatis Infections (Causative Organism: Chlamydia trachomatis)
• Adults and adolescents
– Azithromycin, 1 gm PO once or
– Doxycycline, 100 mg PO 2 times/day × 7 days
• Children <45 kg
– Erythromycin base/ethylsuccinate, 12.5 mg/kg PO 4 times/day × 14 days
• Children ≥45 kg but < 8 years
– Azithromycin, 1 gm PO once
• Children ≥8 years
– Azithromycin, 1 gm PO once or
• Pregnant women
– Azithromycin, 1 gm PO once
• New-borns: ophthalmia or pneumonia
– Erythromycin base/ethylsuccinate, 12.5 mg/kg PO 4 times/day × 14 days
• Lymphogranuloma venereum
Tadesse B. (PhD) 62
Summary: Drug Therapy Recommendations for STIs…
Gonococcal Infections (Gonorrhea): (Causative Organism:

Neisseria gonorrhoeae)
• Urethritis, cervicitis, proctitis:
– Ceftriaxone (250 mg IM once) plus azithromycin (1 gm PO once)
• Pharyngitis:
– Ceftriaxone (250 mg IM once) plus azithromycin (1 gm PO once)
• Disseminated gonococcal infection (DGI) in adults:
– Ceftriaxone (1 gm IM or IV every 24 hr) plus azithromycin (1 gm PO once)
• DGI with meningitis:
– Ceftriaxone (1-2 gm IV every 12 hr × 10-14 days) plus azithromycin (1 gm PO
once)
• DGI with endocarditis:
– Ceftriaxone (1-2 gm IV every 12 hr × 28 days or more) plus azithromycin (1 gm
PO once)
Tadesse B. (PhD) 63
Gonococcal Infections (Gonorrhea): (Causative Organism: Neisseria
gonorrhoeae)
• Conjunctivitis:
– Ceftriaxone (1 gm IM once) plus azithromycin (1 gm PO once)
• Ophthalmia neonatorum prophylaxis for neonates:
– Erythromycin 0.5% ophthalmic ointment in each eye at birth
• Neonates with ophthalmia neonatorum: 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 × 7 days) (10-14 days if meningitis is present) or
– Cefotaxime (25 mg/kg IM or IV every 12 hr × 7 days) (10-14 days if meningitis is present)
• Children with bacteremia or arthritis:
– ≤45 kg: ceftriaxone (50 mg/kg IM or IV once daily × 7 days)- not to exceed 1 gm
– >45 kg: ceftriaxone (1 gm IM or IV once daily × 7 days)
• Children with vulvovaginitis, cervicitis, proctitis, pharyngitis, urethritis
– ≤45 kg: ceftriaxone 25–50 mg/kg (not to exceed 125 mg) IM or IV once
– >45 kg: same as adult
Tadesse B. (PhD) 64
Nongonococcal Urethritis
• Causative Organisms: Chlamydia trachomatis,
Ureaplasma urealyticum, Trichomonas vaginalis,
Mycoplasma genitalium
• Acute infection
– Azithromycin (1 gm PO once) or
– Doxycycline (100 mg PO 2 times/day × 7 days)
• Recurrent/persistent infection
– Azithromycin (1 gm PO once) if original treatment was with
doxycycline
– Moxifloxacin (400 mg PO daily × 7 days) if original treatment
was azithromycin
– Metronidazole (2 gm PO once) or
– Tinidazole (2 gm PO once) in areas where Trichomonas outbreaks
are common
Tadesse B. (PhD) 65
Pelvic Inflammatory Disease

• Causative Organisms: Neisseria gonorrhoeae, Chlamydia
trachomatis, Others)
• Inpatients
– Doxycycline (100 mg IV or PO every 12 hr) plus either cefoxitin (2 gm
IV every 6 hr) or cefotetan (2 gm IV every 12 hr)
or
– Clindamycin (900 mg IV every 8 hr) 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 hr)
• Outpatients
– Doxycycline (100 mg PO 2 times/day × 14 days) plus either cefoxitin
(2 gm IM once) boosted with probenecid (1 gm PO once) or
– Ceftriaxone (250 mg IM once) with or without metronidazole (500 mg
PO 2 times/day × 14 days)
Tadesse B. (PhD) 66
Sexually Acquired Epididymitis

• Causative Organisms: Chlamydia trachomatis, Neisseria
gonorrhoeae, Enteric Organisms)
• Sexually acquired epididymitis without history of insertive anal
sex
– Ceftriaxone (250 mg IM once) plus doxycycline (100 mg PO 2
times/day × 10 days)
• Sexually acquired epididymitis with history of insertive anal sex
– Ceftriaxone (250 mg IM once) plus either levofloxacin (500 mg
PO daily × 10 days) or
– Ofloxacin (300 mg PO 2 times/day × 10 days)
Tadesse B. (PhD) 67
Syphilis (Causative Organism: Treponema pallidum)

• Primary syphilis, secondary syphilis, and early latent syphilis
– Adults: Benzathine penicillin G (2.4 million units IM once)
– Children: Benzathine penicillin G (50,000 units/kg IM once) (up to a max. of
2.4 million units)
• Late latent syphilis 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)
(up to a max. of 7.2 million units over the course of treatment)
• 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)
administered by continuous infusion or in separate doses of 3-4 million units each
every 4 hr
• Congenital syphilis
– Aqueous crystalline penicillin G (50,000 units/kg IV every 12 hr for the first 7
days of life) followed by 50,000 units/kg every 8 hr for the next 3 days or
– Procaine penicillin G (50,000 units/kg IM once daily for 10 days)
Tadesse B. (PhD) 68
Bacterial Vaginosis: Causative Organisms: Gardnerella vaginalis,
Mycoplasma hominis, Various Anaerobes
– Metronidazole (500 mg PO 2 times/day × 7 days) or
– Metronidazole gel (0.75%) (1 full applicator (5 gm) intravaginally
once/day × 5 days) or
– Clindamycin cream (2%) (1 full applicator (5 gm) intravaginally at
bedtime × 7 days)
Trichomoniasis
• Causative Organism: Trichomonas Vaginalis
– Metronidazole (2 gm PO once) or
– Tinidazole (2 gm PO once)
Proctitis
• Causative Organisms: Chlamydia trachomatis, Neisseria gonorrhoeae,
Treponema pallidum, Herpes Simplex Virus
– Ceftriaxone (250 mg IM once) plus doxycycline (100 mg PO 2
times/day × 7 days)
Tadesse B. (PhD) 69
Genital Herpes Simplex Virus Infections (Causative Organism: Herpes Simplex Virus)
• First episode • Recurrent episodes

– Acyclovir (400 mg PO 3 – Acyclovir (800 mg PO 2 times/day ×
times/day × 7-10 days or longer) 5 days) or
or – Acyclovir (800 mg PO 3 times/day ×
– Acyclovir (200 mg PO 5 2 days) or
times/day × 7-10 days or longer) – Acyclovir (400 mg PO 3 times/day ×
or 5 days) or
– Famciclovir (250 mg PO 3 – Famciclovir (125 mg PO 2 times/day
× 5 days) or
times/day × 7-10 days or longer)
or – Famciclovir (1 gm 2 times/day × 1
day) or
– Valacyclovir (1 gm PO 2 – Famciclovir (500 mg once, followed
times/day × 7-10 days or longer) by 200 mg 2 times/day for 2 days) or
• Severe infection – Valacyclovir (500 mg PO 2 times/day
– Acyclovir (5-10 mg/kg IV every × 3 days) or
8 hr for 2-7 days) or until clinical – Valacyclovir (1 gm PO once/day × 5
improvement, then PO acyclovir days)
to complete at least 10 days
Tadesse B. (PhD) 70
Genital Herpes Simplex Virus Infections (Causative Organism:

Herpes Simplex Virus)
• Daily suppressive therapy
– Acyclovir (400 mg PO 2 times/day) or
– Famciclovir (250 mg PO 2 times/day) or
– Valacyclovir (500 mg PO once/day) or
– Valacyclovir (1 gm PO once/day)
• Neonatal herpes
– Acyclovir (20 mg/kg IV every 8 hr × 14 days) (for skin or mucous
membrane infection) or × 21 days (for disseminated or CNS infection)
Tadesse B. (PhD) 71
Key Points
• Chlamydia trachomatis is the most common bacterial cause of STIs.
– Two drugs: doxycycline and azithromycin are preferred agents for treating
chlamydial infection in non-pregnant adolescents and adults.
• Gonorrhea is caused by Neisseria gonorrhoeae, a gram-negative diplococcus often
referred to as the gonococcus.
– Gonorrhea is the second most common bacterial STI in the United States.
– Ceftriaxone is the preferred drug for treating gonorrhea. It should be given in
combination with either azithromycin or doxycycline.
• Syphilis is caused by the spirochete Treponema pallidum.
– Penicillin G is the drug of choice for treating all stages of syphilis.
• Bacterial vaginosis can be caused by multiple microorganisms, including Gardnerella
vaginalis, Mycoplasma hominis, and various anaerobes.
– It can be treated orally with metronidazole, or intravaginally with metronidazole or
clindamycin.
– In pregnant patients, bacterial vaginosis is treated only with oral medication, either
metronidazole or clindamycin.
• Most genital herpes infections are caused by herpes simplex virus type 2.
– Genital herpes can be treated with three drugs: acyclovir, famciclovir, and
valacyclovir.
– These agents do not eliminate the virus, but they can reduce symptoms & shorten
the duration of viral shedding and pain.
Tadesse B. (PhD) 72
Pharmacology of Uterotonics, Uterine
relaxants, Abortifacients, and Drug used in
Pregnancy
Tadesse B. (PhD) 73
Introduction
• Human parturition is a complicated process that is not yet
completely understood.
• There are several pathways through which parturition can be
initiated.
• The process itself begins long before ―labor‖ can be clinically
detected.
• Both biochemical and hormonal factors prepare the uterus
and cervix for delivery of the fetus.
• Clinicians have long sought to identify drugs that could be
used to both induce and arrest labor.
– Medications currently used for these purposes are referred to as
uterotonics and tocolytics, respectively.
• Some of these medications have additional indications such as
the treatment of uterine atony or cervical ripening.
• Most drugs are not FDA approved and their use in obstetrics
is considered off-label
Tadesse B. (PhD) 74
Pharmacology of Uterotonics
Tadesse B. (PhD) 75
Pharmacology of Uterotonics
• Uterotonics are uterine contraction agents
• Uterotonics are the most common drugs administered on any labor and
delivery suite.
• Clinically, they are used primarily for labor induction/ augmentation
& to control postpartum hemorrhage
– Postpartum hemorrhage is excessive bleeding after childbirth
• All agents in this category cause uterine contraction, but each does so
through a different pathway.
• It includes Pitocin (oxytocin), Ergot alkaloids (Ergometrine or
Ergonovine, Methylergometrine also known as methylergonovine sold
under the Brand name Methergine) and Prostaglandins (PGE2
(Misoprostol) and PGF2α)
Tadesse B. (PhD) 76
Pitocin (Oxytocin)
• Oxytocin is a naturally occurring hormone in the body.
– It is a hormone produced by hypothalamus and stored and
secreted from posterior pituitary gland
– Its secretion occurs by sensory stimulation from cervix, vagina
and from suckling at breast
• Pitocin is the synthetic drug created to mimic one of this
hormone's primary actions: bringing about labor
– A polypeptide composed of nine amino acids.
– Identical in structure to its endogenous counterpart, oxytocin.
– One of the most potent uterotonic agents available.
Tadesse B. (PhD) 77
Pitocin (Oxytocin)…
Uses of Pitocin
• Currently approved for medically indicated
– Labor induction (drug of choice) (slow IV infusion)
• Preventing the early rupture of membranes or aiding placental
insufficiency
– Labor augmentation (slow IV infusion), and
– As an adjunctive therapy in the management of an incomplete or
inevitable abortions in the first and second trimester. .
• Additionally, it is a first-line agent for the treatment of postpartum
hemorrhage secondary to uterine atony or subinvolution (delayed
return of the enlarged uterus to normal size and function) (IM drip)
• Impaired milk ejection
• One puff or nasal spray (40U/ml) in each nostril 2-3 min before nursing
• Induce abortion (at high dose)
• Mild preeclampsia (a serious condition developing in late
pregnancy, characterized by sudden hypertension, proteinuria,
and edema)
Tadesse B. (PhD) 78
Oxytocin
causes
contraction
of the
fundus only.
Tadesse B. (PhD) 79
Mechanism of Action of Pitocin
• It stimulates uterine contractions by ing intracellular calcium.
• It binds to the oxytocin receptor located on the myometrial cell membrane
and stimulates phospholipase C (PLC)
• This leads to ed production of inositol triphosphate (IP3) & DAG
(diacylglycerol)
– Which acts to mobilize intracellular Ca2+ by promoting release from the
sarcoplasmic reticulum (SR)
• Binding to the oxytocin receptor also induces an influx of extracellular Ca2+
through non-selective, cation channels on the myometrial cell membrane
• Intracellular Ca2+ then binds with calmodulin (CAM) to form the calcium-
calmodulin complex
– Which activates myosin light-chain kinase (MLCK), the key regulator of
smooth muscle contractility.
• MLCK phosphorylates myosin which in turn binds actin, initiating
myometrial smooth muscle contraction (Figure 1).
Tadesse B. (PhD) 80
Fig.1: Contractant and relaxant pathways of a
myometrial cell.
Ptase: Phosphate kinase; MLCK: Myosin light-chain
kinase; CaCAM: Calcium–calmodulin complex;
CAM: Calmodulin; PLC: Phospholipase C;
PIP2: Phosphatidylinositol 4,5-biphosphate; IP3:
Inositol triphosphate; Pg: Prostaglandin; Oxy:
Oxytocin; SPR: Sarcoplasmic reticulum Tadesse B. (PhD) 81
Pharmacokinetics of Pitocin (Oxytocin)…
• Not effective orally
• Not bound to plasma proteins
• Administered intravenously* (*S.C or IM  difficult to
monitor)
– Also as nasal spray (to improve milk ejection, 2-3 minutes before
breast feeding)
• Pitocin is widely distributed throughout the extracellular fluid, and
has a half-life of 3-10 minutes.
• Pitocin is primarily metabolized by the kidney, and it is rapidly
removed from plasma.
– This rapid metabolism can in part be attributed to the 50% increase in
glomerular filtration rate observed during pregnancy.
– Additionally, the half-life is further reduced in late pregnancy and
during lactation secondary to inactivation by oxytocinase.
Tadesse B. (PhD) 82
• Side Effects
– Hypertension; Uterine rupture; Neonatal jaundice
– Fetal death (due to constriction of placental blood vessel
→Ischemia)
– Water intoxication – due to anti-diuretic hormone like effect
– Allergic reactions
• Contraindications
– Hypersensitivity; Prematurity; Abnormal fetal position;
Evidence of fetal distress
– Cephalopelvic disproportion (occurs when there is mismatch between
the size of the fetal head and size of the maternal pelvis, resulting in "failure
to progress" in labor for mechanical reasons)
• Precautions
– Multiple pregnancy, Previous cesarean section (CS)-to avoid
rupture of the uterus, HTN
Tadesse B. (PhD) 83
Cephalopelvic disproportion
Fetus’s head
is much larger
than the pelvic
outlet.
Tadesse B. (PhD) 84
Ergot Alkaloids
• It includes
– Ergometrine (Ergonovine)
• (0.5 mg/ml) injection ( IM or IV)
• Tablet 0.5 mg
– Methylergometrine/Methylergonovine (Sold under
the brand name Methergine)
• 0.2 mg/ml injection
• Tablet 0.125 mg
Tadesse B. (PhD) 85
Ergot Alkaloids…
– Alkaloid derivatives induce tetanic
contraction of uterus without
relaxation in between
• Does not resemble the normal
physiological contractions
– It causes contractions of uterus as a
whole i.e. fundus and cervix (tend
to compress rather than to expel
the fetus)
– Not used anymore for labor
augmentation
• Mechanism – Direct stimulate
contraction
– Partial agonists at α, dopamine
and serotonin receptor
– Inhibit the release of endothelial-
derived relaxation factor
Tadesse B. (PhD) 86
Ergot alkaloids (PKs)
• Absorption, fate and excretion
– Absorbed orally from GIT (tablets)
– Usually given I.M
• NOT given IV  because it causes severe vasoconstriction
– Extensively metabolized in liver
• 90% of metabolites are excreted in bile
• Use – Post-partum hemorrhage (3rd stage of labor)
– Expulsion of the placenta
• Uterus responds to Ergots more than Oxytocin
Tadesse B. (PhD) 87
Ergot alkaloids…
• Clinical Uses
– Postpartum hemorrhage (used only at the 3rd stage of
labor, when the baby’s head or shoulder start to appear)
• Preparations
– Syntometrine (ergometrine 0.5 mg + oxytocin 5 I.U), I.M
– If used I.V ↑↑↑↑ blood pressure
• Why should we use this combination ?

– Ergots have slow onset of action (7min) but have a long half-
life.
– Yet, oxytocin has a fast onset of action, 1-2 minutes, with a
short half-life.
Tadesse B. (PhD) 88
Ergot alkaloids…
• Side Effects
– Nausea, vomiting, diarrhea
– Hypertension due to contraction of blood vessels
– Gangrene
• Due to vasoconstriction of peripheral blood vessels ( toes
& fingers)
• Contraindications
– 1st and 2nd stage of labor
– Vascular disease
– Impaired hepatic and renal functions
– Cardiac diseases (Angina, myocardial infraction, ischemia)
– Severe HTN
– Pregnancy
Tadesse B. (PhD) 89
Prostaglandins (PGE2 and PGF2α)
• It includes Prostaglandin E₂ (Dinoprostone), Carboprost (PGF2α) and
Misoprostol
• Prostaglandin E₂: a naturally occurring prostaglandin with
oxytocic properties that is used as a medication.
– Used in labor induction, bleeding after delivery, termination of
pregnancy, and in new-born babies to keep the ductus arteriosus open
• Carboprost: a synthetic prostaglandin analogue of PGF2α with
oxytocic properties.
– It's main use is in the obstetrical emergency of postpartum hemorrhage
which reduces postpartum bleeding
• Misoprostol: a synthetic prostaglandin medication
– Used to prevent and treat stomach and duodenal ulcers, induce labor,
cause an abortion, and treat postpartum bleeding due to poor contraction
of the uterus.
– Taken by mouth when used to prevent gastric ulcers in persons taking NSAIDs
Tadesse B. (PhD) 90
Prostaglandins (PGE2 and PGF2α)…
• Contract uterine smooth muscle
– Difference between PGs and Oxytocin
• PGs contract uterine smooth muscle not only at term (as
with oxytocin) but throughout pregnancy
• PGs soften the cervix (ripening) whereas oxytocin does
not
• PGs have longer duration of action than oxytocin
Tadesse B. (PhD) 91
• Therapeutic use
– Induction of abortion (pathological) - Gestation weeks 12
to 20)
• Used due to the uterus is sensitive to PGs in early stages
– Induction of labor (fetal death in utero)
• Dinoprostone and misoprostol (ripening of cervix) as
alternative to oxytocin
– Postpartum hemorrhage - Carboprost
• When the myometrium is unresponsive to oxytocin,
ergonovine, or methylergonovine
Tadesse B. (PhD) 92
• Side Effects:- Nausea , vomiting, abdominal pain, diarrhea
– Bronchospasm (PGF2α), flushing (PGE2), carcinogenic
• Contraindications:
– Mechanical obstruction of delivery
– Fetal distress (due to umbilical cord vessels’ vasoconstriction)
– Predisposition to uterine rupture
– Acute pelvic inflammatory disease,
– Drug hypersensitivity, or
– An active renal, hepatic, or cardiovascular disorder
• Precautions
– Asthma, cervicitis, vaginitis, hyper or hypotension, anemia,
jaundice, diabetes, or epilepsy, glaucoma, Uterine rupture,
multiple pregnancy
– Not used with oxytocin – Can cause uterine rupture
Tadesse B. (PhD) 93
Difference between oxytocin and ergometrine
Tadesse B. (PhD) 94
Difference between oxytocin and PGs
Character Oxytocin Prostaglandins
Contraction Only at term Throughout pregnancy
Cervix Don’t soften cervix Soften the cervix
Duration of Shorter Longer
action
Uses • Not used for abortion • Used for abortion in the 2nd
• To induce and augment trimester
labor • Used as Vaginal suppository
• For post-partum hemorrhage (PGE2) for induction of labor
• For post-partum hemorrhage
Tadesse B. (PhD) 95
Uterotonics Summary
• Can be used for both labor induction/augmentation and control of
postpartum hemorrhage.
• All of these medications have extensive side effect profiles and the
potential for maternal and/or fetal toxicity.
– Thus, a good understanding of their administration and dosing is
essential for safe and effective use.
• Uterotonics includes Pitocin, methergine, and prostaglandins
• In general, this class of medications works to promote myometrial
contraction by increasing intracellular calcium concentrations.
• Pitocin increases intracellular calcium via the phospholipase C/IP3
pathway
• Methergine is thought to bind to α-adrenergic receptors on the
myometrial cell and alter transmembrane calcium channel activity,
resulting in calcium influx.
• Prostaglandins not only increase intracellular calcium by altering
transmembrane permeability, but they also promote gap junction
formation and upregulate expression of oxytocin receptors
Tadesse B. (PhD) 96
Pharmacology of Uterine Relaxants
(Tocolytics)
Tadesse B. (PhD) 97
Pharmacology of Uterine Relaxants
• Uterine relaxation agents are called tocolytics
• Preterm birth is a leading cause of neonatal morbidity and
mortality worldwide.
• There are several pathogenic processes that can trigger
uterine contractions and cervical dilation with subsequent
delivery of the preterm neonate.
• The goal of tocolysis is to arrest uterine contractions and
prolong pregnancy to allow for administration of steroids
and possibly transport to a tertiary care center.
• Available treatments are intended to arrest uterine
contractility and are not necessarily geared toward the
underlying pathogenic process initiating labor.
• Presently, no agent is FDA approved for this indication and
all are used off-label.
Tadesse B. (PhD) 98
Tocolytics (Uterine relaxants)
• Relax the uterus and arrest threatened abortion or delay premature
labor
– β-adrenergic-receptor agonists
– Calcium channel blockers
– Prostaglandin (PG) synthesis inhibitors (Cyclooxygenase
(COX) inhibitors)
• Other agents - Hydroxyprogesterone, MgSO4, nitric oxide donors,
and oxytocin receptor antagonists (atosiban)
– Atosiban: is an inhibitor of the hormones oxytocin and vasopressin.
• Used as an intravenous medication as a labour repressant to halt premature labor.
• Use: Prevention of premature labor
– Combined with corticosteroids (betamethasone or
dexamethasone)
• Used to enhance lung surfactant production
Tadesse B. (PhD) 99
Tocolytics (Uterine relaxants)…
β-adrenergic-receptor agonists
• It includes Ritodrine, terbutaline, salbutamol (albuterol)
• They are short-acting β2-adrenoreceptor agonist
• Terbutaline as a tocolytic to delay preterm labor for up to 48
hours
– Selective β2-agonist used specifically as a uterine relaxant
– Activate enzyme adenylate cyclase, ↑ the level of cAMP
• cAMP ↓ intracellular Ca2+ level, hence ↓ sensitivity of
actin myosin contractile unit
• Side Effect
– Tremor, nausea, vomiting, flushing, sweating, tachycardia
(high dose), hypotension, hyperglycemia, hypokalemia
Tadesse B. (PhD) 100

Calcium Channel Blockers
• Nifedipine
– Causes relaxation of myometrium
– Markedly inhibits the amplitude of spontaneous and
oxytocin-induced contractions
• Side Effects
• Headache, dizziness, hypotension, flushing, constipation,
ankle edema, coughing, wheezing, tachycardia
PG synthesis inhibitors
• NSAID,s: Aspirin, indomethacin, ibuprofen
– Depletion of PGs prevents stimulation of uterus
– Increase the length of gestation
– Prolong spontaneous labor or interrupt premature labor
• Side Effects
– Ulceration, Premature closure of ductus arteriosus, Decrease
amniotic fluid volume Tadesse B. (PhD) 101
Fig.1: Contractant and relaxant pathways of a
myometrial cell.
Ptase: Phosphate kinase; MLCK: Myosin light-chain
kinase; CaCAM: Calcium–calmodulin complex;
CAM: Calmodulin; PLC: Phospholipase C;
PIP2: Phosphatidylinositol 4,5-biphosphate; IP3:
Inositol triphosphate; Pg: Prostaglandin; Oxy:
Oxytocin; SPR: Sarcoplasmic reticulum Tadesse B. (PhD) 102
Magnesium sulphate (MgSO4)
• Reduces striated muscle contractions and blocks peripheral
neuromuscular transmission by reducing acetylcholine release at the
myoneural junction.
• Prevents convulsions in preeclampsia and directly uncouples
excitation–contraction in myometrial cells through inhibition of
cellular action potentials
• Trigger cerebral vasodilation, thus, reducing ischemia generated
by cerebral vasospasm during an eclamptic event.
• Competitively blocking intracellular calcium channels,
decreasing calcium availability.
– ↓ calcium uptake by competing for its binding sites and thus
inhibiting smooth muscle contractility
– Activating adenylyl cyclase (thereby ↓ intracellular calcium)

Magnesium sulphate (MgSO4)
• Preferred over β-adrenergic agonists in patients with
– Heart disease
– Diabetes
– Hypertension, or
– Hyperthyroidism
• Side Effects:
– Lose of reflex, respiratory depression and cardiac arrest

• Contraindications to tocolytics
– Acute fetal distress (except during intrauterine
resuscitation)
– Chorioamnionitis (an infection of the placenta & the amniotic
fluid)
– Eclampsia or severe preeclampsia
– Fetal demise (of a singleton pregnancy), fetal maturity and
maternal hemodynamic instability
Precaution to tocolytics
• Should be used with extreme care because they can cause
– Pulmonary edema, myocardial infarction, respiratory arrest,
cardiac arrest and death
– In newborns: Respiratory depression, intraventricular
hemorrhage, necrotizing enterocolitis

Tocolytics Summary
• It is important to choose a tocolytic based on efficacy and safety, and the choice at
times will be patient and situation specific (i.e. not administering indomethacin to a
patient greater than 32 weeks’ gestation or adjusting the nifedipine dose for a
patient with mild hypotension).
• It is important to remember appropriate fetal surveillance when indicated, especially
with indomethacin administration.
• Magnesium is thought to function as a calcium channel blocker, thereby reducing
intracellular calcium and preventing myometrial contraction.
• β-Adrenergic-receptor agonists bind β2-adrenergic receptors on the myometrial cell.
– This interaction leads to ↑ed cAMP and activation of protein kinase.
– Protein kinase inactivates MLCK and prevents contraction.
• Nitric oxide donors relax smooth muscle via interaction with guanylyl cyclase.
– This leads to ↑ cGMP and inactivation of MLCK.
• Calcium channel blockers both directly block the entry of calcium ions into the
myometrial cell and prevent intracellular calcium release from the sarcoplasmic
reticulum.
• COX inhibitors prevent prostaglandin formation and thus block their contractile
effects on the myometrium.
• Oxytocin receptor antagonists competitively inhibit oxytocin from binding oxytocin
receptors.

Abortifacients

Abortifacients
• An abortifacient is any substance that is used to terminate
a pregnancy (induces abortion).
• Induced abortion is the termination of an implanted embryo
by artificial measures
• Medical abortion is a safe, reliable and non-surgical means of
abortion for people who have made an informed decision
that is the best option for them
• Medication abortion is an alternative to surgical abortion in
the early weeks of pregnancy (up to 9 weeks).
• Medication abortion is not suitable for everyone.
• It may not be recommended if you have certain medical
conditions, take some medicines (such as blood thinners or
steroids) or had allergic reactions
Abortifacients…
Why Women have Abortions?
• There are several reasons why a woman who desires a child would want
her pregnancy terminated by induced abortion.
• First of all: Her physical health may be in danger because of being
pregnant, so the abortion is needed due to the threat of severe illness or
death.
– Maternal disorders that threaten a pregnant woman include diabetes, kidney
disease, and disorders of the circulatory system.
– Therapeutic abortion is an induced abortion to prevent harm to the woman
• Second: Amniocentesis, fetoscopy, ultrasound, or fetal blood tests may
have indicated grave fetal abnormalities and a woman or couple may
choose to terminate the pregnancy to avoid giving birth to a severely
handicapped infant.
– Amniocentesis is performed most effectively around the 16th week of
pregnancy and it can take several weeks for the results of some of the
tests to be known.
– Therefore, in these cases, induced abortion in the second or early third
trimester must be done at some discomfort or even risk to the woman

Abortifacients…
Why Women have Abortions?
• In another category is the termination of unwanted pregnancies.
• Why would a pregnancy be unwanted?
• One reason could be because it occurred
– “By accident” as a result of coitus between a couple with no
long-term relationship or,
– As the result of incest or rape.
• Another reason could be that a couple that originally wanted a child
changed their minds; perhaps their financial situation worsened or a
divorce is imminent.
• An unwanted pregnancy often occurs because a contraceptive
– Measure failed or
– Was not used properly or
– Was simply not used at all.
• Thus, termination of a potentially healthy fetus carried in a
physically healthy woman can occur because of threats to the
emotional health and well-being of the potential parent(s)
Abortifacients…
• Historically, lead & quinine have been used as abortifacients, but now
OTC preparations such as aspirin, acetaminophen, iron, and herbal
preparations are more commonly used to induce abortion.
• Common abortifacients used in performing medical abortions include
mifepristone & misoprostol to terminate a pregnancy
– Both drugs are taken orally.
• Mifepristone ends a pregnancy by blocking the action of the hormone
(progesterone) that supports the pregnancy.
• Misoprostol causes the cervix to soften and the uterus to contract to
expel the pregnancy.
– The combined use of mifepristone followed by misoprostol 1-2 days later is
approved for use up to 10 weeks' gestation (70 days after the start of the last
menstrual period)
• Synthetic oxytocin, which is routinely used safely during term labor, is
also commonly used to induce abortion in the second or third
trimester.
• Herbal abortifacients is also given to women who seek to terminate a
pregnancy, although their use may carry risks to the health of the woman
Abortifacients…
• Methotrexate: a drug used to treat cancer, ectopic pregnancy,
and arthritis
– Can be used instead of mifepristone in combination with misoprostol
to induce early abortion
– For this reason contraception is often advised while using methotrexate
for management of a chronic condition
• The greatest dangers of abortifacients are the effect of the toxin
on the mother and the potential teratogenic effect on the fetus.
• Most attempts to chemically abort a fetus are made in the first
trimester.
• In addition, women who present with significant vaginal
bleeding should be questioned about possible abortifacient use

Abortifacients…
Pharmaceutical abortifacients (Most Widely Drugs)
• Mifepristone, a progesterone receptor competitive antagonist
– First approved in 1988 under the trade name Mifegyne for medical
termination of early pregnancy in conjunction with a prostaglandin
analogue.
• Misoprostol, a synthetic prostaglandin E1 (PGE1) analogue
– First approved in 1988 under the trade name Cytotec for reducing the
risk of NSAID-induced gastric ulcers.
• Misoprostol is approved in France under the trade name GyMiso
for use with mifepristone for medical abortion.
• Misoprostol is used off-label with mifepristone for medical
abortion in the U.S.
• Some other abortifacients include:
– Methotrexate, Progesterone, Migraine, Sumatriptan, Ergotamine,
Mercaptopurine

Abortifacients…
Herbal Abortifacients
• Many herbs and plants sold "over the counter" today may act as
abortifacients, including wild carrot, black cohosh, slippery elm,
pennyroyal, nutmeg, mugwort, papaya, vervain, common rue, &
tansy
• There is no available data on the efficacy of these plants in humans.
– Some animal studies have found them to be effective.
• The use of herbs to induce abortion should be avoided due to the risk
of serious side effects.
• King's American Dispensatory of 1898 recommended a mixture
of brewer's yeast & pennyroyal tea as "a safe and certain abortive".
• An older 'remedy' popular in the 1970s for unwanted pregnancy is
using Vitamin C.
– "A Woman's Book of Choices: Abortion, Menstrual Extraction, RU-486"
by Rebecca Chalker and Carol Downer, says to take 6-10 grams of
ascorbic acid (pure Vitamin C) a day for 5-10 days.

Abortifacients…
Advantages and disadvantages of medication abortion
• Medication abortion is not suitable and may not work for everyone
Advantages of medication abortion include:
• Effective for around 95 to 98% pregnancies (up to 9 weeks) and
no further treatment is needed.
• Does not need to take place in a hospital or day surgery so it doesn't
require a surgeon, anaesthetist or other medical staff.
– This makes it a suitable alternative for people in remote areas as
long as they have access to emergency care.
• A less clinical & non-surgical procedure, which some may prefer
• Some people feel it is a more natural process.
• It happens in a home environment.
• Usually have more choice about the timing.
Abortifacients…
Advantages and disadvantages of medication abortion…
• Medication abortion is not suitable and may not work for everyone.
Disadvantages of medication abortion include:
• Tend to be more time consuming than surgical abortions
– There may be more doctor visits and tests.
• It may not work for some people so the medication needs to be
repeated or a surgical abortion is needed.
• Pain & bleeding generally last longer than following a surgical
abortion.
• It is difficult to predict when a medication abortion is complete
– It may take longer than the expected 3 -10 hours, after taking the
second medication
• She need to stay within 1-2 hours of emergency services for 2 weeks
after a starting your tablets.
• Abortion medications are not suitable for some people
Drug Used in Pregnancy

Drug Used in Pregnancy
• Pregnancy is a unique period in a woman’s life.
• Many changes are happening to her body that may affect the
pharmacology of medications.
• During pregnancy:
– A woman’s gastric pH is ↑ed & gastric motility is reduced
• Which may interfere with the rate & extent of medication absorption
– Maternal plasma volume is ↑ed leading to changes in the volume of
distribution.
– In addition, ↑es in progesterone & estradiol levels may affect the
hepatic metabolism of some medications.
– Glomerular filtration rate is ↑ed due to ↑ renal blood flow which may
affect renally cleared medications.
• Despite the changes, the pharmacology of most medications is not
altered enough to require dosing changes

Drug Used in Pregnancy…
• Drugs are used in over half of all pregnancies, and prevalence of use
is increasing.
• The most commonly used drugs include antiemetics, antacids,
antihistamines, analgesics, antimicrobials, diuretics, hypnotics,
tranquilizers, and social and illicit drugs.
• Despite this trend, firm evidence-based guidelines for drug use during
pregnancy are still lacking.
Regulatory information about drug safety during pregnancy
• Until recently, the FDA classified over-the-counter & prescription
drugs into 5 categories of safety for use during pregnancy (A, B, C,
D, X).
– However, few well-controlled studies of therapeutic drugs have been
done in pregnant women.
• Most information about drug safety during pregnancy is derived from
animal studies, uncontrolled studies, and post-marketing
surveillance.
• Consequently, the FDA classification system led to confusion and
difficulty applying available information to clinical decisions.
Regulatory information about drug safety during pregnancy
• In December 2014, the FDA responded by requiring that the pregnancy categories
A, B, C, D, and X be removed from the labelling of all drugs.
• Instead of categories, the FDA now requires that labelling provide information
about the specific drug in a consistent format (called the final rule or Pregnancy
and Lactation Labelling (Drugs) Final Rule).
• The information required by the FDA has 3 subsections:
• Pregnancy:
– Information relevant to the use of the drug in pregnant women (e.g. dosing, fetal risks)
and
– Information about whether there is a registry that collects and maintains data on how
pregnant women are affected by the drug
• Lactation:
– Information about using the drug while breastfeeding (e.g. the amount of drug in
breast milk, potential effects on the breastfed child)
• Females and males of reproductive potential:
– Information about pregnancy testing, contraception, and infertility as it relates to
the drug
• The pregnancy and lactation subsections each include 3 subheadings (risk
summary, clinical considerations, and data) that provide more detail.
• The final rule does not apply to non-prescription (over-the-counter) drugs.
• The FDA has categorized the potential teratogenic risk of
medications by an A, B, C, D, X system.
• Category A:
– Controlled studies in women have failed to demonstrate a risk to
the fetus in the 1st trimester and there is no evidence of risk in later
trimesters.
– The possibility of fetal harm appears remote.
– Medications in this class are considered safe to use in pregnancy.
– Examples of medications in this class are vitamins & levothyroxine
• Category B:
– Either animal‐reproduction studies have not demonstrated a fetal risk
but there are no controlled studies in pregnant women, or
– Animal studies have demonstrated risk to the fetus that was not
confirmed in controlled studies in pregnant women in the 1st
trimester and there is no evidence of a risk in later trimesters.
– Medications in this class are generally considered safe.
– Examples of medications in this class are acetaminophen and
amoxicillin.
• Category C:
– Studies in animals have revealed adverse effects on the fetus and there are
no controlled studies in women, or studies in women and animals are not
available.
– Drugs from this class can be given to pregnant women if the benefit to the
mother outweighs the risk to the fetus.
– Examples of medications in this class are diltiazem & spironolactone.
• Category D:
– Evidence of human fetal risk has been documented, but the benefits to the
mother may be acceptable despite the risk to the fetus.
– Drugs in this class may be used in pregnancy if the benefits to the mother
outweigh the risk to the fetus (i.e. a life threatening situation or a serious
disease for which safer medication cannot be used or are not efficacious).
– Examples of medications in this class are phenytoin and valproic acid.
• Category X:
– Studies in animals or humans have demonstrated teratogenic effects.
– The risk to the fetus clearly outweighs any potential benefit to the mother
– Drugs in this category are contraindicated in pregnancy.
– Examples of medications in this class are thalidomide and warfarin
Effects of drug use during pregnancy
• During pregnancy, drugs are often required to treat certain
disorders.
• In general, when potential benefit outweighs known risks, drugs
may be considered for treatment of disorders during pregnancy.
• Not all maternal drugs cross the placenta to the fetus.
• Some drugs that cross the placenta may have a direct toxic
effect or a teratogenic effect.
• Drugs that do not cross the placenta may still harm the fetus by
– Constricting placental vessels and thus impairing gas and nutrient
exchange
– Producing severe uterine hypertonia that results in anoxic injury
– Altering maternal physiology (e.g. causing hypotension)

Effects of drug use during pregnancy…
• Drugs diffuse across the placenta similarly to the way they cross
other epithelial barriers.
• Whether and how quickly a drug crosses the placenta depend on
the:
– Drug’s molecular weight, extent of its binding to another
substance (e.g. carrier protein), area available for exchange across
the placental villi, and amount of drug metabolized by the
placenta.
• Drugs with low molecular weight (< 500 daltons), low
maternal protein binding, low ionization, and high
lipophilicity
– Are more likely to cross the placenta and enter the fetal circulation
• Substances with a high mol. weight (e.g. protein-bound drugs)
usually do not cross the placenta.
– One exception is immune globulin G, which may be used to treat
disorders such as fetal alloimmune thrombocytopenia.
Vaccines During Pregnancy
• Immunization is as effective in women who are pregnant as in those
who are not.
• Influenza vaccine:
– Recommended for all pregnant women in the 2nd or 3rd
trimester during influenza season.
• The tetanus-diphtheria-pertussis (Tdap) vaccine:
– Recommended for all pregnant women during the 3rd trimester
• COVID-19 vaccination:
– The CDC recommends for all people 5 years and older,
including people who are pregnant, breastfeeding, trying to
get pregnant now, or might become pregnant in the future.
– The benefits of receiving a COVID-19 vaccine outweigh any
known or potential risks of vaccination during pregnancy.

Vaccines During Pregnancy…
• Other vaccines: should be reserved for situations in which the
woman or fetus is at significant risk of exposure to a hazardous
infection and risk of adverse effects from the vaccine is low.
– Vaccinations for cholera, hepatitis A, hepatitis B, measles,
mumps, plague, poliomyelitis, rabies, typhoid, and yellow
fever may be given during pregnancy if risk of infection is
substantial.
• Live-virus vaccines: should not be given to women who are or
may be pregnant.
– Rubella vaccine: an attenuated live-virus vaccine, may cause
subclinical placental and fetal infection.
– Varicella vaccine: another attenuated live-virus vaccine that
can potentially infect the fetus; risk is highest between 13
weeks and 22 weeks gestation.
• This vaccine is contraindicated during pregnancy.

Drug Used in Pregnancy: Antibiotics

Drug Used in Pregnancy: Antibiotics…

Drug Used in Pregnancy: Antiepileptic Drugs

Drug Used in Pregnancy: Antiepileptic Drugs…

Drug Used in Pregnancy: Antiepileptic Drugs…

Drug Used in Pregnancy: Cough and Cold

Drug Used in Pregnancy: Cough and Cold…

Drug Used in Pregnancy: Diabetes Mellitus

Drug Used in Pregnancy: Diabetes Mellitus…

Drug Used in Pregnancy: Analgesics
137
Tadesse B. (PhD)
Drug Used in Pregnancy: Analgesics…

Drug Used in Pregnancy: Immunizations

Pharmacology of Contraceptives

Introduction
• Birth control can be accomplished by interfering with
the reproductive process at any step from gametogenesis
to nidation (implantation of a fertilized ovum).
• Pharmacologic methods of contraception include:
– Oral contraceptives, etonogestrel implants, injectable
medroxyprogesterone acetate, intrauterine devices (IUD),
vaginal rings, and transdermal patches
• Non-pharmacologic methods include:
– Surgical sterilization (tubal ligation, vasectomy),
– Mechanical devices (condom, diaphragm, cervical cap), &
– Avoiding intercourse during periods of fertility (calendar
method, temperature method, cervical mucus method)

Hormonal methods of contraception
• Oral contraceptives (OCs) - There are two types
– Combined oral contraceptive pills (COC) - Containing both
estrogen plus a progestin
• More widely used; e.g. Ethinyl estradiol/norethindrone
– Progestin-only pills (minipills) - Contains only progestin
• E.g. Norethindrone
• Injectable preparations
• Implants

Combination Oral Contraceptives
• Since their introduction in the late 1950s, combination OCs have become one of
the most widely prescribed families of drugs.
• These drugs are both safe and effective, although minor side effects are common
• Estrogen content usually is ethinyl estradiol and mestranol
• Progestin - May be norethistrone or levonorgestrel
• Generally a pill with low estrogen and progestin is preferred
• Mechanism of action
– Combination OCs reduce fertility primarily by inhibiting ovulation
– Estrogen suppresses the release of FSH from the anterior pituitary by a
negative feed back effect → suppresses development of ovarian follicles
– Progestin in the hypothalamus and pituitary suppress secretion of LH →
prevents ovulation
– Progesterone and estrogen make the uterus unfavorable for implantation
• Secondary mechanisms include thickening of the cervical mucus (creating a barrier
to the penetration of sperm) and alteration of the endometrium, making it less
hospitable for implantation

Table: Progestins Used in Combination Oral Contraceptives

Combined oral contraceptives…
Types of preparation of Combined OC
• The 28-day regimens are subdivided into four groups:
Monophasic, Biphasic, Triphasic, and Quadriphasic (four-
phasic).
• Monophasic regimen: the daily doses of estrogen and progestin
remain constant throughout the cycle of use.
• Other regimens: Either the estrogen or the progestin changes
(or both change) once or twice as the cycle progresses.
• The biphasic, triphasic, and quadriphasic schedules reflect efforts
to more closely simulate ovarian production of estrogens and
progestins.
– However, these preparations appear to offer little or no
advantage over monophasic OCs
• Triphasic form of COC

• Side Effects
– Weight gain due to fluid retention and anabolic effect of
both estrogen and progesterone
– Mild nausea, flushing, dizziness and depression
– Skin changes like acne and increased pigmentation
– Amenorrhea of variable duration, risk of cardiovascular
diseases like thromboembolism, myocardial infraction (MI),
stroke, hypertension (HTN)
• Drug interactions: Combined OC are metabolized by CYP450
– Enzyme inducers like Rifampicine, carbamazepine,
phenytoin may ↓ contraceptive effectiveness

Progestin-only Oral Contraceptives
• Contain a progestin but no estrogen.
• Because they lack estrogen, minipills do not cause headaches,
thromboembolic disorders, nausea, or most of the other adverse
effects associated with combination OCs
• Usually contain norethistrone and levonorgestrel
• Mechanism of action
– Makes cervical mucus inconvenient for sperm migration
– Prevents ovulation
• Preferred in lactating women and in whom estrogen is
contraindicated
• Main disadvantage: Less reliable, menstrual irregularity and
risk of pregnancy due to missed pills is very much higher in this
case than the COCs

Emergency (Post coital) contraceptives
• Contraception used within 72 hours of unprotected intercourse
• Shouldn’t be used in place of normal family planning methods
• Emergency Contraceptive: can be accomplished in two basic ways:
– Taking an emergency contraceptive pill (morning after pill) or
– Inserting a copper-T intrauterine device (IUD)
• Use
– A woman has made sex against her will (raped)
– A condom has broken
– An intrauterine device (IUD) come out of its place
– A woman has missed two or more pills or late to have an injection
of medroxy progesterone acetate
– Sex took place with out contraception

Emergency (Post coital) contraceptives…
• Dosage
– Post pill: Most commonly used & contains levonorgestrel 0.75
mg
• Take 1 tab. as soon as possible and same dose after 12hrs
– Low dose Combined OCs containing ethinyl estradiol 0.03mg &
levonorgestrel 0.15 mg may also be used as alternative in two
doses of 4 tablets in 12 hours difference and
– If the estrogen content is 0.05mg, two doses of 2 tablets in 12
hours difference can be given
– The latter two methods are less effective and with more unwanted
effects than postpill
• N.B.
– The sooner pills are taken the better
– Extra pills will not make the method more effective
– Intauterine device (IUDs) may also be used for emergency
contraception
Long acting contraceptives
• A) Depot Medroxy progesterone acetate (DMPA)
– Administered intramuscularly (Depo-Provera) or Sc (Depo-
SubQ Provera 104 )
– Protects against pregnancy for 3 months or longer by
inhibiting secretion of gonadotropins
– Effective and safe
– Menstrual irregularities are common but may be corrected
after repeated uses
– The drug thereby:
• Inhibits follicular maturation and ovulation,
• Thickens the cervical mucus, and
• Causes thinning of the endometrium, making implantation unlikely
– When injections are discontinued, return of fertility is delayed
(by an average of 9 months
Long acting contraceptives…
• B) Subdermal Etonogestrel Implants
– A subdermal system (Nexplanon) for delivery of etonogestrel
is available for long-term, reversible contraception.
– Nexplanon is among the most effective contraceptives available
– Nexplanon consists of a single 4-cm rod that contains 68 mg
of etonogestrel, a synthetic progestin
– The rod is implanted subdermally in the groove between the
biceps and triceps in the non-dominant arm.
– Etonogestrel then diffuses slowly and continuously, providing
blood levels sufficient for contraception for 3 years, after
which the rod is removed.
– If continued contraception is desired, a new rod is implanted

Long acting contraceptives…
B) Subdermal Etonogestrel Implants…
• Pharmacokinetics
– Daily release of etonogestrel is 60 to 70 mcg initially and gradually
declines to 25 to 30 mcg over 3 years.
– Absorbed drug is slowly metabolized by the liver.
– When the rod is removed, etonogestrel becomes undetectable within
5 to 7 days
• Mechanism of Action
– Etonogestrel suppresses ovulation and thickens cervical mucus.
– In addition, it causes the endometrium to become involuted and
hence hostile to implantation.
– Six non biodegradable capsules containing levonorgestrel are
implanted subcutaneously
– The tubes release their progestin content over 5 years
• Adverse effects: Irregular bleeding, headache

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Reproductive System Module

By: Tadesse B. (PhD)

• Pharmacology of agents used for treatment of sexual and

• Pharmacology of uterotonics, abortifacients, uterine relaxants,

• Pharmacology of contraceptives (2 hrs)

• Hepatic metabolism converts testosterone to

Actions and Effects

• Testes: Testosterone is responsible for spermatogenesis and

Consequences of Androgen Deficiency

Consequences of Androgen Deficiency…

• Most common reason:

Disease Causative Organism

• Acquired Immunodeficiency Syndrome

Gonococcal Infections (Gonorrhea): (Causative Organism:

Pelvic Inflammatory Disease

Sexually Acquired Epididymitis

Syphilis (Causative Organism: Treponema pallidum)

• First episode • Recurrent episodes

Genital Herpes Simplex Virus Infections (Causative Organism:

• Why should we use this combination ?

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• Triphasic form of COC

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