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Drugs affecting the genitourinary

tract and uterine motility1, 2

1 Reference: Eckman M, Labus D. Eds. Clinical Pharmacology Made Incredibly Easy! 3rd Ed. Philadelphia: Lippincott Williams &
Wilkins. 2009.
2

Drugs affecting uterine motility. In:

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Genitourinary Drugs

Types of drugs used for the GU tract include

1. Diuretics (discussed under CVS drugs)
2. Urinary tract antispasmodics
3. Erectile dysfunction therapy drugs
4. Hormonal contraceptives

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Urinary tract antispasmodics

Urinary tract antispasmodics

Urinary tract antispasmodics
Urinary tract antispasmodics help decrease urinary tract muscle
spasms. They include darifenacin, flavoxate, oxybutynin,
solifenacin, tolterodine, and trospium.
Adverse reactions
Possible adverse reactions to urinary tract antispasmodics include:
blurred vision
headache
somnolence
urinary retention
dry mouth
dyspepsia
constipation

nausea
vomiting
weight gain
pain
acute and secondary angleclosure glaucoma.

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Urinary tract antispasmodics

Pharmacokinetics
Flavoxate, oxybutynin, tolterodine, darifenacin, and solifenacin are most
often administered orally and are rapidly absorbed.
Trospium is administered orally but is poorly absorbed.
Oxybutynin is also available as a dermal patch.
These drugs are all widely distributed, metabolized in the liver, and
excreted in urine. Urinary tract antispasmodics also cross the placenta and
are excreted in breast milk.
Pharmacodynamics
Urinary tract antispasmodics relieve smooth muscle spasms by inhibiting
parasympathetic activity, which causes the detrusor and urinary muscles
to relax. Flavoxate and oxybutynin also exhibit many anticholinergic effects.
Pharmacotherapeutics
Urinary tract antispasmodics are used for patients with overactive
bladders who have symptoms of urinary frequency, urgency, or
incontinence.

Urinary tract antispasmodics

How oxybutynin works
When acetylcholine is released within the bladder, it attaches to receptors on the
surface of smooth muscle in the bladder, stimulating bladder contractions.
Oxybutynin suppresses these involuntary contractions by blocking the release
of acetylcholine. This anticholinergic effect is what makes oxybutynin useful in
the treatment of overactive bladder.
Urgent symptoms
Trospium is also indicated for patients with overactive bladders who have
symptoms of urge urinary incontinence, and oxybutynin acts as an
antispasmodic for uninhibited or reflex neurogenic bladder.
Drug interactions
Urinary tract antispasmodics have few drug interactions:
Use with anticholinergic agents may increase dry mouth, constipation, and
other anticholinergic effects.
Urinary tract antispasmodics may decrease the effectiveness of phenothiazines
and haloperidol.
Trospium may interfere with the elimination of certain drugs excreted through
the kidneys (such as digoxin, metformin, and vancomycin), resulting in
increased blood levels of these drugs

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Erectile dysfunction therapy drugs

Erectile dysfunction therapy drugs
Erectile dysfunction therapy drugs treat penile erectile dysfunction that results
from a lack of blood flowing through the corpus cavernosum. This type of erectile
dysfunction usually stems from vascular and neurologic conditions. Drugs used
for erectile dysfunction include alprostadil, sildenafil, tadalafil, and vardenafil.
Adverse reactions
Adverse reactions to erectile dysfunction drugs include:
decreased supine blood pressure and cardiac output
increased risk of cardiovascular events, including myocardial infarction,
sudden cardiac death, ventricular arrhythmias, cerebrovascular hemorrhage,
transient ischemic attack, and hypertension
headache
dizziness
flushing
dyspepsia
vision changes
prolonged erections (more than 4 hours), which can result in irreversible
damage to erectile tissue
penile pain (with alprostadil).

Erectile dysfunction therapy drugs

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Erectile dysfunction therapy drugs

Pharmacotherapeutics
Alprostadil, sildenafil, tadalafil, and vardenafil are all used in the
treatment of erectile dysfunction. Sildenafil is also indicated for the
treatment of pulmonary arterial hypertension.
Drug interactions
Erectile dysfunction drugs may interact with other drugs in the
following ways:
Nitrates and alpha-adrenergic blockers used in combination
with erectile dysfunction drugs may cause severe hypotension
and potentially serious cardiac events.
Ketoconazole, itraconazole, and erythromycin may result in
increased levels of vardenafil or tadalafil.
Protease inhibitors, such as indinavir or ritonavir, may cause
increased tadalafil or vardenafil levels

Hormonal Contraceptives
Hormonal contraceptives
Hormonal contraceptives inhibit ovulation.
Contraceptives typically contain a combination of
hormones.
For example, ethinyl estradiol may be combined with
desogestrel, levonorgestrel, norethindrone, norgestimate, or
norgestrel.
Also, mestranol may be combined with norethindrone.
Ethinyl estradiol or ethynodiol diacetate may also be used
alone as a contraceptive.

Pharmacokinetics
Hormonal contraceptives are absorbed from the GI tract
and are widely distributed. Theyre metabolized in the
kidneys and excreted in urine and feces.

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Hormonal Contraceptives

Hormonal Contraceptives
Drug interactions
Hormonal contraceptives can interact with other medications in
various ways:
Antibiotics, oxcarbazepine, phenobarbital, phenytoin, topiramate,
and modafinil may decrease the effectiveness of oral contraceptives.
A patient taking these drugs with a hormonal contraceptive needs to
use a barrier contraceptive.
Atorvastatin may increase serum estrogen levels.
Cyclosporin and theophylline have an increased risk of toxicity when
taken with hormonal contraceptives.
Prednisone increases the therapeutic and possibly toxic effects of
hormonal contraceptives.
Several herbal medications can affect serum levels of hormonal
contraceptives.

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Hormonal Contraceptives
Adverse events
Potentially serious adverse reactions to hormonal contraceptives
include arterial thrombosis, thrombophlebitis, pulmonary
embolism, myocardial infarction, cerebral hemorrhage or
thrombosis, hypertension, gallbladder disease, and hepatic
adenomas.
Other adverse reactions include:
acne
bleeding or spotting
between menstrual
periods
bloating
breast tenderness or
enlargement
changes in libido

diarrhea
difficulty wearing contact lenses
unusual hair growth
weight fluctuations
upset stomach
vomiting

Combination of ethinyl estradiol and norgestimate is also used to

treat moderate acne in females younger than age 15.

Some forms of hormonal

contraceptives

1.
2.
3.
4.

Illustrations of
Pills
Patch
Hormonal IUD
Implant

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Drugs affecting uterine motility

Uterine Stimulants

There are three clinical uses for uterine stimulants:

To induce abortion in the first half of pregnancy
(illegal in the Philippines and unacceptable for
Christians and many other religions)
To induce or augment labor in late gestation
To prevent or arrest postpartum hemorrhage
Uterine contractions are naturally phasic allowing
for resumption of normal utero-fetal-placental
hemodynamics between contractions in pregnancy
Post-partum hemorrhage
stimulation of tonic contractions is necessary to
avert excessive blood loss.

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Four groups of compounds used

clinically to stimulate uterine motility
1. Oxytocin
2. Prostaglandins
3. Ergot Alkaloids
4. Progesterone receptor antagonists

Oxytocin (OT)
The most potent and specific, which is commonly used to
induce or augment labor in late gestation.
nonapeptide hormone is synthesized in the
hypothalamus and stored in the posterior pituitary
MOA
Physiological regulation of parturition is not yet completely clear
There is a marked increase in the concentration of OT
receptors in the uterus at the time of parturition, suggesting
that OT plays an important functional role in mediating this event.

Pharmacokinetics
administered parenterally. given IV by infusion pump to induce or
augment labor
half-life of 1 to 6 minutes.
produces clonic uterine activity.
For prophylaxis or treatment of postpartum hemorrhage, OT can
be given intramuscularly (IM) or IV in large doses, which result in
tonic, sustained contractions.

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Oxytocin
Side Effects
Hyperstimulation, this is usually easy to recognize by the
appearance of frequent (<2 minute interval) contractions,
or of a prolonged tetanic contraction usually accompanied
by maternal pain and often fetal bradycardia.
If there is no reduction in tone or continued fetal bradycardia, it
may be necessary to administer 2-adrenergic agonists IV
Uterine hypertonus, rupture, hypotension, H2O intoxication
with severe hypernatremia
Hypoxia in Fetus

Prostaglandins (PGs) of the E or F families.

in combination with mifepristone to induce early abortion (illegal in the
Philippines and unacceptable for Christians and many other religions)
MOA
principally PGE2 and PGF2
the role of this process in normal labor is controversial.
stimulate uterine activity at any time during gestation and for this
reason are used as abortifacients
They are also commonly used in late gestation and can ripen the cervix
as well as cause myometrial contraction
Pharmacokinetics
For the termination of pregnancy in the second trimester, PGF2 is
given into the amniotic fluid.
Uterine activity often does not occur for up to 12 hours, indicating an
indirect mechanism
Intracervical, intravaginal, IV
Once the cervix is ripe, it is common to switch to IV OT. OT should not
be given for at least 6 hours after the last administration of a PG to avert
hyperstimulation.
Misoprostol
given orally to induce labor at term. It appears to be effective and
safe.
Methylated PGs
more resistant to metabolism, more efficacious, and have longer
actions.

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Prostaglandins
Side Effects
Uterine hypertonus, rupture, vomiting, diarrhea, fever,
bronchospasm
Hyperstimulation resulting from PG gel insertion into the
cervix or vagina may be a greater problem, but in severe
cases, saline can be used to wash out the PG.
increased incidence of uterine rupture during labor in
women who have had a previous cesarean section
gastrointestinal and pulmonary problems

Ergot alkaloids
cause intense tonic myometrial contractions, which
are undesirable for stimulating labor but useful for
treating postpartum hemorrhage
MOA
Unclear
Most evidence suggests their contractile effects are mediated by
interaction with 1-adrenergic receptors but they also bind to
serotonin and dopamine receptors.

Pharmacokinetics
Oral, IM, IV
Half life: approx 2 hours

Side Effects
used to control postpartum hemorrhage
a serious risk is hypertension.
myocardial ischemia and infarction

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Progesterone receptor antagonists

mifepristone is the most widely used
useful for termination of early pregnancy when uterine
quiescence is dependent principally on progesterone
(illegal in the Philippines and unacceptable for Christians and
many other religions)

They have also recently been used to induce labor in late

gestation.
MOA
molecular mechanisms are poorly understood

Pharmacokinetics
Oral
Half life: 20-30 hrs
mifepristone is increasingly used for early (<8 weeks gestation)
termination of pregnancy.
It is most effective when used in concert with a PG analogue
(usually misoprostol)

Side Effects
has very few systemic side effects.

Uterine Relaxants
There are four clinical uses for uterine
relaxants:
1. To prevent or arrest preterm labor
2. To reverse inadvertent overstimulation
3. To facilitate intrauterine manipulations
4. To relieve painful contractions during
menstruation, referred to as
dysmenorrheal

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Uterine Relaxants
Tocolytics
groups of agents used to stop uterine
contractions
most commonly administered between 20
and 35 weeks of gestation
nonspecific and also cause relaxation of
other smooth muscle beds, including
blood vessels.

2-Adrenergic receptor agonists

Usually ritodrine or terbutaline,
Use is declining because of maternal side effects.
MOA
stimulation causes relaxation, an effect mediated by activation
of adenylyl cyclase and inhibition of myosin light chani
kinase (MLCK) activity

Pharmacokinetics
IV or oral
HL: 2hrs
Ritodrine
tocolytic agent in late pregnancy.
administered by an IV infusion pump

Terbutaline and other 2-agonists have also been used as

tocolytics
Drugs often lose their effectiveness as a result of tachyphylaxis

Side effects
Hypotension, tachycardia, palpitations, dysrhythmias, pulmonary
edema, hyperglycemia, hypokalemia
Tachycardia in fetus

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Nonsteroidal antiinflammatory drugs (NSAIDs)

and PG synthesis inhibitors
Potential adverse effects on the fetus.
MOA
NSAIDs inhibit PG synthesis by inhibiting cyclooxygenase
Increased PG generation noted at parturition appears to result
predominantly from increased COX-2.

Pharmacokinetics

Oral, rectal
HL: 4-5 hrs
Birth could be delayed for 48 hours through use of the NSAIDs.
Intravenous infusions of selective COX-2 inhibitors such as
celecoxib.

Side effects
Indomethacin caused the fetal ductus arteriosus to be
constricted
Gastrointestinal bleeding, nausea, headaches, myelosuppression
Fetal Renal toxicity
Intracranial hemorrhage, patent ductus arteriosus, and
necrotizing enterocolitis in neonates receiving indomethacin

Magnesium sulfate
lack of evidence of effectiveness from welldesigned trials
MOA
its mechanism of action is unclear but may be related
to its actions as a divalent cation and competition
with Ca2+ in myometrial cells.

Pharmacokinetics
IV or IM
excreted by the kidney

Side Effects
may cause obtundation, a loss of deep tendon
reflexes, respiratory depression, and myocardial
depression.
often the tocolytic drug of choice because of its low
toxicity when given at low infusion rates.

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Calcium-channel blockers
Principally nifedipine
Efficacy has not been proven
MOA
ability to limit Ca2+ influx by blocking L-type Ca2+ channels in
smooth muscle
in animals showed that Ca2+-channel blockers produce
metabolic acidosis in the fetus

OT antagonist
Atosiban inhibitor of oxytocin and vasopressin

Nitric oxide (NO) donor

inhibits uterine contractility, enhances uterine
quiescence

Progesterone
Prevent preterm labor in high-risk women
No side effects

Relation of mechanisms of action to clinical response

Induction/augmentation of labor
Induction of labor must include ripening of the cervix
Pre-induction use of PGE2 preparations will facilitate labor in
such instances.
it takes several hours for cervical ripening by PGE2.
Mechanical devices are also used to ripen the cervix, and their
effects may be partially mediated by induction of PGE2
synthesis.
In the presence of a ripe cervix, infusion of OT IV is the best way
to stimulate or augment contractions
Induction of contractions requires more OT than
augmentation. Induction at term usually requires less OT than
preterm, which is a result of increased OT receptors at term.

Care must be taken to avoid overstimulation,

two types of stimulants should generally not be used
together
At least 4 to 6 hours should elapse from the most recent
use of PGE2 before beginning OT infusion.

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Early pregnancy termination (illegal in the

Philippines and unacceptable for Christians and many
other religions)
Few OT receptors in the myometrium in early pregnancy,
and OT is of little use in stimulating activity at this time.
The antiprogestin mifepristone can disrupt embryonic
and placental development.
given alone, there is a high rate of incomplete abortion that may
still require surgical completion.
When given in combination with a PG analog, mifepristone is
very successful in inducing abortion in pregnancies at less than 8
weeks' gestation.
Surgical abortion is usually preferred beyond 8 weeks' gestation.

However, administration of PGs locally is also efficacious,

particularly after 18 weeks' gestation.

Treatment of preterm labor

Vascular relaxation, subsequent decreases in blood
pressure, and tachycardia are the most common side
effects

Treatment of dysmenorrhea
The most common form of dysmenorrhea is primary
dysmenorrhea, consisting of uterine spasm without
underlying pathology.
results from the release of PGs from degenerating endometrial
cells.

NSAIDs have been extremely effective in preventing or

ameliorating this
administered a few hours before expected menstruation, or at the
first sign of bleeding, and taken 1 to 2 days thereafter.

An alternative approach is to use oral contraceptives to

inhibit ovulation, reducing synthesis of PGs in the
endometrium and resulting in less uterine spasm during
menstruation.

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On Abortion
Illegal in the Philippines and unacceptable for
Christians and many other religions
There are several reasons why some people
consider abortion
The developing baby has a birth defect or genetic
problem
The pregnancy is harmful to the woman's health
(therapeutic abortion)
The pregnancy resulted after a traumatic event such as
rape or incest
The woman may not wish to be pregnant (elective
abortion)

What do you think?

As he went along, he saw a man blind from

birth. His disciples asked him, "Rabbi, who
sinned, this man or his parents, that he was
born blind? Neither this man nor his
parents sinned," said Jesus, "but this
happened so that the work of God might be
displayed in his life.
- John 9:1-3, NIV -

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Questions?
Thank you for your kind attention!

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