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A lecture by Dr. Ballacua
Citation preview
9/7/2015
1
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:
http://www.google.com.ph/url?sa=t&rct=j&q=drugs%20affecting%20uterine%20motility&source=web&cd=1&ved=0CCIQFjAA&url
=http%3A%2F%2Fimages.clark12kent.multiply.multiplycontent.com%2Fattachment%2F0%2FSPHYegoKCCwAAElMI-
U1%2FDrugs%2520affecting%2520uterine%2520motility.doc%3Fkey%3Dclark12kent%3Ajournal%3A10%26nmid%3D11979639
0&ei=_SObUM2cHvCVmQXE4IGoCg&usg=AFQjCNGqDAqsnVl3oBDwlL5_IL_719jO9Q
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 angle-
closure 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 antispasmodicsHow 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 drugsErectile 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, ornorgestrel.
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
Illustrations of
1. Pills
2. Patch
3. Hormonal IUD
4. Implant
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Drugs affecting uterine motility
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.
Uterine Stimulants
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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 (
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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 (
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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.
Uterine Relaxants
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 well-designed 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!