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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:

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!