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40 Cards in this Set

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What are the MOAs of antiandrogenic drugs?
1. Antagonists block testosterone receptors

2. GnRH agonists act at the pituitary gland to shut off the release of LH and FSH

3. Antagonist of the GnRH receptor blocks the release of LH and FSH
What are the androgen receptor antagonists?
bicalutamide

flutamide

spironolactone
Biclutamide and Flutamide MOA?
-- Competitively block androgen receptors
-- blockade of receptors in the hypothalamus results in loss of feedback inhibition of LH secretion
-- plasma LH and thus testosterone are increaed markedly
Biclutamide and Flutamide therapeutic use?
-- treatment of prostatic carcinoma

-- must be given w/ GnRH analog since the increased plasma testosterone competes w/ the drug for the androgen receptors (and limits its anti-androgenic effects)
Biclutamide and Flutamide toxicity?
Biclutamide preferred over Flutamide -- biclutamide has less hepatic toxicity and can be taken once a day
Spironolactone MOA?
1. Competitive steroid antagonist of Aldo receptors
2. Partial agonist at androgen, estrogen and progesterone receptors (remember, partial agonist is antagonistic against full agonist)
3. Also partially inhibits the CYP17 which synth testosterone
Spironolactone therapeutic use?
Used to treat hirsuitism in females
What are the GnRH (analogs) receptor agonists? Availability?
leuprolide acetate -- available in 3-4m depot prep for i.m. injection

goserelin acetate -- i.m. implant lasts 3m
leuprolide, goserelin MOA?
1. Initially stim release of FSH and LH in males and females -- plasma testosterone rises initially in males

2. However, if given continuously in NON-pulsatile fashion, pituitary GnRH receptors become desensitized, leading to decreased LH secretion

3. Plasma testosterone suppressed to about 10% of normal values
Medical uses of leuprolide, goserelin?
1. Prostatic carcinoma
-- used w/ bicalutamide to prevent initial testosterone flare that can cause bone pain from metastases
-- If no metasteses, can use GnRH alone

2. Treatment of endometriosis and uterine fibroid tumors

3. Treatment of central precocious puberty
Adverse effects leuprolide and goserelin?
1. hot flushes, sweating
2. edema
3. gynecomastia
4. decreased libido
What are the obstructive symptoms of BPH?
1. urgency
2. hesitancy
3. diminished force of urinary stream
4. nocturia
What drugs do we use to treat BPH?
a1-adrenoceptor antagonists:

1. terazosin
2. doxazosin
3. tamsulosin
What is the MOA of the a1-adrenoceptor antagonists?
1. a1-adrenoceptors abundant in smooth muscle of prostate, prostatic capsule, prostatic urethra and bladder neck
-- 70% are of a1A subtype

2. pharmacologic blockade of the receptors causes a reversible relaxation of smooth muscle resulting in decreased resistance to urethral flow

3. These drugs improve the symptoms of urgency, hesitancy, weak stream and nocturia w/in 2 weeks (some have almost immediate relief)
terazosin and doxazosin general info?
-- terazosin was first a-adrenoceptor antagonist approved for BPH
-- terazosin and doxazosin produce identical therapeutic effects, but doxazosin has half life of 22h, while terazosin has half life of 12h
Therapeutic use of terazosin and doxazosin?
-- Used to treat HTN

-- Have proved efficacious for improving HTN and BPH at the same time
Adverse effects terazosin and doxazosin?
1. dizziness
2. postural hypotension (blockade vascular a1-adrenoceptors)
3. sombolence
4. asthenia = loss of energy and strength = fatigue
5. nasal congestion (unopposed cholinergic vasodilation)
6. peripheral edema
7. impotence (failure to ejaculate) - 2%
Tamsulosin use? side effects?
half-life of 12-15h

-- as efficacious as terazosin and doxazosin
-- less dizziness and orthostatic hypotension
-- increased receptor selectivity for a1A-adrenoceptors increases incidence of ejaculatory dysfxn (10%)
-- ejaculatory dysfxn consisted of failure to ejaculate, decreased volume of ejaculate, or retrograde ejaculation
finasteride, dutasteride MOA?
**5a-reductase inhibitors

1. 5a-reductase, enzyme which converts testosterone into DHT, exists in two molecular forms
-- TYPE1 - liver, skin
-- TYPE2 - prostate
2. FINASTERIDE selectively inhibits the type 2 enzyme; DUTASTERIDE inhibits both forms
3. Inhibition prevents conversion of testosterone to DHT
4. Finasteride - causes plasma DHT conc to fall by 70% and plasma T concentration to rise by 10%
5. Finasteride - causes conc of DHT w/in the prostate gland to decrease by more than 70%
6. Plasma LH is not changed
finasteride, dutasteride clinical effect in BPH?
1. decrease in size prostate gland noted by 3 months; shrinkage continues for next 1-2yrs
2. Avg size reduction is 25%, and shrinkage assoc w/ decreased BPH symptoms
3. Decreased size maintained w/ continued use of meds
4. The larger the prostate, the greater the response
5. Treatment with 5a-reductase inhibitors decreases need for TURP
finasteride, dutasteride clinical effect in male pattern baldness?
1. Inhib 5a-reductase in hair follicles can prevent hair loss
2. Used in conjuction w/ topical prep of the arterial vasodilator minoxidil to treat alopecia
Adverse effects finasteride, dutasteride?
1. impotence (decreased volume of ejaculate) and decreased libido

2. Finasteride (5mg p.o.) suppresses plasma conc of PSA by up to 50%, so patients must have periodic rectal exams to screen for prostatic cancer

3. Finasteride (1mg p.o.) does not suppress PSA

4. Trtmt w/ dutasteride for 3 months reduces serum PSA by 40%; trtmt for 6-12 months reduces the serum PSA by 50%

New baseline PSA must be made one year after beginning trtmt BPH w/ 5a-reductase inhibitor
What are the strategies for treating children w/ nocturnal enuresis?
1. Behavioral therapy preferred

2. Inhibit bladder contraction by blocking muscarinic receptors in GU tract

3. Decrease nocturnal production of urine
What are the drugs to treat nocturnal enuresis?
oxybutynin, DDAVP
oxybutynin MOA?
blocks muscarinic receptors and exerts direct anti-spasmodic effect on the detrusor muscle
DDAVP MOA?
-- long-acting synthetic analog of AVP; duration of action 6-20h

-- selective for the vasopressin V2 receptor (ration V2:V1 is 40000:1) found in principle cells of late distal tubule and collecting duct

-- can be given by nasal spray before bedtime to enhance the renal reabsorp of water and thus decrease urinary vol

-- allergic rhinitis or nasal congestion from URI slow its absorption
How do we treat overactive bladder?
muscarinic receptor antagonists:

tolteradine
solifenacin
darifenacin
tolteradine
**twice daily

- muscarinic receptor antagonist

- S/Es include somnolence, dry mouth, blurred vision, and constipation
solifenacin
**once daily

- a selective M3-muscarinic receptor antagonist

- increases the Q-Tc in normal volunteers, but is less than that caused by FQ moxifloxacin

- fewer CNS effects

- less dry mouth compared to tolteradine
darifenacin
**once daily -- best choice

- selective M3-muscarinic receptor antagonist

- no CNS or CV effects, including no increase in Q-Tc

- less dry mouth compared do tolterodine
What is impotence?
Sexual dysfxn that can result from inability to achieve an erection (ED) or inability to ejaculate.

Can be organic, psychogenic, or a mixture of the two causes.
Organic causes of ED?
1. atherosclerosis
2. DM
3. spinal cord injury
4. prostatectomy
5. treatment w/ antidepressant drugs (esp SSRIs)
6. smoking cigarettes
What is the International Index of Erectile Dysfunction (IIEF)?
-- It is a questionnaire that estimates the severity of ED

-- 5 questions in which patient rates 5 areas of sexual fxn from 1 to 5 (1 is poor, 5 is great)

-- A total of 5 is very bad, whereas a score of 25 is very good
ED exists in what percent of men worldwide?
10-20%
What are options for treating ED?
Penile erection requires relaxation of smooth muscle of corpus cavernosa; can be induced by:
1. inhibition of type 5 phosphodiesterase (PDE5)
2. blockade of a1 receptors
3. stimulation of PGE1 receptors
Alprostadil MOA?
PGE1 receptor agonist
-- erection in 5 min, subsides in 60-90 min

-- injection within "Triple P" coctail causes erection within 10 minutes, and lasts 15-20 minutes
Topical alprostadil
1. Muse (urethral suppository) onset in 5-10 min; subsides after 30-60 min

2. Topiglan (gel) and Alprox-TD (cream) are applied to penile head -- erection occurs w/in 30-40 minutes

Used for patients who do not respond to sildenafil.
PDEase inhibitors?
sildenafil
onset = 30-60min; lasts 4-5h
-- taken one hour before sexual activity produces an erection that lasts 30 min to 2 h

vardenafil
onset = 60 min; lasts 4-5h

tadalafil
onset = 30-45min; lasts for 24h
Adverse effects of the PDEase inhibitors?
1. "Smurf" vision and impairment of blue-green color discrimination results from partial blockade of PDEase type 6, b/c cGMP is involved in signal transduction ointhe cones of the retina

2. NAION = non-arteritic ischemic optic neuropathy which results from decreased flow to optic nerve; serious, but reversible

3. headache and flushing
Adverse drug-drug interactions of PDEase inhibitors?
1. Do not use any nitrate in any form in presence of type 5 because this can result in severe hypotension which in turn precipitates chest pain, MI or ischemic stroke

2. Do not use inhibitors of PDEase type 5 in patients taking any of the a-blockers used to treat BPH. Again, untoward hypotension can result.