Drugs for Male GU Disorders and Incontinence (Martin)

Question 1

where in the testes is testosterone made?

Answer 1

Leydig cells of the testes

In Leydig cells, the 11 and 21 hydroxylases (present in adrenal cortex) are absent but CYP17 (17 -hydroxylase) is present. Thus, androgens and estrogens are synthesized; corticosterone and cortisol are not formed.

Question 2

testosterone is metabolized to two other active steroids….

Answer 2

dihydrotestosterone

estradiol

ii) Some effects of testosterone are mediated by testosterone itself, some by dihydrotestosterone, and others by estradiol

Question 3

function of 5 alpha reductase

Answer 3

converts testosterone to dihydrotestosterone

Question 4

type 1 5-alpha reductase is found where

Answer 4

predominantly in non-genital skin, liver, bone

Question 5

type 2 5 alpha reductase is found predominately where

Answer 5

urogenital tissue in men and genital skin in men and women

Question 6

function of CYP19 P450 aromatase and location?

Answer 6

(1) Conversion of testosterone to estradiol by aromatase occurs primarily in the liver and adipose tissue
(2) This conversion results in approximately 85% of circulating estradiol in men (the remainder is secreted directly by the testes)

Question 7

in the liver, what is testosterone metabolized to

Answer 7

v) Testosterone is metabolized in the liver to androsterone and etiocholanolone, which are biologically inactive

Question 8

does testosterone or dihydrotesterone bind with higher affinity to the androgen receptor

Answer 8

i) Testosterone can act as an androgen either directly, by binding to the androgen receptor, or indirectly by conversion to dihydrotestosterone (by 5 alpha reductase), which binds to the androgen receptor with higher affinity than testosterone

Question 9

how can testosterone act as an estrogen

Answer 9

by conversion to estradiol (by CYP19 aromatase) which binds to the estrogen receptor

Question 10

what are the physiologic effects of testosterone

Answer 10

(1) Tissue growth (e.g., muscle, penis, scrotum, bone, prostate, seminal vesicles)
(2) Appearance of pubic, axillary, and beard hair
(3) Increased activity of sebaceous glands; skin becomes thicker and oilier
(4) Larynx grows and vocal cords become thicker (responsible for a lower-pitched voice)
(5) Stimulate skeletal growth and epiphysial closure
(6) Stimulate and maintain sexual function
(7) Metabolic effects include increased liver synthesis of clotting factors and triglyceride lipase, increased renal erythropoietin, and decreased HDL levels

Question 11

exogenous androgens effects on nitrogen excretion

Answer 11

(4) Reduction of nitrogen excretion in the urine, indicating an increase in protein synthesis or a decrease in protein breakdown (more pronounced in women and children compared to normal men)

Question 12

androgens clinical uses gynecologically

Answer 12

(1) Example applications include breast engorgement during the postpartum period, replacement therapy in postmenopausal women to eliminate endometrial bleeding, chemotherapy of breast carcinoma in premenopausal women (rare, unclear mechanism)
(2) Undesirable effects in women greatly limit use

Question 13

in aging, how are androgens used clinically

Answer 13

(1) The decline in androgen production in men may contribute to the decline in muscle mass, strength, and libido
(2) Androgen replacement increases lean body mass and hematocrit while decreasing bone turnover

Question 14

adverse effects of androgens

Answer 14

masculinizing actions (women)

rare sodium retention and edema (more common in pt’s with heart and kidney disease)

hepatic dysfunction

• early on in course of treatment
• clinical jaundice and increases in bilirubin
• hepatic adenomas

Prostatic hyperplasia in older males –> urinary retention

replacement therapy causes acne, sleep apnea, erythrocytosis, gynecomastia, azoospermia

behavioral effects

• aggressive
• psychotic

Question 15

in what patients/disorders are the use of androgens contraindicated

Answer 15

i) Contraindicated in pregnant women or women who may become pregnant during therapy
ii) Should not be administered to male patients with carcinoma of the prostate or breast
iii) Avoid in infants and young children (somatropin is more useful and safe for growth stimulation)
iv) Use with caution in patients with renal or cardiac disease predisposed to edema (if edema occurs, diuretics are effective)

Question 16

Leuporlide

Answer 16

prototypical GnRH analog

Question 17

pulsatile secretion of GnRH

Answer 17

stimulates FSH and LH

Every 1-4 hours

Question 18

flare response of GnRH administration

Answer 18

continuous administration of leuprolide

(1) During the first 7-10 days of administration, an agonist effect results in increased concentrations of gonadal hormones (referred to as a flare)

Question 19

after the first 7-10 days of continued administration of GnRH what occurs

Answer 19

(2) After the first 7-10 days, the continued presence of GnRH (or analog) results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids (due to receptor down-regulation and changes in the signaling pathways activated by GnRH)

Question 20

clinical uses of GnRH

Answer 20

stimulation–> male infertility

suppression–> prostate cancer

Question 21

toxicity of Leuprolide in males

Answer 21

v) Toxicity in males includes hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, and asthenia

Question 22

GnRH antagonists

Answer 22

synthetic competitive antagonists of GnRH receptors inhibit the secretion of FSH and LH in a dose-dependent manner

ii) Clinical pharmacology
(1) Suppression of gonadotropin production (GnRH antagonists have been shown to more completely suppress gonadotropin production compared to GnRH agonists)

Question 23

clinical uses of GnRH antagonists

Answer 23

advanced prostate cancer

GnRH antagonists reduce concentrations of gonadotropins and androgens more rapidly than GnRH agonists and avoids the testosterone surge

Ganirelix/Cetrorelix used in ovarian hyperstimulation procedures

Abarelix and Degarelix used in advanced prostate cancer

Question 24

ketoconazole

Answer 24

steroid synthesis inhibitor

• antifungal (inhibits fungal cytochrome P450 enzymes, reducing synthesis of ergosterol)
• inhibits mammalian P450 enzymes and other enzymes requires for adrenal and gonadal steroid synthesis
• increases estradiol;testosterone ratio in plasma when used at high doses causing reversible gynecomastia in men
• prostate cancer

Question 25

MOA of 5 alpha reductase inhibitors

Answer 25

inhibition of 5α-reductase reduces levels of dihydrotestosterone within 8 hours of administration

Question 26

clinical uses of 5 alpha reductase inhibitors

Answer 26

Benign prostatic hyperplasia

• decreases size of prostate
• urine flow rate increases

Question 27

adverse effects of 5 alpha reductase inhibitors

Answer 27

impotence and decreased libido

Question 28

Finasteride

Answer 28

preferentially antagonizes type II 5 alpha reductase

-used in treatment of male pattern baldness

treats hirsutism in women

Question 29

dutasteride

Answer 29

antagonist of types I and II 5 alpha reductase

longer half life than finasteride

Question 30

Cyproterone

Answer 30

steroid structure
acts as antagonist at androgen receptor
used for palliative treatment of advanced prostate carcinoma

(3) Acetate form has a marked progestational effect that suppresses the feedback enhancement of LH and FSH, leading to a more effective antiandrogen effect

Question 31

flutamide, bicalutamide, nilutamide

Answer 31

nonsteroidal androgen receptor inhibitors

(2) Used for metastatic advanced prostate carcinoma
(3) May be used in combination with a GnRH analog to suppress tumor flare

Question 32

adverse effects of flutamide, bicalutamide, nilutamide

Answer 32

gynecomastia = reversible

Question 33

spironolactone

Answer 33

antagonist at the androgen receptor

reduces 17 alpha hydroxylase activity which lowers plasma levels of testosterone and adnrostenedione

most commonly used in management of heart failure (also an aldosterone/mineralcorticoid antagonist) and may be used to treat hirsutism

Question 34

what are the clinical manifestations of Benign prostatic hyperplasia

Answer 34

increased frequency of urination nocturia
hesitancy
urgency
weak urinary stream

Question 35

what are the 2 drugs that are the cornerstone for treatment of symptoms of BPH

Answer 35

5 alpha reductase (finasterid and dutasteride)

• LONG term reduction in prostate volume
• reduces the need for surgery

alpha adrenergic receptor antagonists

• smooth muscle tone in the prostate is mediated by alpha 1 receptors. Antagonism of alpha 1 receptors is more efficacious in treatment of BPH compared to alpha 2 receptors due to increased density of alpha 1 receptors in the prostate
• more effective for SHORT term treatment of BPH

NOTE
iii)	The use of agents from both classes (5α-reductase inhibitors and α1-adrenergic receptor antagonists) in combination may be superior to using either class alone

Question 36

what are the five long acting alpha 1 antagonists

Answer 36

terazosin - 1/2 life 9-12 hrs

doxazosin
-half life of 22 hrs

alfuzosin
-half life of 3-5 hours

tamsulosin

silodosin

Question 37

what is the short acting alpha 1 antagonist

Answer 37

Prazosin

may be used for BPH but requires more frequent dosing and use is accompanied by more frequent cardiovascular side effects compared to the long-acting agents

Question 38

ADR’s of Prazosin

Answer 38

(c) Adverse effects include palpitations and orthostatic hypotension (postural hypotension and syncope are sometimes seen 30-90 minutes after a patient takes an initial dose)

Question 39

how is tamsulosin different than the other alpha blockers and what are the adverse side effects

Answer 39

selective for alpha 1 A NOT alpha 1 B

(c) Effective in the treatment of BPH with little effect on blood pressure
(d) Half-life 5-10 hours
(e) Major adverse effect is abnormal ejaculation

Question 40

What must be intact in order for an erection to occur

Answer 40

parasympathetic innervation AND NO synthesis must be active

ii) NO activates guanylyl cyclase, which increases the concentration of cyclic guanine monophosphate (cGMP)

cGMP stimulates the dephosphorylation of myosin light chains, which results in relaxation of the smooth muscle

Question 41

MOA of Phosphodiesterase isoform 5 (PDE-5) inhibitors

Sildenafil, Tadalafil, Avanafil, Vardenafil

Answer 41

selective inhibition of PDE-5 increases intracavernosal cGMP levels and causes relaxation of the nonvascular smooth muscle of the corpora cavernosa

these drugs have no effect in the absence of sexual stimulation

Tadalafil is longer lasting - 36 hours !!!

Question 42

what are the adverse effects of PDE-5 inhibitors

Answer 42

potent vasodilators which means that concomitant use of PDE-5 inhibitors and nitrates can lead to severe hypotension and syncope

MI’s have also been reported

visual changes (color changes, blurred vision, increased sensitivity)

Hearing loss

Question 43

in which men will PDE 5 inhibitors NOT work

Answer 43

ix) Of no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido

Question 44

Alprostadil

what pt’s is this used in?

Answer 44

Prostaglandin E1 analog that relaxes trabecular smooth muscle by dilation of cavernosal arteries when injected along the penile shaft, allowing blood to flow and entrapment in the lacunar spaces of the penis

ii) Commonly used in patients who do not respond to PDE-5 inhibitors

Question 45

Adverse effects of Alprostadil

Answer 45

penile pain

lasts up to 1 hour

Question 46

what must be blocked in the treatment of prostate cancer?

Answer 46

hormonal stimulation (androgen deprivation- ADT)

a) Carcinoma of the prostate is uniquely dependent upon hormonal stimulation with androgens
c) Greater than 90% of men have a positive initial response (disease regression or stabilization and relief of cancer-related symptoms) to primary hormonal therapy with ADT
d) The average time to disease progression is 18-36 months, making ADT one of the longest lasting beneficial treatments in any advanced solid tumor
e) Disease progression after ADT signifies an androgen-independent state, with subsequent median survival of only 12 months

Question 47

what are common side effects of all forms of antiandrogen therapy

Answer 47

vasomotor flushing

loss of libido

gynecomastia

increased weight

loss of bone mineral density

loss of muscle mass

Question 48

what is the prototype antimuscarinic compound and what is its MOA

Answer 48

atropine

ii) MOA: antagonist at the muscarinic acetylcholine receptor (mAChR)

Question 49

effects of atropine on the Genitourinary tract

Answer 49

(a) Antimuscarinic agents relax smooth muscle of the ureters and bladder wall and slow voiding, making them useful agents in the treatment of urinary incontinence
(b) mAChR antagonists have no significant effect on the uterus

Question 50

how is atropine used in the treatment of urinary disorders

Answer 50

(1) Atropine and other antimuscarinic agents have been used to provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders
(2) Selectivity for the M3 subtype is preferred for agents that reduce urinary frequency (overactive bladder, urinary urge incontinence)

Question 51

drug that is the prototype in disorders of the genitourinary tract

Answer 51

oxybutynin

(a) The prototype agent used in disorders of the genitourinary tract is oxybutynin, which is somewhat selective for M3 mAChRs with side effects that include dry mouth, dizziness, constipation, blurred vision, dry eyes, and urinary tract infections among others

Question 52

why are (c) Darifenacin, solifenacin, fesoterodine, and tolterodine advantageous in urinary disorders

Answer 52

advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation (they are still common adverse effects, however)

Question 53

ADR’s of atropine and other anticholinergic agents

Answer 53

i) Treatment with atropine or other antimuscarinic agents directed at one organ system typically induces undesirable effects in others (e.g., mydriasis and cycloplegia may be adverse effects of antimuscarinic agents used to reduce micturation speed)
ii) At high concentrations, atropine causes a block of all parasympathetic function (dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare), but is still relatively safe in adults
iii) Moderate to high doses of atropine in children and infants can cause death due to hyperthermic effects

Question 54

overdose of atropine or other antimuscarinics treated with what

Answer 54

cholinesterase inhibitors (physostigmine)

but are generally treated symptomatically, such as temperature control with cooling blankets and seizure control with diazepam (a benzodiazepine)

Question 55

in what patients are antimuscarinic agents contraindicated ?

Answer 55

v) Antimuscarinic agents are contraindicated in patients with glaucoma (reduce secretions)

and should be used with caution in elderly men with a history of prostatic hyperplasia (difficult to differentiate between symptoms attributable to detrusor over-activity and those caused by bladder-outlet obstruction secondary to benign prostatic enlargement).

Men with hyperplasia would be at risk for acute urinary retention.

Question 56

what are some common drugs that iinduced alterations in sexual response (impotence, erectile dysfunction)

Answer 56

Antidepressants –> SSRI’s ***

Spironolactone and thiazide diuretics

Antipsychotics - phenothiazine ***(50%)

Benzodiazepines, alcohol***, cocaine, marijuana

nonselective beta blockers - so switch to selective

centrally acting sympatholytics (clonidine )

Question 57

in certain men, the PDE-5 inhibitors for ED don’t work . …. which men

Answer 57

men who suffer loss of potency due to cord injury or damage to innervation and in men lacking libido

Question 58

PDE-5 inhibitors are contraindicated with what other drugs

Answer 58

nitrates (nitroglycerin and isosorbide dinitrate) - myocardial ischemia can result