Drugs for Male GU Disorders and Incontinence (Martin) Flashcards
where in the testes is testosterone made?
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.
testosterone is metabolized to two other active steroids….
dihydrotestosterone
estradiol
ii) Some effects of testosterone are mediated by testosterone itself, some by dihydrotestosterone, and others by estradiol
function of 5 alpha reductase
converts testosterone to dihydrotestosterone
type 1 5-alpha reductase is found where
predominantly in non-genital skin, liver, bone
type 2 5 alpha reductase is found predominately where
urogenital tissue in men and genital skin in men and women
function of CYP19 P450 aromatase and location?
(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)
in the liver, what is testosterone metabolized to
v) Testosterone is metabolized in the liver to androsterone and etiocholanolone, which are biologically inactive
does testosterone or dihydrotesterone bind with higher affinity to the androgen receptor
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
how can testosterone act as an estrogen
by conversion to estradiol (by CYP19 aromatase) which binds to the estrogen receptor
what are the physiologic effects of testosterone
(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
exogenous androgens effects on nitrogen excretion
(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)
androgens clinical uses gynecologically
(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
in aging, how are androgens used clinically
(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
adverse effects of androgens
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
in what patients/disorders are the use of androgens contraindicated
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)
Leuporlide
prototypical GnRH analog
pulsatile secretion of GnRH
stimulates FSH and LH
Every 1-4 hours
flare response of GnRH administration
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)
after the first 7-10 days of continued administration of GnRH what occurs
(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)
clinical uses of GnRH
stimulation–> male infertility
suppression–> prostate cancer
toxicity of Leuprolide in males
v) Toxicity in males includes hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, and asthenia
GnRH antagonists
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)
clinical uses of GnRH antagonists
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
ketoconazole
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
MOA of 5 alpha reductase inhibitors
inhibition of 5α-reductase reduces levels of dihydrotestosterone within 8 hours of administration
clinical uses of 5 alpha reductase inhibitors
Benign prostatic hyperplasia
- decreases size of prostate
- urine flow rate increases
adverse effects of 5 alpha reductase inhibitors
impotence and decreased libido
Finasteride
preferentially antagonizes type II 5 alpha reductase
-used in treatment of male pattern baldness
treats hirsutism in women
dutasteride
antagonist of types I and II 5 alpha reductase
longer half life than finasteride
Cyproterone
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
flutamide, bicalutamide, nilutamide
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
adverse effects of flutamide, bicalutamide, nilutamide
gynecomastia = reversible
spironolactone
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
what are the clinical manifestations of Benign prostatic hyperplasia
increased frequency of urination nocturia
hesitancy
urgency
weak urinary stream
what are the 2 drugs that are the cornerstone for treatment of symptoms of BPH
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
what are the five long acting alpha 1 antagonists
terazosin - 1/2 life 9-12 hrs
doxazosin
-half life of 22 hrs
alfuzosin
-half life of 3-5 hours
tamsulosin
silodosin
what is the short acting alpha 1 antagonist
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
ADR’s of Prazosin
(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)
how is tamsulosin different than the other alpha blockers and what are the adverse side effects
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
What must be intact in order for an erection to occur
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
MOA of Phosphodiesterase isoform 5 (PDE-5) inhibitors
Sildenafil, Tadalafil, Avanafil, Vardenafil
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 !!!
what are the adverse effects of PDE-5 inhibitors
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
in which men will PDE 5 inhibitors NOT work
ix) Of no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido
Alprostadil
what pt’s is this used in?
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
Adverse effects of Alprostadil
penile pain
lasts up to 1 hour
what must be blocked in the treatment of prostate cancer?
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
what are common side effects of all forms of antiandrogen therapy
vasomotor flushing
loss of libido
gynecomastia
increased weight
loss of bone mineral density
loss of muscle mass
what is the prototype antimuscarinic compound and what is its MOA
atropine
ii) MOA: antagonist at the muscarinic acetylcholine receptor (mAChR)
effects of atropine on the Genitourinary tract
(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
how is atropine used in the treatment of urinary disorders
(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)
drug that is the prototype in disorders of the genitourinary tract
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
why are (c) Darifenacin, solifenacin, fesoterodine, and tolterodine advantageous in urinary disorders
advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation (they are still common adverse effects, however)
ADR’s of atropine and other anticholinergic agents
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
overdose of atropine or other antimuscarinics treated with what
cholinesterase inhibitors (physostigmine)
but are generally treated symptomatically, such as temperature control with cooling blankets and seizure control with diazepam (a benzodiazepine)
in what patients are antimuscarinic agents contraindicated ?
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.
what are some common drugs that iinduced alterations in sexual response (impotence, erectile dysfunction)
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 )
in certain men, the PDE-5 inhibitors for ED don’t work . …. which men
men who suffer loss of potency due to cord injury or damage to innervation and in men lacking libido
PDE-5 inhibitors are contraindicated with what other drugs
nitrates (nitroglycerin and isosorbide dinitrate) - myocardial ischemia can result
