Term
| hemodynamic mechanism of erection |
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Definition
acetylcholine and NO release -> endothelial NO production -> smooth muscle relaxation -> arterial dilation -> corpora cavernosa filling
sexual arousal activates release of neurotransmitters (NTs, mainly acetylcholine and nitric oxide) from nerve terminals in the penis
the NTs activate endothelial cells of the small arteries and arterioles
the activated endothelial cells produce more NO
NO enters nearby smooth muscle cells and causes elevation of intracellular cGMP
the vascular smooth muscle cells relax (arterial and arteriole dilation)
the dilation causes filling of the sinusoids in the corpora cavernosa
filling of the corpora cavernosa compresses veins which helps to maintain an erection
erectile dysfunction (ED) is defined as initiation and/or maintenance of an erection insufficient for satisfactory intercourse
[image]
A
in the flaccid state, the arteries, arterioles, and sinusoids are contracted; the intersinusoidal veins and subtunical venous plexuses are wide open, with free flow to the emissary veins
B
in the erect state, the smooth muscle cells of the sinusoidal wall and the arterioles are relaxed, allowing maximal flow to the sinusoidal spaces in the corpora cavernosa; venules are compressed between the expanding sinusoids; the larger venules are sandwiched and flattened between the distended sinusoids and the tunica albuginea; this effectively reduces the venous flow to a minimum |
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Term
| interaction between endothelial cells and smooth muscle cells (SMCs) in the ARTERIAL WALL |
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Definition
[image]
a major source of NO is produced in endothelial cells in response to agonists released by axon termini (mainly ACh from parasympathetic system) following sexual arousal:
1. AGONIST BINDING
the neurotransmitters (agonists) released by the axon bind receptors on endothelial cells
2. INCREASED INTRACELLULAR CALCIUM
calcium channels in the cytoplasmic membrane and sarcoplasmic reticulum membrane are opened causing increased intracellular concentration
3. ENOS ACTIVATION AND NO SYNTHESIS
calcium binds and activates calmodulin (CaM) and the calcium-CaM complex activates endothelial nitric oxide synthase (eNOS); the eNOS synthesizes NO from the amino acid L-arginine
4. NO DIFFUSION
5. GUANYLYL CYCLASE ACTIVATION
the NO diffuses into nearby SMCs where guanylyl cyclase is activated and cGMP is subsequently produced
6. SMC RELAXATION
7. VASODILATION
the rise in intracellular cGMP (and opening of K channels) causes SMC relaxation and widening of the vessel lumen (vasodilation) thus decreasing resistance to blood flow in arterial vessels thereby filling the sinusoids |
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Term
| regulation of VASCULAR TONE by smooth muscle cells (SMCs) |
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Definition
[image]
vascular tone (contraction vs. relaxation) is the result of signaling events inside SMCs
the above illustrates the opposing intracellular signaling in smooth muscle cells
SMC relaxation is crucial for formation and maintenance of an erection
CONTRACTION:
intracellular Ca is increased causing activation of myosin light chain kinase (MLCK)
MLCK phosphorylates the myosin light chain (myosin-LC-P) causing crossbridging (between actin and myosin) and cell contraction thereby increasing vascular resistance (vasoconstriction)
RELAXATION:
NO (from nearby endothelial cells) diffuses into SMCs and activates guanylyl cyclase which increases cGMP
myosin-LC phosphatase (removes phosphate from proteins) is activated
myosin-LC in the nonphosphorylated form causes SMC relaxation
NO also opens potassium channels causing hyperpolarization thereby promoting relaxation |
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Term
| pharmacologic treatment of ED with phosphodiesterase (PDE) inhibitors |
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Definition
these compounds (sildenafil, vardenafil, and tadalafil) are reversible (competitive type) inhibitors of phosphodiesterase (PDE)
sildenafil and vardenafil clearly resemble the purine ring in cGMP indicated by the gray circled area
the structure activity relationship of tadalafil is less clear
specifically, these drugs target an isoform of PDE
however, the specificity is not absolute |
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Term
| selectivity of PDE inhibitors |
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Definition
the family of PDE enzymes includes 11 main subtypes
the members are expressed in certain tissues (for example, PDE-6 in retina, PDE-3 in platelets, and PDE-5 in SMCs of the corpora cavernosa)
all 3 inhibitors (sildenafil, vardenafil, tadalafil) have highest selectivity for PDE-5
some side effects are attributed to inhibition of other PDE members
these three compounds are often referred to as "PDE-5" specific
visual effects (red/green color discrimination defect) thought to be due to inhibition of PDE-6
the slight cardiovascular risk with these drugs are thought to be due to PDE-3 inhibition in the platelets |
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Term
PDE-5 inhibitors (sildenafil, vardenafil, tadalafil):
mechanism, ADRs, pharmacodynamic interactions |
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Definition
mechanism:
increases smooth muscle cell cGMP and activates protein kinase G (PKG)
all three are reversible (competitive type) inhibitors of PDE (the enzyme that catalyzes phosphodiester bond hydrolysis in cGMP)
PDE-5 is the dominant isozyme (member) expressed in penile vascular smooth muscle cells
inhibition of PDE-5 causes increased cGMP, activation of protein kinase G (PKG), vasodilation and then filling of corpora cavernosa sinusoids and compression of surrounding veins
ADRs:
priapism is rare with normal doses and in patients with no underlying risk factors
visual problems are transient, dose related and attributed to inhibition of ocular PDE-6
visual effects correlate with peak plasma concentration
these drugs are contraindicated in groups with high cardiovascular risk
mechanism of cardiovascular effect is not known (effect on platelet PDE-5 is under investigation)
pharmacodynamic interactions:
vasodilators
caution is advised when used in combination with any vasodilator especially alpha adrenergic blockers and nitrates (used to treat angina pectoris) |
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Term
| therapeutic mechanism of PDE-5 inhibitors |
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Definition
[image]
normally NO diffuses into SMCs (source may be axon termini or adjacent endothelial cells)
NO binds heme moiety and activates guanylyl cyclase
the enzyme catalyzes conversion of GTP to cGMP
cGMP activates protein kinase G (PKG) which is associated with myosin light chain de-phosphorylation (smooth muscle cell relaxation)
note: cGMP is metabolized to 5'-GMP by the PDE-5 enzyme
inhibitors of PDE-5 increase intracellular cGMP promoting smooth muscle cell relaxation through PKG (activation of PKG causes decreased intracellular calcium and de-phosphorylation of myosin light chain) |
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Term
| pathologic classification of processes affecting the prostate |
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Definition
INFLAMMATION
acute and chronic inflammation (prostatitis) can occur as a result of bacterial infection but commonly, chronic prostatitis occurs without any history of bacterial infection (bacterial urine cultrues are negative, referred to as abacterial prostatitis)
BENIGN ENLARGEMENT
(BPH) benign prostatic hyperplasia is very common in males over age 50
BPH is characterized by hyperplasia of both stromal and epithelial cells in the prostate
TUMORS
tumors or prostate cancer usually arise from malignancy in epithelial cells in the peripheral zone of the gland (prostate) |
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Term
| difference between hyperplasia and hypertrophy? |
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Definition
hyperplasia is an increase in the number of cells, but the cell size is the same
hypertrophy is bigger cell size but the same number of cells |
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Term
| mechanism of androgen action on prostate |
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Definition
[image]
1. DHT production
2. activation of gene transcription
3. growth factor effects
benign prostatic hyperplasia (BPH) is characterized by hyperplasia of both stromal and epithelial cells in the prostate
the main androgen in the prostate is dihydrotestosterone (DHT) (it is formed by conversion of circulating testosterone by the enzyme 5alpha-reductase (type 2) in stromal cells)
epithelial cells do not contain the enzyme
DHTpromotes transcription of genes encoding growth factors the growth factors act in autocrine and paracrine fashions
DHT has higher affinity for androgen receptor compared to testosterone
conversion of testosterone by type 1 5alpha-reductase can occur in the liver and skin |
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Term
| hyperplasia is the result of imbalance between cell proliferation and cell death |
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Definition
[image]
in addition to having direct effects on cell proliferation, androgens (primarily DHT) regulates transcription of genes encoding growth factors
left side depicts agonist effects of certain growth factors (promote cell proliferation/division) and right side depicts antagonistic effects (promotes cell death/apoptosis)
prostate hyperplasia (increased number of both stromal and epithelial cells) is due to imbalance between cell proliferation and cell death |
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Term
| pharmacologic treatment of BPH |
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Definition
alpha1-adrenergic antagonists:
terazosin
doxazosin
TAMSULOSIN
ALFUZOSIN
SILODOSIN
5alpha-reducatse inhibitors:
dutasteride
finasteride
2 major pharmacologic approaches exist for treatment of BPH (alpha1 aadrenergic receptor antagonists and 5alpha reductase inhibitors)
terazosin and doxazosin are structural analogs of prazosin and indicated for both hypertension and BPH
after the efficacy of alpha1 antagonists was established other drugs were designed to be more selective for alpha receptors in the prostate (thought to be alpha1 receptor subtype A)
the newer, more selective (for prostate smooth muscle) antagonists are not indicated for hypertension |
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Term
alpha1 adrenergic antagonists (terazosin, doxazosin, tamsulosin, alfuzosin, silodosin):
MOA, ADRs |
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Definition
mechanism:
relaxation of prostatic and urethral smooth muscle
smooth muscle cells in the vasculature and other sites have alpha1 adrenergic receptors
in BPH, hyperplasia of SMCs (in addition to epithelial cells) causes compression of urine outflow from the bladder
the urinary problems associated with BPH are relieved by this class of drugs because they cause SMC relaxation
ADRs:
postural hypotension
QT prolongation concern
as anticipated, these drugs cause orthostatic hypotension (most common during therapy initiation) which is worsened by other vasodilators (nitrates, phosphodiesterase inhibitors), calcium channel blockers)
headache is common |
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Term
5alpha reductase inhibitors (finasteride, dutasteride):
MOA, ADRs |
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Definition
mechanism:
blocks androgen dependent growth
finasteride is specific for the type II reductase, whereas dutasteride inhibits both type I (skin, liver) and II (reproductive tissues) reductase
the drugs block production of DHT, thus decreasing androgen-dependent growth of the prostate cells
symptom relief and prostate shrinkage requires several months of treatment
ADRs:
sexual dysfunction
teratogenic
erection and ejaculation problems are more common adverse effects
women who are pregnant or trying to become pregnant should no come into physical contact with these tablets or semen from men taking these inhibitors |
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Term
| benign prostatic hyperplasia |
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Definition
[image]
the drawing depicts hyperplastic (left) and normal (right) prostatic tissue
prostatic tissue is made of epithelial cells, fibroblasts (fibrous stroma) and smooth muscle cells
normally the epithelial cells are arranged in ducts (right, glandular epithelium)
in BPH, cell adjacent to the urethra proliferate forming nodules which compress the urethral lumen and destroy the ducts leaving epithelial cell fragments (left)
5alpha reductase inhibitors reduce prostate size (decrease cell number)
alpha receptor antagonists cause relaxation of smooth muscle cells thereby increasing urine outflow |
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Term
| normal lifespan serum testosterone in males |
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Definition
[image]
above is a graph of normal serum testosterone over a male lifespan
testosterone is needed for devleopment of reporductive organs during gestation (first and second peak)
the importance of the third peak during infancy is uncertain (likely important for sexual development)
testosterone rises to the highest concentration during puberty (causes further development of reproductive organs, and development and maintenance of secondary sex characteristics) and then declines throughout adulthood |
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Term
| common causes of low testosterone in males |
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Definition
Klinefelter's syndrome - XXY syndrome; the most common chromosomal disorder associated with low testosterone in males
uncorrected cryptorchidism - presence of one or both un-descended testes
chronic disease (HIV infection, COPD, end stage renal disease)
hyperprolactinemia
medications (opiates, anabolic steroids)
aging
alcoholism |
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Term
androgen replacement therapy (fluoxymesterone, methyltestosterone, testosterone esters and preparations)
benefits and ADRs |
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Definition
benefits:
anabolic and androgenic effects
muscle, bone, libido
may elevate mood, help maintain bone mass, red cell count, and muscle mass
may help with ED and increase libido
may also improve cognitive ability
ADRs:
potentiates BPH and prostate cancer
monitor hematocrit - abnormally high red blood cell production (erythrocytosis)
hepatic effects - hepatic dysfunction (increase bilirubin and hepatic enzymes); hepatic malignancy
edema, sodium retention
teratogenic - very harmful to fetal development
oily skin and acne
worsens sleep apnea
may lower HDL and increase LDL (but overall increase in cardiovascular disease inconclusive |
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Term
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Definition
1. DHT binding
2. nuclear transport and dimerization
3. factor recruitment
4. transcription
the effects of testosterone and DHT are mediated through the androgen receptor
the androgen receptor, like all steroid hormone receptors, has DNA and hormone binding domanes
the steps in receptor signaling are outlined above
mutations in the receptor can cause androgen insensitivity ranging from almost complete to partial loss of function
mutations may interfere with DNA or androgen binding |
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