Exam 1 - Erectile Dysfunction Flashcards
What is erectile dysfunction?
the inability to achieve and maintain erection sufficient to permit sexual intercourse
What was the first drug approved for use of ED? when was it approved?
Oral sildenafil approved by the FDA in 1998
Is cytosolic calcium higher or lower during erection? Why?
lower
during erection, smooth muscle is relaxed, so calcium is lower
How is smooth muscle contraction different from skeletal muscle contraction?
smooth muscle myosin has a regulatory light chain that is phosphorylated to allow myosin to interact with actin
Describe the mechanism of smooth muscle contraction starting with elevated cytosolic calcium.
elevated cytosolic calcium forms a complex with calmodulin called the Calmodulin-Ca++ complex
that complex activates myosin light chain kinase (MLCK)
MLCK phosphorylates the regulatory light chain
myosin can bind to actin, resulting in cross bridge cycling and smooth muscle contraction (flaccid state, detumescence)
Describe the mechanism of smooth muscle relaxation starting with low cytosolic calcium.
low cytosolic calcium decreases the activity of myosin kinase, meaning myosin phosphatase has a relatively higher activity (it is always active but less than MLCK during contraction)
myosin phosphatase de-phosphorylates the regulatory light chain, which prevents myosin from binding to actin and no muscle contraction occurs (erection)
Describe the nervous control of smooth muscle contraction, starting with the sympathetic/parasympathetic innervation.
sympathetic innervation releases norepi that activates receptors on smooth muscle cells
Gq-protein is activated
Inositol triphosphate (IP3) increases
IP3 stimulates release of calcium from ER and entry of extracellular calcium
Rise in cytosolic calcium leads to contraction (flaccid state, detumescence)
Describe the nervous control of smooth muscle relaxation involving the activation of parasympathetic innervation.
parasympathetic innervation releases acetylcholine (ACh) that activates receptors on endothelial cells
endothelial cells and parasympathetic nerves release nitric oxide (NO)
NO stimulates guanylyl cyclase
guanylyl cyclase increases intracellular smooth muscle cGMP
cytosolic cGMP activates specific protein kinases
kinases decrease cytosolic calcium, which results in inactivation of MLCK and no muscle contraction (erection)
How does the parasympathetic innervation directly affect the sympathetic innervation?
parasympathetic innervation inhibits norepi release from the sympathetic nerves
What is the secondary pathway that contributes to smooth muscle relaxation?
locally produced prostaglandin E1 stimulates G protein linked receptors
causes increase adenylyl cyclase activity (cAMP)
increase cAMP activates protein kinases
kinases decrease cytosolic calcium which inactivates MLCK and reinforces the parasympathetic nitric oxide pathway (leading to relaxation and erection)
What causes an erection to end?
PDE5 hydrolyzes cGMP to 5’GMP, which stops it from activating protein kinases
deactivated protein kinases —>
increase in calcium—>
return of smooth muscle contraction (flaccid state, detumescence)
What is the basic action of PDE5?
break down cGMP, which in turn causes and increase in calcium and muscle contraction (loss of erection)
What is the role of PDE5 inhibitors?
block the hydrolysis/breakdown of cGMP, allow it to continue activating protein kinases, decreasing calcium and relaxing smooth muscle (erection)
What are the generic and brand names of 3 PDE5 inhibitors?
sildenafil/Viagra
vardenafil/Levitra
tadalafil/Cialis
Why is PDE5 the phosphodiesterase chosen to inhibit for erectile dysfunction purposes (opposed to PDE1-4 or 6)?
PDE5 is the phosphodiesterase most localized to the corpus cavernosum and vascular smooth muscle
What is an IC50?
the concentration in the blood needed to inhibit to 50% activity
As PDE5 inhibitor increases in concentration, the PDE activity should…
decrease
If sildenafil causes PDE5 to reach 50%/0% activity before it causes PDE4 to reach 50%/0% activity, then sildenafil is…
more selective for PDE5 than PDE4
What is a selectivity ratio? What does it indicate?
the IC50 of one PDE / the IC50 of another
indicates that a drug is – times more selective for PDE – than PDE –.
Lower selectivity ratio indicates…
more inhibition of that PDE
—– and —— have lower selectivity ratios for PDE1 and PDE6 while —– does not have any low selectivity ratios.
viagra/sildenafil and levitra/vardenafil
cialis/tadalafil
What is C max?
the maximum concentration measured over the time post-dose
What is T max?
The time at which concentration was the highest over the time post-dose
What is the most different/unique property of Cialis/tadalafil from the other ED drugs?
T 1/2
cialis/tadalafil has a half like of 17.5 hours while the others have a half life of around 4 hours
gives it the nickname “the weekend pill”
What is T 1/2?
The time at which 1/2 of the concentration (C max) remains/has been cleared
Do ED drugs cause erection?
No. Neural input is still needed along with the vascular changes.
What kind of drugs should not be taken with PDE5 inhibitors? Why?
nitrate drugs/vasodilators like nitroglycerin (used for angina pain) or amyl nitrate (recreational drugs, “poppers”)
Vasodilators in combination can severely drop blood pressure leading to fainting, stroke, or heart attack
What is priapism? What is the treatment?
rare condition causing persistent and often painful erection
treated with injection of phenylephrine (a a1 receptor agonist) or surgical drainage
a1 receptors activate the sympathetic pathway (like natural norepinephrine would) and causes smooth muscle contraction
What are the alternative treatments for ED (besides PDE5)?
alprostadil - synthetic prostaglandin E1 (activate adenylyl cyclase/cAMP, protein kinases, lower calcium, dephos. MLCK, etc.)
Overall, reinforces parasympathetic NO pathway.
Administered as a transurethral pellet or intracavernous injection
What are potential complications of intracavernous injection of alprostadil?
can cause Peyronie’s disease - build up of scar tissue and deformity of the tunica albuginea which can cause curvature of the penis
