Shared Flashcard Set

Details

Men's and Women's Health EXAM 3
Men's and Women's Health EXAM 3 - Schober
19
Pharmacology
Graduate
12/07/2011

Additional Pharmacology Flashcards

 


 

Cards

Term
hemodynamic mechanism of erection
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
Term
interaction between endothelial cells and smooth muscle cells (SMCs) in the ARTERIAL WALL
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
Term
regulation of VASCULAR TONE by smooth muscle cells (SMCs)
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
Term
pharmacologic treatment of ED with phosphodiesterase (PDE) inhibitors
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
Term
selectivity of PDE inhibitors
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
Term
PDE-5 inhibitors (sildenafil, vardenafil, tadalafil):
mechanism, ADRs, pharmacodynamic interactions
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)
Term
therapeutic mechanism of PDE-5 inhibitors
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)
Term
pathologic classification of processes affecting the prostate
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)

Term
difference between hyperplasia and hypertrophy?
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

Term
mechanism of androgen action on prostate
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

Term
hyperplasia is the result of imbalance between cell proliferation and cell death
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
Term
pharmacologic treatment of BPH
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
Term
alpha1 adrenergic antagonists (terazosin, doxazosin, tamsulosin, alfuzosin, silodosin):

MOA, ADRs
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
Term
5alpha reductase inhibitors (finasteride, dutasteride):

MOA, ADRs
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
Term
benign prostatic hyperplasia
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
Term
normal lifespan serum testosterone in males
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
Term
common causes of low testosterone in males
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

Term
androgen replacement therapy (fluoxymesterone, methyltestosterone, testosterone esters and preparations)

benefits and ADRs
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
Term
androgen receptor
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
Supporting users have an ad free experience!