Term
| erectile dysfunction etiologies |
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Definition
vascular: peripheral vascular disease, arteriosclerosis, hypertension
neurologic: spinal cord injury, stroke, diabetes
hormonal: primary or secondary hypogonadism
psychogenic: malaise, depression, performance anxiety, Alzheimer's disease, mental disorder, hypothyroidism |
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Term
| molecular mechanism of an erection |
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Definition
[image]
acetylcholine mediated vasodilation
increased production of NO
stimulates muscle cell receptors to increase adenyl cyclase
4 areas are highlighted as possible targets for drug treatment of ED: ACh, PGE-1, phosphodiesterase-5, and phosphodiesterase-2, 3, and 4
all of these targest intervene in the cGMP cascade |
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Term
| medications that may cause ED |
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Definition
ANTICHOLINERGIC AGENTS
antihistamines, antiparkinsonians, TCAs, phenothiazines
proposed mechanism: anticholinergic activity; increased amounts of ACh are needed to treat ED
DOPAMINE ANTAGONISTS
proposed mechanism: inhibit prolactin inhibitory factor -> increased prolactin levels
ESTROGENS, ANTI-ANDROGENS
proposed mechanism: suppress testosterone-mediated stimulation of libido
CNS DEPRESSANTS
proposed mechanism: suppress perception of psychogenic stimuli
AGENTS THAT DECREASE PENILE BLOOD FLOW
diuretics, peripheral beta adrenergic antagonists, etc.
proposed mechanism: reduce arteriolar flow to corpora |
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Term
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Definition
testosterone stimulates libido
hypogonadism -> subphysiological levels of testosterone
relationship between testosterone and ED:
the relationship between testosterone and ED is NOT direct
it is through the association with libido
testosterone can be used therapeutically to treat ED in cases when no other etiology is related to the problem |
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Term
| testosterone replacement therapy: benefits and risks |
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Definition
BENEFITS
improved sexual performance and desire
more energy and improved quality of life
more energy and sense of well-being
increased bone mineral density
improved muscle mass and strength
improved (lower) low-density lipoprotein profile
decreased irritability and depression
improved cognitive function
increased hemoglobin levels to the physiological range
thickened body hair and skin
RISKS
stimulated growth of preexisting prostate cancer
greater chance for benign prostatic hyperplasia
increased hemoglobin levels to above the physiological range
probelms with voiding; symptoms include poor urine flow and hesitancy before urinating
increased potential for liver damage from oral preparations
sleep apnea
breast tenderness and swelling (gynecomastia)
testicular shrinkage (testicular atrophy)
infertility (decreased spermatogenesis)
skin reaction from patches or gel
pain, soreness, or bruising from injection
increased fluid retention
increased skin problems (acne, oily skin)
increased body hair
DO NOT MEMORIZE
know that there are some benefits, but there are also risks (even though it is an endogenous hormone) |
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Term
| testosterone replacement therapy products |
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Definition
[image]
injectables (IM)
oral
transdermal - matrix type, reservoir type, gel
problems with testosterone used as a drug:
first pass metabolism; b/c of this most testosterone replacement therapy is done as injectables (IM) or an analog of testosterone is used
transdermal administration also avoids first pass metabolism
oral: methyltestosterone and fluoxymesterone; not widely used and not commercially available |
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Term
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Definition
research is trying to separate the anabolic effect from the androgenic effect; cannot completely separate both, there is no androgen that can be only metabolic or only androgenic
ANDROGENIC EFFECT
[image]
steroid nucleus
oxygen functionalities at 3 (not important but increases androgenic activity) and 17 (ESSENTIAL)
5 alpha-androstane
sp2 hybridized carbon in ring A - double bond or keto group
position 17:
need oxygen group
need to protect the oxygen group from metabolism (most structural modification at this position is to maintain activity and to protect it from metabolism); protection with either esters or ethers
ethynyl groups can be added at 17 alpha (along with the oxygen group); adding and ethynyl group makes the molecule look like progesterone = will have both androgen and progestin activity
long chains decrease activity
ANABOLIC EFFECT
[image]
steroid nucleus
prototype: 17 alpha-methyltestosterone
[image]
hydroxylation in 2 (OH) and 4 (=CHOH) causes more anabolic and less androgenic activity
[image]
halogenation at 4 or 9 increases anabolic effect without decreasing androgenic effects
[image]
sp2 hybridized carbon at position 3 = more anabolic effect
to decrease anabolic effect can put an OH at position 3 while keeping a double bond at 4-5 causing increased androgenic effects
[image]
19-norsteroids: favorable ratio of anabolic to androgenic effect
19-norsteroids (19-nortestosterone) - do not have carbon 19; elimination of the methyl 19 will increase anabolic effects |
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Term
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Definition
[image]
PDE-5 is the major cGMP hydrolizing PDE in the corpora cavernosa
PDE-5 is the main target b/c it is mainly present in the corpora cavernosa (other PDEs are in other places in the body)
PDE-5 participates in the phosphorylation of GMP
level of cGMP is determined by the relative rates of cGMP synthesis
imbalance of cGMP synthesis and breakdown can compromise the accumulation of cGMP
PDE-5 INHIBITORS STOP THE BREAKDOWN OF CGMP
PDE-5 inhibitors:
[image]
sildenafil has 4 extra carbons than vardenafil and the nitrogens are in different positions
the heterocycle of vardenafil is MORE POTENT than the heterocycle of sildenafil
[image]
the heterocycle mimics cGMP (tadalafil has the same mechanism of action)
competitive and reversible inhibitors of cGMP hydrolysis by the catalytic site of PDE-5
sildenafil, vardenafil, and tadalafil mimic the purine ring of cGMP |
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Term
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Definition
bioavailability: 1/3 for sildenafil and vardenafil, unknown for tadalafil
onset of effect: 0.25-1.5 hours. sildenafil and vardenafil may be delayed by a heavy meal (advantage for tadalafil = absorption not delayed by a meal)
metabolism: in the liver by CYP450 enzymes
excretion primarily in the feces |
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Term
| benign prostatic hyperplasia |
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Definition
pathophysiologic mechanisms unknown
dihydrotestosterone and type II 5 alpha reductase:
BPH has been linked to DHT levels (DHT is produced throug the conversion of testosterone by the 5 alpha reductase enzyme)
[image]
conversion of testosterone to DHT
evidence - castration causes an enlarged prostate to shrink; patients with type II 5 alpha reductase deficiency do not develop BPH
pathogenesis of BPH:
static - anatomic enlargement of the prostate gland -> obstruct urinary flow
dynamic - excessive alpha-adrenergic tone of the stromal component of the prostate gland, bladder neck, and posterior urethra -> contraction of the prostate around the urethra (causes patient to not be able to completely empty their bladder and have a constant need to urinate) |
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Term
| 5 alpha reductase inhibitors MOA |
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Definition
[image]
steroid structure
finasteride and dutasteride have nitrogens in the steroid nucleus
all are analogs of progesterone
MOA: prevent the conversion of testosterone to DHT
need to interact with the 5 alpha reductase enzyme in the same way that testosterone does
mimic testosterone and interact with the enzyme (compete with testosterone for the enzyme) |
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Term
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Definition
NADPH-dependent 3-oxo-5alpha-steroid-delta4-dehydrogenase
aa homology of only 50%
type I: liver, skin, sebaceous glands, and hair follicles
type II: genital skin, beard and scalp hair follicle, and the prostate
highly lipophilic, associated with intracellular membranes
affinity for testosterone: type II >> type I
5 alpha reductase inhibitors are mainly active against type II 5 alpha reductase enzymes
[image]
how testosterone is reduced to DHT:
testosterone binds to the enzyme in the active site
the co factor (NADPH) will also bind to the enzyme and will reduce the double bond
once the double bond is reduced, the DHT is released as well as the NADP+
5 alpha reductase inhibitor:
NADPH will bind after the inhibitor binds
in order for the enzyme to work again it has to release the substrate and cofactor, in this case, it is stuck with the substrate that cannot be released and the enzyme is inhibited |
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Term
| common features of 5 alpha reductase inhibitors |
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Definition
[image]
3-oxo-steroid
double bond at 4,5
17 BETA substituent (NOT 17 ALPHA!) |
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Term
| properties of finasteride and dutaseride |
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Definition
finasteride:
high affinity against type II and low for type I
effective in suppressing DHT plasma levels without affecting testosterone
time dependent (irreversible inhibitor)
pharmacokinetics: well absorbed (GI), highly protein bound, extensively metabolized to inactive metabolites
dutasteride:
inhibits type I and type II so it WILL effect levels of testosterone
pharmacokinetics: absolute bioavailability ~ 60%, highly bound to plasma albumin, extensively metabolized |
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Term
| 5 alpha reductase inhibitors SAR |
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Definition
there can be many different functional groups
[image]
MAIN POINTS
an alpha H is preferred at position 5
at position 4 there should be a double bond or an N and the biggest substituent is a methyl group |
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Term
| alpha adrenergic drugs MOA |
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Definition
act as alpha adrenoreceptor antagonists
used for treatment of different diseases: asthma, hypertension, common cold
act through:
adrenoreceptors -> NE
neurons that release NE
does not treat BPH, just the symptoms
in the prostate, there is the alpha1 adrenoreceptor subtype; inhibitors used for BPH are alpha1 adrenergic inhibitors (can selectivly inhibit this subtype)
tamsulosin is selective for alpha1 receptor subtype (prostate) -> not for hypertension like other alpha1 inhibitors (doxazosin, terazosin, prazosin) |
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Term
| alpha1 adrenergic drugs SAR |
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Definition
[image]
differences afford pharmacokinetic changes
furan ring more lipophilic than tetrahydrofuran ring
tamsulosin has a similar structure to NE (the endogenous alpha1 substrate) |
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Term
| pharmacokinetics of alpha1 adrenergic drugs |
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Definition
bioavailability: 50-90%
t1/2: 2-12 hours
metabolized in the liver ~10% excreted unchanged |
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