Men's Health Flashcards
Men's Health Drugs: Androgens AR Antagonists 5alpha reductase I Alpha1 antagonists PDE5 Misc minoxidil
Androgens - hypogonadism, HIV wasting, red blood cell production stimulation (sludgy)
AR Antagonists - Prostate cancer (usually in castrated males). Only useful when testes are taken out (massive release of LH and testosterone from blocking negative feedback that outcompete antagonist features)
5alpha reductase I’s - male pattern baldness, BPH
alpha 1 antagonists - Relax prostrate so urine can flow from urethra to the outside
PDE5 I’s - Biggest class, big problem.
Misc - minoxidil (vasodilator BP drug that is noticed to grow hair)
PDE5 inhibitor mechanism
SE particularly
Androgens
Synthetic anabolic steroids “Lones”
testosterone, oxymetholone, oxandrolone, nadrolone
For decreased libido, ED, decreased vitality, muscle mass, increased adiposity, depression, osteoporosis
Androgen deficiency
Functional and actual lack of testosterone Late onset hypogonadism ADAM PADAM testosterone deficiency syndrome andropause
Measure this with total testosterone levels (total testosterone <250ng/dL or free t <6.5ng/dL) = hypogonadal (less in the morning, higher in the evening
How high is normal testosterone levels?
Free testosterone levels can be 4x as high as the low level cut-off
Androgen SE
Linked to CV disease (questionable), but if given to hypogonadal males the levels do not exceed normal levels and therefore do not experience the sodium and fluid retention in the kidneys.
Obstructive sleep apnea - problem in abusers, not so much old men
Erythropoesis - helpful if anemic patients (common in older people, but keep your eye on it)
Prostate cancer - even if hypogonadal, do not give to african americans, first degree relative with prostate cancer, PSA > 3ng/mL
Personal thought is to not give these unless hypogonadal.
How does androgen therapy work in HIV patients?
Increase lean body mass
Improve weight gain and well-being
May not be more effective than appetite stimulants
Concern in females
AR antagonists
Flutamide, Biclutamide, NIlutamide, Enzalutamide
Used primarily for prostate cancer (only useful in castrated males)
Stage I - IV (metastatic and invasive is stage 4)
Prostate cancer - prostate cancer does not cause urinary retention (unlike BPH). Diagnosed by digital examination and PSA levels. PSA levels are only useful when individual levels are compared over time.
What does the prostate do?
Controls urinary flow
If removed, common SE is incontinence
Prostetectomy causes erectile dysfunction because of damage to the pelvic and pudendal nerves. Robotic surgeries lessen the likelihood of damage to these nerves. (Controls blood flow to the penis which controls erection) Detruser muscle goes all around the…
Chemical castration
GnRH agonists cause chemical castration
Prostate gland histology
Gleason stages (1-5) Histological irregularities that occur as the cancer progresses
- Small uniform gland, well-differentiated
- More space between glands
- Irregular masses, few glands
- Lack of glands, sheets of cells, poorly differentiated
5 alpha steroid reductase inhibitors
Finasteride, dutasteride
Used for BPH, MPB
Dose differs between the two applications
Shrink prostrate driven by androgens
Inhibitors prevent formation of DHT (10x more potent than T)
MPB dose of finasteride is 1mg/day compared to 5mg/day for BPH
Hair growth phases
Irregular hair growth throughout life, 4 phases
- Anagen - growing phase (2-7 years) of individual hair follicle
- Catagen - regression (10 days)
- Telogen - resting (up to 3 months)
- Go back to growth phase - Early anagen/anagen onset OR exogen (shedding)
Finasteride will not work overnight for MPB because a population of hair has to be influenced.
Target of DHT in hair follicles
Dermal papilla in the bottom of the hair shaft
DHT in hair follicles
DHT activates androgen receptors in the dermal papilla which causes death (miniaturization) in hair follicles. Hair falls out, get sparse hair. Prevent conversion of T to DHT can effectively make a difference in the number of functional hair follicles left on the scalp. Finasteride prevents formation of this toxic compound in hair follicles.
Who can benefit from finasteride in MPB?
Not men who are already bald. People who are going bald but not have lost many of their hair follicles yet.
What does minoxidil do in MPB?
It shortens telophase in the hair growth cycle. It is reversible when you stop taking finasteride.
Other finasteride counseling points
MPB - If you stop, the hair growth effects are reversible
Extremely teratogenic to male fetuses
Primitive gonad
XY male, XX female
Start off bipotent, male or female
Primitive gonad is precursor to either testes or ovaries
Puff of DHT/T, primitive gonad goes towards testes
Mullerian ducts give rise to uterus and tubes
Wolffian ducts - vas deferent and epididymus
Testosterone causes regression on Mullerian ducts and expansion of Wollfian ducts.
Y chromosome is important in this (has sex-determining region, which induces puff of testosterone)
End up with testes and no fallopian tubes/uterus
Highly dependent on testosterone. If you block formation of DHT, then will feminize a masculine fetus that is genotypically XY
Default is female
6-8 weeks is the window. No problems with female fetuses.
Alpha-1 receptor antagonists
Same as hypertension
Short acting, non-selective: prazosin, alfuzosin
Long acting, non selective: Terazosin, Doxazosin
Long acting, alpha-1 selective: tamsulosin, silodosin
Used for urinary retention secondary to BPH
Relax prostate and relax the smooth muscle; increase size of the pipe.
Indication: hypertension and BPH
LUTS (obstructive systems like urinary retention or irruptive symptoms lie burning and urgency to urinate)
Anatomic issues like enlarged prostate (most males)
Dynamic issues - state of muscle contraction of smooth muscle in neck of the bladder and the tissue that is the prostate.
How much of the urethral pressure is due to the alpha adrenergic tone and how much is due to the state of the prostate?
They are about equal. 40% due to alpha adrenergic tone and 53% due to the state of the prostate. So alpha-1 antagonists reduce the 40% due to the alpha adrenergic tone.
Can give centrally or locally in the smooth muscles surrounding the urethra
BPH
> 50% by age 60
90% by age 80
Hypertrophy of bladder neck
Contraction of smooth muscle = obstructive voiding
What are some of the obstruction symptoms of BPH?
hesitancy, weak stream, straining to void, prolonged voiding, incomplete bladder emptying
What are some of the irritative symptoms of BPH?
urgency, frequency, nocturia, urge incontinence (due to anatomical issues like enlarged prostate or dynamic issues like the smooth muscle tone in the bladder neck)
PDE5 inhibitors
Representative agents (afils) Used primarily for ED ED = consistent inability to attain or maintain a penile erection of sufficient quality to permit satisfactory sexual intercourse.
Which PDE5 also has an indication for BPH?
Tadalafil
If you relax the smooth muscle in the prostate, then you can increase the diameter of the lumen of the urethra. Dose for this application is much smaller than dose for erectile dysfunction.
Insurance won’t pay for erectile dysfunction, but will pay for BPH.
Only duration of action of this drug is unique. Otherwise the others are similar.
Pulmonary hypertension indication of PDE5 inhibitor?
Sildenafil
What percentage of males ages 40-49 have ED? Partial ED?
5%, 17%
What percentage of males age 70-79 have ED? Partial ED?
17%, 34%
What are the causes of ED?
vascular, anatomic, neurologic, psychogenic, neurogenic, hormonal, drug-induced
Hormonal causes of ED?
Hypogonadism
Hyperprolactinemia
Drug-induced causes of ED?
Antihypertensive (CCB, BB, methyldopa, clonidine, reserpine, guanethidine)
Cardiac drugs
Antidepressants (tranquilizers)
H2 antagonists
Hormones - estrogens, progesterones, corticosteroids, LHRH (same asGnRH analogs - when given to castrated males), 5a reductase inhibitors (because of reduced DHT, negative influence on libido and erectile function)
Alcohol abuse
Cigarette smoking
Cannabinoids are not on this list!! CB2 receptors
Diseases that can cause ED?
Diabetes mellitus
Metabolic syndrome
Risk factors for ED?
Metabolic syndrome
Hyperglycemic - treat diabetes, can add PDE5 inhibitor. Control other problems first to increase efficacy.
Hypertensive
Mechanism of venogenic erectile dysfunction
Breakdown in the vascular supply of the penis.
Veins are not able to maintain back pressure.
Need to dilate vasculature going to the penis and constrict the veins leaving the penis to increase the amount of blood inside the penis.
Insufficient compression of subtunical veins can be behind the inadequate constriction. Inadequate construction is also associated with diabetes. Decreased sinusoid compliance can include compromised and leaky holes. Smooth muscle between sinusoids are dying and smaller.
What does erection consist of?
Complex neuromuscular process in which nerves, endothelium of sinusoids and blood vessels and smooth muscles all participate.
Drugs that cause contraction (blood vessels to the penis)
These are bad
Noradrenaline, endothelia’s, angiotensin II, serotonin, prostanoids (PGF2a, TXA2), tumor necrosis factor
Drugs that cause relaxation (blood vessel to the penis)
Good (like PDE5 inhibitors)
ACh, DA, ATP, adenosine, Vip and related peptides, adrenomedullin, CGRP, prostanoids (PGE1), endocannabinoids
PDE5 mechanism
Endothelial cells line the vasculature.
Smooth muscle cells (below endothelial cells)
In close contact with each, gap is there - sub-intimal space
NO is generated in endothelial cells (L-arginine produces through eNOS)
NO goes into suboptimal space, into smooth muscle cells and stimulates guanylyl cyclase to produce cGMP.
cGMP activates cGMP dependent kinases, which phosphorylate proteins which leads to decreased intracellular Ca and relaxation of smooth muscle. Enhanced blood flow into the penis, and erection. NO is extremely labile, but doesn’t last very long.
cGMP has a timer (same as cAMP) which is phosphodiesterase called PDE5 (in penile smooth muscle).
Two reasons for SE’s with PDE5 drugs
- PDE5 is expressed in more areas than the penis. 2. The PDE5 inhibitors that we have are selective, but not specific. Therefore, we have side effects.
What are some common side effects of PDE5 inhibitors?
Visual disturbances.
Photon signaling pathway. Photon activates receptor rhodopsin with retinal (via A aldehyde) imbedded. Retinal isomerizes photon which causes a shape change in rhodopsin which activates its G protein which is called transducer. Transducin’s effector is PDE6 in rods and cones. This is similar to PDE5. (Vardenifil has 5-fold selectivity of PDE5 over PDE6, so there are a lot of visual side effects.
What is the effect of cAMP compared to cGMP?
Pretty similar.
ATP activates adenylyl cyclase to produce cAMP, which is phosphorylated by cAMP kinase. cAMP is broken down by PDE2, 3, and 4 (instead of 5).
Functionally, cAMP has the same effect as cGMP in decreased calcium levels, smooth muscle relaxation, vasodilation, and erection.
What are the two sources of NO?
Endothelial cells and the cavernous nerve.
A cavernous nerve, a branch of the parasympathetic nervous system NANC (non-adrenergic, non-cholinergic) seems to release NO.
Another neurotransmitter is releases by this neuron: vasoactive intestinal peptide.
What are the PDE iso forms?
There are 11.
There is a high degree of similarity between the GAF-containing PDE’s (a domain in which cGMP binds) and non-GAF containing PDEs.
We want to inhibit PDE5.
The catalytic domain of the PDE’s are highly conserved. The other areas are also very similar. Some are cAMP specific and some are cGMP specific, and others are both.
If you had a drug that was 100% selective for PDE5, would you have any side effects?
Yes, because there are PDE5 receptors in the vascular smooth muscle, which is also located in the brain and could cause headaches. There are also receptors in the lung, muscle, platelets, and heart.
What are the cAMP specific PDE’s?
4
7
8
What are the dual cGMP and cAMP PDE’s?
1 2 3 10 11
What are the cGMP specific PDE’s?
5
6
9
Where are PDE6 receptors located?
In photoreceptors (rods and cones)
IC50 for Sildenafil in PDE5 and PDE6.
Sildenafil is 11x more selective for PDE5 than PDE6. But the PDE6 potency is still pretty good, and therefore there will still be visual disturbances.
IC50 for Vardenafil
The highest potency for PDE5 at 0.14nm. However, there is only a 4-fold difference between PDE6 and PDE5. Visual disturbances.
IC50 fr Tadalafil
The highest IC50 for PDE5, therefore the lowest potency. BUT, although it is the weakest, it is the most selective for PDE5. There is 187 times more selectivity for PDE5 over PDE6. Tadalafil also has long lasting effects.
How is cGMP hydrolysis important in visual cycle?
Hydrolysis of cGMP to GMP. Shut cation channel, which kicks off an action potential that makes you aware that you have seen a photon of light.
This is critical for signal transduction for vision.
Effects ability to drive motored vehicles if you can’t see!!
Talk about this when you counsel.
What other tissues use PDE5?
Corpus cavernous, adipose tissue, pulmonary vascular system, heart, endothelial cell, and muscle. Two types of adverse effects
Selective types and non-selective types.
There should be a more significant SE profile of these drugs than there actually are considering all the tissues there are which have receptors for PDE. Muscle aches and visual changes are the major SE’s.
Do these drugs bind similar to PDE5?
Yes, they all bind to the same pocket of these PDE5s.
What differentiates tadalafil from sildenafil and vardenafil?
Tadalafil has no effect with food (doesn’t have to be taken on an empty stomach), is the most selective, and has the most long-lasting effects.
What do you do if a PDE5 inhibitor gives you side effects? If the dose is ineffective.
Start with the middle dose. If there are SE’s, go down. If it doesn’t work, then go to the highest dose.
How many times would you try the maximum dose before ending the trial?
6 times
if it still doesn’t work, then investigate hypogonadism. However if there is a first-degree relative with prostate cancer they are out of luck.
What CI’s are there? What are the different risk levels in men with coronary artery disease and want to undergo treatment for erectile dysfunction?
Low (controlled disease) - Possible use of PDE5 inhibitor
Intermediate (atherosclerosis, CHF, stroke) - Further evaluation by a cardiologist
High (unstable angina and any of these risk factors - uncontrolled hypertension
