Module 3 Pharmacology

Front 1

What are the MOAs of antiandrogenic drugs?

Back 1

1. Antagonists block testosterone receptors

2. GnRH agonists act at the pituitary gland to shut off the release of LH and FSH

3. Antagonist of the GnRH receptor blocks the release of LH and FSH

Front 2

What are the androgen receptor antagonists?

Back 2

bicalutamide

flutamide

spironolactone

Front 3

Biclutamide and Flutamide MOA?

Back 3

-- Competitively block androgen receptors
-- blockade of receptors in the hypothalamus results in loss of feedback inhibition of LH secretion
-- plasma LH and thus testosterone are increaed markedly

Front 4

Biclutamide and Flutamide therapeutic use?

Back 4

-- treatment of prostatic carcinoma

-- must be given w/ GnRH analog since the increased plasma testosterone competes w/ the drug for the androgen receptors (and limits its anti-androgenic effects)

Front 5

Biclutamide and Flutamide toxicity?

Back 5

Biclutamide preferred over Flutamide -- biclutamide has less hepatic toxicity and can be taken once a day

Front 6

Spironolactone MOA?

Back 6

1. Competitive steroid antagonist of Aldo receptors
2. Partial agonist at androgen, estrogen and progesterone receptors (remember, partial agonist is antagonistic against full agonist)
3. Also partially inhibits the CYP17 which synth testosterone

Front 7

Spironolactone therapeutic use?

Back 7

Used to treat hirsuitism in females

Front 8

What are the GnRH (analogs) receptor agonists? Availability?

Back 8

leuprolide acetate -- available in 3-4m depot prep for i.m. injection

goserelin acetate -- i.m. implant lasts 3m

Front 9

leuprolide, goserelin MOA?

Back 9

1. Initially stim release of FSH and LH in males and females -- plasma testosterone rises initially in males

2. However, if given continuously in NON-pulsatile fashion, pituitary GnRH receptors become desensitized, leading to decreased LH secretion

3. Plasma testosterone suppressed to about 10% of normal values

Front 10

Medical uses of leuprolide, goserelin?

Back 10

1. Prostatic carcinoma
-- used w/ bicalutamide to prevent initial testosterone flare that can cause bone pain from metastases
-- If no metasteses, can use GnRH alone

2. Treatment of endometriosis and uterine fibroid tumors

3. Treatment of central precocious puberty

Front 11

Adverse effects leuprolide and goserelin?

Back 11

1. hot flushes, sweating
2. edema
3. gynecomastia
4. decreased libido

Front 12

What are the obstructive symptoms of BPH?

Back 12

1. urgency
2. hesitancy
3. diminished force of urinary stream
4. nocturia

Front 13

What drugs do we use to treat BPH?

Back 13

a1-adrenoceptor antagonists:

1. terazosin
2. doxazosin
3. tamsulosin

Front 14

What is the MOA of the a1-adrenoceptor antagonists?

Back 14

1. a1-adrenoceptors abundant in smooth muscle of prostate, prostatic capsule, prostatic urethra and bladder neck
-- 70% are of a1A subtype

2. pharmacologic blockade of the receptors causes a reversible relaxation of smooth muscle resulting in decreased resistance to urethral flow

3. These drugs improve the symptoms of urgency, hesitancy, weak stream and nocturia w/in 2 weeks (some have almost immediate relief)

Front 15

terazosin and doxazosin general info?

Back 15

-- terazosin was first a-adrenoceptor antagonist approved for BPH
-- terazosin and doxazosin produce identical therapeutic effects, but doxazosin has half life of 22h, while terazosin has half life of 12h

Front 16

Therapeutic use of terazosin and doxazosin?

Back 16

-- Used to treat HTN

-- Have proved efficacious for improving HTN and BPH at the same time

Front 17

Adverse effects terazosin and doxazosin?

Back 17

1. dizziness
2. postural hypotension (blockade vascular a1-adrenoceptors)
3. sombolence
4. asthenia = loss of energy and strength = fatigue
5. nasal congestion (unopposed cholinergic vasodilation)
6. peripheral edema
7. impotence (failure to ejaculate) - 2%

Front 18

Tamsulosin use? side effects?

Back 18

half-life of 12-15h

-- as efficacious as terazosin and doxazosin
-- less dizziness and orthostatic hypotension
-- increased receptor selectivity for a1A-adrenoceptors increases incidence of ejaculatory dysfxn (10%)
-- ejaculatory dysfxn consisted of failure to ejaculate, decreased volume of ejaculate, or retrograde ejaculation

Front 19

finasteride, dutasteride MOA?

Back 19

**5a-reductase inhibitors

1. 5a-reductase, enzyme which converts testosterone into DHT, exists in two molecular forms
-- TYPE1 - liver, skin
-- TYPE2 - prostate
2. FINASTERIDE selectively inhibits the type 2 enzyme; DUTASTERIDE inhibits both forms
3. Inhibition prevents conversion of testosterone to DHT
4. Finasteride - causes plasma DHT conc to fall by 70% and plasma T concentration to rise by 10%
5. Finasteride - causes conc of DHT w/in the prostate gland to decrease by more than 70%
6. Plasma LH is not changed

Front 20

finasteride, dutasteride clinical effect in BPH?

Back 20

1. decrease in size prostate gland noted by 3 months; shrinkage continues for next 1-2yrs
2. Avg size reduction is 25%, and shrinkage assoc w/ decreased BPH symptoms
3. Decreased size maintained w/ continued use of meds
4. The larger the prostate, the greater the response
5. Treatment with 5a-reductase inhibitors decreases need for TURP

Front 21

finasteride, dutasteride clinical effect in male pattern baldness?

Back 21

1. Inhib 5a-reductase in hair follicles can prevent hair loss
2. Used in conjuction w/ topical prep of the arterial vasodilator minoxidil to treat alopecia

Front 22

Adverse effects finasteride, dutasteride?

Back 22

1. impotence (decreased volume of ejaculate) and decreased libido

2. Finasteride (5mg p.o.) suppresses plasma conc of PSA by up to 50%, so patients must have periodic rectal exams to screen for prostatic cancer

3. Finasteride (1mg p.o.) does not suppress PSA

4. Trtmt w/ dutasteride for 3 months reduces serum PSA by 40%; trtmt for 6-12 months reduces the serum PSA by 50%

New baseline PSA must be made one year after beginning trtmt BPH w/ 5a-reductase inhibitor

Front 23

What are the strategies for treating children w/ nocturnal enuresis?

Back 23

1. Behavioral therapy preferred

2. Inhibit bladder contraction by blocking muscarinic receptors in GU tract

3. Decrease nocturnal production of urine

Front 24

What are the drugs to treat nocturnal enuresis?

Back 24

oxybutynin, DDAVP

Front 25

oxybutynin MOA?

Back 25

blocks muscarinic receptors and exerts direct anti-spasmodic effect on the detrusor muscle

Front 26

DDAVP MOA?

Back 26

-- long-acting synthetic analog of AVP; duration of action 6-20h

-- selective for the vasopressin V2 receptor (ration V2:V1 is 40000:1) found in principle cells of late distal tubule and collecting duct

-- can be given by nasal spray before bedtime to enhance the renal reabsorp of water and thus decrease urinary vol

-- allergic rhinitis or nasal congestion from URI slow its absorption

Front 27

How do we treat overactive bladder?

Back 27

muscarinic receptor antagonists:

tolteradine
solifenacin
darifenacin

Front 28

tolteradine

Back 28

**twice daily

- muscarinic receptor antagonist

- S/Es include somnolence, dry mouth, blurred vision, and constipation

Front 29

solifenacin

Back 29

**once daily

- a selective M3-muscarinic receptor antagonist

- increases the Q-Tc in normal volunteers, but is less than that caused by FQ moxifloxacin

- fewer CNS effects

- less dry mouth compared to tolteradine

Front 30

darifenacin

Back 30

**once daily -- best choice

- selective M3-muscarinic receptor antagonist

- no CNS or CV effects, including no increase in Q-Tc

- less dry mouth compared do tolterodine

Front 31

What is impotence?

Back 31

Sexual dysfxn that can result from inability to achieve an erection (ED) or inability to ejaculate.

Can be organic, psychogenic, or a mixture of the two causes.

Front 32

Organic causes of ED?

Back 32

1. atherosclerosis
2. DM
3. spinal cord injury
4. prostatectomy
5. treatment w/ antidepressant drugs (esp SSRIs)
6. smoking cigarettes

Front 33

What is the International Index of Erectile Dysfunction (IIEF)?

Back 33

-- It is a questionnaire that estimates the severity of ED

-- 5 questions in which patient rates 5 areas of sexual fxn from 1 to 5 (1 is poor, 5 is great)

-- A total of 5 is very bad, whereas a score of 25 is very good

Front 34

ED exists in what percent of men worldwide?

Back 34

10-20%

Front 35

What are options for treating ED?

Back 35

Penile erection requires relaxation of smooth muscle of corpus cavernosa; can be induced by:
1. inhibition of type 5 phosphodiesterase (PDE5)
2. blockade of a1 receptors
3. stimulation of PGE1 receptors

Front 36

Alprostadil MOA?

Back 36

PGE1 receptor agonist
-- erection in 5 min, subsides in 60-90 min

-- injection within "Triple P" coctail causes erection within 10 minutes, and lasts 15-20 minutes

Front 37

Topical alprostadil

Back 37

1. Muse (urethral suppository) onset in 5-10 min; subsides after 30-60 min

2. Topiglan (gel) and Alprox-TD (cream) are applied to penile head -- erection occurs w/in 30-40 minutes

Used for patients who do not respond to sildenafil.

Front 38

PDEase inhibitors?

Back 38

sildenafil
onset = 30-60min; lasts 4-5h
-- taken one hour before sexual activity produces an erection that lasts 30 min to 2 h

vardenafil
onset = 60 min; lasts 4-5h

tadalafil
onset = 30-45min; lasts for 24h

Front 39

Adverse effects of the PDEase inhibitors?

Back 39

1. "Smurf" vision and impairment of blue-green color discrimination results from partial blockade of PDEase type 6, b/c cGMP is involved in signal transduction ointhe cones of the retina

2. NAION = non-arteritic ischemic optic neuropathy which results from decreased flow to optic nerve; serious, but reversible

3. headache and flushing

Front 40

Adverse drug-drug interactions of PDEase inhibitors?

Back 40

1. Do not use any nitrate in any form in presence of type 5 because this can result in severe hypotension which in turn precipitates chest pain, MI or ischemic stroke

2. Do not use inhibitors of PDEase type 5 in patients taking any of the a-blockers used to treat BPH. Again, untoward hypotension can result.