Phar422: Drugs for Erectile Dysfunction

Alprostadil (MUSE® pellet, Caverject®, Edex®) is TYPICALLY not used in patients who failed ________ or are not candidates for ________ use

PDE5 inhibitors; PDE5 inhibitors

Male Sexual Physiology: -The PENIS has 3 "columns" -the sponge-like erectile tissue called the ______ -the cavernosal arteries -the corpora cavernosal space

1) corpus cavernosum

Name 5 types of drugs used to treat Erectile Dysfunction

1. PDE5 inhibitors 2. Localized Prostaglandins 3. α-2 adrenergic receptor antagonists 4. testosterone 5. Apomorphine other drugs used for ED: -dopamine receptor agonists -papaverine -alpha1 adrenergic antagonists

Name 4 drugs (brand and generic) that are PDE-5 inhibitors and are used to treat ED

1. Sildenafil (Viagra) 2. Tadalafil (Cialis) 3. Vardenafil (Levitra) 4. Avanafil (Stendra)

How do Phosphodiesterase type 5 inhibitors improve ED? A. inhibits PDE-5 in the smooth muscle of the corpora cavernosa of the penis, resulting in increased levels of cGMP, resulting in vasodilation and increased blood flow B. inhibits PDE-5 in the smooth muscle of the corpora cavernosa of the penis, resulting in increased levels of GMP, resulting in vasoconstriction and decreased blood flow

A

Alprostadil is available in which of the following TWO formulations? Choose the correct two answers: A. intraurethral suppository (MUSE® pellet) B. intracavernosal injection (Caverject® , Edex®) C. oral tablet (Erecto®) D. topical patch 2.5% (Penaderm®)

A and B A. intraurethral suppository (MUSE® pellet) -MUSE=medicated urethral system for erection -sit, stand, or walk for about 10 minutes while erection develops B. intracavernosal injection (Caverject® , Edex®) KNOW THE NAMES AND ROUTE OF ADMINISTRATION

To initiate an erection, NON-adrenergic and NON-cholinergic (NANC) autonomic plexus nerves trigger the release of local vasodilators from the vascular endothelium and the smooth muscle cells of the sinusoids (space). The local vasodilators released include: (Choose all that apply): A. nitric oxide B. vasoactive intestinal peptide (VIP) C. endothelin D. norepinephrine

A, B, C Penile erection is initiated by sexual stimuli, including auditory, visual, and olfactory stimuli, and erotic cognitions. Spinal cord sexual arousal occurs as a result of tactile stimulation of the penis. The neurotransmitter mediating these sexual signals is nitric oxide (NO), initially termed endothelium-derived relaxing factor. NO is produced by the endothelium in the absence of cholinergic or adrenergic influences. NO stimulates smooth muscle guanylate cyclase, upregulating synthesis of cyclic guanine monophosphate (cGMP), which plays a pivotal role in penile arteriolar vasodilatation and relaxation of penile corporeal smooth muscle. Oxygen levels are important in NO-mediated responses, which vary widely from penile flaccidity to erection. Decreasing oxygen tension levels progressively inhibit NO responses, and elevation of oxygen to normal levels restores NO-dependent activities

Which of the following have drug interactions with PDE5 inhibitors? Choose all that apply A. alpha adrenergic receptor blocks and other anti-hypertensives B. yohimbine C. strong/potent CYP2C19 inhibitors or inducers D. strong/potent CYP3A4 inhibitors or inducers E. Ritonavir

A, B, D, and E A. alpha adrenergic receptor blocks and other anti- hypertensives -hypotension effects potentiated (increased) B. yohimbine -alpha-2 adrenergic receptor blocker that is also clinically used for ED D. strong/potent CYP3A4 inhibitors or inducers -dose adjustments may be necessary for CYP3A4 inducers E. Ritonavir is a strong CYP3A4 inhibitor

Semen is ejected through the urethra via: Choose all that apply A. rhythmic contractions B. non-rhythmic contractions C. under the control of spinal reflex (involuntary control) of the ischiocavernosus muscles D. under the control of spinal reflex (involuntary control of the bulbocavernosus muscle

A, D

Detumescence (a decrease in erection) is predominated by which branch of the autonomic nervous system: A. sympathetic nervous system B. parasympathetic nervous system

A.

Which of the following muscles in the PENIS is involved in Ejaculation? A. Bulbospongiosus muscle B. Ischiocavernosus muscle C. Gluteus maximus muscle D. Superficial transverse perineal muscle

A. Bulbospongiosus muscle

ALL of the PDE-5 inhibitors are metabolized by: A. CYP3A4 B. CYP2C9 C. CYP2D6 D. CYP90210

A. CYP3A4 HOWEVER, Sildenafil (Viagra) and Avanafil (Stendra) are ALSO metabolized by CYP2C9

Ejaculation can occur before the start of puberty A. True B. False

A. False. after puberty bc it involves testosterone

Unique Adverse Effects of PDE-5 inhibitors: Visual Disturbances is associated with which of the following PDE-5 inhibitors? Choose all that apply A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

A. Sildenafil (Viagra) C. Vardenafil (Levitra)

Apomorphine (Apokyn®) effectiveness in treating erectile dysfunction is very questionable A. True B. False

A. True

Ejaculation occurs AFTER a threshold level of stimulation. A. True B. False

A. True

Penile erection is basically a spinal reflex that can be initiated by stimuli from the periphery AND from the central nervous system. A. True B. False

A. True

Up to 25% of all Erectile Dysfunction (ED) cases are drug-induced A. True B. False

A. True

PDE-5 inhibitors can have activity on other PDE isotypes in the body (i.e. PDE-6 in the retina) A. True B. False

A. True Adverse effects from the other PDEs: -visual disturbances from activity on PDE-6 in the retina -potential effects in testicles and prostate from PDE-11 in those tissues (clinical effects not well-established)

Alprostadil (MUSE® pellet, Caverject®, Edex®) is NOT for WOMEN A. True B. False

A. True -obviously also not for children

A patient is taking a drug called **Ritonavir** (a STRONG CYP3A4 inhibitor) and one of the PDE-5 inhibitors. You should call his doctor and recommend that he/she: (choose the best answer out of the two following choices) A. reduce the dose of the PDE-5 inhibitor B. increase the dose of the PDE-5 inhibitor

A. reduce the dose of the PDE-5 inhibitor -Since Ritonavir is inhibiting the CYP3A4 enzyme that metabolizes the PDE-5 inhibitor, it can accumulate and increase the risk of causing adverse effects

Caverject®, Edex®: intracavernosal INJECTION(Alprostadil) has which of the following drug interaction? A. increased risk of hypotension when taken with beta-2 agonists (i.e. albuterol, salmeterol) B. increased risk of bleeding when taken with anticoagulants (i.e. warfarin, heparin)

B

Nitrates, when taken along with any PDE-5 inhibitors, can cause: A. prolonged and unpredictable hypertension B. prolonged and unpredictable hypotension

B

Benign Prostatic Hyperplasia (BPH), enlargement of the prostate, can be due to which of the following? Choose all that apply A. decreased dihydrotestosterone (DHT) activity in the prostate B. increased dihydrotestosterone (DHT) activity in the prostate C. decreased adrenergic tone (alpha-adrenergic receptors) in the prostate D. increased adrenergic tone (alpha-adrenergic receptors) in the prostate

B and D BPH can be caused by one of these issues, or by both B. increased dihydrotestosterone (DHT) activity in the prostate D. increased adrenergic tone (alpha-adrenergic receptors) in the prostate

What occurs or can possibly occur AFTER ejaculation? Choose all that apply A. Tumescence (volume expansion; erection) B. Detumescence (decrease in erection) C. Orgasm D. Urination to flush out semen from urethra

B, D -urination is often followed by a refractory time period that is difficult to initiate another erection

PDE-5 Inhibitors--Other Considerations: Precautions: Patients must seek treatment after ___ hours of erection. A. 2 hours B. 4 hours C. 6 hours D. 8 hours

B. 4 hours

Erection: Erection is initiated by stimuli from adrenergic and cholinergic autonomic plexus nerves A. True B. False

B. False Erection is initiated by stimuli from NON-adrenergic and NON-cholinergic (NANC) autonomic plexus nerves

Which of the following muscles in the PENIS is involved in erection? A. Bulbospongiosus muscle B. Ischiocavernosus muscle C. Gluteus maximus muscle D. Superficial transverse perineal muscle

B. Ischiocavernosus muscle

Unique Adverse Effects of PDE-5 inhibitors: BOTH back pain AND myalgias (muscle pain) is associated with which of the following PDE-5 inhibitors? A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

B. Tadalafil (Cialis)

A male patient with erectile dysfunction comes into your pharmacy and asks you what is the best PDE-5 inhibitor to use if he plans on engaging in a "sex marathon" tomorrow with his beloved wife (having intercourse for breakfast, lunch, and dinner)? He only wants to take one pill tomorrow A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

B. Tadalafil (Cialis) -bc Cialis has the longest duration of action (HAS A HALF-LIFE OF 18 HOURS) ----Cialis has the longest duration of action BUT has the slowest onset of action (takes longer to kick in) Other PDE-5 inhibitors: half-life=3-5 hours

Unique Adverse Effects of PDE-5 inhibitors: Back-pain is associated with which of the following PDE-5 inhibitors? Choose all that apply A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

B. Tadalafil (Cialis) D. Avanafil (Stendra)

Yohimbine, an alkaloid derived from the bark of the yohimbe tree in Central Africa, treats Erectile dysfunction by: A. stimulating alpha-2 adrenergic receptors, causing smooth muscle constriction of blood vessels within the penis B. antagonizing alpha-2 adrenergic receptors, causing smooth muscle relaxation of blood vessels within the penis C. stimulating alpha-1 adrenergic receptors, causing smooth muscle constriction of blood vessels within the penis D. antagonizing alpha-1 adrenergic receptors, causing smooth muscle relaxation of blood vessels within the penis

B. antagonizing alpha-2 adrenergic receptors, causing smooth muscle relaxation of blood vessels within the penis

Ejaculation is associated with: Choose all that apply A. low blood pressure B. high blood pressure C. low heart rate D. high heart rate E. heavy breathing

B. high blood pressure C. high heart rate D. heavy breathing

Which of the following mechanisms would work to maintaining an erection (vasodilation)? Choose all that apply: A. decreased activity of guanylate cyclase B. increased activity of guanylate cyclase C. decreased activity of Phosphodiesterase Type 5 D. increased activity of Phosphodiesterase Type 5 E. inhibition of venous drainage from the shaft of the penis F. increased amount of venous drainage from the shaft of the penis

B. increased activity of guanylate cyclase -converts more GTP to cGMP, resulting in vasodilation>increased blood flow>erection C. decreased activity of Phosphodiesterase Type 5 >less cGMP is converted to GMP, so arteries stay dilated>increased blood flow>erection E. inhibition of venous drainage from the shaft of the penis -if you lose blood in the shaft, the erection will be lost, so inhibiting the veins from draining the blood of the penis shaft would maintain an erection

Which of the two formulations of Alprostadil APPEARS to be more effective in treating Erectile Dysfunction? A. intraurethral suppository (MUSE® pellet) B. intracavernosal injection (Caverject® , Edex®)

B. intracavernosal injection (Caverject® , Edex®) THE INJECTION FORMULATION IS MORE EFFECTIVE

Which of the following correctly describes the mechanism of action of alprostadil in treating erectile dysfunction (ED)? A. is a synthetic prostaglandin E2 (PGE2), that stimulates adenylyl cyclase in smooth muscle, increasing cAMP levels, leading to dilation of penile arteries B. is a synthetic prostaglandin E1 (PGE1), that stimulates adenylyl cyclase in smooth muscle, increasing cAMP levels, leading to dilation of penile arteries C. is a synthetic prostaglandin E2 (PGE1), that inhibits adenylyl cyclase in smooth muscle, decreasing cAMP levels, leading to dilation of penile arteries D. B. is a synthetic prostaglandin E1 (PGE1), that inhibits adenylyl cyclase in smooth muscle, decreasing cAMP levels, leading to dilation of penile arteries

B. is a synthetic prostaglandin E1 (PGE1), that stimulates adenylyl cyclase in smooth muscle, increasing cAMP levels, leading to dilation of penile arteries -Alprostadil also decreases release of NE from adrenergic nerves -similar to misoprostol (Cytotec) for G.I. uses

Which of the following branches of the nervous system predominates activities of an ERECTION? A. sympathetic nervous system B. parasympathetic nervous system

B. parasympathetic nervous system

Enlargement of the prostate gland causes BOTHERSOME LOWER URINARY TRACT SYMPTOMS -VOIDING symptoms (problem with urinating) such as hesitancy, straining, a sense of incomplete emptying, intermittency, a weak stream, and post-void dribbling -FILLING symptoms, such as frequency, nocturia, urgency, and urge incontinence. This disease is medically referred to as _________

Benign Prostatic Hyperplasia (BPH) -85% of males affected by age 80)

Which of the following enzymes converts cGMP to GMP, resulting in vaso loss of erection? A. guanylate cyclase B. adenylyl cyclase C. phosphodiesterase type 5 D. GMP synthase

C.

Which of the following drugs used to treat Erectile Dysfunction CANNOT be taken by mouth (P.O.)? A. tadalafil B. yohimbine C. alprostadil D. sildenafil

C. alprostadil

Men taking testosterone increases their risk of developing: Choose all that apply A. hypotension B. weight loss C. benign prostatic hyperplasia (BPH) D. prostate cancer

C. benign prostatic hyperplasia (BPH) -up to 2% D. prostate cancer -up to 1.2%

The MOST common adverse effect of PDE-5 inhibitors is: A. increased sense of hearing B. hypertension C. headache D. fatigue

C. headache (10-16%)

Which of the following SECOND messengers are MOST DIRECTLY responsible in erection of the penis (vascular smooth muscle dilation)? A. increased levels of intracellular cAMP B. decreased levels of intracellular cAMP C. increased levels of intracellular cGMP D. decreased levels of intracellular cGMP

C. increased levels of intracellular cGMP Other chemicals that may be involved: -prostaglandin E1 -decrease in NE -dopamine

What is Apomorphine's (Apokyn®) MAIN mechanism of action? A. non-selective dopamine receptor antagonist B. selective dopamine receptor antagonist C. non-selective dopamine receptor agonist D. selective dopamine receptor agonist

C. non-selective dopamine receptor agonist -Activates both D1-like and D2-like dopamine receptors

Erection: Volume expansion of the penis (swelling of penis tissue), or another fancy name for an erection, is called: A. ejaculation B. orgasm C. tumescence D. detumescence

C. tumescence

Apomorphine (Apokyn®) is a POTENT emetic, and therefore, should be administered with an anti-emetic (e.g. Domperidone (Motilium) or prochlorperazine (Compazine)), BUT NOT with which of the following type of anti-emetic drugs? A. Antihistamines (H1 receptor antagonists) B. Dopamine antagonists C. Anticholinergic D. 5HT-3 receptor antagonists

D. 5-HT3 receptor antagonists

What is the brand name of Apomorphine? A. Morphal® B. Apostrophe® C. Amoril® D. Apokyn®

D. Apokyn® NOte: Apomorphine has NO morphine-like activity; actually its an aporphine derivative

If you want to make some vomit, which of the following drugs would be the best choice? A. Viagra B. Cialis C. Yohimbine D. Apomorphine

D. Apomorphine

Adverse effects are PROBABLE when taking PDE-5 inhibitors along with Ritonavir (a strong CYP3A4 inhibitor) and dose-adjustments are usually necessary. Which of the following PDE-5 inhibitors should ABSOLUTELY NOT be taken Ritonavir (because of no guidelines for dose-adjustment?) A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

D. Avanafil (Stendra)

Nitrates, when taken along with any PDE-5 inhibitors, can cause prolonged and unpredictable hypotension. Which of the following PDE-5 inhibitors APPEARS to produce the LEAST of this effect? A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

D. Avanafil (Stendra)

A male patient walks into your pharmacy to seek your medical advice and asks you what PDE-5 inhibitor starts working the fastest (fastest onset). What is the correct answer? A. Sildenafil (Viagra) B. Tadalafil (Cialis) C. Vardenafil (Levitra) D. Avanafil (Stendra)

D. Avanafil (Stendra) -has the shortest onset of action (works the fastest)=0.25-0.5 hours Other PDE-5 inhibitor's onset of action: Sildenafil (Viagra): 0.5-1 hr Tadalafil (Cialis): 1-2 hours<<TAKES THE LONGEST TO "KICK-IN") Vardenafil (Levitra): 0.5-1 hr

Other clinical uses of PDE-5 inhibitors include which of the following? A. prolonged hypotension B. priapism C. CHF (congestive heart failure) D. pulmonary hypertension

D. pulmonary hypertension caused by: -excessive vasoconstriction of the lung vasculature -PDE5 inhibitors dilate the pulmonary vasculature -DO NOT STOP THE DRUG SUDDENLY--CAN WORSEN PULMONARY HYPERTENSION

EJACULATION is mediated by: A. norepinephrine B. acetylcholine C. dopamine D. serotonin (5-HT)

D. serotonin (5-HT)

PDE5 inhibitors--treatment of pulmonary hypertension 1. Sildenafil (REVATIO) -same as Viagra, but is a reduced dose (20 mg tablet) {Viagra is available in 25. 50, and 100mg tablets) -Revatio is also available in IV and Oral powder for suspension 2. Tadalafil (Adcirca) -same as Cialis (tadalafil), but only available in 20mg oral tablet [Cialis (tadalafil) is available in 2.5, 5, 10, and 20mg tablets]

FYI: The generic version of Revatio (sildenafil) is available as a 20 mg tablet. It is so much cheaper per month that even taking 2 - 2 ½ tablets of the generic version (to get 50 mg for ED) would be cheaper than taking one 50mg Viagra . You can save your patient money by asking their physician to switch to Revatio!!

Special Application techniques of Alprostadil (MUSE® pellet, Caverject®, Edex®) 1)MUSE® pellet: intraurethral suppository ADVERSE EFFECTS: -penile and/or urethral pain -vaginal pain to woman who comes into contact -priapism -hypotension (3%) -dizziness DRUG INTERACTIONS> NONE! 2) Caverject®, Edex®: intracavernosal injection [this has to be painful :( ] ADVERSE EFFECTS: -penile pain -injection site pain and bruising -priapism

Image of MUSE pellet administration

PDE-5 inhibitors are contraindicated with concurrent use of _______ because it can cause severe _______

Nitrates; hypotension -prolonged and unpredictable***

Apomorphine (Apokyn®) is typically used as a last-line treatment of _________

Parkinson's disease

When using PDE-5 inhibitors to treat pulmonary hypertension, a patient should NOT _________

STOP THE DRUG ABRUPTLY (suddenly just stop taking the PDE-5 inhibitor) -bc it can make the condition worse

Erection: Can occur during sleep (3-5 times; REM sleep -reticular activating system ("ARAS") in brain; locus ceruleus; sleep and awake

Upon stimulation, chemicals are released in the brain that cause signals to pass down the spinal cord and outward through special nerves (nervi erigentes) into the penis. These nerves release another chemical (Nitric Oxide) that causes the aforementioned smooth muscle to relax and blood rushes into the erectile bodies, causing erection. Anxiety or fear can prevent the brain signals from reaching the level required to induce erection. Medical conditions can block the erection arteries or cause scarring of the spongy erection tissue and prevent proper blood flow or trapping of blood and, therefore, limit the erection. Thus, the erection mechanism is much like a tire; a firm tire is dependent upon a hose that can deliver air in adequate amounts in a speedy fashion and a valve mechanism that holds the air in place. In the penis the hose is represented by the erection arteries, which rapidly carry blood into the erectile bodies and the valve mechanism, while complicated in its structure, ensures that the blood is trapped inside the erectile bodies until ejaculation occurs or the sexual stimulus has passed.

Drug-Induced Erectile Dysfunction: Which of the following drugs have been linked to causing Erectile dysfunction? choose all that apply A. anti-adrenergic drugs (estrogens, cimetidine, spironolactone) B. anticholinergic drugs ( TCAs, anticholinergic antihistamines, some phenothiazines [e.g. chlorpromazine]) C. Nicotine D. Chronic alcohol consumption

all of them note: there are a lot more (see pg. 12) -Nicotine reduces Nitric oxide (NO) in penis -the anticholinergics reduce the role of the parasympathetic nervous system (which predominates erection) -anti-adrenergic drugs (i.e. estrogens, cimetidine, spironolactone) reduces libido (sex-drive)

Contraction of the _______ muscles produces the rigid-erection phase

contraction of the ischiocavernosus muscles

Apomorphine (Apokyn®) is a POTENT _____(emetic or anti-emetic?)

emetic -used for inducing emesis in veterinary medicine

The inability for a male to obtain rigidity (stiff erection) sufficient to permit intercourse of adequate duration (to his and his partner's satisfaction) is medically referred to as __________

erectile dysfunction (ED) ("impotence") -not just a "lifestyle" disorder; may be related to CV diseases and/or diabetes -most commonly in middle-aged/elderly males

Testosterone is ONLY useful in patients with ED who have a LOW _______ LEVEL

low testosterone level -several formulations of testosterone are available (gels, patches, etc.) -generally effective at APPROPRIATE doses -generally has tolerable side effects at APPROPRIATE doses (weight gain, edema, hypertension)

After reaching the threshold level of stimulation, ejaculation begins with an _______

orgasm

Men who take Alprostadil intraurethral suppository (MUSE® pellet) should avoid exposing this drug to ___________

pregnant women note: PG drugs can cause abortion

PDE-5 Inhibitors--Other Considerations: Precautions: Use of PDE-5 inhibitors may cause ________, a painful erection lasting more than 6 hours

priapism---a medical emergency: permanent tissue damage and permanent loss of future erection (due to prolonged hypoxia (low oxygen supply))

Tumescence: volume expansion of penis; swelling of penis tissue; erection: RAPID VASODILATION (cavernosal smooth muscles) of the________ARTERY and the ________ -inhibition in venous draining from the shaft

rapid vasodilation of: 1) Cavernosal artery 2) Corpora Cavernosal Sinusoids

The Testes is developed high in the abdominal cavity (near the kidneys), and descends into the _______ during the last two months before birth or shortly after birth

scrotum

The temperature in the Testes is approximately 3°C BELOW body temperature, which is necessary for the production of viable ______

sperm -sperm is produced in the testes Note: The testes can be pulled closer to the body when it is cold or the male is sexually aroused (warmth)

Ejaculation begins with an orgasm. This results in the contraction of the ______, where semen is ejected

urethra