UT5 - Andrologia (1)

Question 1

Erection?

Answer 1

❑ Erection is a neurovascular phenomenon under hormonal control
❑ Tactile, visual, olfactory and imaginative stimuli 🡪 central processing 🡪 penile erection
❑ Mediated by coordinated spinal activity in the autonomic pathways to the penis and in the somatic pathways to the perineal striated muscles
↳ assim a ereção é mediada por mecanismos ligados ao SNCentral e SNAutónomo
❑ Balance between factors that control the contraction of the smooth muscle of the corpora cavernosa (CC) 🡪 functional state of the penis
❑ Erection implies arterialdilation, trabecular smooth muscle relaxation,and activation of the corporeal veno-occlusive mechanism

Question 2

Mechanisms of penile smooth-muscle relaxation?

Answer 2

❑ A → os corpos cavernosos são constituídos por células musculares lisas, endoteliais e são revestidos pela túnica albugínea. Numa situação de pénis flácido normal, as células musculares lisas estão tonicamente contraídas.
❑ B → na ereção normal, as células musculares lisas relaxam, os sinusoides preenchem-se com sangue, expandem e comprimem o plexo venoso dorsal, ocorrendo a ereção.
❑ C → a disfunção erétil ocorre quando há diminuição da irrigação, disfunção veno-oclusiva ou diminuição do relaxamento das células musculares lisas. Esta situação ocorre na diabetes mellitus e na doença de Peyronie, por exemplo.

Question 3

Erection - Mecanismos de Ação?

Answer 3

❑ O NO é produzido nas células endoteliais e nas fibras não-adrenérgicas e não-colinérgicas.
❑ Atua depois nas células dos sinusoides cavernosos, aumentando o GMPc que diminuí o Ca2+ intracelular e relaxa o músculo liso.
❑ Também o AMPc diminui o Ca2+ intracelular.

Question 4

Erection - Formas de alterar o Mecanismos de Ação?

Answer 4

❑ A diabetes mellitus, o tabaco, o síndrome metabólico e a dislipidemia são alguns exemplos de fatores de risco e doenças que atuam na síntase do NO, diminuindo-a e levando à apoptose das células musculares lisas e endoteliais, levando à disfunção erétil.
❑ O alprostadil aumenta o AMPc.
❑ Os inibidores da PDE5 (como é o viagra), impedem a degradação do GMPc.

Question 5

Erectile Dysfunction - Definition and epidemiology?

Answer 5

❑ Erectile Dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance (é um sintoma)
– ED may affect physical and psychosocial health and may have a significant impact on the quality of life (QoL) of sufferers and their partners
– ED is a potential warning sign of cardiovascular disease (CVD) → é um sinal precoce de doença cardiovascular e doença vascular periférica

❑ Epidemiology:
– The Massachusetts Male Aging Study (MMAS) reported an overall prevalence of 52% ED in non-institutionalized men aged 40-70 years (Boston area)

Question 6

Erectile Dysfunction - Etiopathogenesis?

Answer 6

❑ Vasculogenic (muitos fatores de risco em comum com as doenças cardiovasculares)
* Cardiovascular disease
* Hypertension
* Diabetes mellitus
* Dyslipidemia
* Smoking
❑ Neurogenic
❑ Anatomical or structural
❑ Hormonal
❑ Drug-induced

Question 7

Erectile Dysfunction - Cardiovascular risk factors?

Answer 7

❑ ED shares common risk factors with cardiovascular disease: lack of exercise, obesity, smoking, hypercholesterolemia, diabetes, hypertension, metabolic syndrome
❑ Lifestyle modification (regular exercise and decrease in body mass index) can improve erectile function → com reversão dos fatores de risco
❑ Endothelial dysfunction promotes atherosclerosis affecting coronary and penile arteries

Question 8

Erectile Dysfunction - Predictor of coronary disease?

Answer 8

❑ Link between ED and CAD (70% dos indivíduos com CAD têm disfunção erétil prévia)
❑ Systemic nature of atherosclerosis
❑ The artery size hypothesis (o lúmen da artéria peniana é cerca de 1/3 do calibre das coronárias)
❑ ED as a marker of CAD (ED precede cerca de 3 anos a CAD – importância da intervenção

Question 9

Erectile Dysfunction - Diagnostic evaluation (basic work-up)?

Answer 9

❑ Se possível, também se deve tentar perguntar a história médica e sexual ao parceiro/a.
❑ É muito importante perguntar também:
✔ Relações prévias, estado emocional, início e duração do problema e tratamentos prévios realizados;
✔ Frequência, rigidez e duração das ereções; estimuladas ou não; ereções noturnas/matinais;
✔ Líbido, ejaculação, orgasmo;
✔ Excluir sintomas de hipogonadismo (como fadiga, défice cognitivo, diminuição da líbido) e LUTS.
❑ Deve-se também preencher um questionário psicométrico: o Índice Internacional de Disfunção Erétil, que avalia desejo sexual, função erétil, orgásmica e satisfação global.

Question 10

Erectile Dysfunction - Diagnostic evaluation (basic work-up) - Exame Físico?

Answer 10

❑ É importante fazer um exame físico genitourinário, endócrino, vascular e neurológico.
❑ Nas deformidades penianas importa ver curvaturas, efimoses, tumores.
❑ Nos sinais de hipogonadismo, devem-se procurar carateres sexuais secundários.
❑ No estado CV e neurológico deve-se avaliar a TA, FC, calcular o IMC, ver o perímetro de cintura abdominal (se não realizado nos últimos 3 meses).

Question 11

Erectile Dysfunction - Diagnostic evaluation (basic work-up) - Testes Laboratoriais?

Answer 11

❑ É essencial adaptar os testes laboratoriais aos fatores de risco e às queixas.
❑ Caso se pense num diagnóstico mais vasculogénico, é importante fazer o perfil glicose-lipídico com HbA1c. Caso for mais hormonal, fazer a testosterona total matinal.
❑ Depois, em casos particulares, pode-se ainda acrescentar outro tipo de exames como PSA, prolactina, hormona lutinizante…

Question 12

Erectile Dysfunction - Diagnostic evaluation (cardiac risk stratification)?

Answer 12

❑ Low-risk category → não é necessária avaliação antes de iniciar a atividade sexual (uma vez estão aptos do ponto de vista físico) ou podem usar terapia para a disfunção sexual.

❑ Intermediate-risk category → os doentes têm condição cardíaca incerta / indeterminada; deve-se avaliar com maior cuidado estes doentes antes de retomar atividade sexual; depois da avaliação com prova de esforço os doentes são inseridos na categoria low risk ou high risk.

❑ High-risk category → os doentes têm condição cardíaca severa / instável, tornando difícil iniciar de imediato o ato sexual; devem fazer uma avaliação pelo cardiologista.

Question 13

Erectile Dysfunction - Diagnostic evaluation (indications for specific diagnostic tests)

Answer 13

❑ Primary ED (not caused by organic disease or psychogenic disorder)
❑ Young patients with a history of pelvic or perineal trauma, who could benefit from potentially curative revascularisation
❑ Patients with penile deformities that might require surgical correction
❑ Patients with complex psychiatric or psychosexual disorders
❑ Patients with complex endocrine disorders
❑ Specific tests may be indicated at the request of the patient or his partner
❑ Medico-legal reasons

Question 14

Erectile Dysfunction - Diagnostic evaluation (recommendations)?

Answer 14

❑ Take a comprehensive medical and sexual history in every patient
❑ Use a validated questionnaire related to erectile dysfunction to assess all sexual function domains and the effect of a specific treatment modality
❑ Include a physical examination in the initial assessment of men with ED to identify underlying medical conditions that may be associated with ED
❑ Assess routine laboratory tests, including glucose-lipid profile and total testosterone, to identify and treat any reversible risk factors and lifestyle factors that can be modified
❑ Include specific diagnostic tests in the initial evaluation only in the presence of the conditions presented (flashcard anterior)

Question 15

Erectile Dysfunction - Treatment algorithm?

Answer 15

❑ Identify and treat ‘curable’ causes of erectile dysfunction
❑ Lifestyle changes and risk factor modifications
❑ Provide education and counseling to patient (and partner, if available)

Question 16

Erectile Dysfunction - PDE5 inhibitors (first-line treatment)?

Answer 16

❑ Sildenafil (Tmax - 0.8-1 hrs; T1/2 - 2.6-3.7 hrs)
❑ Vardenafil (Tmax - 0.9 hrs; T1/2 - 3.9 hrs)
❑ Tadalafil (Tmax - 0.5-0.75 hrs; T1/2 - 6-17 hrs)

❑ They are not initiators of erection and require sexual stimulation to facilitate an erection
❑ Efficacy is defined as an erection with rigidity sufficient for penetration

Question 17

Erectile Dysfunction - Sildenafil?

Answer 17

❑ Doses of 25, 50, and 100 mg (on-demand)
❑ The recommended starting dose is 50 mg and should be adapted according to response and side-effects. Caso surja disfunção erétil severa, como ocorre após prostectomia radical, iniciar logo em full dose.
❑ Effective from 30-60 minutes after administration, com pico plasmático aos 60 minutos.
❑ Efficacy may be maintained for up to 12 hours
❑ Efficacy is reduced after a heavy, fatty meal (delayed absorption)
❑ Improved erections by 56%, 77%, and 84% of a general ED population taking 25, 50, and 100 mg of sildenafil, respectively, compared to 25% of men taking a placebo
❑ Effective in almost every subgroup of patients with ED (diabetes, depression, spinal cord injury, multiple sclerosis, cardiovascular disease, hypertension, LUTS)

Question 18

Erectile Dysfunction - Tadalafil?

Answer 18

❑ Doses of 5 (daily dose), 10 and 20 mg (on-demand)
❑ The recommended starting dose is 10 mg and should be adapted according to response and side-effects
❑ Effective from 30 minutes after administration, with peak efficacy after 2 hours
❑ Efficacy is maintained for up to 36 hours
❑ Efficacy not affected by food
❑ Improved erections by 67% and 81% of a general ED population taking 10 and 20 mg tadalafil, respectively, compared to 35% of men in the placebo group
❑ Effective in almost every subgroup of patients with ED
❑ Daily tadalafil 5mg has also been licensed for the treatment of LUTS secondary to BPH 🡪 useful in patients with concomitant ED and LUTS (ligeiros a moderados)

Question 19

Erectile Dysfunction - Vardenafil?

Answer 19

❑ Doses of 5, 10 and 20 mg (on-demand)
❑ The recommended starting dose is 10 mg and should be adapted according to response and side-effects
❑ Effective from 30 minutes after administration
❑ Efficacy is reduced by a heavy, fatty meal (> 57% fat).
❑ Improved erections were reported by 66%, 76%, and 80% of a general ED population taking 5, 10, and 20 mg vardenafil, respectively, compared with 30% of men taking a placebo
❑ Effective in almost every subgroup of patients with ED
❑ Recently, an ODT form (orodispersível) of vardenafil has been released

Question 20

Erectile Dysfunction - Avanafil – último a ser lançado?

Answer 20

❑ Doses of 50, 100, and 200 mg (on-demand)
❑ Avanafil is a highly-selective PDE5-I, tendo menos efeitos adversos (como hipotensão postural, cefaleias etc)
❑ The recommended starting dose is 100 mg and should be adapted according to response and side-effects
❑ Effective from 15 minutes after administration
❑ Food may delay the onset of the effect, but avanafil can be taken with or without food
❑ Mean percentage of attempts resulting in successful intercourse was 47%, 58%, and 59% in a general ED population taking 50 mg, 100 mg, and 200 mg avanafil, respectively, compared with 28% for men taking a placebo
❑ Effective in almost every subgroup of patients with ED

Question 21

Choice or preference between the different PDE5Is?

Answer 21

❑ No data are available comparing the efficacy and/or patient preference for sildenafil, tadalafil, vardenafil, and avanafil
❑ Choice of drug will depend on the frequency of intercourse and the patient’s personal experience and costs.
❑ Patients need to know whether a drug is short- or long-acting, its possible disadvantages, and how to use it
❑ ED patients who prioritize high efficacy must use sildenafil 50 mg whereas those who optimize tolerability should initiate with tadalafil 10 mg treatment (meta-analysis)
❑ Tadalafil, 5 mg once daily – alternative for couples who prefer spontaneous and/or frequent sexual activity
❑ Continuous dosing may also be used in men with LUTS and ED

Question 22

PDE5 inhibitors – Cardiovascular Safety?

Answer 22

❑ No increase in myocardial infarction rates in patients receiving PDE5-I
❑ No adverse effect on total exercise time or time-to-ischemia during exercise testing in men with stable angina
❑ Chronic or on-demand use is well tolerated with a similar safety profile

All PDE5Is are contraindicated in patients:
❑ Who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months
❑ With resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood pressure > 170/100 mmHg)
❑ With unstable angina, angina with sexual intercourse, or congestive heart failure (NYHA class IV)

Question 23

PDE5 inhibitors – Nitrates Safety?

Answer 23

❑ Concomitant use of nitrates (nitroglycerine, isosorbide mononitrate, isosorbide dinitrate) or NO donors – vasodilatadores potentes
❑ Nitroglycerine must be withheld for:
* 24 hours if sildenafil or vardenafil is used
* 48 hours if tadalafil is used
* 12 hours if avanafil is used

Question 24

PDE5 inhibitors – Co-administration with antihypertensive drugs or α-blockers?

Answer 24

❑ Small additive decreases in blood pressure (risk of orthostatic hypotension; no contraindication)
❑ The patient should be stable in his therapy before initiating a PDE5-I
❑ Alfuzosin, tamsulosin, and silodosin are the preferred α-blockers
❑ Devem ser iniciados com as doses mais baixas de 5PDEI’s

Question 25

PDE5 inhibitors – Dose adjustments?

Answer 25

❑ CYP3A4 inhibitors – increase plasma concentrations of PDE5-I and may require a dose reduction
– Ketoconazole, Itraconazole
– Erythromicyn, Clarithromycin
– HIV protease inhibitors (Ritonavir, Saquinavir)
❑ CYP3A4 inducers – decrease plasma concentrations of PDE5-I and may require an increased dose
– Rifampin
– Phenobarbital, Phenytoin, Carbamazepine

Question 26

PDE5 inhibitors – Warnings and precautions?

Answer 26

❑ Cardiovascular disease
❑ Hypotension or uncontrolled hypertension
❑ History of stroke
❑ Renal/ liver insufficiency
❑ Retinitis pigmentosa or history of severe vision loss (including NAION – neuropatia ótica isquémica anterior não artrítica é um efeito lateral desta classe de fármacos)
❑ Erection that lasted more than 4h or blood cell disease predisposing priapism

Question 27

PDE5 inhibitors – non-responders?

Answer 27

❑ The average efficacy rate of 60-70%
❑ Why do patients fail to respond to a PDE5-I?
– Incorrect use (como dose inadequada ou estimulação incorreta)
– Lack of efficacy

✔ At least 6 attempts
✔ Identify the underlying cause
✔ Check for licensed medication, proper prescription, and correct use

❑ Patient education can help salvage an apparent non-responder to a PDE5-I
– Dose e toma com alimentos
– Timing entre ato sexual e toma do fármaco
– Sexual stimulation (os fármacos não iniciam a ereção!)

Question 28

Vacuum erection devices?

Answer 28

❑ Usados independentemente da causa
❑ Efficacy: up to 90%
❑ Satisfaction rates: 27% to 94%
❑ High discontinuation rates: >50% (after 2 years)
❑ Common adverse events (<30%): pain, inability to ejaculate, petechiae, bruising, and numbness
❑ Serious adverse events (skin necrosis) – relatively rare - can be avoided if patients remove the constriction ring within 30 minutes after intercourse
❑ Contraindicated in patients with bleeding disorders or on anticoagulant therapy
❑ May be the treatment of choice in older patients with infrequent sexual intercourse and comorbidity requiring non-invasive, drug-free management of ED

Question 29

Second-line therapy – intraurethral/topical alprostadil?

Answer 29

❑ Inpatients who prefer a less-invasive, although less-efficacious treatment
→ Têm grau de satisfação maior ou eficácia melhor quando associados a tratamento oral.
❑ Topical alprostadil (125-1000 μg) in a medicated pellet
❑ Topical alprostadil (200 and 300μg) in a cream that includes a permeation enhancer to facilitate absorption through the urethral meatus

Question 30

Second-line therapy – intracavernous injections?

Answer 30

❑ Alprostadil was the first and only drug approved for intracavernous treatment of ED
❑ Intracavernous alprostadil is most efficacious as monotherapy at a dose of 5-40 μg
❑ TThe erection appears after 5-15 minutes and lasts according to the dose injected
❑ TAn office-training programme is required for the patient to learn the correct injection process: deve-se alterar o ponto de injeção.
❑ Efficacy rates of >70%
❑ Complications: penile pain (50% of patients reported pain only after 11% of total injections), prolonged erections (5%), priapism (1%), and fibrosis (2%) com potencial formação de curvaturas penianas; equimoses; systemic side- effects are rare (most common is mild hypotension for higher doses)

❑ Contraindications: history of hypersensitivity to alprostadil, risk of priapism, and bleeding disorders.
❑ Drop-out rates of 41-68% (most occurring within the first 2-3 months)

Question 31

Third-line therapy – penile prosthesis?

Answer 31

❑ For patients who do not respond to pharmacotherapy or who prefer a permanent solution to their problem
❑ Types of prosthesis: inflatable (2- and 3-piece) and malleable (non-inflatable) devices
❑ Surgical approaches for penile prosthesis implantation: penoscrotal (+ frequente) and infrapubic (menor exposição do campo cirúrgico)
❑ Satisfaction rates: 92-100% in patients and 91-95% in partners

Complications
❑ Mechanical failure and infection