Tratamentul disfunctiei erectile -punctul de vedere al

endocrinologului

Monica Gheorghiu, 2012

“Man survives earthquakes, experiences the horrors of illness, and all of the tortures of the soul. But the most tormenting tragedy of all time is, and will be, the tragedy of the bedroom.”

Tolstoy

Definitia disfunctiei erectile

“ Incapacitatea de a obtine si de a mentine o erectie peniana satisfacatoare pentru actul sexual ”

(Nu include tulburarile de ejaculare)

Incidence

20-30 million American men suffer ED Age dependent

2% men age <40 years25% men age 6575% men >75 years

Not a necessary occurrence of the aging process

ERECTILE DYSFUNCTION: Increases With Age

40 45 50 55 60 65 70Age

Pre

vale

nce.

%

25

0

50

75

Feldman, H.A. et al. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. Journal of Urology 1994; 151:54–61

Complete Moderate Minimal

How Does an Erection Occur?

The brain controls all sexual functions, from perceiving arousal to initiating and controlling the psychological, hormonal, nerve, and blood flow changes that lead to an erection.

Hormones, including testosterone, control the male sex drive

How Does an Erection Occur?(cont.) Nerve impulses relay signals of arousal

and sensation to and from the penis Arteries deliver extra blood to the penis

that causes it to stiffen. Veins then drain the blood out of the penis

after intercourse.

Physical orPsychological Stimuli Results Sacral parasympathetics (S2,3,4)

stimulation to the penile nerves Dilation of the penile arteries Relaxation of the smooth muscle in the

corporal bodies of the penis Decrease venous outflow

(Kandell, Koussa, Swerdloff, Endocr Rev, 2001)

Mechanism ofSmooth Muscle Relaxation Release of Neurotransmitters-nitric oxide

Conversion of GTP to cGMP - erection

Breakdown of cGMP by PDE type 5 - detumesence

Mecanismul molecular al relaxarii musculaturii netede peniene

Lue T: NEJM 342, iunie 2000

Mecanismul molecular al contractiei musculaturii netede peniene

Lue T: NEJM 342, iunie 2000

Clasificarea Disfunctiei Erectile

Psihogenica Organica:

NeurogenicaEndocrinaVasculara (Arteriogenica, Cavernoasa si

mixta)Anatomica (Peyronie )

Medicamentoasa Asociata cu imbatranirea, boli

sistemice s.a.

Cause of ED

Psychogenic Causes:AnxietyDepressionFatigueGuiltStressMarital DiscordExcessive alcohol consumption

Causes of ED

Organic CausesCardiovascular diseaseDiabetes mellitusSurgery on colon, bladder, prostateNeurologic causes (lumbar disc, MS, CVA)PriapismHormonal deficiency

A Practical Evaluation of Men with EDBasic evaluation

Medical History

Cardiovascular history

Endocrine history

Sexual history/questionnaire

A Practical Evaluation of Men with EDBasic evaluation (cont.)

Physical exam:Focused neurovascular examSize of testisDRE

Lab testsUATestosterone, CMP, Lipid panelPSA in men >50 years

Algoritm de tratament pentru disfunctia erectila

(Cunningham G, Hirshkowitz M, in Becker Texbook of Endocrinology, 2001)

Algoritm de tratament pentru disfunctia erectila

(Cunningham G, Hirshkowitz M, in Becker Texbook of Endocrinology, 2001)

Treatment OptionsGoal directed therapy4

Find out what the patient wants Try to tailor the treatment to the patients

needs and wants Etiology rarely affects treatment choice for the

patient

4 Lue TF, World J. Urol 8:67,1990

Treatment Options

Nonpharmacologic Non-invasive Minimally invasive Invasive Counseling and/or sex therapy

Treatment Options

Oral medications – testosteron (in hipogonadism)

- Viagra, Cialis, Levitra Urethral suppositories (MUSE) Injection therapy - Caverject, Trimix, Bimix Vacuum constriction device Surgery Sex therapy

Counseling and/or Sex Therapy

Rule out depression Try oral medication in patient with

psychogenic impotence Refer to sex therapist or psychiatrist for

sever psychopathology

Nonpharmacologic Treatment Options

Lifestyle changes: Reduce fat and cholesterol in diet Decrease or limit alcohol consumption Eliminate tobacco use and substance

abuse Weight loss if appropriate Regular exercise

Tratamentul medicamentos noninvaziv al disfunctiei erectile

Oral Hormoni

Inhibitori selectivi de fosfodiesteraza 5

Agonisti ai receptorilor pt. dopamina

Antagonisti ai receptorilor adrenergici

Agonisti ai receptorilor beta adrenergici Agonisti ai receptorilor de serotonina

Antagonisti de opioizi

Donori de NO

Derivati xantinici

Androgeni (T, DHEA, DHT)

Sildenafil (Viagra)

Tadanafil (Cialis)

Vardenafil (Nuviva)

Zaprinast, Avanafil

Apomorfina (Uprima, Spontane)

Bromocriptina, cabergolina s.a.

Yohimbina

Fentolamina (Vasomax)

Delaquamina (rec alfa2)

Isoxuprine (Vasodilan)

Trazodona

Naltrexona

L-Arginina

Pentoxifilin

Tratamentul medicamentos noninvaziv al disfunctiei erectile- continuare

Intrauretral Prostaglandine (modularea adenilciclazei)

PGE-1 (Alprostadil, MUSE)

PGE-2 (Dinoprostone)

Transdermic (topic)

Vasodilatatoare

Nitrati (nitroglicerina, isosorbid dinitrat)

PGE-1, 2

Papaverina

Aminofilina

Co-dergocrina mesilat

Minoxidil

Sildenafil

Mecanism Inhibitor specific de fosfodiesteraza 5

! efect doar daca exista stimulare sexuala

Doza 25-100 mg (50 mg la inceput), doza unica/zi, preferabil inainte de masa

Farmacocinetica

- initierea efectului - dupa 30-120 min (1 h),

- durata efectului – circa 4 ore

Eficienta La 70 – 87 % (21 studii clinice, >3000 subiecti)

La DZ , leziuni medulare, boli neurologice, chirurgie prostata, iradiere pelvina – efect la 35-67%

Creste nr. erectiilor, rigiditatea peniana, orgasmul, satisfactia actului sexual, satisfactia sexuala in ansamblu. Nu creste libidoul

Sildenafil - eficienta

Pacientii cu DE, inainte de tratament

Pacientii cu DE, dupa sildenafil

Grup – martor de aceeasi varsta si fara

DE

(dupa Textbook of Erectile Dysfunction, 1999)

Sildenafil – eficienta

(dupa Textbook of Erectile Dysfunction, 1999)

Sildenafil

Interactiuni medicamentoase

Nitrati si donori de NO scaderea rezistentei vasculare si hipotensiune arteriala (> 25 mmHg)

Medicamente care ii prelungesc timpul de injumatatire (eritromicina, cimetidina, ketoconazol)

Reactii adverse

(majoritatea usoare/moderate, autolimitate)

Cefalee 16%

Flushing 10%

Dispepsie 7%

Congestie nazala 4%

Tulburari de vedere (tenta colorata, sensibilitate crescuta la lumina – PDE 6) 3%

Rar- reactii severe cardiovasculare (4/100 pacienti-ani, versus 5,7 la placebo)

Precautii Afectiuni cardiace, insuficienta renala, insuficienta hepatica, boli retiniene, deformari peniene (fibroza, boala Peyronie)

                                                              

           

(Lue T, NEJM 342, iun. 2000)

                                                              

           

(Lue T, NEJM 342, iun. 2000)

Alti inhibitori de fosfodiesteraza 5

Tadalafil (Cialis) Vardenafil (Nuviva)Doza 2 -50 mg 5-20 mg

Durata actiunii 17 ore Efect la 40 min, T1/2 - 4,5 ore

Eficienta 70-90% in DE usoara/moderata

73-80% in DE de diverse grade

Reactii adverse

Cefalee la pana la 23% (placebo, 17%), dispepsie 11% (placebo, 7%), durere coloana vert. 4.7% (placebo, 0%), mialgii 4.1% (placebo, 2.4%).

Fara r. severe CV

Cefalee (7-15%), flushing (10-11%),dispepsie sau rinita pana la 7%.

Bibliografie Porst H. Int J Impot Res 2001 Feb;13(1):2-9

Porst H, Rosen R, Padma-Nathan H,Goldstein I, Giuliano F, Ulbrich E, Bandel T. Int J Impot Res2001 Aug;13(4):192-9 )

Yohimbina

Mecanism Alcaloid indolic din scoarta arborelui african Pausinystalia yohimbine – efect simpatolitic prin blocarea receptorilor alfa 2 adrenergici; posibil efect central pe alte tipuri de neuroni, dar si periferic adrenergic.

Doza 4,5-6 mg de 3 ori/zi, necesita 4-6 sapt pt instalarea efectului

Eficienta In general slaba (10-20% pe populatia cu DE).

La 33-71 % cu disfunctii psihogene, fara afectare organica (versus 45% la placebo)(metaanaliza Ernst E et al, J Urol, 1998). Asociata cu trazodona (100-200 mg la culcare), efect 56%. Fara efect la DE organice.

Poate creste libidoul.

Poate ameliora disfunctiile sexuale induse de SSRI.

Reactii adverse Palpitatii, tremor fin, cresterea TA, anxietate

Precautii La HTA

Pacienti tratati cu antidepresive triciclice

Fentolamina

Mecanism Antagonist receptor adrenergic (alfa 1 si 2) si antagonism functional indirect prin efect noradrenergic mediat de endoteliu, posibil prin activarea NO sintetazei; posibil si efect central anxiolitic

Doza 40 – 80 mg,

Farmacocinetica

Efectul apare in 30-40 min. Alcoolul anuleaza efectul.

Eficienta La 40-59% cu disfunctii usoare/medii (versus 17% placebo) (Goldstein I et al, Int J Impot Res 2000 Mar; 12 Suppl 1:S75-80).

Reactii adverse

Congestie nazala 7,7%

Cefalee < 3%

Flushing

Precautii Ischemie cardiaca

Apomorfina

Mecanism Agonist dopaminergic (alcaloid natural – efectele psihotrope ale nufarului ) – scade pragul de raspuns pentru reflexele erectile si ejaculatorii; receptori D1 si D2.

Doza 2-4 mg sublingual (20min); se poate repeta dupa minim 8 ore

Farmacocinetica

- initierea efectului - dupa 20 min (30% dupa 10 min, inca 40% dupa 40 min),

- durata efectului – circa

Eficienta La 65-70 % cu disfunctii usoare/medii, fara afectare organica majora – efectul poate fi potentat de stimularea sexuala vizuala.

Reactii adverse

Greata 7-17% (4% necesita antiemetic)

Cefalee 7%, ameteli 4%, cascat, rar sincopa

Posibil pathological gambling and increased libido

Precautii HTA necontrolata, hTA istoric/actuala, insuficienta hepatica sau renala (2 mg)

Apomorfina - aparitia efectului

( Heaton JPW, Int J Impot Res, 13, suppl 3, 2001)

Apomorfina - eficienta

( Heaton JPW, Int J Impot Res, 13, suppl 3, 2001)

Alti agonisti de dopamina (receptor D2)

BromocriptinaPergolidCabergolina

Indicatie: in hiperprolactinemii - incidenta:17% la pacienti cu DE (Becker, 2001)In prolactinoame = efect pozitiv asupra DE (de obicei au testosteron mic)Daca PRL < 50 ng/ml + testosteron normal = nu restabilesc potentaDaca PRL > 50 ng/ml, chiar daca testosteron normal = cresc libidoul si potenta

Reactii adverse: greata, varsaturi, hipotensiune ortostatica

Precautii: se incepe cu doza mica (1/2 cp), seara la culcare, dupa ingestie de alimente

Melatonina II (analog sintetic de alfa-melanocyte- stimulating hormone)

Actiune postreceptor de dopaminaInjectata s.c. – a initiat erectia la barbati cu disfunctie erectila psihogena (in studiu)

Naltrexona

Mecanism Antagonist pentru opioide

Doza 25-50 mg/zi. Varf plasmatic la 1 ora, efect 12-18 ore.

Eficienta Studii cu nr. mic de pacienti - Creste frecventa erectiilor matinale, creste nr actelor sexuale reusite si restabileste functia erectila complet la 20% din pacienti. Efectul poate fi mai bun daca se asociaza cu yohimbina.

(Kandell, Koussa, Swerdloff, Endocr Rev 22, 2001).

Reactii adverse

Greata (10%) , cefalee (7%)

Toxicitate hepatica la doze mari. Precautii La pacienti cu afectare hepatica

Trazodona

Mecanism Antidepresiv - Derivat triazolopiridinic care influenteaza functiile alfa-adrenergice (blocare), dopaminergice si serotoninergice (inhiba recaptarea).

Doza 150 mg/zi (mai multe prize) – 400 mg/zi

Eficienta Eficienta controversata. Dupa unele studii, imbuntateste erectia la 60 % (sau la 78% din pacientii sub 60 ani care nu au factori de risc pt DE).

La 200 pacienti depresivi tratati s-au raportat cresteri ale libidoului, imbunatatirea erectiei,cresterea duratei acesteia, si priapism. Asociata cu yohimbina ar avea un efect mai bun (Kandell, Koussa, Swerdloff, Endocr Rev 22, 2001).

Reactii adverse

somnolenta, ameteala, cefalee

Alprostadil intrauretral (MUSE) –

dispozitivul de administrare

Din Textbook of Erectile Dysfunction, 1999)

Alprostadil - intrauretral

Mecanism Prostaglandina E1, efect vasodilatator direct prin relaxarea musc.netede prin intermediul adenilat-ciclazei

Doza 125-1000 ug (500ug)

Farmacocinetica

Absorbtie transuretrala in circa 10 min, durata erectiei 30-60 min. Pentru stimularea absorbtiei se recomanda efectuarea unui masaj circular al penisului minimum 10 secunde.

Eficienta La 40-60% (la domiciliu doar 40%). Necesita initierea terapiei in cabinet, pentru titrarea dozei . Aplicarea unui inel la baza penisului creste procentul de acte sexuale la 69%.

Reactii adverse

Frecvente (la 75%), dar usoare/moderate: durere peniana la 32-44,8%, durere sau arsura uretrala12-20%, singerare sau traumatism uretral 8,7%, durere testiculara 8,3%, hipotensiune arteriala 7,6%, ameteala 7,1%, priapism 1%, hematurie 1,2%. La partenera: Iritatie vaginala (10%), avort spontan.

Precautii Pacienti cu tulb. de coagulare sau tratati cu anticoagulante, antihipertensive

Tratamente locale (crema, spray, plasturi)

PGE-2 (crema) Erectie la 30% din subiecti (nr.mic)

PGE-1 (crema) Erectie la 2/10 vs nici una la placebo

Minoxidil (spray) Erectie la 25% din pacientii cu leziune medulara (nr mic)

Isosorbid dinitrat +aminofilina+ co-dergocrina mesilat (crema)

Erectie completa la 58% cu DE de diverse cauze si la 82% cu DE psihogena (Kandeel et al, End Rev, 2001

Papaverina 15-20% (gel)

Erectie completa la 3/17, durata 38 min. La aceiasi pacienti a avut efect si placebo, durata 8 min.

Nitroglicerina (crema) Comparativ cu inj. Papaverina la pacienti cu leziune spinala, efect la 61% vs 93% . Cefalee la 21%. La papaverina complicatii la 32%

Precautii Admin. numai cu 2-6 ore inainte de actul sexual; Admin acetaminofen inainte de aplicare; Prezervativ

Reactii adverse Cefalee, scaderea TA si a AV la pacient si/partenera

Alte tratamente

Pentoxifilin 400 mg x 3/zi

La 9/18 pacienti erectie suficienta pt act sexual, 6 nu au incercat, 3 fara efect (Becker Textbook, 2001)

L-arginina Donor de NO;

Raspuns pozitiv estimat la 30-45% - controversat

Plante Ginseng rosu corean (studiu dublu-orb, crossover) 900 mg in 3 prize/zi – imbunatatirea erectiei la 60% (Hong B et al, J Urol 2002, 168(5)

Maca – creste libidoul, energia

Catuaba – afrodisiac, stimulant al SNC

Tribulus – creste testosteronul liber

Wild yam – stimulator hormonal

Black Cohosh – relaxant nervos

Damiana – tonis prostatic, antidepresiv, nutritiv pentru gonade

Sunatoarea – tonic nervos

Saw palmetto – reglator de prostata si sistem reproductivWithania somnifera, Eurycoma longifolia, Avena sativa, Ginko

biloba, Psoralea coryifolia

Vacuum Constriction Devices

Mechanism of Action: Penis placed in plastic tube Air evacuated from the tube Blood trapped in penis with

constricting ring

Vacuum Constriction Device

Erection limited to 30 minutes Results: 80%-90% Contraindications: bleeding disorders, sickle cell

disease, anticoagulation Complications: coolness, petechiae, numbness,

pain with ejaculation High drop out rate Considered an alternative if patient fails oral

therapy and does not want to proceed with surgery

Penile Prosthesis

Indications: Patients who have failed other therapies Peyronie’s disease Severe vasculogenic disease

-Paired rod corpora cavernosa

-repair arteries obstruction

-Proteze maleabile

sau

gonflabile (cu 2 sau 3 piese)

Proteza peniana

Penile Prosthesis

Advantages: Low-morbidity Low-mortality surgery Low complication rates High success rates – 5% malfunction rate at

5 years High satisfaction rate – 87% High partner satisfaction rate

Penile Prosthesis

Disadvantages: Surgery Expensive Possible mechanical failure