La Seguridad de los Inhibidores de PDE-5 Dr Fernando Rodríguez Rergis.

La Seguridad delos Inhibidores de PDE-5Dr Fernando Rodrguez Rergis

La Seguridad delos Inhibidores de PDE-5

La Seguridad delos Inhibidores de PDE-5Actualmente el tipo de tx,mas utilizado por los mdicos y preferido por los pacientes,es sin lugar a duda,los erectognicos orales y de ellos,los inhibidores de PDE5.

Existen 3 disponibles:

SildenafilVardenafilTadalafil.

Chemical Structures of PDE5 Inhibitors vs cGMP

cGMP=cyclic guanosine monophosphate.1. Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2003. 2. Cialis (tadalafil) prescribing information. Lilly ICOS LLC: Indianapolis, Ind and Bothell, Wash; 2003. 3. Levitra (vardenafil) prescribing information. Bayer Pharmaceuticals Corp: West Haven, Conn; 2003. 4. Corbin JD, Francis SH. Int J Clin Pract. 2002;56:453-459.

The chemical structures of PDE5 inhibitors and that of cyclic guanosine monophosphate (cGMP) are shown here. Note that tadalafil is structurally distinct from sildenafil and vardenafil.1-4All 3 agentssildenafil, tadalafil, and vardenafilinhibit PDE5, which is the enzyme that breaks down cGMP. As a result of therapy with the PDE5 inhibitors, levels of cGMP are increased.1-4The molecular structures of sildenafil and vardenafil are similar, having a ring structure that resembles the purine moiety in cGMP. Although the structure of tadalafil is different from sildenafil and vardenafil, all 3 agents have a high affinity for the same catalytic site on PDE5.51.Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2003.2.Cialis (tadalafil) prescribing information. Lilly ICOS LLC: Indianapolis, Ind and Bothell, Wash; 2003.3.Levitra (vardenafil) prescribing information. Bayer Pharmaceuticals Corp: West Haven, Conn; 2003.4.Corbin JD, Francis SH. Int J Clin Pract. 2002;56:453-459.5.Francis SH, Corbin JD. Curr Urol Rep. 2003;4:457-465.

La Seguridad delos Inhibidores de PDE-5A pesar de ser de la misma familia,son entre si diferentes,compartiendo como semejanza el parecido al GMPc,su sustrato.Lo que les permite ocupar el zurco cataltico en la PDE5,y asi inhibirla.

Assumed Role of PDE Isoenzymes1,2

1. Francis SH et al. In: Moldave K, ed. Progress in Nucleic Acid Research and Molecular Biology. Vol. 65. New York: Academic Press; 2001:1-52. 2. Soderling SH, Beavo JA. Curr Opin Cell Biol. 2000;12:174-179.

The PDE isoenzymes exert a variety of inhibitory effects.1PDE1 is particularly well represented in neurons of the central nervous system (CNS), suggesting that it may participate in a variety of neural functions. Its abundance in olfactory cilia suggests a role in olfaction, and high levels are found in proliferating vascular smooth muscle cells, suggesting a role in vasodilation.1PDE2 is particularly abundant in the adrenal system, where it may play a role in BP regulation by stimulating hydrolysis of cAMP, which results in decreased production of aldosterone. It is also believed to be important in olfactory signaling, platelet aggregation, and regulation of Ca2+ channels.1PDE3, which is found extensively in adipose tissue, cardiac muscle, vascular smooth muscle, and platelets, may play a role in insulin secretion1 and control of cardiac contractility.2PDE4 is found in neural and endocrine tissues and appears to play a role in growth and fertility.1,3The tissue distribution of PDE5 is relatively limited compared with that of the other PDEs.1 PDE5 is found in cavernosal and vascular smooth muscle and platelets and is thought to have a role in vasoconstriction.1,4 PDE6 is found in the rods and cones of the retina, and plays a key role in the visual response to light.1,2PDE7 is found in lymphoid tissue, where it appears to play a role in the regulation of T-cell activity, and the immune response.1,3The role of the remaining PDEs, PDE8 through PDE11, remains uncertain.1 It has been suggested that PDE8 may play a role during germ-cell development.31.Francis SH et al. In: Moldave K, ed. Progress in Nucleic Acid Research and Molecular Biology. Vol. 65. New York: Academic Press; 2001:1-52.2.Sadovsky R et al. Int J Clin Pract. 2001;55:115-128.3.Soderling SH, Beavo JA. Curr Opin Cell Biol. 2002;12:174-179.4.Ballard SA et al. J Urol. 1998;159:2164-2171.


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Potencia inhibitoria

El efecto inhibitorio in vitro es una medida de la potencia propuestaLa CI50 se define como la concentracin que se requiere de un inhibidor para reducir la actividad de la PDE en 50% En teora, a menor CI50 , ms potente ser el agente

CI50

El efecto inhibitorio in vitro es una medida de su potencia propuesta.

La potencia se indica con un valor de CI50, es decir, la concentracin que se necesita para lograr 50% del efecto inhibitorio mximo cuando se mide funcionalmente. Para un inhibidor de PDE de inters para el tratamiento, o tratamiento potencial, de la DE, esta ser una medida de la capacidad del agente para relajar al msculo liso del pene. Mientras ms bajo sea el valor de la CI50, ms potente ser el inhibidor.

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Potencia de inhibidores de PDE5 medicin de CI50 (nmol)

1 Corbin, Simposio Satlite de Viagra, 9a Reunin Mundial sobre Impotencia, Perth, nov. 20002 Angulo, Cartel, XVI Congreso EAU, Ginebra, abril 20013 Bischoff, Int J Impot Res 2000; 12 (Suppl.3)

Sildenafil, vardenafil y tadalafil son inhibidores altamente selectivos y potentes de la PDE5.

La determinacin de la potencia y la selectividad depende en gran medida de los ensayos utilizados y est sujeta a variabilidad entre los distintos laboratorios.


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Frmacoscardiovasculares

Origen del binomio: Relacin causal y no casual

Edad

Hipertensin arterial

Diabetes mellitus

Tabaquismo

Dislipidemia

Depresin

Disfuncin erctil

enfermedadcardiovascular

12-3


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BAJOINTERMEDIO( indeterminado )ALTO

1. Factores de riesgo mayores

2. Enfermedad cardiovascular

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Estratificacin del riesgo: enfermedad cardiovascular y disfuncin sexual

RIESGOABSOLUTO

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Factores de riesgo mayores

Edad Hombre o mujer posmenopusica Diabetes mellitus Hipertensin arterial Dislipidemia Tabaquismo Obesidad Vida sedentaria

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BAJO

1. Asintomtico2. < 3 factores de riesgo mayores (excluido sexo)3. Hipertensin arterial controlada4. Angina en clase funcional I (definida y/o bajo Tx)5. Revascularizacin coronaria (cualquier variedad)6. Infarto del miocardio no complicado (sin isquemia residual)7. Valvulopata leve8. Insuficiencia cardaca compensada (clase funcional I - NYHA)

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DeBusk R, et al. Am J Cardiol 2000;86:175

RIESGO

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INTERMEDIO

1. 3 factores de riesgo mayores (excluido el sexo)2. Angina estable, clase funcional II3. Infarto del miocardio reciente (entre 2 y 6 semanas) )4. Insuficiencia cardaca compensada (clase funcional II - NYHA)5. Secuelas no cardacas de arterioesclerosis (enfermedad vascular cerebral y perifrica)

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RIESGO

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1. Angina en clase funcional III y IV 2. Hipertensin arterial descontrolada3. Insuficiencia cardaca descompensada (clase funcional III y IV - NYHA)4. Arrtmias graves5. Miocardiopata hipertrfica u otras miocardiopatas6. Valvulopata moderada a severa7. Pericarditis aguda

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ALTO



RIESGO

La Seguridad delos inhibidores de PDE-5

Sexual Activity and Cardiac Risk Assessment

Reprinted from Am J Cardiol, Volume 86, DeBusk R, Drory Y, Goldstein I et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel, pages 175181, Copyright (2000), with permission from Excerpta Medica Inc.

Princeton Guidelines

Low Risk

Initiate or resume sexual activity or treatment for sexual dysfunction

In June 1999, a multidisciplinary international conference on sexual activity and cardiac risk convened in Princeton, New Jersey, and issued recommendations for the management of ED in patients with cardiovascular disease (CVD).1Unlike the ACC/AHA Expert Consensus Document, these recommendations emphasized the importance of considering the risk of cardiac events associated with sexual activity.1-3 They noted that patients with 3 or more of the following major cardiac risk factors are at increased risk during sexual activity: age, HTN, DM, obesity, cigarette smoking, dyslipidemia, and a sedentary lifestyle.1The Princeton Guidelines provide a system to stratify these patients at the time of the initial assessment based upon cardiovascular status: low, high, and indeterminate risk categories.11.DeBusk R et al. Am J Cardiol. 2000;86:175-181.2.Cheitlin MD et al. J Am Coll Cardiol. 1999;33:273-282.3.Jackson G et al. Int J Clin Pract. 1999;53:445-451.


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Anlisis de Seguridad CVEstudios Fase III con VardenafilSignos Vitales

Cambios promedio de la toma basal a la ltima visita de mediciones tomadas entre los 11 minutos y 5 horas despus de la toma del medicamento

an=160 y 460 ptes. para placebo y vardenafil, respectivamentebn=176 y 511 ptes. para placebo y vardenafil, respectivamente

Kloner et al ACC, 2003

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Placebo

Vardenafil

Promedio

Cambio Promedio

(DE)

Promedio

Cambio Promedio

(DE)

Acostadoa

PAS, mm Hg

PAD, mm Hg

FC, lpm

134.9

81.7

70.9

-0.1 (15.4)

0.3 (9.2)

-0.6 (9.3)

132.3

81.3

68.6

-4.6 (14.6)

-3.9 (8.9)

1.8 (9.4)

De pieb

PAS, mm Hg

PAD, mm Hg

FC, lpm

132.7

81.8

74.6

-0.1 (15.8)

-0.1 (10.3)

-0.4 (10.3)

130.7

81.0

72.9

-4.8 (13.9)

-3.2(8.5)

2.0 (10.3)

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Anlisis de seguridad CV en estudios Fase IIIcon Vardenafil Porcentaje de Eventos Adversos CV

Kloner et al ACC, 2003

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Evento Adverso

Placebo

(n=1199)

Vardenafil

(n=2203)

Hipertensin

11 ( 0.9%)

36 ( 1.6%)

Taquicardia

3 ( 0.3%)

15 ( 0.7%)

Palpitaciones

3 ( 0.3%)

11 ( 0.5%)

Edema Perifrico

3 ( 0.3%)

10 ( 0.5%)

Sncope

1 (


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Respuesta cardiovascular al ejercicio en pacientes con CI y tx con Vardenafil Resultados Vardenafil 20 mg

Tiempo Total Tiempo de Aparicin Tiempo de Aparicin de de Esfuerzo de Angina Depresin >1.0 mm del ST

N 36 36 36 36 36 35 valor de p ns ns ns

Tiempo (segundos)

Thadani U et al J Am Coll Cardiol 2002;40:2006-12

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Inhibidores de PDE5 - Recomendaciones para su prescripcin

1. Precisar su indicacin 2. Revisar tratamiento concomitante (interacciones y contraindicaciones)3. Investigar, si est clnicamente indicado, funcin heptica y renal4. Considerar dosis bajas iniciales en pacientes sin contraindicacin absoluta y con riesgo de efectos colaterales5. Advertir al paciente sobre efectos colaterales potenciales6. Monitorear efectos colaterales potenciales7. Evitar abuso8. En casos de descompensacin aguda de cualquier enfermedad cardiovascular debe interrogarse intencionadamente sobre el uso de inhibidores de PDE5 en las 24 h previas, antes del inicio de vasodilatadores

Documento de consenso de expertos ACC/AHA. J Am Coll Cardiol 1999;33:273

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Tratamiento de DE en el paciente con enfermedad cardiovascular

PDE5 Inhibitors: Onset and Duration of Activity

*Home setting; stopwatch recording.Statistically significant. RigiScan.Sexual Encounter Profile question 3 (SEP Q3).Not reported.1. Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2003. 2. Padma-Nathan H et al. Urology. 2003;62:400-403. 3. Cialis (tadalafil) prescribing information. Lilly ICOS LLC: Indianapolis, Ind and Bothell, Wash; 2003. 4. Padma-Nathan H. J Urol. 2001;165(suppl):224. Abstract 923. 5. Porst H et al. Urology. 2003;62:121-126. 6. Levitra (vardenafil) prescribing information. Bayer Pharmaceuticals Corp: West Haven, Conn; 2003. 7. Padma-Nathan H. et al. J Androl. 2003;(suppl):48. Abstract 41.

Several techniques may be used to assess the onset, hardness, and duration of an erection following drug administration. In the laboratory, RigiScan evaluations during sexual stimulation provide an objective measurement. Another method uses an in-home setting in which the patient records the time the drug was taken in a sexual activity event log, then starts a stopwatch and begins sexual stimulation. The stopwatch is stopped when an erection considered hard enough for sexual intercourse is achieved, or no erection is achieved and the patient discontinues attempts. A third technique measures the proportion of successful intercourse attempts at various times after dosing according to patient self-reporting using the Sexual Encounter Profile (SEP) diary.In a stopwatch study, 228 patients with ED who had been successfully treated with sildenafil (100 mg) for at least 2 months were randomized to 4 weeks of double-blind treatment with either sildenafil (n=115) or placebo (n=113).1 Within 14 minutes of dosing, 35% of sildenafil-treated patients had an erection that led to successful intercourse. The median time to successful intercourse following sildenafil dosing was 36 minutes. RigiScan results from 8 double-blind, placebo-controlled, crossover studies of patients with either psychogenic or organic ED showed that the effect of sildenafil persisted for up to 4 hours, although the response was less than that at 2 hours.2The time of onset and period of responsiveness of tadalafil were assessed in 2 phase 2 studies, one using RigiScan measurements and the other using stopwatch measurements in the home setting.3 In the pilot, double-blind, crossover, RigiScan study in 61 patients with ED, a response trend was noted 30 minutes after a 10-mg dose of tadalafil, and a statistically significant response compared with placebo occurred at 45 minutes (P=.034) and 24 hours (P

Sildenafil: Tolerability 1,2*

*Phase 2/3 AEs 2%.1. Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2002. 2. Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (VIAGRATM) in the treatment of erectile dysfunction. Int J Impot Res. 1998;10:69-74. With permission from Dr. Morales and from the Nature Publishing Group.

In flexible-dose, placebo-controlled phase 2 and 3 studies, the most common AEs of all causes reported by 2% or more of patients with ED receiving sildenafil (25 mg to 100 mg) as needed were headache (16%), flushing (10%), and dyspepsia (7%).1,2Other AEs reported more frequently by sildenafil-treated patients than by those receiving placebo included nasal congestion, urinary tract infections, abnormal vision, diarrhea, dizziness, and rash.1,21.Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2003.2.Morales A et al. Int J Impot Res. 1998;10:69-74.

Tadalafil: Tolerability*

*Phase 2/3 AEs 2%.With permission from Brock GB et al. J Urol. 2002;168:1332-1336, and from Lippincott Williams & Wilkins. http://lww.com.

Integrated analyses of 5 double-blind, placebo-controlled, parallel-group trials assessed the efficacy and safety of tadalafil in 1112 men with mild-to-severe ED of at least 3 months duration whose mean age was 59. The patients were randomly assigned to receive either tadalafil or placebo for 12 weeks. Tadalafil was administered at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg.Results of these analyses showed that all doses of tadalafil were well tolerated. AEs reported by 2% or more of patients are listed in the slide. The most frequently reported AE in both the tadalafil and placebo arms was headache (14% with tadalafil, 6% with placebo), followed by dyspepsia (10% with tadalafil, 2% with placebo), and back pain (6% with tadalafil, 5% with placebo).Brock GB et al. J Urol. 2002;168:1332-1336.

Vardenafil: Tolerability*

*Phase 2b AEs 5% in any treatment arm.With permission from Porst H et al. Int J Impot Res. 2001;13:192-199.

More than 400 patients received vardenafil (5 mg to 20 mg) for up to 12 weeks in the first large-scale, randomized, double-blind, placebo-controlled trial. AEs occurring in 5% or more of patients in any treatment arm are listed on this slide. The most common side effects reported by vardenafil-treated patients were headache (10% versus 4% with placebo) and flushing (11% versus 1% with placebo).Other side effects, including dyspepsia and rhinitis, were reported less frequently. Minor vision changes, consisting of transiently increased brightness to light or mild haziness, occurred in 6 patients, with both vardenafil and placebo.Porst H et al. Int J Impot Res. 2001;13:192-199.

Emergency Administration of Nitrates Following PDE5 Inhibitor Use

*Under close medical supervision and patient monitoring. Although these are the recommendations, all PDE5 inhibitors are contraindicated with any form of nitrates.1. Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2003. 2. Cheitlin MD et al. J Am Coll Cardiol. 1999;33:273-282. 3. Cialis (tadalafil) prescribing information. Lilly ICOS LLC: Indianapolis, Ind and Bothell, Wash; 2003. 4. Kloner RA et al. J Am Coll Cardiol. 2003;42:1855-1860. 5. Levitra (vardenafil) prescribing information. Bayer Pharmaceuticals Corp: West Haven, Conn; 2003.

DrugTime Interval for Nitrate Administration* During Medical Emergency

SildenafilHas not been definitively determined1,2After 24 hours, may be considered based on pharmacokinetic profile2

TadalafilAt least 48 hours should elapse after the last dose before nitrate therapy considered3,4

VardenafilHas not been definitively determined, but clinical data show additional blood pressure and heart rate changes were not detected when drug dosed 24 hours before nitrate administration5

Organic nitrates are frequently prescribed to manage the symptoms of angina pectoris. However, the coadministration of nitrates and PDE5 inhibitors significantly increases the risk of potentially life-threatening hypotension and is contraindicated.1-3The time interval for nitrate administration during a medical emergency to patients who have taken either sildenafil or vardenafil has not been definitively determined.1-3 However, administration of nitrates may be considered if at least 24 hours has elapsed since the ingestion of sildenafil, based on the pharmacokinetic profile of a 100-mg oral dose of sildenafil in healthy volunteers.1,4Tadalafil has been specifically studied to determine the time course of nitrate interaction.3,5 A total of 150 male subjects received daily doses of placebo or tadalafil 20 mg for 7 consecutive days. On day 7 and beyond, after the last dose of placebo or tadalafil, subjects received repeated doses of sublingual nitroglycerin (SL NTG). Subjects were crossed over to the alternate treatment after a washout period of 10 to 21 days. The hemodynamic interaction between tadalafil and SL NTG lasted 24 hours, but was not seen at 48 hours and afterwards. In a patient who has received tadalafil when nitrate administration is deemed medically necessary, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered.3,5Similar to other PDE5 inhibitors, tadalafil should not be administered in combination with organic nitrates.1-3In emergency situations, other therapies besides nitrates can be considered, including morphine, aspirin or other thrombolytic medications, beta-blockers, and calcium channel blockers.61.Viagra (sildenafil) prescribing information. Pfizer Inc: New York, NY; 2002.2.Levitra (vardenafil) prescribing information. Bayer Pharmaceuticals Corp: West Haven, Conn; 2003.3.Cialis (tadalafil) prescribing information. Lilly ICOS LLC: Indianapolis, Ind and Bothell, Wash; 2003.4.Cheitlin MD et al. J Am Coll Cardiol. 1999;33:273-282.5.Kloner RA et al. J Am Coll Cardiol. 2003;42:1855-1860.6.Heart attack and acute coronary syndrome. Health and Age Web site. Available at: http://www.healthandage.com/PHome/ gm=0!gc=9!gid6=1206. Accessed: February 25, 2004.

Sildenafil: 12-Week Efficacy Evaluation in Men With Diabetes Mellitus (DM)*

*Self-reported event log (N=268); 25 to 100 mg not more than once a day.Did the treatment improve your erections?P

Tadalafil: Efficacy Evaluation inMen With DM*

*Patients (N=216) with type 1 or type 2 DM.Has the treatment you have been taking improved your erections? P72%) had moderate-to-severe disease. Men with a history of HTN, hypercholesterolemia, and poor responses to other treatments were included. A total of 73 patients received tadalafil 10 mg, 72 received tadalafil 20 mg, and 71 received placebo.At study end or at discontinuation, patients were asked the GAQ question: Has the treatment you have been taking improved your erections? A total of 56% of tadalafil 10-mg recipients and 64% of tadalafil 20-mg recipients gave positive responses, compared with 25% of placebo recipients. The percentages in the 2 tadalafil treatment groups were significantly higher than those in the control group (P

Vardenafil: 12-Week Efficacy Evaluation in Men With DM*

*N=452.Has the treatment you have been taking improved your erections?P

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La Seguridad de los Inhibidores de PDE-5 Dr Fernando Rodríguez Rergis.

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Transcript of La Seguridad de los Inhibidores de PDE-5 Dr Fernando Rodríguez Rergis.