x Review Article

Avanafil: Phosphodiesterase-5 (PDE-5) Inhibitors

. .

Avanafil: New Drug in Phosphodiesterase-5 (PDE-5) Inhibitors

Jeerisuda Khhumsikiew
Division of Pharmacy Practices, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Warinchamrab

..
2542
37.5

Phosphodiesterase-5 inhibitors

PDE-5
cGMP cGMP
nitric oxide
Avanafil
second-generation PDE-5 inhibitors

15-30
Avanafil
PDE-5 PDE1, PDE-6, PDE-11
Sildenafil,
Vardenafil Tadalafil PDE
isozymes
Sildenafil Vardenafil
PDE-6

- (cyanopsia) Tadalafil
PDE-11
Avanafil

PDE-5 inhibitors

Erectile dysfunction (ED) is still an essential mens

health problem because its affect the quality of life and
couple relationship. In year 1999, the prevalence of ED
was 37.5 % in Thai men. That prevalence number is
expected to grow with important risk factors such as
increasing age and cardiovascular diseases. Phosphodiesterase-5 (PDE-5) Inhibitors have been used as
first-line therapy for ED. The mechanism of action of this
drug class is inhibition of the enzyme PDE-5 which is
an enzyme breaks down cGMP. Without destroying
cGMP, the vasodilatory effect of nitric oxide (NO) is
enhanced and subsequently penile erection. Avanafil is
a novel second-generation PDE-5 inhibitors which may
differentiate itself from other PDE-5 inhibitors with its
faster onset (can taken 15-30 minutes before sexual
intercourse) and not be affected when eating with high
fatty food. Avanafil has been designed to be highly
selective Phosphodiesterase type 5 inhibitors and low
affinity with PDE-1, PDE-6, and PDE-11. It was noted
that avanafil was particularly well tolerated and showed
a very low incidence of adverse drug reaction that tend
to be reported with PDE-5 inhibitors such as Sildenafil,
Vardenafil and Tadalafil which higher affinity with other
PDE isoenzyme. For example, Sildenafil and Vardenafil
associated with blurred vision and cyanopsia side
effect because there are high affinities with PDE-6. In
addition, Tadalafil associated with myalgia and muscle
pain because it is high affinity with PDE-11.

2557; 29 (3): 311-320. Srinagarind Med J 2014 ;29 (3): 311-320.

2557; 29 (3) Srinagarind Med J 2014 ;29 (3)

311

Avanafil: Phosphodiesterase-5 (PDE-5) Inhibitors

The National Institutes of Health Consensus Development Panel on Impotence

(Erectile dysfunction)



1

30
..2544-2545
4 50 17
60 47
75 2
.. 2542
37.5
19.1
13.7 4.7 3



4
Phosphodiesterase-5 inhibitors
Sildenafil (Viagra), Tadalafil (Cialis) Vardenafil
(Lavitra)5

Avanafil second-generation PDE5 inhibitors

.. 2555
Stendra6
,

7 Avanafil
Phosphodiesterase-5 inhibitors

312

Avanafil: New Drug in Phosphodiesterase-5 (PDE-5) Inhibitors

1. (vascular system)
3 ( corpora)
corpora cavernosa 2 corpus spongiosum
1 3

fibrous tissue membrane
tunica albugina corpora
(flaccid state)

corpora corpora
arterial flow venous outflow
(erection phase)
arterial flow
sinusoids corpora


corpora
(venous outflow ) ( 1)9
corpora
acetylcholine (Ach) Ach
arterial flow co-neurotransmitter
nonpeptidinergic intracellular neurotransmitters
cyclic guanosine monophosphate (cGMP), cyclic adenosine
monophosphate (cAMP) Vasoactive intestinal
polypeptide

Acetylcholine (Ach) 2 pathway

1) Ach
nitric oxide (NO) endothelial cells
nonadrenergic-noncholinergic (NANC) neurons NO
guanylate cyclase cGMP cGMP

(intracellular calcium)
(penile arteries) cavernosal
sinuses
corpora
2) Ach cell membrane
adenyl
cyclase ATP cAMP (potent
muscle relaxant) cAMP cAMP
cGMP

2557; 29 (3) Srinagarind Med J 2014; 29 (3)

Jeerisuda Khhumsikiew

( 3)10
clinical efficacy rates
70
10
Phosphodiesterase-5 Inhibitors

(onset of action),
(duration of action)
PDE isozymes (selectivity ratio)
( 1 2) Sildenafil Vardenafil
onset duration of action

Tadalafil

8, 10, 11 Avanafil
Tadalafil
(
15 30 )
Phosphodiesterase-5
inhibitors
PDE-5
IC50 Avanafil 5.2 nM13

PDE-5 ( 4)
PDE-5 inhibitors
PDE isozyme Sildenafil,
Vardenafil Tadalafil PDE isozyme
PDE-5
Sildenafil Vardenafil
PDE-6 PDE-6

- (cyanopsia)
Tadalafil PDE-11
PDE-11
8, 14 Avanafil
PDE-5 PDE-6
121 Sildenafil (16 )
Vardenafil (21 ) PDE11 Tadalafil ( 19,000
1 9
25 )13
(Flaccid state) ()
Avanafil
(Erection state) ()
PDE-5 PDE-1, PDE-6, PDE-

2. (nervous system and psychogenic

stimuli)
sacral nerve reflex arc

peripheral
cholinergic nerve corpora
inhibitory sympathetic neurons (T11-L2),
proerectogenic parasympathetic neurons (S2-S4)
proerectogenic somatic neurons (S2-S4)

3. (hormonal system) testosterone

testosterone 300-1,100 /
testosterone

Phosphodiesterase-5
inhibitors
PDE-5 inhibitors

4 Sildenafil, Vardenafil, Tadalafil
Avanafil heterocyclic nitrogen-containing double-bond system
purine base cGMP ( 2)8, 10, 11
PDEs cGMP
(reversible competitive antagonist)
PDE5 cGMP
corpora

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313

Avanafil: Phosphodiesterase-5 (PDE-5) Inhibitors

Avanafil: New Drug in Phosphodiesterase-5 (PDE-5) Inhibitors

2 PDE-5 Inhibitors8, 10, 11

4 PDE-5
3 Nitric oxide-cGMP signaling pathway PDE-5 inhibitors13
cavernosal smooth muscle10
* IC50
Ca = calcium
PDE-5 50
cG = cyclic guanosine
IC50 PDE-5
cGMP = cyclic guanosine monophosphate

GTP = guanosine triphosphate

PDE5 = phosphodiesterase 5
PKG = protein kinase G

314

2557; 29 (3) Srinagarind Med J 2014; 29 (3)

Jeerisuda Khhumsikiew

1 PDE-5 inhibitors8, 10-12

Parameter

Sildenafil

50
Initial dose (mg)
41
Bioavailability (%)
30-60
Onset of action (min)
Up to 12
Duration of action (h)
560
Maximum plasma concentration (Cmax) (ng/ml)
29% decrease
Change in Cmax with food (High fat diets)
1 (0.52.0)
Time to maximum concentration (Tmax) (h)
105
Volume of distribution (L)
96
Protein binding (percentage bound)
35
Half-life (h)
CYP3A4 / 2C9
Metabolism
Yes
Active metabolite
80/13
Percentage excreted in feces/urine

11

( 2)
Avanafil

PDE-5
PDE isozymes 15
Avanafil
- : 100 .
30 1
(
50 . 200 .)
-
(Mild
to Moderate) Clcr 30 ./ ChildPugh class A or B
Avanafil
- 18

-
-
(Severe)
Clcr < 30 ./ dialysis Child-Pugh
class C
PDE-5 Inhibitors
PDE-5 inhibitors

Vardenafil

Tadalafil

10
15
30-60
Up to 10
17
20% decrease
0.7 (0.253.00)
208
95
45
CYP3A4/2C9
Yes
92/5

10
Undetermined
60-120
Up to 36
378
No change
2 (0.56.0)
63
94
17.5
CYP3A4
No
61/36

Avanafil
100
Undetermined
15-30
Up to 6
747.83
No change
0.593 (0.6860.555)
156
99
1.19
CYP3A4/CYP2C
Yes
62/21

Classspecific side effects headache ( 11), facial

flushing ( 12) dyspepsia ( 5) nasal congestion ( 3.4) dizziness ( 3)
14,16-19
PDE-5

20
Sildenafil, Vardenafil Avanafil
SBP 8-10
. DBP 3-6 . 1
4


nitrate

Tadalafil

(cardiac risk)
8, 21

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315

Avanafil: Phosphodiesterase-5 (PDE-5) Inhibitors

Avanafil: New Drug in Phosphodiesterase-5 (PDE-5) Inhibitors

2 Selectivity ratio* PDE-5 inhibitors PDE-5 inhibitors the Princeton Consensus Guide PDE isozyme 12, 13
line Conference II ( 3)22
PDE isozyme selectivity versus PDE5
PDE
Sildenafil Vardenafil
(fold difference)
isozyme

-
Avanafil Sildenafil Vardenafil Tadalafil
( 2 -3)
10,500
1,012
375
10,192
PDE1
PDE 6 photoreceptor cells retinal
27,3810 >25,000
39,375
9,808
PDE2
rods
cones
>25,000
26,190
16,250
>19,231
PDE3
14,750
14,286
3,125
1,096
PDE4
100 .23
1
1
1
1
PDE5
Tadalafil
550
21
16
121
PDE6
Avanafil PDE 6
>25,000
17,857
13,750
5,192
PDE7B

2,308 >62,500 1,000,000 >25,000
PDE8A

>25,000
16,667
>19,231 2,250
PDE9A
Non-Arteritic
8,750
17,857
3,375
1,192
PDE10A
25
5,952
4,875
>19,231
Anterior Ischemic Optic Neuropathy (NAION)
PDE11A
PDE5 inhibitors
* Selectivity ratio IC50 for PDEXi IC50 for PDE-5 Selectivity ratio
PDEs optic nerve

24
PDE-5
NAION
3 PDE-5 inhibitors
the Second Princeton Consensus Conference22

-
* < 3
- well-controlled hypertension
- mild, stable angina
- mild congestive heart failure (NYHA class I)
- mild valvular heart disease
- myocardial infarction > 6
- > 3
- moderate, stable angina
- moderate congestive heart failure (NYHA class II)
- myocardial infarction 6
- unstable angina angina
- uncontrolled hypertension
- severe congestive heart failure (NYHA class III IV)
- myocardial infarction stroke 2
- moderate severe valvular heart disease
- cardiac arrhythmias
- obstructive hypertrophic cardiomyopathy

PDE-5 inhibitors

PDE-5 inhibitors;

316

2557; 29 (3) Srinagarind Med J 2014; 29 (3)

macular degeneration
diabetic retinopathy
PDE5
inhibitors NAION

Tadalafil PDE 11
,

( 7 30) 10
100 .25

(Priapism)
Sildenafil, Vardenafil Avanafil
(half-life) Tadalafil Priapism
PDE5 inhibitors

Avanafil
- > 10 : Central nervous system Headache ( 5 -12)
- 2 10 :
o Cardiovascular Flushing ( 3-10),
ECG abnormal ( 1-3)
o Central Nervous System Dizziness (
1-2)
o Neuromuscular and Skeletal Back pain
( 1-3)
o Respiratory Nasopharyngitis ( 1-5),
Nasal congestion ( 1-3), Upper respiratory infection ( 1-3)
- < 2 (Postmarketing /
case reports) Abdominal discomfort, ALT increased,
Angina, Arthralgia, Balanitis, Bronchitis, Color vision
change, Constipation, Cough, Depression, Diarrhea,
DVT, Dyspepsia, Dyspnea (exertional), Epistaxis,
Extremity pain, Fatigue, Gastritis, Gastroesophageal
reflux, Hearing loss, Hematuria, Hyperglycemia,
Hypertension, Hypoglycemia, Hypotension, Influenza,
Insomnia, Muscle spasms, Musculoskeletal pain,
Myalgia, Nausea, Nephrolithiasis, Nonarteritic ischemic
optic neuropathy (NAION), Oropharyngeal pain,
Palpitations, Peripheral edema, Pollakiuria, Priapism,
Pruritus, Rash, Sinusitis, Sinus congestion, Somnolence,
Tinnitus, Urinary tract infection, Vertigo, Vision loss

Jeerisuda Khhumsikiew

(temporary or permanent), Vomiting, Wheezing

Avanafil
- Nitrates: nitrate
PDE-5 inhibitors
1) nitrate
2) nitrates nitric oxide donors
guanylate cyclase cGMP
PDE-5 inhibitors Nitrate
- Alpha-Blockers: PDE5 inhibitors alpha-blockers




- Antihypertensives: PDE5 inhibitors

avanafil
amlodipine enalapril
3 5 .

- Phosphodiesterase Inhibitors (Tadalafil,

Vardenafil, Sildenafil):
PDE5 inhibitors
avanafil
- Alcohol: alcohol PDE5 inhibitors

alcohol 3
avanafil
(orthostatic signs and symptoms)


- Strong CYP3A4 Inhibitors: anavafil
CYP 3A4
anavafil Strong CYP
3A4 inhibitors ketoconazole, itraconazole,
clarithromycin, nefazadone, ritonavir, saquinavir,
nelfinavir, indinavir, atanazavir, ritonavir
avanafil
Ketoconazole (400 . ) AUC
Cmax anavafil 50 . 13 3
Half-life 9 .
anavafil Strong CYP3A4 Inhibitors
- Moderate CYP 3A4 Inhibitors: anavafil

2557; 29 (3) Srinagarind Med J 2014; 29 (9)

317

Avanafil: Phosphodiesterase-5 (PDE-5) Inhibitors

CYP 3A4
anavafil moderate CYP 3A4
inhibitors erythromycin, amprenavir, aprepitant,
diltiazem, fluconazole, fosamprenavir, verapamil
avanafil 50 . 24 .
moderate CYP3A4 inhibitors
Erythromycin (500 . 2 ) Cmax
AUC anavafil 200 . 2 3
Half- life 8 .
- CYP 3A4 Substrates:
avanafil CYP3A4 substrates
amlodipine avanafil amlodipine
Cmax AUC avanafil 22
70 Half- life 10 .
Cmax AUC amlodipine
9 4

- Cytochrome P450 Inducers:

Cytochrome P450 Inducers
avanafil
avanafil CYP inducers ( CYP
inducers barbiturates, bosentan, carbamazepine,
dexamethasone, phenytoin/fosphenytoin, nevirapine,
rifabutin, rifampin, rifapentine, troglitazone)
- Desipramine: weak inhibitor
CYP2D6 avanafil avanafil 200 . AUC
Cmax desipramine 50 . CYP2D6 substrate 5.7 5.2
- Omeprazole: weak inhibitor
CYP2C19 avanafil avanafil 200 .

Avanafil: New Drug in Phosphodiesterase-5 (PDE-5) Inhibitors

AUC Cmax omeprazole 40 . CYP2C19

substrate 5.9 8.6
- Rosiglitazone: weak inhibitor
CYP2C8 avanafil avanafil 200 . AUC
rosiglitazone 8 . CYP2C8 substrate
2.0 Cmax 14

Avanafil
- Nitrates


12 avanafil
- strong CYP3A4 inhibitors ketoconazole, ritonavir, atazanavir,
clarithromycin, indinavir, itraconazole, nefazodone,
nelfinavir, saquinavir and telithromycin Avanafil
CYP 3A4 CYP
3A4 Avanafil
Avanafil moderate CYP3A4 inhibitors erythromycin, amprenavir, aprepitant,
diltiazem, fluconazole, fosamprenavir, and verapamil
Avanafil 50 .
1 24 .
- PDE5 inhibitors

PDE5 inhibitors
-
retinitis pigmentosa
- (< 90/50 .
) (> 170/100
.); unstable angina angina
life-threatening arrhythmias, stroke, MI,
coronary revascularization 6 ; cardiac
4 PDE-5 failure coronary artery disease
inhibitors ( 1)6, 25-28
unstable angina
- Avanafil
Sildenafil
Vardenafil
Tadalafil
Avanafil
Avanafil (Stendra)
- Headache - Flushing
- Headache - Headache
Avanafil
- Flushing - Headache - Dyspepsia - Flushing
- :
- Dizziness - Dyspepsia - Dizziness - Nasopha

ryngitis
- Dyspepsia - Nausea
- Flushing

- Nasal
- Dizziness
- Nasal
- Nasal
congestion - Rhinitis
congestion congestion
Avanafil
- Altered
- Back pain,

vision

318

myalgia

2557; 29 (3) Srinagarind Med J 2014; 29 (3)

o
left ventricular outflow obstruction (

aortic stenosis, idiopathic hypertrophic subaortic

stenosis)



o
myocardial infarction, stroke,
life-threatening arrhythmia, or coronary
revascularization 6
o
resting hypotension (BP < 90/50 .
) hypertension (BP > 170/100
.)
o
unstable angina, angina with sexual
intercourse, CHF NYHA Class
2
- :
4 . priapism (
6 .) PDE-5
inhibitors
4 .


( angulation,
cavernosal fibrosis, Peyronies disease)
priapism ( sickle cell
anemia, multiple myeloma, leukemia)
- :

PDE-5 inhibitors Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)

- :

PDE5 inhibitors

NAION cup-to-disc ratio (crowded disc)

50
- :

Avanafil AlphaBlockers
Avanafil Avanafil

Jeerisuda Khhumsikiew

- :

(Erectile Dysfunction)


PDE-5 Inhibitors
Sildenafil, Tadalafil, Vardenafil Avanafil

Avanafil

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