By
Nashwa Naeem Elfar
Ass. lecturer
Phosphodiesterase enzymes (PDE)
• Phosphodiesterases are a diverse family of enzymes that
degrade the phosphodiester bond of cyclic nucleotides
and thus play a key role in regulating intracellular levels of
the second messengers cAMP and cGMP, and hence cell
function.
• PDEs
are therefore important regulators of
signal
transduction mediated by these second messenger
molecules.
PDE family: 11 isoenzymes families (PDE 1-PDE 11) with
over 50 isoforms
PDE
Main tissue localization
1
2
3
Brain, heart, vascular smooth muscle
4
5
Lung, mast cells, vascular smooth muscle
6
7
8
Retina
9
10
11
Adrenal cortex, brain, heart, corpus cavernosum
Heart, corpus cavernosum, vascular smooth muscle, platelets, liver
pancreas
Corpus cavernosum, lung, vascular smooth muscle, platelets,
brain, esophagus
Skeletal muscle, T cells
Testis, thyroid
Broadly expressed, not well characterized
Brain, testes
Skeletal muscle, prostate, liver, kidney, pituitary, testis
Phosphodiesterase Inhibitors
 Drugs
that
block
subtypes
of
the
enzyme
phosphodiesterase (PDE), therefore preventing the
inactivation of the intracellular second messengers
cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP) by the respective
PDE subtype(s).
 They are classified into non-selective PDE inhibitors
and selective PDE
Classification:
A) Nonselective phosphodiesterase inhibitors
 caffeine
 aminophylline
 IBMX (3-isobutyl-1-methylxanthine)
 paraxanthine
 pentoxifylline,
 Theobromine,
 Theophylline.
They act as competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP,
activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce inflammation and innate
immunity and nonselective adenosine receptor antagonists
B) Selective phosphodiesterase inhibitors
PDE1 selective inhibitors
 Vinpocetine
PDE2 selective inhibitors
 EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)
 Anagrelide
PDE3 selective inhibitors
 Enoximone and milrinone, used clinically for short-term treatment of
cardiac failure.
 These drugs mimic sympathetic stimulation and increase cardiac
output.
 PDE3
is
sometimes
referred
to
as
cGMP-inhibited
phosphodiesterase.
PDE4 selective inhibitors
 Mesembrine,
Rolipram,
Ibudilast,
Piclamilast,
Luteolin,
Drotaverine,
 PDE4 is the major cAMP-metabolizing enzyme found in
inflammatory and immune cells, have proven potential as antiinflammatory drugs, especially in inflammatory pulmonary
diseases such as asthma, COPD, and rhinitis.
 They suppress the release of cytokines and other inflammatory
signals, and inhibit the production of reactive oxygen species.
 PDE4 inhibitors may have antidepressive effects and have also
recently been proposed for use as antipsychotics.
PDE5 selective inhibitors
 PDE5 has only one subtype, PDE5A, of which there are 4
isoforms in humans called PDE5A1-4.
 PDE5 enzyme is specific for cGMP which means it only
hydrolyzes cGMP but not cAMP, the selectivity is mediated
through network of hydrogen bonding which is favorable
for cGMP but unfavorable for cAMP in PDE5.
 PDE5 is responsible for the degradation of cGMP in the
smooth muscle cells lining the blood vessels supplying the
corpus cavernosum of the penis, which leads to erectile
dysfunction (ED).
Mechanism of action:
In response to sexual stimulation,
Nitric
oxide
released
from
nonadrenergic-noncholinergic
neurotransmission
and
the
endothelium of the cavernous smooth
muscle is probably the principal
neurotransmitter for penile erection.
Within the muscle, nitric oxide activates
a guanylyl cyclase that raises
intracellular concentrations of cyclic
guanosine monophosphate (GMP).
Cyclic GMP in turn activates a
specific protein kinase which
results in the opening of the
potassium
channels
and
hyperpolarization and causes
sequestration of intracellular
calcium and blocks calcium
influx. As a result of this drop
in cytosolic calcium, smooth
muscle
relaxation
leading to erection.
occurs
Activation of the NO-cGMP pathway results in trabecular smooth
muscle relaxation, leading to increased blood flow into the penis with
pooling of blood in sinuses; and increase in corpus cavernosum pressure,
resulting in penile erection.
On return to the flaccid state, cyclic GMP is hydrolyzed to guanosine
monophosphate by phosphodiesterase type 5.
PDE-5 inhibitors do not increase the nitric oxide level,
but they potentiate the nitric oxide effect to stimulate
erection. Without sexual arousal, this effect activates
the nerve-nitric oxide pathway, these inhibitors are
ineffective
Examples of PDE5 Inhibitors
Sildenafil,
Tadalafil,
Vardenafil (10 times more potent than sildenafil)
and the newer:
Udenafil ,
Avanafil,
Lodenafil
parameter
Sildenafil
Vardenafil
Tadalafil
Doses available
25 mg, 50 mg, 100 mg
5 mg, 10 mg, 20 mg
5 mg once daily, 20 mg
Administration
Take 60 minutes prior to
sexual
activity
Take 60 minutes prior
to sexual
activity
Take from 16 min to 30
min prior
to sexual activity
Food interaction
Yes, with high fat foods
Yes, with high fat. Not
affected by a normal
meal foods.
None
Mean time to peak
concentration
Cmax (min.)
60
60
120
T1/2
3–5hr
4–5hr
17.5hr
Metabolism
Cytochrome P450 3A4
Cytochrome P450 3A4
Cytochrome P450 3A4
> 65 yrs of age
Half life increased, dose
adjustment should be
considered
Half life increased, dose
adjustment required,
recommend
lower starting dose
Half life increased, no
dose
adjustment
recommended
Selectivity
 For PDE1:
Nonselectivity of PDE5 inhibitors with respect to all PDE1
subtypes may induce vasodilatation, flushing, and
tachycardia.
 PDE5 inhibitors may also indirectly inhibit
PDE3, thereby
elevating heart rate and vasodilation while inhibiting
platelet aggregation.

 For
PDE6:
Inhibition of this enzyme can induce visual disturbances, which
have occurred at the highest clinically applied dose of sildenafil
and to a lesser extent with vardenafil.
No visual disturbances have been reported with tadalafil use.
 For PDE11:
Musculoskeletal pain, in particular back pain, more significant
with tadalafil than with sildenafil or vardenafil AS tadalafil
presented a five fold higher selectivity for PDE11A.
Adverse reactions
Tadalafil
Vardenafil
Sildenafil
Headache
Flushing
Headache
Dyspepsia
Headache
Flushing
Dizziness
Dyspepsia
Dizziness
Flushing
Nausea
Dyspepsia
Nasal congestion
Dizziness
Nasal congestion
Back pain, myalgia
Rhinitis
Altered vision
PDE5 Inhibitors & ED
According to the 2006 American Urological Association
(AUA) Guidelines:
 PDE5 inhibitors are considered to be the first line of therapy in
the management of ED, unless contra-indicated.
 the management of ED begins with the identification of organic
comorbidities and psychosexual dysfunctions; both should be
appropriately treated.
 For patients with a definite endocrinopathy, endocrine therapy
for hypogonadism, hyperprolactinemia, and thyroid disorders is
an appropriate intervention.
Indications
Oral Phosphodiesterase-5 Inhibitor therapy as medically necessary in
males for the treatment of erectile dysfunction when ANY of the
following criteria are met:
1- Age 60 or older
2-
Hormonally-induced erectile dysfunction with EITHER of the
following:
 erectile dysfunction persists despite correction of an abnormal
testosterone, prolactin, or thyroid level
 correction of the hormonal deficiency is contraindicated due to
comorbidity (e.g., a low testosterone in a man with prostate cancer)
3- Neurogenic erectile dysfunction such as resultant from
spinal
cord
injury,
multiple
sclerosis,
pituitary
microadenoma with hyperprolactinemia, cerebral vascular
accident
(CVA),
diabetes,
radical
prostatectomy
or
surgically induced impotence
4- Vasculargenic erectile dysfunction such as resultant
from aortic aneurysm, atherosclerosis, hypertension,
hyperlipidemia, or peripheral vascular disease (PVD)
5- Pelvic trauma-induced erectile dysfunction such as
resultant from compression injuries or radiation.
6- Pharmacologic-induced erectile dysfunction where the
patient has tried ONE alternate, non-erectile dysfunctioncausing medication and erectile dysfunction persists,
OR there is a contraindication to making medication
changes.
Contraindications& drug interaction
 The PDE5I can potentiate the hypotensive effects of
nitrates. Therefore, PDE5I are contraindicated in
patients who are using any form of organic nitrate,
either regularly and/or intermittently because of the
risk of severe hypotension. PDE5 inhibitors can
potentiate the vasodilatation of nitrates and result in
potentially dangerous hypotension.
 Caution is advised when PDE5I are co-administered
with
alpha
blocking
agents
and/or
anti-
hypertensives because both have vasodilatory
effects and an additive effect on blood pressure
lowering may be anticipated.
 The longer half-life of tadalafil imposes increased
risk for drug interactions in patients taking potent
cytochrome
P450
erythromycin,
ketoconazole,
protease inhibitors.
(CYP450)
inhibitors
cimetidine
or
e.g:
the
safety concerns
 This has been the area of primary concern due to reports
of myocardial infarction and death.
These concerns have however been ameliorated as studies
have not shown an increased rate of myocardial infarction,
ischemic heart disease or mortality.
BUT..Treatment of ED in a patient with cardiovascular
disease is complicated by a small increase in risk of
myocardial infarction related to sexual activity.
In some cases, the sudden hearing loss was
accompanied by tinnitus and/or dizziness.
Non-arteritic
anterior
ischemic
optic
neuropathy
(NAION) has been reported rarely in temporal
relationship with the use of PDE5I.
rare reports of prolonged erections more than four
hours and priapism (painful erections more than six
hours in duration) for this class of compounds
Patients Failing to Respond to their Initial PDE5
Inhibitor
Patients who have failed to respond to a PDE5 inhibitor will not
necessarily fail to respond to other drugs in the class.
Patients should not be deemed true treatment failures until they have
failed to respond to maximum dose medication on at least eight
occasions.
Non-responding patients may derive benefit from a regular dosing
schedule, suggesting that in some patients reversal of ED may result
from more continuous exposure to PDE5 inhibitors.
Some patients also fail to respond to ED treatment for other reasons,
such as associated androgen deficiency. This may be overcome by
instituting treatment with androgen replacement therapy
Recommendations for treatment optimisation with
PDE5- inhibitors
 Control medical and lifestyle risk factors.
 Emphasize the need for sexual stimulation.
 Titrate dose if lower doses are not effective.
 Counsel patients on how to take the drug properly.
 Explain that excessive use of alcohol should be avoided, as this can have a negative
impact on erectile function.
 Manage expectations and inform patient that most patients respond to treatment after
one or two doses; some patients may need seven or eight attempts before they are
successful. The first few attempts at intercourse may be emotionally charged for both
the patient and partner, especially if patients have not been sexually active for a long
time.
 Discuss side effects.
Uses of PDE-5 inhibitors beyond ED
 Premature ejaculation (PE):
The concomitant use of SSRIs and sildenafil may represent an
appropriate approach for PE.
The possible mechanism may be that an improved erection
(firmness, duration or both) resulting from the PDE-5
inhibitor provides inhibition of ejaculation via down-regulation
of receptors involved in somatosensory latency times.
A reduction in performance anxiety may exist on a
subconscious level.
 Anorgasmia in women:
PDE5 is expressed in clitoral corpus cavernosum and in vaginal smooth
muscle and epithelium. Therefore it is possible that PDE5 inhibitors
could affect female sexual arousal disorder.
Increased levels of cGMP have been shown to occur in human-cultured
vaginal smooth muscle cells treated with a PDE5 inhibitor suggesting
involvement of the NO/cGMP axis in the female sexual response.
SSRI antidepressants commonly produce iatrogenic sexual dysfunction.
Sildenafil (100 mg) and vardenafil (10 mg) have been used to reverse
SSRI-induced anorgasmia in women.
 Pulmonary hypertension
Pulmonary hypertension is the result of upregulation of PDE5
gene expression, causing vasoconstriction in the lung.
PDE5 inhibitors are used as potent pulmonary vasodilators
reducing Pulmonary hypertension and inhibiting vascular
remodelling.
 Raynaud's phenomenon
Sildenafil has been shown to be effective in treating severe
Raynaud's
phenomenon
associated
sclerosis and digital ulceration.
with
systemic
 Heart failure
Sildenafil has shown promise in the treatment of congestive cardiac failure.
It has also been shown to reduce aortic pressure through vasodilation, reduced arterial
stiffness and wave reflection and could be used in the management of systemic
hypertension.
 Vascular disease
Sildenafil has been shown to significantly improve neurovascular coupling without
affecting overall cerebral blood flow by increasing brain levels of cGMP. This data
suggest that PDE5 inhibitors may have a role in promoting recovery from stroke.
 Irritable bowel syndrome (IBS)
NO is a major inhibitory neurotransmitter in gastrointestinal tract.
Sildenafil causes relaxation of smooth muscles in various organs by increasing levels
of NO.