Drugs for ED 3.2.1

Question 1

What are examples of phosphodiesterase 5 inhibitors?

Answer 1

Sildenafil (viagra)

Tadalafil (cialis)

Vardenafil

Question 2

What are examples of the following intracaversonal therapy for ED

A) Prostaglandin E1

B) Non selective alpha blocker

C) Smooth muscle relaxant

Answer 2

A)

• Alprostadil

B)

• Phentolamine

C)

• Papaverine

Question 3

What does erectile function depend on?

Answer 3

Depends on complex interactions between physiological and psychological factors.

Question 4

What are the physiological factors to EF?

Answer 4

Physiological (endothelial NO)

Vasorelaxation in the arteries and arterioles –> increases penile blood flow –> increase in sinusoidal filling compresses the venules, occluding venous outflow and causing erection.

Question 5

What are the psychological factors to EF?

Answer 5

During sexual intercourse, reflex contraction of the ischiocavernosus muscles compresses the base of the corpora cavernosa –> significant increase in intracavernosal pressure during rigid erection.

Question 6

How does a non-erect penis come erect?

Answer 6

Nitric oxide released from endothelial cells and nitrergic nerves –> vasorelaxation in the arteries and arterioles –> increases penile blood flow –> increase in sinusoidal filling –> compresses the venules, occluding venous outflow –> causing erection.

• Nitrergic nerves and endothelium release nitric oxide (or a related nitrosothiol) which diffuses into smooth muscle cells Æ activates guanylyl cyclase
• Activates protein kinase G
• Increase cytoplasmic cGMP mediated vasodilatation
• Penile erection

Question 7

What is the MOA of PDE5 inhibitors? What dot they need to work?

Answer 7

Phosphodiesterase V (PDE5) is the isoform that inactivates cGMP.

Inhibition of PDE5

–> increased level of cGMP

–> potentiates the effect of NO on penile vascular smooth muscle

–> NO released from endothelium and nitrergic nerves that are activated by sexual stimulation

–> PDE5 inhibitors do not produce an erection without sexual stimulation and activity.

> only work with sexual stimulation

Question 8

What is the peak plasma concentration of sildenafil?

Answer 8

• approx 30 -120 min after an oral dose
• delayed by eating
• to be taken an hour or more before sexual activity
• given as a single dose as needed

Question 9

True or false

Tadalafil has a longer half-life than sildenafil, so can be taken longer before sexual activity

Answer 9

True

Question 10

What are PDE5 inhbitors metabolised by (caution drug interactions)

Answer 10

Inducers of CYP3A4: carbamazepine, rifampicin and barbiturates –> reduce efficacy

Inhibitors of CYP3A4: cimetidine, erythromycin, fluoxetine –> increase toxicity

Question 11

What is the main drug interaction of PDE-5 inhibitors? What happens if taken together?

Answer 11

A clinically important drug interaction of all PDE5 inhibitors occurs with all organic nitrates

Both work through increasing cGMP

Marked potentiation of effect of nitrates (GTN or nicorandil) by PDE5 inhibitors –> profound hypotensive response that may be fatal.

PDE5 inhibitors must NOT be used in men taking long-acting nitrates.

Question 12

What is the MOA of alprostadil?

Answer 12

Dilates cavernosal arteries

Relaxes smooth muscle of corpus cavernosum and spongiosum

Question 13

Common AE of alprostadil?

Answer 13

Penile pain, erection lasting 4-6 hours, fibrotic change (may be more likely with increasing duration of use)

Question 14

Infrequent AE of alprostadil?

Answer 14

Fainting, painful erection, erection lasting >6 hours, testicular pain, bruising, injection site reactions, hypotension, dizziness

Question 15

MOA of phentolamine? Why does reflex tachycardia occur?

Answer 15

• Reversible competitive a receptor blocker
• Block postsynaptic a1-adrenoceptors

VASODILATION - Dilate both arteries and veins

• Dilates cavernosal arteries.
• BUT little effect on relaxation of smooth muscle
• Block presynaptic a2-adrenoceptors

REFLEX TACHYCARDIA due to noradrenaline release

• Shorter acting (half-life ~20 min after IV administration)

Question 16

Compare the effects of noradrenaline, phentolamine and prazosin on heart rate

Answer 16

• Noradrenaline: Noradrenaline (NE) activates presynaptic α2- adrenergic receptors (α2), and this inhibits the formation of cyclic adenosine monophosphate (cAMP) and decreases the release of NE.
• Phentolamine: blocks α2 receptor-mediated inhibition of NE release. This increases the stimulation of cardiac β1- adrenergic receptors (β1) and results in reflex tachycardia
• Prazosin: a selective α1- blocker, does not block α2 receptor-mediated inhibition of norepinephrine release. Therefore, prazosin causes less reflex tachycardia than does phentolamine.

Question 17

Phentolamine AE? What are its effects regrding BPH?

Answer 17

• Orthostatic hypotension
• Dizziness
• Impotence
• Reflex tachycardia
• Blurred vision
• Diarrhoea
• Fatigue

but causes micturition (urination) helpful in relieving BPH symptoms

Question 18

What is papaverine? What is its MOA?

Answer 18

• An opium alkaloid isolated from poppy –> Papaver somniferum
• Causes direct smooth muscle relaxation –> filling of the corpus cavernosum with blood –> erection
• Nonspecific inhibition of phosphodiesterase –> increased levels of cGMP and cAMP
• Also impairment of calcium influx through inhibition of voltage-dependent calcium channels