Module 3.2.1 (Drugs for ED) Flashcards
What are examples of phosphodiesterase 5 inhibitors?
Sildenafil (viagra)
Tadalafil (cialis)
Vardenafil
What are examples of the following intracaversonal therapy for ED
A) Prostaglandin E1
B) Non selective alpha blocker
C) Smooth muscle relaxant
A)
- Alprostadil
B)
- Phentolamine
C)
- Papaverine
What does erectile function depend on?
Depends on complex interactions between physiological and psychological factors.
What are the physiological factors to EF?
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.
What are the psychological factors to EF?
During sexual intercourse, reflex contraction of the ischiocavernosus muscles compresses the base of the corpora cavernosa –> significant increase in intracavernosal pressure during rigid erection.
How does a non-erect penis come erect?
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
What is the MOA of PDE5 inhibitors? What dot they need to work?
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
What is the peak plasma concentration of sildenafil?
- 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
True or false
Tadalafil has a longer half-life than sildenafil, so can be taken longer before sexual activity
True
What are PDE5 inhbitors metabolised by (caution drug interactions)
Inducers of CYP3A4: carbamazepine, rifampicin and barbiturates –> reduce efficacy
Inhibitors of CYP3A4: cimetidine, erythromycin, fluoxetine –> increase toxicity
What is the main drug interaction of PDE-5 inhibitors? What happens if taken together?
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 or MI that may be fatal.
- Do not give a nitrate unless it is >12 hours since the last dose of avanafil, >24 hours for sildenafil or vardenafil or >48 hours for tadalafil; a longer interval may be needed if PDE5 inhibitor half-life is prolonged, eg by a drug interaction. Monitor carefully.
PDE5 inhibitors must NOT be used in men taking long-acting nitrates.
What is the MOA of alprostadil?
Dilates cavernosal arteries
Relaxes smooth muscle of corpus cavernosum and spongiosum
Common AE of alprostadil?
Penile pain, erection lasting 4-6 hours, fibrotic change (may be more likely with increasing duration of use)
Infrequent AE of alprostadil?
Fainting, painful erection, erection lasting >6 hours, testicular pain, bruising, injection site reactions, hypotension, dizziness
MOA of phentolamine? Why does reflex tachycardia occur?
- 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)
