Tadalafil

Long-half-life PDE5 inhibitor (17.5 hr) that turns into a smooth daily background vasodilator at 2.5-5 mg — the only PDE5i where "low-dose daily" is FDA-approved. Best-evidenced indications: ED, BPH, pulmonary hypertension. Emerging observational signal (~20-30% lower dementia incidence in PDE5i users) makes it a plausible long-game brain-vascular play, but no RCT confirms cognitive enhancement yet. For Dylan: OPTIONAL-ADD daily 2.5 mg if he wants the vascular/cognitive-flow upside; not necessary at 20yo with no ED, no BPH, no CV risk factors.

Tadalafil selectively inhibits phosphodiesterase type 5 (PDE5), the enzyme that breaks down cyclic GMP (cGMP) in vascular smooth muscle.

The cGMP pathway in plain English:

1. Endothelium senses shear stress / acetylcholine / sexual arousal / hypoxia → releases nitric oxide (NO).
2. NO diffuses into vascular smooth muscle and activates soluble guanylate cyclase, which makes cGMP.
3. cGMP relaxes the smooth muscle → vessel dilates → blood flow increases.
4. PDE5 degrades cGMP, ending the vasodilation.

Tadalafil blocks step 4. The endogenous NO signal still has to fire — tadalafil doesn't create dilation, it amplifies and prolongs whatever NO-signal is already there. That's why food, sleep, exercise, and arousal still matter; tadalafil makes the body's own vasodilation last longer and reach higher peaks.

Tissue distribution of PDE5:

• Corpus cavernosum (penis) — densest expression; primary FDA indication.
• Pulmonary vasculature — basis for Adcirca/PAH approval at 40 mg daily.
• Prostatic and bladder smooth muscle — basis for BPH approval (Cialis 5mg daily).
• Systemic peripheral vasculature — modest BP drop (~5 mmHg systolic).
• Cerebral vasculature — present, mechanism for the cognitive blood-flow hypothesis.
• Skeletal muscle and mitochondria — emerging area; PDE5 inhibition appears to support mitochondrial biogenesis and endothelial function in trained muscle.

Why tadalafil specifically (vs sildenafil, vardenafil, avanafil):

• Half-life 17.5 hours vs sildenafil ~4 hr, vardenafil ~4 hr, avanafil ~6 hr. This is the differentiator.
• A 2.5 mg daily dose hits steady-state by day 5 — meaning 24/7 mild PDE5 inhibition rather than peak-and-trough.
• No food interaction (sildenafil is blunted by fatty meals).
• Slightly less PDE6 cross-reactivity than sildenafil → less blue-tint visual side effect.
• Tradeoff: more PDE11 cross-reactivity → muscle/back aches more common than with other PDE5i.