Chemistry of Nitrates & PDE5 Inhibitors

Organic Nitrates are used for?

unstable angina

Organic nitrates movement

incr preload → incr amount of blood ejected by heart → decr O2 consumption

Organic nitrates MOA

nitrate [NO3] → nitric oxide [NO] → soluble guanylyl cyclase [sGC ~ GTP → cGMP] = vasodilation, platelet inhibition

Flow chart when you incr cGMP

activate protein kinases → activate myosin phosphatases → dephosphorylate myosin → relax smooth muscle → VASODILATION

Nitroglycerin

onset is 1-4min, DOA: 30min ~~ taken sublingually to prevent 1st pass

Isosorbide Dinitrate [ISDN]

Oral t1/2 = 1h & F=29%

Isosorbide 5- Mononitrate [ISMN]

Oral t1/2 = 5h & F=100%

Hydralazine

-used in combo with ISDN

-decr mortality & decr rate of 1st hospitalization in HF pt who are black

Hydralazine MOA

directly relaxes smooth muscle = vasodilation!!

Nitrate Tolerance & Dependence

-lose efficacy with continued use

-AE: reflex tachycardia/hypotension & vasodilation [flushing, HA]

Sodium Nitroprusside

MOA: spontaneously [no enzymatic involvement like nitrates] release NO → activate sGC → vasodilate artery & vein

Parenteral Use: in HTN emergency or HF, decr BP in 230 sec

Caution: Keep away from light!

Cyanide Toxicity with Sodium Nitroprusside

decomposes into NO & cyanide -→ cyanide metabolized in liver to thiocyanate which undergoes renal excretion ~~ toxicity can happen if prolonged admin or renal insufficiency leads to a build-up.

Cyanide Toxicity Antidote

Cyanocobalamin [cobalt -CN]

Fenoldopam

Indication: short-term treatment of severe HTN [parenteral use]

Class: Selective peripheral DA1 Agonist

DA1 Receptor MOA

DA receps on smooth muscle mediates vasodilation, causes diuresis, & incr cAMP

can lower BP super quickly

Pro: no BBB penetration = no CNS effects!

PDE5 Inhibitors

Indication: erectile dysfunction

cause smooth muscle relaxation

PDE5 Inhibitor MOA

stimulate release of NO → NO diffuse into smooth muscle → NO activates guanylyl cyclase → incr cGMP → smooth muscle relax = inflow of blood

PDE5 Inhibitors on PDE5

they enhance the effect of NO by inhibiting PDE5 ~~ [PDE5 is responsible for degradation of cGMP]

Non-Oral Drug for ED: Phentolamine

a1 antagonist

Non-Oral Drug for ED: Alprostadil

stims adenylate cyclase to incr cAMP = smooth muscle relax

Non-Oral Drug for ED: Papaverine

PDE 2, 3, and 4 Inhibitor

PDE 5 Inhibitor: nucleotide-like structure ~ Sildenafil

PDE 5 Inhibitor: nucleotide-like structure ~ Vardenafil

PDE5 Inhibitor: non-nucleotide-like ~ Tadalafil

Onset Action = 30-120min, DOA: 36h

PDE5 Inhibitor: non-nucleotide-like ~ Avanafil

PDE6 Inhibition

color disturbances that are reversible

PDE5 Inhibitors Contraindication + Caution

potentiate hypotensive response of nitrates SO if have heart issues/hypotensive = no use!

caution: decr in BP & all metabolized by CYP3A4

Soluble Guanylate Cyclase [sGC] Stimulators

Overall: stabilize NO binding to heme group of sGC

MOA: directly stim sGC at diff site than NO → incr cGMP conc = vasodilation

Soluble Guanylate Cyclase [sGC] Properties ~ Riociguat

for PAH & CTEPH [diff types of HTN], shorter DOA, TID dosing

Soluble Guanylate Cyclase [sGC] Properties ~ Vericiguat

For HF, longer DOA, QD dosing