Phosphodiesterase Inhibitors

Phosphodiesterase Inhibitors

1. Definition & overview

• Phosphodiesterase (PDE) inhibitors are drugs that block the cyclic-nucleotide phosphodiesterase enzymes, which hydrolyse the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) to their inactive 5′-monophosphates (5′-AMP, 5′-GMP); inhibition therefore raises cellular cAMP and/or cGMP and amplifies their downstream signalling (G&G 14e Ch.35, pp.698–9; Ch.44, p.882).
• The cyclic nucleotide PDEs comprise a superfamily of enzymes that hydrolyse 3′-5′ cyclic nucleotides to their cognate 5′-monophosphates; eleven isoenzyme families (PDE1–PDE11) exist, differing in substrate preference (cAMP-specific, cGMP-specific, or dual), tissue distribution, and regulation (G&G 14e Ch.35, p.700).
• The therapeutic logic of the class is isoenzyme- and tissue-selectivity: because individual PDE isoforms predominate in particular tissues, an inhibitor selective for one isoform produces a relatively organ-specific elevation of cyclic nucleotide and hence a targeted physiological effect — e.g. PDE5 in the corpus cavernosum and pulmonary vasculature, PDE3 in cardiac and vascular smooth muscle, PDE4 in inflammatory cells (G&G 14e Ch.35, p.700; Ch.44, p.882).
• Net cellular consequence of ↑ cyclic nucleotide:
  • ↑ cAMP → activation of protein kinase A (PKA) → smooth-muscle relaxation (vasodilation, bronchodilation), positive cardiac inotropy/lusitropy, inhibition of inflammatory-cell activation, inhibition of platelet aggregation (G&G 14e Ch.44, p.879; Ch.36).
  • ↑ cGMP → activation of protein kinase G (PKG) → vascular smooth-muscle relaxation (especially in the corpus cavernosum and pulmonary artery), antiproliferative and antiplatelet effects (G&G 14e Ch.35, pp.698–9).
• The class is cross-cutting by design, spanning respiratory (bronchodilation, anti-inflammatory), cardiovascular (inotropy, vasodilation, pulmonary hypertension, antiplatelet), urogenital (erectile dysfunction), and dermatological/rheumatological (psoriasis, psoriatic arthritis) systems (synthesised across G&G 14e Ch.35, Ch.44, Ch.36; KDT 8e Ch.38).