Mechanism of Action of Sildenafil (Viagra)

Introduction

• Presenter: Kevin Tokeoff
• Platform: Catalyst University
• Topic: Mechanism of action of Sildenafil (Viagra)

Background

• Original Use: Sildenafil was initially marketed as a vasodilator for heart disease and cardiovascular conditions.
• Cardiovascular Benefit: Acts by decreasing blood pressure through vasodilation; reducing overall cardiovascular load.
• Secondary Effect Noticed: Improvement in erectile dysfunction (ED) in patients aged 50-60.
  • Current Use: Now primarily marketed for treating ED.

Mechanism of Action (Baseline)

Key Players

• Nitric Oxide (NO): Crucial for vasodilation.
• Enzymes:
  • Endothelial Nitric Oxide Synthase (eNOS): Converts arginine to NO in endothelial cells.
  • Guanylate Cyclase: Activated by NO; converts GTP to cyclic GMP in smooth muscle cells.
  • Cyclic GMP Phosphodiesterase: Converts cyclic GMP to GMP, deactivating its effects.
• Cells Involved:
  • Endothelial Cells: Produce NO.
  • Smooth Muscle Cells: Respond to NO to facilitate vasodilation.

Process Steps

1. NO Production: eNOS converts arginine to NO in endothelial cells.
2. Diffusion: NO diffuses into smooth muscle cells.
3. Activation: NO activates guanylate cyclase by binding to its heme group.
4. cGMP Formation: Guanylate cyclase converts GTP to cyclic GMP.
5. cGMP Effects:
   • Activates cyclic GMP protein kinase.
   • Decreases calcium influx into smooth muscle cells.
   • Promotes muscle relaxation and vasodilation.
6. Deactivation: Cyclic GMP phosphodiesterase converts cyclic GMP to GMP, ceasing the vasodilation effect.

Mechanism of Erectile Dysfunction

• Age Factor: Reduced nitric oxide and cyclic GMP levels with age lead to inadequate vasodilation for erection maintenance.
• Phosphodiesterase Role: Increased activity results in more cyclic GMP conversion to GMP.

Sildenafil Mechanism

Key Points

1. Inhibition: Sildenafil inhibits cyclic GMP phosphodiesterase.
2. Effect on cGMP: Prevents degradation of cyclic GMP, maintaining its elevated levels longer.
3. Prolonged Action:
   • Sustains activity of cyclic GMP protein kinase.
   • Maintains reduced calcium levels and continued vasodilation.
   • Helps sustain blood flow necessary for erection maintenance.

Practical Implication

• Erection Maintenance: Prolonged vasodilation aids in maintaining an erection.
• Side Effect Warning: Prolonged action can lead to extended erections; requires medical consultation if lasting more than 4 hours.
• Termination: With reduced sildenafil levels, phosphodiesterase can resume its action, degrading cGMP and ending vasodilation.

Summary

• Primary Function: Sildenafil elevates cyclic GMP levels by inhibiting its degrader, cyclic GMP phosphodiesterase.
• Main Effect: Prolonged vasodilation supporting erection maintenance.

Closing

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