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L07 Clinical Pharmacology ACE inhibitors and angiotensin receptor blockers

ACE inhibitors & ARBs

RAAS system

Pathway

Step 1

renin released from juxtaglomerular cells in kidney cleaves angiotensingen from liver into angiotensin I

Step 2

Angiotensin converting enzyme (ACE)turns Angiotensin I into angiotensin II

Step 3

Angiotensin II then is the main active messenger and bind to Angiotensin II receptors

Angiotension II receptors

  • At1 just isnt good Mediates pathologcial hypertensive effects hypertension, fibrosis, hypertrophy, vasoconstriction

  • At2 is good inhibits cell proliferation antifibrotic, vasodilating

Effects of Angiotensin II

vasoconstrictor stimulating aldosterone release and aldosterone promotes salt and water retention, increasing bp mineralocorticoid and profibrotic

Ang II can lead to heightened NA and therefore increased sympathetic signalling via AT1R

Sympathetic activation can increase Ang II production

Drugs.

The RAAS can be modified at each of its points

  • Reducing renin release (beta blockers and renin inhibitors)
  • Reducing Ang II production (ACE inhibitors)
  • Inhibiting At1 receptors (ARB inhibitors)
  • Decreasing alddosterone mediated effects (Mineralcorticoid receptor inhibitor)

ACE inhibitors (‘pril)

inhibits free and fixed ACE

Effects

  • Decreases levels of Ang II released
    • Reduces Ang II induced arterial vasocontriction reducing systemic vascular resistance (reduced afterload)
    • Increases venous vasodilation (reduced preload)
  • Increases levels of bradykinin by stopping ACE from breaking it down
  • reduces aldosterone production
    • promote Na+ excretion and water excretion reducing plasma volume
    • inhibit cardiac and vascular remodeling and fibrosis associated with CVD

Enalapril

For drug profile see link ^

Therapeutic uses

Primary and renovascular hypertension

  • Effects on cardiovascular system Produces arterial and venous dilatione reduces arterial and venous pressures

  • Effects on kidney Promotes natriuresis and diuresis Decreases Blood volume (lowers BP)

Effective in hyper-reninemic hypertension but still reduces BP in patients with low to normal renin levels (maybe due to bradykinin)

Additionally different ethnicities produce different levels on renin and will respond differently

Inhibition of Ang II production also crucial for proinflammatory and profibrotic effects of HTN

Chronic heart failure

reduced afterload reduced preload reduced sympathetic activation

and renal disease diabetes post MI stroke prophylaxis etc (MED3)

Adverse effects

  • bradykinin related ADRs
    • persistent dry cough and rarely angioedema
  • initial hypotension
  • rash
  • disturbed sense of taste
  • foetal abnormalites
  • can lead to renal issues contraindicated in angioedema can cause swelling

ARBs (‘sartans)

selectively inhibits AT1R

  • a lot of the same effects of ACE-Is have minus kinin accumulation and AT2R block
    • may channel Ang II to AT2Rs to get increased positive effects
  • additionally blocks Ang II no matter how its formed

Indications

  • same for ACE inhibitors
  • generally used when patient cannot tolerate an ACE-i due to ADR
    • hypertension
    • heart failure
    • renal injury

Candesartan Celixitil

Click link for drug profile

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