DRUGS ACTING ON RAAS

DRUGS ACTING ON RAAS


Introduction:

  • RAAS system results in vasoconstriction, salt & water retention, increase in blood pressure.

Actions: 

  • Decreases blood pressure.

Drug groups included:

  • ACE inhibitors
  • angiotensin receptor blockers (ARBs)
  • Renin inhibitors.
  • β blockers, ACE inhibitors, AT, & Aldosterone antagonists.
Classification:

Drugs increasing plasma renin activity:

  • Diuretics
  • Vasodilators
  • CCBs, ACE inhibitors

Drugs which lower plasma renin activity:

  • β-blockers
  • Clonidine
  • Methyldopa

1. Renin inhibitors:

  • Decreases plasma BNP levels, urinary BNP & aldosterone levels.

1st generation drugs: 

  • Enalkiren, zankiren, CGP38560A, & remikiren.
  • Orally active
  • Low potency, poor bioavailability & short t1/2.Not approved.

2nd generation drugs:

  • Aliskiren, remikiren & enalkiren.
  • Low molecular weight renin inhibitor.
  • Orally used for chronic hypertension treatment.
  • Renoprotective.

Important drug description:

Aliskiren: 

  • Added as adjuvant therapy to heart failure treatment regime.
  • Provides favorable neurohormonal effects in heart failure cases.

2. Angiotensin Converting Enzyme Inhibitors (ACEI’s):

Classification:

Sulfhydryl-containing ACE inhibitors:

  • Captopril.

Dicarboxyl-containing ACE inhibitors:

  • Enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril and perindopril)

Phosphorus-containing ACE inhibitors:

  • Fosinopril.
  • All are prodrugs.
  • Except captopril & lisinopril.
  • Eg: Enatapril –> converted –> active metabolite (enalaprilat).
  • Thus slow acting.
  • All are eliminated primarily by kidneys.
  • Except fosinopril & moexipril.

Actions:

  • Decreases RAAS activity.
  • Potentiates bradykinin’s vasodilator action.
  • Lowers BP in hypertensives, except in primary aldosteronism.

Individual drugs:

Captopril:

  • Less potent.
  • Faster onset & short duration of action – Hence cause postural hypotension.
  • Less absorption in presence of food.

Benazeprilat:

  • In vitro more potent

Enalaprilat:

  • Available as separate drug for hypertensive emergencies by i.v. route.

Ramiprilat:

  • Displays triphasic elimination kinetics.
  • t1/2: 2-4 hours, 9-18 hours & 50 hours.
  • Due to extensive distribution to all tissues (initial t1 /2), clearance of free ramiprilat from plasma (intermediate t1 /2) and dissociation of ramiprilat from tissue ACE (terminal t1 /2).

Temocaprilat (temocapril):

    • Plasma concentration unchanged even in renal failure.
    • Uses: Prevent left ventricular remodeling in patients with CHF.
Other drug effects:

Adverse effects:

Dry cough:

  • Aspirin & iron supplementation reduces cough.
  • Cough disappears on drug discontinuation within 4 days.
  • Hyperkalemia
  • Angioedema
  • Due to elevated levels of bradykinin.

Other adverse effects:

  • Rashes
  • Dysgeusia (altered taste sensation)
  • Acute renal failure (In renal artery stenosis cases).
Drug interactions: 

  • K+-sparing diuretics & K+ supplements exacerbate ACE inhibitor-induced hyperkalemia.

Contraindications:

  • Pregnancy (teratogenic in second half of pregnancy).
  • If serum creatinine is > 3.5 mg/dl.

3. Angiotensin Receptor Blockers (ARB):

Drugs:

  • Losartan, valsartan, irbesartan, candesartan, telmisartan & eprosartan.
  • MOA: Acts by antagonizing Angiotensin II action at AT1 receptors.

Losartan:

  • Competitive antagonist of thromboxane A2 receptor.
  • Attenuates platelet aggregation.
  • Used for stroke prophylaxis.
  • Safe and highly effective in portal hypertension with cirrhosis without compromising renal function.

Irbesartan & losartan:

  • Approved for diabetic nephropathy.

Valsartan:

  • Approved for heart failure patients with ACE inhibitor intolerance.
  • Category C drugs for 1st trimester.
  • Category D for 2nd & 3rd trimester.

Adverse effects:

  • Cause hypotension & hyperkalemia.

Exam Important

  • Valsartan is approved for heart failure patients with ACE inhibitor intolerance.
  • Irbesartan & losartan approved for diabetic nephropathy.
  • Losartan is a competitive antagonist of thromboxane A2 receptor.
  • Losartan used for stroke prophylaxis.
  • K+-sparing diuretics & K+ supplements exacerbate ACE inhibitor-induced hyperkalemia.
  • Temocaprilat (temocapril) prevents left ventricular remodeling in patients with CHF.
  • Ramiprilat displays triphasic elimination kinetics.
  • Angiotensin Converting Enzyme Inhibitors (ACEI’s) are all prodrugs except captopril & lisinopril.
  • Aliskiren is added as adjuvant therapy to heart failure treatment regime.
  • Drugs increasing plasma renin activity include diuretics, vasodilators & CCBs, ACE inhibitors.
  • Drugs which lower plasma renin activity include β-blockers, Clonidine & Methyldopa.
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