1 / 110

DRUGS ACTING ON RAAS

DRUGS ACTING ON RAAS. DR SHREETAL RAJAN NAIR. The Renin Angiotensin Aldosterone System (RAAS). Most important neurohormonal system that maintains vascular tone and fluid-electrolyte balance in our body

wilma-farmer
Download Presentation

DRUGS ACTING ON RAAS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. DRUGS ACTING ON RAAS DR SHREETAL RAJAN NAIR

  2. The ReninAngiotensinAldosterone System (RAAS) • Most important neurohormonal system that maintains vascular tone and fluid-electrolyte balance in our body • Is involved in the pathophysiology of most cardiovascular diseases and hence its importance • Works through a negative feedback loop in our body

  3. Pathophysiology of RAS

  4. Factors stimulating renin release • Low arterial blood pressure • Decreased sodium concentration in the distal tubule • Decreased blood volume • Increased beta -1 sympathetic activity

  5. Drugs influencing PRA • Increasing PRA • ACEI • ARBs • Vasodilators • Diuretics • Decreasing PRA • Adrenergic blockers • Renin inhibitors

  6. DRUGS ACTING ON RAAS • ACE Inhibitors • Angiotensin receptor blockers • Aldosterone antagonists • Renin inhibitors • New therapeutic pathways

  7. ACE Inhibitors

  8. Historical aspects • ACE was initially discovered from the venom of pit viper and named bradykinin potentiating factor and later it was found that this kininase and ACE were the same. • Teprotide was the first ACEI to be synthezised • But it had limitations • Later , captopril was developed as the first ACEI in 1977

  9. ACEI • ACE inhibitors differ • in the chemical structure of their active moieties, • in potency, • in bioavailability, • in plasma half-life, • in route of elimination, • in their distribution and affinity for tissue-bound ACE, and • in whether they are administered as prodrugs.

  10. ACE Inhibitors CLASSIFICATION • Class I : Containing a sulfhydryl group - Captopril ( proline derivative) • Class II : Prodrugs • Class III : Water soluble - Lisinopril ( Lysine derivative )

  11. ACEI • Captopril is the prototype of the sulfhydryl-containing ACE inhibitors; others are fentiapril, pivalopril, zofenopril, and alacepril. • In vitro studies suggest that the presence of the sulfhydryl group may confer properties other than ACE inhibition to these drugs, such as free-radical scavenging and effects on prostaglandins • In vivo no much benefit has been found

  12. ACEI – salient features • Captopril by itself is active and its metabolites are also active • Prodrugs by itself are not active and need to be converted to the active diacids in the liver and prodrugs have better bioavailability • Lisinopril is active and is not metabolised and excreted unchanged • All ACEI are excreted exclusively via renal system except fosinopril,spirapril and trandolapril which are excreted via the biliiary system and feces.

  13. ACEI – salient features • Bioavailability : highest – captopril; least – perindopril • Most prodrugs are carboxyl derivatives except fosinopril • Time to peak action – fastest captopril ( 1 hr) • Elimination t ½ - longest with ramipril (8-48 hrs) • ACEI with duration of action > 24 hrs : enalapril,lisinopril,ramipril and perindopril • Captopril is the only ACEI to cross BBB but its clinical significance is unknown

  14. ACEI – pharmacokinetics in a nut shell Nancy J. Brown, MD; Douglas E. Vaughan, MD Circulation. 1998;97:1411-1420.

  15. ACEI- hemodynamic effects • ACEI are beneficial in many ways • Prevents generation of angiotensin II • Useful in conditions in which the reninangiotensin system is dysregulated like essential hypertension and renovascular hypertension • Decreases the peripheral vascular resistance • Fall in systolic and diastolic BP • No effect on cardiac output

  16. INDICATIONS OF ACEI 1. Heart failure • Chronic heart failure due to any cause 2. AMI • Early phase • AMI with HF 3. Hypertension 4. Chronic Renal Disease 5. Diabetic nephropathy 6. Risk prevention

  17. ACEI – other indications Non – cardiovascular • Diabetic and non- diabetic nephropathy • Scleroderma crisis ( captopril test to diagnose renovascular hypertension )

  18. Adverse effects

  19. Adverse effects • First dose hypotension more in diuretic treated patients • Hyperkalemia more in patients with impaired renal function and those taking potassium sparing diuretics and NSAIDs • Cough : occurs in patients within 1-8 weeks ; subsides in 7-21 days after discontinuation ;not dose related- earlier it was believed to be due to inhibition of bradykinin degradation; now it is believed to be mediated by substance P as kininase II is also believed to be degrade substance P. More in women

  20. Adverse effects • Angioedema: the pathogenesis is found to be similar to the cough; cough and angioedema found in higher incidence in those concomitantly using DPP IV inhibitors as DPP is also responsible for substance P breakdown. • Rashes,urticaria: do not need drug stoppage • Dysguesia is a reversible alteration in the taste sensation – found in captopril treated patients and believed to be due to the sulfhydryl moiety

  21. ADAPTED from www./spo.escardio.org/eslides

  22. Adverse effects • Granulocytopenia and proteinuria very rare but warrant withdrawal • Headache,dizziness ,nausea and bowel upset- in 1-4 % • ARF in bilateral RAS due to dilatation of efferent arterioles and fall in GFR and hence contraindicated • Fetopathic effects- 1st trimester produces cardiovascular malformations ( PDA ) and 2nd and 3rd trimester responsible for oligohydramnios, fetal calvarial hypoplasia, fetal pulmonary hypoplasia, fetal growth retardation, fetal death, neonatal anuria, and neonatal death and hence contraindicated in pregnancy.

  23. Interactions • NSAIDs especially in elderly, taking diuretics and ACEI • Potassium sparing diuretics/ on K+ supplements • Antacids decrease absorption • Reduce Lithium clearance and predispose to toxicity in those taking lithium • Caution in Impaired renal function, hypovolemia or dehydration

  24. Contraindications • Bilateral RAS • Pregnancy • Hyperkalemia • Known allergy or hypersensitivity • Serum creatinine (>2.5 – 3.0 mg/dl ) arbitrary cut off in patients with heart failure

  25. Pharmacogenomics • Found to be less effective in young and elderly blacks because are found to have less PRA. • Adding drugs which increase PRA like diuretics have found to increase response to therapy • An insertion (I)/deletion (D) polymorphism in the ACE gene that correlates with ACE activity such that ACE levels are highest in patients who are homozygous for the ACE D allele, lowest in patients homozygous for the ACE I allele, and intermediate in those who are heterozygous . Persons with the D/D phenotype had subdued response to the ACEI • Angioedema more in whites.

  26. Some new concepts in ACE inhibition • ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death . • The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure

  27. Some new concepts in ACE inhibition • ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure • The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probioticLactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions ( discovered in Japan IN 1991)

  28. ACEI in heart failure • Panel A- ACEI in HF with depressed EF in a post AMI metaanalysis • Panel B – ACEI in HF with depressed EF including postinfarction trials (metaanalysis) • Benefit from therapy is seen very early and persisted long term

  29. Omapatrilat • Omapatrilat was a novel antihypertensive agent that inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). • NEP inhibition results in elevated natriureticpeptide levels, promoting natriuresis, diuresis, vasodilation, and reductions in preload and ventricular remodeling. • This was being promoted for CHF but was not approved by the FDA due to angioedema safety concerns

  30. Omapatrilat - trials • The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study: Omapatrilat was as good as enalapril but not better • In the OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study 25,267 hypertensives were randomised to Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of Omapatrilat was seen. • Significantly more cases of angioedema were seen with Omapatrilat in both trials.

  31. IMPRESS randomised trial • Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure • Showed a trend in favour of omapatrilat

  32. Angiotensin receptor blockers (ARBs)

  33. ARBs • The ARBs act on the next step in RAAS and they block the angiotensin II receptor through which angiotensin II exerts its effects • Why the need of ARBs arose after ACEI ? • Clinical and experimental studies showed the initial suppression of angiotensin II after the administration of angiotensin-converting enzyme (ACE) inhibitors is later reversed and returns almost to pretreatment levels. • The ESCAPE phenomenon was hypothesized which was strengthened by the discovery that angiotensin II can also be generated through non-ACEs 2. Increased incidence of adverse effects with ACEI therapy

  34. Advantages of ARBs over ACEI • Do not interfere with degradation of bradykinin and other ACE substrates • More complete inhibition of AT1 receptor activation • Indirect activation of AT2 receptor • Other molecular effects apart from the receptor action

  35. Losartan was the first ARB to be synthezised and it was a imidazole derivative • All ARBs expect for losartan are highly selective for the AT1 receptor. In fact, ARBs show 10,000–30,000 times greater affinity for the AT1 receptor than for the AT2 receptor • The majority of ARBs produce insurmountable antagonism ( non competitive inhibition )

  36. What is the advantage of AT1 receptor specificity ? • AT2 receptor may be exposed to a higher concentration of Ang II • It increases the Ang II-induced AT2 receptor stimulation which may cause anti-cell proliferation and vasodilation

  37. Other effects of ARBs • Inverse agonism of AT1 receptor • Anti platelet effects • Anti – inflammatory effects • Reduction in serum uric acid levels

  38. Benefits of Inverse agonism 1. Sometimes AT1 receptors are mutated and have constitutive activity which means the receptors can get activated in the absence of its ligand • Constitutive has also been found in wild type receptors • Losartan,valsartan,olmesartan and candesartan have significant inverse agonism

  39. Benefits of inverse agonism 2. AT1 receptor mRNA levels are upregulated by myocyte stretching over time • Studies have demonstrated that the AT1 receptor is activated by the mechanical stretching of cultured rat myocytes and constriction of the transverse aorta in angiotensinogen knockout mice without the involvement of Ang II, and these adverse effects were suppressed by an inverse agonist

  40. Anti platelet effects • Losartan has some degree of antagonistic action on the thromboxane A2 receptor which is responsible for the platelet antiaggregatory effects

  41. Anti inflammatory effects • Ang II induces inflammation in vasculature and vascular remodeling, and subsequently promotes atherosclerosis. Ang II stimulates monocytechemoattractant protein-1 (MCP-1), interleukin (IL)-8, tumor necrosis factor-a and IL-6 production • Decrease in MCP-1 levels seen with irbesartan and losartan • Increase in adiponectin expression seen with irbesartan,losartan,candesartan and telmisartan

More Related