Hypertension drugs classification pharmaocology

Hypertension drugs classification pharmaocology

1. ADVANCED THERAPIES IN HYPERTENSION Presented by , Nanda Kocharekar . Roll no.48

2. HYPERTENSION Definition: Hypertension or High blood pressure ,sometimes called arterial hypertension, is a chronic medical condition in which blood pressure in the arteries is elevated. Blood pressure: It is pressure exerted by blood upon the walls of the blood vessels especially arteries. Blood pressure is summarised by two measurements: a)Systolic i.e Heart muscle is contracting. b)Diastole i.e. Heart muscle is relaxed.

3. Classification of Hypertension : a) Primary or essential hypertension: Primary hypertension is most common form of hypertension, accounting for 90-95% of all cases of hypertension. Hypertension results from a complex interaction of genes and enviromental factors. where definite cause for the rise in BP is unknown but sympathetic and renin-angiotensin system may overactive and do contribute to the tone of blood vessels and cardiac output in hypertension. b) Secondary hypertension : Secondary hypertension from an identifiable cause. Secondary to renal (chronic diffuseGlomerulonephritis , pyelonephrities , polycystic kidneys); endocrine (Cushing’s syndrome, pheochromocytoma , primary hyperaldosteronism ); and vascular (renal artery disease, pulmonary artery disease, coarctation of aorta) lesion.

4. Mechanism of Hypertension : Arterial blood pressure is directly proportional to cardiac output and peripheral vascular resistance. These is controlled by baroreflexes andrenin angiotensin-aldosterone system..

5. Drug Therapy: Antihypertensive Agents 1.DIURETICS -First line drug therapy for hypertension -Low doe diuretic therapy is safe,inexpensive and effective in preventing Stroke,Congestive heart failure. A. Thiazide diuretics Eg . Hydrochlorthiazide,Chlorthalidone Adverse Effect: Hypokalemia , Hyperuricemia , Hypomagnesemia B. Loop Diuretics Eg . furesemide , Bumetanide , torsemide C. Potassium sparing diuretics Eg . Amiloride , triamteren

6. 2. β - Adrenoreceptor blocking Agents: Eg . Acebutanol , Atenolol , Labetalol , Metoprolol 3.ACE Inhibitors: Eg . Enalapril , Lisinopril , Benazepril

7. 4.Angiotensin II –Receptor blocking Agents: Eg.Losartan,Valsartan,Telmisartan Decrease activation of angiotensin -I receptors by Angiotenin II Produce arteriolar and venous dilation and block Aldosterone secretions Decreased salt and water Retention Decreased Blood Pressure

8. 5. Calcium Channel Blocker: Eg . Diphenylalkylamine:Verapamil Benzodiazepines:Diltiazem Dihydropyridines:Nifedipine,Amlodipine,Nicardipine . Calcium channel agonist blocks inward movement of calcium by binding to L-type calcium channel in heart and smooth muscle of Coronary and peripheral arteriolar vascular smooth muscle relax Dilation of arteriole Decreaed Blood Pressure

9. NEW THERAPIES IN HYPERTENSION 1.Dual vasopeptidase inhibitors : Angiotensin -converting enzyme, two other zinc metalloproteinases neprilysin (also called neutral endopeptidase ) and endothelin -converting enzyme are pharmacological targets for hypertension. Inhibition of these three enzymes aimed to not only improve blood-pressure control in patients with hypertension,but also to reduce target organ damage through enhanced antiproliferative , antifibrotic , and anti- infl ammatory effects . Two reasons for this focus: (1) neprilysin and angiotensin -converting enzyme are both metallopeptidases sharing several structural similarities, catalytic mechanisms, and substrates, which allowed for the design of dual vasopeptidase inhibitors that bore similar inhibitory activities against both enzymes in a molecule with a binding affinity in the nanomolar range; (2)these vasopeptidase inhibitors have complementary mechanisms of action for lowering blood pressure.

10. Omapatrilat was the first in a new class of highly specific , non- peptidergic,orally active, dual vasopeptidase inhibitors, and was more effective for lowering blood pressure than were angiotensin -converting enzyme inhibitors . Ilepatril ( Sanofi -Aventis), is characterised by prolonged, intense inhibition of angiotensin -converting enzyme compared with other selective angiotensin Converting enzyme inhibitors, such as ramipril .

11. Daglutril (Solvay Pharmaceuticals), a potent inhibitor of combined neprilysin and endothelinconverting enzyme, is presently in phase 2 clinical development in patients with hypertension. Adverse Effect : Angio -oedema attributed to accumulation of bradykinin

12. 2.Dual-acting angiotensin receptor- neprilysin inhibitors: To overcome the risk of angio -oedema, neprilysin inhibitors have been combined with angiotensin-2 type-1 receptor blockers, which have no effect on metallopeptidases that participate in bradykinin breakdown. LCZ696 (Novartis Pharmaceuticals)- dual-acting angiotensin receptor- neprilysin inhibitor, composed of molecular moieties of valsartanand neprilysin inhibitor prodrug AHU377(1:1).

13. 3.Endothelin antagonists: Endothelin antagonists Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide that acts through endothelin -A and endothelin receptors, and in particular mediates vasoconstriction and inflammation . Bosentan ( Actelion Pharmaceuticals) -highly specifi c, non- peptidergic , orally active -mixed endothelin -A and endothelin -receptor antagonists ( eg , avosentan , enrasentan , tesozentan ) suitable for long-term treatment. -Endothelin-1 antagonists marketed to treat Pulmonary artery hypertension, resistant hypertension Side Effects: liver transaminase , oedema,water retention To Overcome this side effects, Darusentan -a mixed endothelin -A and endothelin -B antagonist that is presently in phase 3 trials (Gilead Sciences), -more effective for lowering clinic and ambulatory blood pressure.

14. Sitaxsentan -It is an endothelin -A receptor selective antagonist which is administered as a once daily oral dose. It is not FDA approved, but is currently in use in Europe and Canada. It is not as hepatotoxic as bosentan . 4.Nitric oxide donors: -Nitric oxide is a powerful vasodilator. -However, clinical use of nitrates for treating hypertensive patients in the long term is limited by their short duration of action; the tolerance event tachyphylaxia ; and Their side- effects , such as headache. -To overcome the occurrence of tolerance(which develops because of the biotransformation of organic nitrates to an active form) , research focuses on drugs that directly release nitric oxide— eg , Nitrosyl-cobinamide (presently in preclinical stage) - nitric oxide-releasing pharmacodynamic hybrids of losartan28 and telmisartan -non- peptidic renin inhibitors nitroderivatives ; and - Naproxcinod , a cyclooxygenaseinhibiting donator of nitric oxide, which is being developed ( NicOx ) to treat patients with hypertension and arthritis,30 in phase trials.

15. 5.Guanylate cyclase stimulators: • Riociguat has a dual mechanism of action: a)To stimulate sGC in an NOdependent and independent mode of action and thereby to enhance cGMP synthesis, producing vasodilatation. b) Riociguat improved pulmonary hemodynamics and prevented adverse structural remodeling . 6.Prostacyclin receptor agonists: • Epoprostenol : Administered Intravenously. It was first prostacyclin analog approved by the US FDA to treat hypertension.It has rapid onset of action with very short half life. • Treprostinil : Administered Subcutaneously.It is a prostacyclin analog with a longer half life. • Iloprost : It is a synthetic prostanoid.Administered by Inhalation through an adaptive aerosol device. • Beraprost : Orally active prostanoids , not FDA approved, but currently used in Japan. It has been shown to improve symptoms of hypertension.

16. • Selexipag : It is a first-in-class orally active prodrug . It’s metabolized to the highly selective prostacyclin receptor agonist, which has a half-life of over six hours. Selexipag exerts vasodilatory activity on both large and small pulmonary arterial branches. These properties show greater vasodilatory activity than with beraprost and iloprost . 7.Tyrosine kinases (TKs) inhibitors: Tyrosine kinase inhibitors are therapeutic effects due to inhibition of cell growth related kinases and attenuate vascular remodeling . • Concentration-dependently and completely reversed the contraction of hypertensive pulmonary arterial due to inhibition of nitric oxide synthase . • Tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their longterm beneficial effect against pulmonary hypertension.

17. • Imatinib : - Imatinib reversed serotonin-induced contractions. - Imatinib inhibited activation of myosin phosphatase which is produced by phosphorylation of myosin light chain phosphatase (Ca2+ desensitization). Acute intravenous administration of imatinib reduced high right ventricular systolic pressure, with little effect on left ventricular systolic pressure and cardiac output. • Sorafenib : - Sorafenib is a multi- kinase inhibitor . It relaxed the induced contraction with a wider spectrum of TK activity than imatinib and shown to attenuate pulmonary vascular remodeling and hemodynamic changes. • Nilotinib : -The second-generation RTK inhibitor. GENE THERAPY FOR HYPERTENSION Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Goal of gene therapy in hypertension • Gene therapy aimed at nullifying the renninAngiotensin system is a speculation, through not in conceivable, approach to the semi-permanent or permanent treatment of hypertension. • In this regard, two approaches have been suggested: A mutant angiotensinogen gene strategy and b) An antisense strategy.

18. 1.Gene Therapy using Adenovirus: • A recombinant adenovirus vector has been used to incorporate the p21 gene, which regulates cell cycle progression of Pulmonary hypertension. • The p21 adenovirus vector was successfully transfected into the tissue and the over expression of p21 inhibited the development of PAH.

19. 2.Gene Therapy using Adeno -Associated Viral • An adeno -associated viral (AAV) vector used to transfect human PGIS to determine the effect on PAH. • The AAV-PGIS was injected and significant pulmonary hypertension was observed that a smaller increase in RV systolic pressures, upregulation of brain natriuretic peptide levels in the RV. • Decrease in pulmonary arterial wall thickening and prolonged survival.

20. 3.Nonviral Gene Therapy • Nonviral approaches have been developed for gene transfer. • Naked gene-transfer of PGIS • Polyplex nanomicelles -used to deliver a therapeutic plasmid with the gene for human adrenomedullin , a vasodilator peptide. • Biocompatible micelle nanovectorsused for gene transfer.