Anti-hypertensives drugs presentation.pptx

Anti hypertensive drugs and moa

1. DRUGS USED IN HYPERTENSION A. Q. Sangalang, MD, FPOGS PRESENTED BY RAWAS LAKHAN SUNIL FYM Pharm 4/6/2021

2. Introduction Blood pressure is the force exerted by the blood against the walls of the blood vessels. The pressure depends on the work being done by the heart and the resistance of the blood vessels. Lifestyle factors are the best way to address high blood pressure. It can lead to severe health complications and increase the risk of heart disease, stroke, and sometimes death. CAUSES kidney disease. diabetes. long-term kidney infections. narrowing of the arteries supplying the kidneys.

3. Types of Hypertension Essential Secondary A disorder of unknown origin affecting the Blood Pressure regulating mechanisms Secondary to other disease processes Environmental Factors Stress Na+ Intake Obesity Smoking

4. 4/6/2021 ACE INHIBITORS Captopril,enalapril,lisinopril . ANGIOTENSIN INHIBITORS Losartan, candesartan CALCIUM CHANNEL BLOCKERS diltiazam, amlodipine, verapamil 4. ß - ADRENERGIC BLOCKERS Propranolol,metaprolol,atenolol. α + ß ADRENERGIC BLOCKERS Labetalol,carvedilol. 6. α - ADRENERGIC BLOCKERS prazosin.,terazosin,phentolamine 7. CENTRAL SYMPATHOLYTICS Clonidine,methyldopa 8. VASODILATORS Hydrazaline , minoxidil . ANTIHYPERTENSIVE DRUGS

5. Angiotensin-converting enzyme (ACE) inhibitors help to relax blood vessels. ACE inhibitors prevent an enzyme in the body from producing angiotensin II, which narrows blood vessels and releases hormones that can raise blood pressure. This narrowing can cause high blood pressure and force the heart to work harder. Types:- Class I : C aptopril Class II (prodrug) : e.g., ramipril, enalapril, perindopril Class III ( water soluble) : lisinopril. ACE inhibitors

6. Reduction of cardiovascular morbidity and mortality in patients with atherosclerotic vascular disease, diabetes, and heart failure. Improvement in glucose tolerance and insulin resistance. Renal glomerular protection effect especially in diabetes mellitus. Do not adversely affect quality of life. Advantages Side effects Cough (10 - 30%) Skin rash (6%). Postural hypotension Renal failure Hyperkaliemia

7. CAPTOPROL 4/6/2021 IUPAC : 1-[(2 S )-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid MECH. OF ACTION : Captopril blocks the conversion of  angiotensin  I to angiotensin II and prevents the degradation of vasodilatory  prostaglandins , thereby inhibiting  vasoconstriction  and promoting systemic  vasodilation .

8. SYNTHESIS 4/6/2021 A chemical synthesis of captopril is done by treatment of L-proline with (2S)-3-acetylthio-2-methylpropanoyl chloride under basic conditions (NAOH) group followed by aminolysis of the protective acetyl group to unmask the drug's free thiol. captopril

9. ENALPRIL IUPAC : (2 S )-1-[(2 S )-2-[[(2 S )-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]pyrrolidine-2-carboxylic acid 4/6/2021 MECH. OF ACTION: Normally,  angiotensin I  is converted to  angiotensin II  by ACE . Angiotensin II constricts blood vessels, increasing blood pressure. the active metabolite of enalapril, inhibits ACE. Inhibition of ACE decreases levels of angiotensin II, leading to less vasoconstriction and decreased blood pressure.

10. SYNTHESIS Enalapril, is synthesized by reacting the  benzyl ester  of l-alanyl-l-proline with the  ethyl ester  of 3-benzoylacrylic acid, which forms the intermediate product which on reduction with hydrogen using a  Raney nickel  catalyst removes the protective  benzyl group , giving the desired  enalapril . 4/6/2021

11. LISINOPRIL IUPAC : (2 S )-1-[(2 S )-6-amino-2-[[(1 S )-1-carboxy-3-phenylpropyl]amino] hexanoyl]pyrrolidine-2-carboxylic acid 4/6/2021 MECH. OF ACTION : Lisinopril prevents the conversion of angiotensin I to angiotensin ll .   Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I. Lisinopril

12. Synthesis 4/6/2021

13. ANGIOTENSIN INHIBITORS Block activation of angiotensin II AT1 receptors Effects include: Vasodilation Reduced secretion of vasopressin Reduced production and secretion of aldosterone Reduction in blood pressure Side effect : Dizziness Headache Hyperkalemia Diarrohea dyspepsia Advantages : Similar metabolic profile to that of ACE-I. Renal protection. They do not produce cough.

14. Bradykinin Inactive peptides Non ACE Pathway Chymase Trypsin Cathepsin, Peptidase, Tonin ACE Increased AG II levels No cough MOA of ARB Angiotensin I AT 1 AT 2 Vasoconstriction Renal sodium reabsorption Cell growth and proliferation (remodelling) Vasodilation Natriuresis Antiproliferation Angiotensinogen Renin Angiotensin II (AT II) Telmisartan ACE

15. LOSARTAN IUPAC : (2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol 4/6/2021 MECH. OF ACTION : losartan blocks the angiotensin receptor. By blocking the  action  of angiotensin,  losartan  relaxes muscle cells and dilates blood vessels thereby reducing blood pressure. Losartan

16. SYNTHESIS 4/6/2021

17. CONDENSARTAN 4/6/2021 IUPAC : 2-ethoxy-1-({4-[2-(2 H -1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1 H -1,3-benzodiazole-7-carboxylic acid MECH. OF ACTION : Candesartan  blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues . Condensartan

18. SYNTHESIS 4/6/2021

19. CALCIUM CHANNEL BLOCKERS They Inhibit influx of Ca 2+ across cardiac & smooth muscle cell membranes . Can be divide in to 4 types : Type 1 Effect on Cardiac and Vascular ( Verapamil, Diltiazem) Type 2 Effect on Vascular predominant ( Dihydropyridine) Type 3 Effect on Vascular selective ( Cinnarizine, Flunarizine) Type 4 Effect on pharmacology complex ( Bepridil, Perhexiline ) 4/6/2021

20. Calcium Channel Blockers - Classification

21. VERAPAMIL IUPAC : 2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile 4/6/2021 MECH. OF ACTION : Verapamil  inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. Verapamil

22. SYNTHESIS 4/6/2021

23. DILTIZAM IUPAC : [2-(2-Dimethylaminoethyl)-5-(4-methoxyphenyl)-3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9,11-trien-4-yl]ethanoate 4/6/2021 MEC. OF ACTION : diltiazam  inhibits the inflow of calcium ions into the cardiac smooth muscle during depolarization. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and, therefore, decreased blood pressure Diltiazam

24. SYNTHESIS 4/6/2021

25. AMLODIPINE IUPAC : 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate 4/6/2021 MECH OF ACTION : Amlodipine  is an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells which inhibits the contraction of cardiac muscle and vascular smooth muscle cells. amlodipine

26. SYNTHESIS 4/6/2021

27. ß - ADRENERGIC BLOCKERS Also called beta-adrenergic blocking agents, treat a variety of conditions, such as high blood pressure and migraines.  Work by blocking the effects of the hormone epinephrine , also known as adrenaline. When you take beta-blockers, your heart beats more slowly and with less force, thereby reducing blood pressure. Beta blockers also help blood vessels open up to improve blood flow.

28. Doctors prescribe beta-blockers to prevent, treat or improve symptoms in a variety of conditions, such as: High blood pressure Irregular heart rhythm (arrhythmia) Heart failure Chest pain (angina) Heart attacks Migraine

29. Side effects may occur in people taking beta blockers. However, many people who take beta-blockers won't have any side effects. Common side effects of beta blockers include: Fatigue Cold hands or feet Weight gain Less common side effects include: Shortness of breath Trouble sleeping Depression

30. PROPANOLOL 1-Propanol  is a  primary alcohol  with the formula CH3CH2CH2OH and sometimes  represented  as  PrOH  or  n -PrOH . It is a colorless liquid and an  isomer  of  2-propanol . IUPAC : Propan-1-ol MECH. OF ACTION : Propranolol  is a non-selective beta receptor antagonist. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart.

31. SYNTHESIS 4/6/2021 It is synthesized by reacting  1-naphthol  with  epichlorohydrin . Opening of the  epoxide  ring gives 1-chloro-3-(1-naphthyloxy)-2-propanol, which is reacted further with  iso -propylamine, giving  propranolol  

32. METOPROLOL 4/6/2021 IUPAC : 1-[4-(2-Methoxyethyl)phenoxy]-3-[(propan-2-yl)amino]propan-2-ol MECH OF ACTION : Metoprolol blocks  β1 adrenergic receptors  in  heart muscle cells , thereby decreasing the slope of phase 4 in the nodal action potential (reducing Na +  uptake) and prolonging repolarization of phase 3 (slowing down K +  release)

33. SYNTHESIS 4/6/2021 i.   Reaction of 4-(2-methoxyethyl)phenol and epichlorohydrin in aqueous alkaline condition produces epoxide. ii. It is distilled under high vacuum for purification. iii. Epoxide is then treated with isopropylamine in isopropyl alcohol at reflux to yield metoprolol.

34. 4/6/2021 Metaprolol synthesis

35. ATENELOL IUPAC : 2-{4-[2-Hydroxy-3-(propan-2-ylamino)propoxy]phenyl}acetamide 4/6/2021 MECH OF ACTION : Atenolol  belongs to a class of drugs known as beta blockers. It works by blocking the  action  of certain natural chemicals in your body, such as epinephrine, on the heart and blood vessels. This  effect  lowers the heart rate, blood pressure, and strain on the heart.

36. LABETALOL Labetalol  is a beta-blocker that affects the heart and circulation (blood flow through arteries and veins).  Labetalol  is used to treat hypertension (high blood pressure).  IUPAC : 2-Hydroxy-5-[1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl]benzamide  MECH OF ACTION :Labetalol decreases blood pressure by decreasing  systemic vascular resistance  with little effect on  stroke volume , heart rate and cardiac output. During long-term use, labetalol can reduce heart rate during exercise while maintaining  cardiac output  by an increase in  stroke volume . Labetalol α + ß ADRENERGIC BLOCKERS

37. SYNTHESIS It is synthesized by the  N -alkylation of  N -benzyl- N (4-phenyl-2-butyl)amine 5-bromacetylsalicylamide and forming  aminoketone  , which is further debenzylated by hydrogen using a palladium–platinum on carbon catalyst into  labetalol . 4/6/2021

38. CARVEDILOL IUPAC : [3-(9 H -carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine 4/6/2021 MECH OF ACTION : Carvedilol is both a non-selective  beta adrenergic receptor blocker  ( β1, β2) and an  alpha adrenergic receptor blocker  ( α1) . Carvedilol reversibly binds to beta adrenergic receptors on cardiac myocytes. Inhibition of these receptors prevents a response to the  sympathetic nervous system , leading to decreased heart rate and contractility . Carvedilol

39. SYNTHESIS 4/6/2021

40. Also called alpha-adrenergic antagonists, treat conditions such as high blood pressure and benign prostatic hyperplasia. Alpha blockers relax certain muscles and help small blood vessels remain open . They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure. These medications can help improve urine flow in older men with prostate problems. α - ADRENERGIC BLOCKERS

41. Headache Pounding heartbeat Weakness Dizziness Weight gain On the positive side, alpha blockers might decrease low-density lipoprotein (LDL) cholesterol (the "bad" cholesterol). 4/6/2021 SIDE EFFECTS :

42. 4/6/2021

43. PRAZOSIN IUPAC : [4-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-1-piperazinyl](2-furyl)methanone. 4/6/2021 MECH OF ACTION : Prazosin is an  α 1 -blocker  that acts as an  inverse agonist  at  alpha-1 adrenergic receptors , including α1A-, α1B-, and α1D-receptor subtypes. [16]  These receptors are found on  vascular smooth muscle , where they are responsible for the  vasoconstrictive  action of  norepinephrine . Prazosin

44. SYNTHESIS i. 2-amino-4,5-dimethoxybenzoic acid reacts with sodium cyanate to give 6,7-dimethoxyquinazoline-2,4-diol. ii. Later compound undergoes chlorination to give 2,4-dichloro-6,7-dimethoxyquinazoline. iii. It than reacts with ammonia to produce 2-chloro-6,7-dimethoxyquinazolin-4-amine. iv. Latter compound reacts with (furan-3-l)(piperazin-1-yl) methanone to give prazosin. 4/6/2021

45. PRAZOSIN SYNTHESIS 4/6/2021

46. TERAZOSIN 4/6/2021 IUPAC : 6,7-Dimethoxy-2-[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]quinazolin-4-amine MECH OF ACTION : Terazosin  is a quinazoline derivative alpha-1-selective adrenergic blocking agent indicated for benign prostatic hyperplasia and hypertension.  Terazosin  blocks adrenaline's  action  on alpha-1 adrenergic receptors, causing relaxation of smooth muscle in blood vessels and the prostate  Terazosin

47. SYNTHESIS 4/6/2021 Reaction of  piperazine  with  2-furoyl chloride  followed by  catalytic hydrogenation  of the  furan  ring leads to an intermediate. This, when heated in the presence of 2-chloro-6,7-dimethoxyquinazolin-4-amine ( 1 ) undergoes direct alkylation to terazosin .

48. PHENTOLAMINE 4/6/2021 IUPAC : 3-[(4,5-Dihydro-1 H -imidazol-2-ylmethyl)(4-methylphenyl)amino]phenol MECH OF ACTION : Phentolamine  produces its therapeutic  actions  by competitively blocking alpha-adrenergic receptors (primarily excitatory responses of smooth muscle and exocrine glands), leading to a muscle relaxation and a widening of the blood vessels. This widening of the blood vessels results in a lowering of blood pressure. Phentolamine

49. SYNTHESIS 4/6/2021 m-(p-toluidino)phenol is refluxed with 2-chloromethylimidazoline to give phentolamine.

50. SYMPATHOLYTICS Sympatholytic drugs : Drugs that inhibit nerve impulses in the sympathetic nervous system. They may block the effect of alpha-adrenergic receptors which is used to reverse pupillary blockage or the effect of beta adrenergic receptors called beta-blockers which block beta 1 and beta 2 receptors) Beta-blockers are used in the treatment of glaucoma. TYPES Alpha 1-receptor blockers : prazocin, doxazocin. Centrally acting alpha 2- agonists: methyldopa, clonidine. Peripherally acting adrenergic antagonists: reserpine. Imidazoline receptor agonists: rilmenidine, moxonidine. 4/6/2021

51. CLONIDINE IUPAC : N -(2,6-Dichlorophenyl)-4,5--1 H -imidazol-2-amine 4/6/2021 MODE OF ACTION Clonidine  stimulates alpha-adrenoceptors in the brain stem. This  action  results in reduced sympathetic outflow from the central nervous system and decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Clonidine

52. SYNTHESIS Clonidine, 2-(2,6-dichlorophenylamino)imidazoline, is synthesized from 2,6-dichloroaniline, the reaction of which with  ammonium thiocyanate  gives N-(2,6- dichlorophenyl)thiourea.  Methylation  of this product, followed by the subsequent reaction with  ethylene diamine  gives clonidine. 4/6/2021

53. METHLDOPA IUPAC :2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid 4/6/2021 MECH OF ACTION :The mechanism of action of methyldopa is not fully clear. Although it is a  centrally acting   sympathomimetic , it does not block reuptake or transporters. It may reduce the  dopaminergic  and  serotonergic  transmission in the  peripheral nervous system  and it indirectly affects  norepinephrine  (noradrenaline) synthesis. Methlyldopa

54. SYNTHESIS 4/6/2021 i. 4-hydroxy-3-methoxy phenylacetone is taken as starting material. ii. It undergoes reaction with ammonium chloride followed by reaction with potassium cyanide to α- amino nitrile compound. iii. L-isomer is separated out by rection with camphosulfonic acid. iv. On reating with sulfuric acid, we get methyldopa as final product.

55. VASODILATORS Diuretics are used effectively in the management of hypertension, and are typically prescribed because of their efficacy, low cost, and low side effects profile. Diuretics are known for their ability to increase the formation and excretion of urine. The increase in excretion allows for more water and sodium to be removed, and ultimately affects the vascular system by leading to a decrease in fluid volume.  The decrease in fluid volume affects blood pressure directly, which is why they are effective in reducing high blood pressure. 4/6/2021

56. MOA Thiazides freely filtered and secreted in proximal tubule Bind to the electroneutral NaCl cotransporter Thiazides impair Na + and Cl - reabsorption in the early distal tubule: “low ceiling” SIDE EFFECTS : Dizziness . Headaches . Dehydration . Muscle cramps . Joint disorders (gout)

57. HYDRALAZINE Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflex  sympathetic  stimulation of the heart . IUPAC : 1-hydrazinylphthalazine MODE OF ACTION : It is a direct-acting  smooth muscle  relaxant and acts as a  vasodilator  primarily in  resistance arterioles vasodilators act to decrease  peripheral resistance , thereby lowering  blood pressure  and decreasing afterload. Hydralazine

58. 4/6/2021

59. MINOXIDIL SODIUM IUPAC : 3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine 4/6/2021 MODE OF ACTION : Minoxidil stimulates  prostaglandin E 2  production by activating  COX-1 and prostaglandin endoperoxide synthase-1 but inhibites  prostacyclin  production. Additionally, expression of the  prostaglandin  E 2  receptor, the most upregulated target gene in the  β-catenin  pathway of DP cells, was enhanced by minoxidil, which may enable hair follicles to grow continuously and maintain the anagen phase.

60. SYNTHESIS 4/6/2021

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