ANTIHYPERTENSIVE DRUGS. BP= CO x PR

BP= CO x PR,Cardiac output,
Peripheral Resistance,Baroreflexes ,vasoactive substances

1. ANTIHYPERTENSIVE DRUGS Mrs.Sandhya Sujeetkumar Ahire Pharmaceutical Chemistry

2. HYPERTENSION Most common CVS condition. Persistent and sustained increased BP has damaging effect on heart, brain, kidney, eye. Research studies indicate that the risk of damage to kidney, heart and brain are directly related to the extent of blood pressure elevation.

3. Hypertension is considered to be present when systolic blood pressure exceeds 140 mm Hg and diastolic value lies above 90 mm Hg. Normal Regulation of Blood Pressure BP = CO x PR (Cardiac output x Peripheral Resistance ) Most drugs control BP by reducing CO & PR

4. According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR) BP = CO × PVR

5. Classification of hypertension on the basis of blood pressure

6. Blood pressure is maintained by Mom e n t - t o - m o me n t r egul a tion of c a r d i ac o ut p ut and pe r i p he r al v ascular r esi s t ance e x er t ed a t th r ee anatomic sites arterioles, postcapillary ( capacitance vessels), and heart. Kidney controlling sodium and water balance, thus maintaining extracellular fluid volume (ECFV) Baroreflexes mediated by autonomic nerves ( c omb i n a ti o n wi t h hum o r al mechani s m s , inc l ud i ng the renin-angiotensin-aldosterone system) Local release of vasoactive substances

7. Sites of action of the major classes of antihypertensive drugs

8. CLASSIFICATION DRUGS ACTING ON SYMPATHETIC SYSTEM : Centrally acting- methyldopa Catacholamines depletors-reserpine Adrenergic blockers- Β adrenergic blockers- timolol α - adrenergic blocker – prazoin Mixed alpha – beta blockers- labetalol Imidazoline receptor agonist- moxonidine Adrenergic neuron blocker- guanethidine

9. e) Ganglion blockers Quaternary ammonium compounds- hexamethonium bromide Secondary amine- mecamylamine hcl Tertiary amine - trimethphan 2. CALCIUM CHANNEL BLOKERS – VERAPAMIL

10. 3. DRUGS ACTING ON ANGIOTENSIN SYSTEM- Drugs which block renin release- propranolol Inhibite angiotensin II – saralasin Drug which inhibite angiotensin II – losartan Drug which inhibit aldosterone- spironolactone ACE inhibitors- captopril

11. 4. VASODILATORS – SODIUM NITROPRUSSIDE 5. MISCELLANEOUS DRUGS – MAO inhibitors – metyrosine Newer drugs - tadalfil

12. DRUGS ACTING ON SYMPATHETIC SYSTEM Antiadrenergic are drugs capable of lowering transmitter output from sympathetic neurons i.e. the sympathetic tone. Their action is hypotensive and are poorly tolerated and have limited therapeutic use.

13. METHYLDOPA MOA It is an α 2 agonist that is converted to alpha methyl norepinephrine formed in the brain from methyldopa which causes the suppression of vasomotor centre neurons of the medulla and reduction of hypothalamus activity. Thus, there is decline in sympathetic impulses to the vessels and the heart which moderately reduced cardiac output and heart rate and finally reduced arterial pressure.

14. USES It is mainly used for management of hypertension in pregnancy, where it has a record of safety . IUPAC- (R)-2-amino-3- (3,4-dihydroxyphenyl)-2-methylpropanoic acid

15. Synthesis of mehyldopa

16. CLONIDINE MOA- Α lpha 2 agonist having lipophilicity due to dichlorophenyl ring permits rapid penetration through the blood brain barrier. The activation of postsynaptic alpha 2 receptors dampens the activity of vasomotor neurons in the medulla oblongata , resulting in a resetting of systemic arterial pressure at a lower level.

17. USES Treatment of mild to severe hypertension anaphylaxis of migraine headache. IUPAC- (2,6-dichlorophenyl)-N-(imidazolidin-2-ylidene) benzenamine.

18. GUANABENZ MOA it is centrally acting alpha 2- adrenergic receptor agonist.which result in decreased sympathetic outflow to the heart, kidney,peripheral vasculature in addition to a decreased systolic and diastolic blood pressure and a slight slowing of pulse rate. Orally active USES Antihypertensive drug 2-[( E )-(2,6-dichlorophenyl)methylideneamino]guanidine

19. GUANETHIDINE MONOPHOSPHATE These drug lower blood pressure by preventing normal physiologic release of nor-epinephrine from postganglionic sympathetic neurons. MOA Act by selectively inhibiting transmitter in post ganglionic nerves. It mainly blocks the release of nor-adrenaline a the nerve endings, besides causing depletion of nor-adrenaline. USES Treatment of moderate, mild, serve hypertension . 1-(2-(azacan-1-yl)ethyl)guanidine

20. RESERPINE- MOA- Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines,probably by interfering with the vesicular membrane associated transporter. USES- Hypertension, stroke, heart attack, kidney problems. methyl (1 R ,15 S ,17 R ,18 R ,19 S ,20 S )-6,18-dimethoxy-17-(3,4,5-trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate

21. 2.CALCIUM CHANNEL BLOCKERS VERMAPIL MOA- Verapamil inhibits entry of calcium ions into arterial smooth muscle as well as the myocytes and conducting tissues . These actions lead to reversal and preventions of coronary artery spasm , reduction in afterload through peripheral vasodilatation and reduction in ventricular rate in patients with chronic atrial flutter or fibrillation and reduction in the occurrence of paroxysmal supraventricular tachycardia. Verapamil reduces BP, relieves angina and slows AV conduction.

22. USES- Angina pectoris Arrhythmias from ischemic myocardial syndromes and supraventricular arrhythmias. 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile 1 5 1 2

23. 3.DRUG ACTING ON ANGIOTENSIS SYSTEM Renin inhibitors A selective renin inhibitor, directly inhibits renin and, thus, acts earlier in the renin–angiotensin–aldosterone system than ACE inhibitors or ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides.

24. ( CH2)n [ Zn+2 binding groups] O N-ring Zn binding groups may be sulfhydryl, carboxylic acid or phosphinic acid N ring must contain carboxylic acid X Usually methyl group ACE INHIBITORS

25. SAR The N - ring must contain a carboxylic ac id to minic the C- terminal carboxylate of ACE substrates. Large hydrophobic heterocyclic rings(i.e the N-ring ) increase potency and alter pharmacokinetic parameters. The zinc binding groups can be either sulfhydryl (A), a carboxylic acid (B) or a phosphoric acid (C). The sulfhydryl groups shows superior binding to zinc ( the side chain mimicking Phe in carboxylate and phosphinic acid compounds compensates for the lack of a sulfhydryl groups)

26. 5. sulfhydryl containing compound produces high incidence of skin rash and taste disturbances. 6. Sulfhydryl containing compounds can form dimmers and disulfides which may shorten duration of action . 7. Compounds which bind to zinc through either a carboxylate or phosphinate mimic the peptide hydrolysis transition state. 8 . Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrug.

27. 9. X is usually methyl to mimic the side chain of alanine.within the dicarboxylate series when X equals n – butylamine ( lysin side chain ) this produces a compound which does not require prodrug for oral activity. 10. Optimum activity occurs when stereochemistry of inhibitor is consistent with L-amino acid stereochemistry present in normal substrates .

28. CAPTOPRIL MOA- Is an angiotensin converting enzyme inhibitor.it blocks the conversion of angiotensin-I to angiotensin-II , a vasoconstrictor and important regulator of arterial blood pressure. captopril acts to suppress the renin-angiotensin system and inhibit pressure responses to exogeneous angiotensin. USES Used in combination with other drugs in the management of hypertension ,in heart failure,myocardial infraction, diabetic nephropathy. (2 R )-1-[(2 S )-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid 1 1 2 3

29. LISINOPRIL MOA It is potent competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin-I to angiotensin-II , a vasoconstrictor and important regulator of arterial blood pressure and is a key component of the renin-angiotensin-aldosterone system. USES High blood pressure Congestive heart failure Acute myocardial infraction

30. ENALAPRIL MOA- It is a prodrug and belongs to ACE inhibitors.It is rapidly metabolized in the liver to enalaprilat following oral administration. It is potent competitive inhibitor of ACE the enzyme responsible for the conversion of angiotensin–I to angiotensin –II. Angiotensin –II regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system. USES- Hypertension, symptomatic ,congestive heart failure and asymptomatic left ventricular dysfunction.

31. BENZAEPRIL HCL MOA Upon clevage of its ester gr by the liver, benzepril is converted into its active form benzaprilat a non-sulfydryl angiotensin-converting enzyme inhibitors. USES Hypertension, congestive heart failure and chronic renal failure. 2-[(3 S )-3-[[(2 S )-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3 H -1-benzazepin-1-yl]acetic acid 1 2 3 4 1

32. QUINAPRIL HCL MOA It is prodrug and belongs to ACE inhibitors it is metabolized to quinaprilat. It is competitive inhibitor administration . It is potent competitive inhibitor of ACE the enzyme responsible for the conversion of angiotensin–I to angiotensin–II . Angiotensin –II regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system USES hypertension, congestive heart failure.

33. 3S)-2-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino} propanoyl ]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride 1 2 3 4 1 2 3 1 2 3

34. 4.VASODILATORS SODIUM NITROPRUSSIDE MOA It activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP , Which stimulate calcium movement from the cytoplasm to the endoplasmic reticulum and reduces calcium available to bind with calmodulin. This leads to vascular s.M.Relaxation and vessel dilation USES Short acting hypertensive drug. Vasodilators disodium;iron(4+);nitroxyl anion;pentacyanide;dihydrate

35. DIAZOXIDE MOA Potent vasodilators. USES Hypotensive drug in acute hypertensive crisis and as anti hyperglycemic agents. 7-chloro-3-methyl-4 H -1 λ 6 ,2,4- benzothiadiazine 1,1-dioxide 1 2 3 4 5 6 7 8

36. MINOXIDIL MOA It is piperidino pyrimidine derivative, it directly relaxes arteriolar smooth muscles.it is mainly beneficial for the patients with severe hypertension who don’t respond to drugs. USES moderate to severe hypertension. 6-piperidin-1-ylpyrimidine-2,4-diamine 3-oxide 1 6 2 3 4 5

37. HYDRALAZINE HCL MOA It is hydrazine derivative and dilates arterioles but not veins.the combination of hydralazine and nitrates is effective in heart failure. USES Severe hypertension and heart failure. phthalazin-1-ylhydrazine

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