Anti hypertensive drugs

General introduction about hypertension and structure activity relationship of Different types of antihypertensive drugs, and related questions that were asked in exams.

detailed SAR and mode of action of ACE inhibitors

1. Anti-hypertensive Drugs Subject - Medicinal Chemistry-II Subject Code - BP-501T Himanshu Joshi Enrollment no. – 17PHM3PHM1030 B.R.Nahata College of Pharmacy, Mandsaur University, Mandsaur , MadhyaPradesh [email protected]

2.  Overview  What’s Hypertension – Introduction, Causes, Types. Antihypertensive drugs – Introduction, Classification. ACE Inhibitors – MOA, Classification, SAR. AT-II Antagonist – SAR, MOA. 4. Adrenoceptor Blocking Agents - α - Adrenergic Blockers β - adrenoceptor Blockers α + β – adrenoceptor Blockers Adrenergic Neuron Blockers Centrally Acting Agents Vasodilators Related Questions?????

3. What’s Hypertension (HTN or HT) ? It’s also known as High Blood pressure (HBP). It’s a condition in which the force of the blood against the artery walls is too high or elevated. HBP doesn’t cause symptoms, but long term HBP however, is found to be major risk factor for coronary heart disease, stroke, heart failure, atrial fibrilation , vision loss, chronic kidney diseases and dementia. Environmental Factors Stress Na+ Intake Obesity Smoking CAUSES OF HYPERTENSION

4. The systolic reading of 130 mmHg refers to the pressure as the heart pumps blood around the body. The diastolic reading of 80 mmHg refers to the pressure as the heart relaxes and refills with blood. The AHA (American Heart Association) 2017 guidelines define the following ranges of blood pressure: Systolic (mmHg) Diastolic (mmHg) Normal blood pressure Less than 120 Less than 80 Elevated Between 120 and 129 Less than 80 Stage 1 hypertension Between 130 and 139 Between 80 and 89 Stage 2 hypertension At least 140 At least 90 Hypertensive crisis Over 180 Over 120

5. Antihypertensive Drugs These agents are used to treat hypertension (HBP). Antihypertensive medication seeks to prevent the complications of HBP, such as stroke and myocardial infarction.

6. Classification of Antihypertensive Drugs Trick:-DAAV-5HT A. Diuretics 1. Potassium Sparing Diuretics – Sprinolactone , T riamterene 2. Thiazide – Chlorothiazide , Hydrochlorothiazide 3. Loop Diuretics – Furosemide B . Agent Acting of Renin-Angiotensin System (RAS) 1. ACE inhibitor – Fossinopril , Captopril , Enalapril 2. Angiotensin Antagonist – Valsartan , Losartan

7. C . Adrenoceptor Blocking Agents 1. α – Adrenergic Blockers – Terazosin , Tolazoline , Prazosin , Phenotolamine 2. β – Adrenergic Blockers – Propanolol , Atenolol , Metoprolol 3. α + β Adrenergic Blockers – Labetalol , Carvedilol 4. Centrally Acting Agents – Methyldopa, Clonidine , Guanfacine , Guanabenz 5. Ganglionic Blocking Agents – Pentolinium , Trimethphan 6. Agents Acting on Adrenergic Neuron Blockers – reserpine , Guanethidine

8. D. Vasodilator a. Directly Acting Vasodilator i ) Potassium Channel agonist – Minoxidil , Diazoxide ii) Arterial Dilators – Hydralazine , Dihydralazine b. Calcium Channel Blockers – Diltiazem , Amlodipine , Nifedipine , Verapamil E. 5-HT (Serotonin) Antagonist - Ketanserine

9. ACE Inhibitors These drug primarily used for treatment of hypertension & Congestive Heart Failure. These agents cause relaxation of blood vessels and also decrease blood volume which leads to low B.P. It also decrease the oxygen demand from the heart.

10. Mode of Action AT-II ( Angiotensin -II) is dominant hormone and having essential role in regulation of fluid, electrolyte balance, blood pressure and blood volume.

11. Mode of Action In body the RAS Renin-Angiotensin System get activated by following factors :- lowering in NA + ion level concentration in body. Lower blood volume. Lower renal pressure. ACE inhibitors directly blocks the formation of AT-II by inhibiting the ACE ( Angiotensin Converting Enzyme).

12. Mode of Action At same time it increases the bradykinin level which reduce the vasoconstriction, reduced NA + and H 2 O reabsorption . Increases the vasodilation and low the B.P. And Blood Volume.

13. Mode of Action Angiotensinogen (Plasma α 2 – globulin) From liver Angiotensin I Angiotensin II VASCONSTRICTION Increased Aldosterone secretion Increased Peripehral Vascular Resistance Increased Na + & H 2 O retention Increased BLOOD PRESSURE Renin (From Kidney) ACE Kininogen Bradykinin Kallikerin Inactive kinin VASODILATION Decreased Peripehral Vascular Resistance Decreased BLOOD PRESSURE ACE INHIBITORs Increase the level of Inhibits

14. Classification of ACE inhibitors on the basis Chemical molecule

15. Structure Activity Relationship (SAR) Substitution on N-ring The N-ring must contain a carboxylic acid to mimic like the C-terminal of ACE substrates. Large hydrophobic heterocyclic rings in the N-ring increase the potency and alter the pharmacokinetics parameters. 2. Substitution on X If X is substituted by methyl group CH 3 to mimic like the side chain of alanine with decarboxylate series. If X is substituted by n-butyl amine it becomes orally active drugs.

16. 3. Substitution on Zn 2+ binding site Compound A, B and C serves as a Zn 2+ binding group. Compound (A) Sulfhydryl group Shows superior binding to Zn 2+ binding site. Sulfhydryl containing drugs produce skin rash and taste disturbances in majority of cases. Sulfhydryl containing compounds can form disulfides, which may shorten duration of action.

17. Dicarboxylate group containing drugs Drug R1 R2 R3 ENALAPRIL CH3 C2H5 ENALAPRILATE --”-- CH3 H LISINOPRIL --”-- (CH 2 ) 4 NH 2 H RANIPRIL CH3 C2H5 Quinapril CH3 C2H5

18. Angiotensin II Antagonist LOSARTAN VALSARTAN

19. SAR Acidic group 1) The " acidic group " is thought to mimic either Tyr phenol or the Asp, carboxylate of angiotensin II. Groups capable of such a role include the carboxylic acid (A ), a phenyl tetrazole (B ), or a phenyl carboxylate (C ). 2) In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho position for optimal activity.

20. SAR 3) The n-butyl group  provides hydrophobic binding and mimics the side chain of Ile of angiotensin II. E.g. candesartan and telmisartan , this n-butyl group can be replaced with a substituted benzimidazole ring. 4) The imidazole ring, or an isosteric equivalent, is required to mimic the His,, side chain of angiotensin II.

21. MOA AT 2 Blocker are competitive inhibitors of AT II, devoid partial antagonistic activity and 10,000 time more selective for AT1 receptor than AT2. Block action of AT II such as vasoconstriction.

22. α - Adrenergic Blockers Drug R Prazosin Terazosin SAR 1. All these drugs are similar in structure ( quinazoline ) . 2. Nature of acyl group has significant effect on pharmacokinetic properties. 3. 4 – amino group is essential for α 1 receptor affinity. 4. Piperazine is essential but it can be replaced with piperdine moiety without loss of activity.

23. MOA They used in treatment of hypertension. They produce their effect by blocking post synaptic α 1 – receptor in blood vessels and cause vasodilation . Tolazoline and Phentolamine both are non-selective α- adrenergic antagonist. Both stimulate gastrointestinal smooth muscle and also increase gastric acid secretion.

24. β - adrenoceptor Blockers Drug Ar R Propanolol H Pindolol H Cardio Selective Beta Blockers Atenolol H Metoprolol H

25. SAR 1. The beta blocker have structural similarity with epinephrine. 2. The aryloxy propanol amine are more potent than aryl ethanolamine. 3. Replacement of ethereal oxygen with S, CH2, or NCH3 is reduction of beta blocking activity. 4. The most effective amine substituent is isopropyl and tertiary butyl. 5. Substitution of methylene carbon with alkyl group generally causes reduction of β blocking potency.

26. MOA It has effect on: - Decreases renin release Resetting of baroreceptors Reduced cardiac output Decreased PVR

27. α + β – adrenoceptor Blockers It combines with both non selective β and α antagonistic activity.

28. Adrenergic Neuron Blockers Guanethidine MOA Acts presynaptically to inhibit release of neurotransmitter from adrenergic neurons. The adrenergic blockade is due to: - Blockade of release & reuptake of NA. Depletion of NA stores at sympathetic nerves ending. Hypotensive effect is due to fall in cardiac output.

29. Reserpine Obtained from Raouwolfia serpentina [ Sarpdgandha ]. It blocks the transport of biogenic amine (NA, adrenaline & 5-HT) in synaptic vesicle from axoplasm in adrenergic nerve  this leads to depletion of NA & produce fall in BP.

30. Centrally Acting Agents These drugs interfere with release of NA. Methyl DOPA is an inhibitor od aromatic D amino acid decarboxylase and it is metabolised in CNS to Methylnephrine  produces antihypertnsive effect  by stimulating α - 2 adrenergic receptor in brain stem. Clonidine is an imidazoline derivative and stimualte α - 2 adrenergic receptor in vasomotor centre of brain  resulting in sympathetic outflow of peripheral vessel and block release of NA.

31. Vasodilators It cause vasodilation by stimulating guanylate cyclase in arteriolar smooth muscle. Stimulant appears to be nitric oxide from local oxidation of hydrazine moiety.

32. Minoxidil It dilates arterioles by opening potassium channels, which causes hyperpolarisation and relaxation of smooth muscles  this lowers PVR (Peripheral vascular resistence )  fall BP

33. Sodium Nitroprusside Causes vasodilation in both arteries & venous. It form an active nitrathiol with glutathione that increases cyclic GMP  Vasodilatation  decrease PVR  Low BP

34. Related Questions Write structural classification of antihypertensive drugs and explain MOA & SAR of ACE inhibitors? Write a short note on hypertension? Classify antihypertensive drugs and explain MOA & SAR of any one drug? Reference of Structural classification Textbook of Medicinal Chemistry by Malleshappa N Noolvi , Anurekha Jain, Harun M Patel, CBS Publisher & Distributors, Page no. 376-379

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