Diuretics and CVS.pptx

SAR of CVS and Diuretics

1. DIURETICS DR. MANJOOR AHAMAD SYED ,                             M .Pharm, Ph.D Associate. Professor  Department of Medicinal Chemistry,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

2. Diuretics Diuretics ("water pills") increase the kidneys' excretion of salt (sodium) and water, decreasing the volume of fluid in the bloodstream and the pressure in the arteries. Diuretics are the oldest and most studied antihypertensive agents. Diuretics (“water pills”) are the drugs which increase the urine output (or) urine volume. 2

3. Therapeutic approaches Diuretics are very effective in the treatment of conditions like: - chronic heart failure nephrotic syndrome chronic hepatic diseases hypertension Pregnancy associated oedema Cirrhosis of the liver. The primary action of most diuretics is the direct inhibition of Na+ reabsorption (increased excretion) at one or more of the four major sites along the nephron.

4. CLASSIFICATION OF DIURETICS I. SITE 1 DIURETICS: CARBONIC ANHYDRASE INHIBITORS Eg. Acetazolamide, Methazolamide, Dichlorphenamide, Chloraminophenamide. II. SITE 2 DIURETICS: LOOP DIURETICS (HIGH CEILING DIURETICS) Eg. Furosemide, Bumetanide and Ethacrynic acid  III. SITE 3 DIURETICS : THIAZIDES AND THIAZIDE LIKE DIURETICS Eg. Chlorothiazide, Hydrochlorothiazide, Benzthiazide, Hydroflumethiazide, Bendroflumethiazide. IV. SITE 4 DIURETICS: POTASSIUM SPARING DIURETICS a. Na+ Channel Inhibitors: Triamterene, Amiloride, b. Aldosterone Antagonists: Spironolactone   V. MISCELLANEOUS: Eg. Mannitol (Osmotic diuretics)

5. SITE 1 DIURETICS : CARBONIC ANHYDRASE INHIBITORS

6. MECHANISM OF CARBONIC ANHYDRASE INHIBITORS Wherever carbonic anhydrase enzyme is involved, it produces HCO 3 – and H + ions by showing its effect on H 2 CO 3 . The H + move out to replace with Na+ ions (NA+ reabsorption occur) to produce Oedema and Hypertension. The above process is prevented by Carbonic anhydrase Enzyme Inhibitors and it prevent reabsorption of Na+ to act as Diuretics.

7. ACETAZOLAMIDE SAR OF ACETAZOLAMIDE Presence of sulphonamide moiety necessary for diuretic activity NH 2 group of sulphonamide remain unsubstituted for its activity If methyl group on N position attachment to retain its activity Eg.Methazolamide USES: Used in the treatment of Drug-induced edema which is caused by CHF and petitmal epilepsy. is a "water pill" (diuretic) used to prevent and reduce the symptoms of altitude sickness. ADR: Drowsiness, Paraesthesia, atoxia , dizziness and thirst

8. Synthesis:

9. METHAZOLAMIDE USES: Methazolamide belongs to a class of drugs known as carbonic anhydrase inhibitors. This medication is used to treat high pressure inside the eye due to certain types of glaucoma. Lowering high pressure inside the eye helps to prevent blindness, vision loss, and nerve damage.

10. SITE 2 DIURETICS : LOOP DIURETICS (HIGH CEILING DIURETICS) Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle. They are very potent diuretics and induced a dramatic and copious flow of urine rich in NaCl hence they are called as High ceiling diuretics . The two prototypical drugs of this group are furosemide and ethacrynic acid

11. FURASAMIDE Adverse effects :  hypokalemia ,  hypomagnesemia,  hypocalcemia USES: Furosemide is a type of medicine called a  diuretic . It's used to treat  high blood pressure ,  heart failure  and oedema (a build up of fluid in the body). It's also sometimes used to help you pee when your kidneys aren't working properly. Diuretics are sometimes called " water  pills/tablets" because they make you pee more.

12. Structural Activity Relationship The substituents at the 1 position must be acidic. The carboxylic group provides optimal diuretic activity, but other groups such as tetrazole impart good activity. A sulfamoyl group at the position 5 is essential for optimal diuretic activity. The ‘activating’ group at the 4 position can be Cl- or CF3- as in thiazide diuretics. Better activity was observed when these groups have been replaced by phenoxy, alkoxy, aniline and benzyl moieties. The substitutions possible on the 2-amino group in 5-sulfamoyl-2- aminobenzoic acid derivatives is limited in the order furfuryl > benzyl > thienyl methyl only In case of 5-sulfamoyl-3-aminobenzoic acid the 3-amino group can be widely substituted without much change in the activity.

13. ETHACRYNIC ACID USES: Ethacrynic acid is a "water pill" (diuretic) that works in your kidneys to increase the amount of urine you make. This helps your body get rid of extra water. This medication is used to decrease swelling ( edema ) caused by conditions such as cancer, congestive heart failure, liver disease, and kidney disease .

14. STRUCTURE ACTIVITY RELATIONSHIP Activating group (Cl- or CH3-) occupy either the 3 position or the 2 and 3 positions. An Acryloyl moiety which reacts with sulfhydryl containing receptor present in renal tissues should be at the para to the oxyacetic acid group. Reduction or epoxidation of the carbon-carbon double bond in the acryloyl moiety yielded compounds with little or no diuretic activity.

15. SITE 3 DIURETICS : THIAZIDES AND THIAZIDE LIKE DIURETICS These agents are 1,2,4-benzothiadiazine-1,1-dioxide derivatives and are known as thiazides and hydrothiazides (lacking double bond at position 3-4). STRUCTURE ACTIVITY RELATIONSHIP Substitutions at position 2 with small alkyl groups such as methyl (- CH3) does not change the activity Substituents at position 3 determine the potency and duration of action of the thiazide diuretics. Loss of the carbon-carbon double bond between the 3 and 4 positions of the thiazide nucleus increases the potency approximately 3 to 10 folds. Direct substitution at 4, 5 or 8 positions with an alkyl group usually diminishes diuretic activity. Substitution at the 6 position with an ‘electron withdrawing’ group is essential for diuretic activity. The best substituents include Cl-, Br-, CF3- and NO2- groups. For example replacement of 6-Cl- by 6- CF3 does not change potency, whereas replacement with CH3 reduces diuretic activity. The sulphonamide group at the position 7 is essential for diuretic activity. Removal of this group yields compounds with little or no diuretic activity.

16. MECHANISM OF ACTION OF THIAZIDE and THIAZIDE LIKE DIURETICS These block the reabsorption of Na+ (and thereby, the reabsorption of Cl-) in the distal convoluted tubules by inhibiting the luminal membrane-bound Na+ /Cl- cotransport system. Adverse Effects Hypersensitivity reactions, Hypokalaemia, slight reduction in the cardiac output USES Extremely useful in the treatment of Edema associated with mild to moderate congestive heart failure. Other uses include hypertension, diabetes insipidus etc.

17. ADR: Volume depletion, Electrolyte imbalance, dry mouth, and thirst. USES: Hydrochlorothiazide is used to treat high blood pressure (hypertension). Hydrochlorothiazide is also used to treat fluid retention ( edema ) in people with congestive heart failure, cirrhosis of the liver, or kidney disorders, or edema caused by taking steroids or estrogen . HYDROCHLORTHIAZIDE Synthesis:

18. CHLORTHIAZIDE USES: Chlorothiazide is a "water pill" (diuretic) that causes you to make more urine. This helps your body get rid of extra salt and water. This medication is also used to decrease swelling ( edema ) caused by conditions such as cancer, congestive heart failure, liver disease, and kidney disease.

19. SITE 4 DIURETICS : POTASSIUM SPARING DIURETICS Three chemically distinct diuretics have emerged that increase Na+ and Cl- excretion without a concomitant increase in the urinary excretion rate of K+ . These agents are known as Potassium-sparing diuretics . A negative feature of all of the above discussed classes of diuretics is that they increase the renal excretion rate of K+ and can induce hypokalaemia. The potassium sparing diuretics are divided into two groups on the basis of mechanism of action. a) Na+ channel inhibitors : Triamterene and amiloride b) Aldosterone antagonists : Spironolactone

20. A) NA+ CHANNEL INHIBITORS Mechanism of action Amiloride and triamterene inhibit the sodium channel in the luminal membrane of collecting tubule and collecting duct. Inhibition of the sodium channel thus not only inhibits Na+ reabsorption but also inhibits secretion of K+ and H+, resulting in conservation of K+ and H+. Triamterene is an aminopteridine derivative and has a structural resemblance to folic acid whereas Amiloride is a pyrazino guanidine derivative TRIAMTERENE USES: Triamterene is a "water pill" (diuretic) that works in your kidneys to increase the amount of urine you make. This helps your body get rid of extra water. This medication is used to decrease swelling ( edema ) caused by conditions such as cancer, congestive heart failure, liver disease, and kidney disease.

21. AMILORIDE USES: Amiloride is used with other "water pills"/diuretics (such as furosemide, thiazide diuretics like hydrochlorothiazide) to treat high blood pressure (hypertension), heart failure, or extra fluid in the body (edema). Amiloride also helps to treat or prevent low blood potassium levels caused by the other diuretics.

22. B) ALDOSTERONE ANTAGONISTS Spironolactone is the only available aldosterone antagonist. A metabolite of spironolactone, “ canrenone ”, is also active. Spironolactone is steroidal derivative, structurally related to progesterone Mechanism of action Aldosterone, by binding to its receptor increases the Na+ reabsorption and Excretion of K + Spironolactone competitively inhibits binding of aldosterone to its receptor to prevent Na+ reabsorption and abolishes its biological effects. SPIRONOLACTONE USES: Spironolactone is used to treat heart failure, high blood pressure (hypertension), or hypokalemia (low potassium levels in the blood). Spironolactone also treats fluid retention (edema) in people with congestive heart failure, cirrhosis of the liver, or a kidney disorder called nephrotic syndrome.

23. MANNITOL (OSMOTIC DIURETICS) MOA: It exerts its effect by increasing the urine flow without markedly increasing the excretion of Na + and Cl - ADR: Headache, polydypsia , nausea, chest pain USES: Mannitol is a diuretic that is used to reduce swelling and pressure inside the eye or around the brain. Mannitol is also used to help your body produce more urine. This medicine is used in people with kidney failure, to remove excess water and toxins from the body.

24. CARDIOVASCULAR AGENTS These are the drugs or agents which are used in the treatment of various cardiac disorders are known as cardiovascular agents. Based on types of cardiac disorder they are classified in to different types. Cardiac agents or cardiac glycosides Antihypertensive agents Antianginal agents Antiarrhythmic drugs Antihyperlipidemic agents Coagulants and anticoagulants

25. CARDIAC GLYCOSIDES DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

26. CARDIOVASCULAR AGENTS These are the drugs or agents which are used in the treatment of various cardiac disorders are known as cardiovascular agents. Based on types of cardiac disorder they are classified in to different types. Cardiac agents or cardiac glycosides Antihypertensive agents Antianginal agents Antiarrhythmic drugs Antihyperlipidemic agents Coagulants and anticoagulants

27. Enhance the tone of the heart Excitability Contractibility of the cardiac muscle Also the improved circulation tends to improve renal secretion This relieves oedema often associated with heart failure CARDIAC GLYCOSIDES Definition: Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by acting on the cellular sodium-potassium ATPase pump. Cardiac glycosides can

28. According to the type of lactone ring: cardiac glycosides are classified in to two types 1 . Cardenolide (one double bond, lactone ring) : Has five member lactone ring (unsaturated) attached at C17 β position of steroidal nucleus. Examples: Digitalis glycosides: Digoxin , Digitoxin, Gitoxin S t ropha n thus gratus glyco s ide : Oubain Strophanthus Kombe glycoside : K- strophanthin 2. Bufadienolide: (contain two double bonds, lactone ring): Has six member ( unsaturated ) lactone ring attached at C-17 alpha – position Example: Squill glycosides ( scillarins ), Toad poison ( Bufotoxin ) 8

29. T he d e fin i te mec h anism o f acti o n i s not known. Some hypotheses have been postulated – Cardiac glycosides inhibit Na + /K + - ATPase , the “sodium pump” which causes more Na to remain inside myocardial cells Incr e as e d in t rac e l l u l a r Na stimulates Na/ Ca exchange th a t b ri n g s more C a i n s i d e heart cells. Increased intracellular concentration may promotes activation of contractile proteins to increase force of contraction. Cardiac glycosides also stimulate the vagus nerve which decrease heart rate. Mechanism of Action of Cardia glycosides

30. Nomenclature : The cardiac glycosides occur mainly in plants from which the names have been derived. Digitalis purpurea, Digitalis lanata, Strophanthus Kombe are the major sources of the cardiac glycosides. Glycosides: Glycosides are compounds which upon hydrolysis yield a glycone (sugar) part (such as glucose, rhamnose, digitoxose, ribose, cymarose) and an aglycone (also called genin, the non-sugar part) part. 10

31. cyclopentanoperh y drophenanthrene 10 AGLYCONE MOIETY(NON SUGAR): The term 'genin' at the end refers to only the aglycone portion (without the sugar). The aglycone portion of cardiac glycosides is more important than the glycone portion. Aglycone part has steroidal nucleus

32. SUGAR MOIETY(GLYCONE) : The glycosides usually contain 3 to 4 sugars attached at C-3 OH. The sugars most commonly used include L-rhamnose, D- glucose, D- digitoxose, D- digitalose, D-digginose. Beside Glucose and Rhamnose they usually contain deoxysugars. These sugars predominantly exist in the cardiac glycosides in the β-conformation. D i g i to x ose D i g i tose 11

33. Most sugars that are found in cardiac glycosides are uncommon deoxy-sugars E.g Digitoxose, Cymarose, Thevetose

34. ST RU C TURE: These are composed of two structural features : the sugar (glycone) moiety and the non-sugar (aglycone - steroid) moieties. 12

35. The R group at the 17-position defines the class of cardiac glycoside. Two classes have been observed in Nature: CARDENOLIDES and BUFADIENOLIDES . The cardenolides have an unsaturated butyrolactone ring While the bufadienolides have an a-pyrone ring. 13

36. Structural actiity and relationship :- The presence of Alpha & Beta unsaturated lactone ring increases the activity of Cardiac Glycosides, but if we make it saturated the Cardiac glycosides will lose its activity. The ring junctions Cis, Trans, Cis make the nucleus very stable so more active. The sugar part increases absorption and distribution of Cardiac glycoside in the body. Sugar part : Glucose, Rhamnose, Cymarose, Digitoxose 16 The presence of OH group in C-14 position makes the glycoside very active and gives rapid action in the body, but if we change it to (H+) group the drug will be inactive or less active.

37. C ar den oli de s Cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting.

38. DIGOXIN Source : It is obtained from the dried leaves of the  foxglove  plant,  Digitalis lanata . USES: Digoxin is used to treat heart failure and abnormal heart rhythms (arrhythmias). It helps the heart work better and it helps control your heart rate.

39. DIGITOXIN Source: USES: Digoxin is used to treat heart failure, usually along with other medications. It is also used to treat certain types of irregular heartbeat (such as chronic atrial fibrillation). It is also may helpful for treating most of the supraventricular tachyarrhythmias. Treating heart failure may help maintain your ability to walk and exercise and may improve the strength of your heart. It is also used in the treatment of atrial fibrillation, atrial flutter, cardiac output, low, shock, cardiogenic, tachycardia, supraventricular conditions. It is obtained from the dried leaves of Digitalis Purpurea and Digitalis lanata (Scrophulariaceae)

40. Bufadienolides Derives name from the generic name for the toad (Bufo) Possesses doubly unsaturated 6- membered lactone ring in position C-17 Bufadienolides are C24 steroid Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolide glycosides (bufadienolides that contain structural groups derived from sugars).

41. Bufadienolides from Squill Uses A potent cardiotonic As expectorant specially in chronic bronchitis As stimulant It is used as a very effective expectotant both in asthma and chronic bronchitis It may possess anticancer Produces diuresis It causes emesis in relatively higher doses These glycosides include the following: Scillarin A Scillarin B

42. MEDICINAL IMPORTANCE OF CARDIAC GLYCOSIDES Cardiotonics Congestive heart failure Rheumatic heart disease Atherosclerosis Diuretics

43. MEDICINAL IMPORTANCE OF CARDIAC GLYCOSIDES Cardiotonics Congestive heart failure Rheumatic heart disease Atherosclerosis Diuretics

44. ANTIHYPERTENSIVE AGENTS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

45. Def: These are the drugs are agents that reduce high blood pressure are known as Antihypertensive agents. Hypertension is defined as either a sustained systolic blood pressure (SBP)of greater than 140 mm Hg or a sustained diastolic blood pressure of greater than 90 mm of Hg . A specific cause of hypertension established in only 10–15% of patients. Patients in whom no specific cause of hypertension are said to have essential or primary hypertension. Patients with a specific etiology are said to have secondary hypertension. Genetic factors, psychological stress, and environmental and dietary factors as contributing to the development of hypertension. The heritability of essential hypertension is estimated to be about 30%.

46. Classification of hypertension on the basis of blood pressure

47. Hypotension may be defined as a physiologic state where there is a Hypertension is devided in to 2 types : 1. Primary hypertension or essential hypertension 2.Secondary hypertension or malignant hypertension .

48. In PRIMARY OR ESSENTIAL HYPERTENSION In majority of casses where etiology Is unknown cause and is known as primary hypertens ion. The following factors may contribute to elevate of B.P Dietary intake of more sodium and less potassium. In some cases primary hypertension may be herediatary. Advancement of age. Decreased vascular synthesis of Nitric oxide (N O )( is useful in vasodialatation)

49. In SECONDARY HYPERTENSION where etiology can be identified. Secondary hypertension is due to Renal disease (kidney disorders ( Chronic glomerular nephritis.) Adrenal disease (endocrine disorders) Pheochromocytoma (tumour on adrenal medulla) which secretes excessive catechol amines like adrenaline and nor adrenaline) Hyper aldosteronism. Muscular disorders: Contraction (narrowing)of aorta. Renal artery stenosis (narrowing of artery ) Toxemia of pregnancy (presence of toxins in the blood stream) Encephalitis (inflammation of the briain) Increased intra cranial pressure . Thyrotoxicosis (toxic condition caused by over activity of thyroid gland) oral contraceptives .

50. CAUSES OF HYPERTENSION

51. CLASSIFICATION DIURETICS Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide High ceiling: Furosemide, Torsemide, ethacrynic acid . K+ Sparing: Spironolactone, Amiloride II. ACE INHIBITORS: Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril , etc. III. ANGIOTENSIN (AT1 RECEPTOR) BLOCKERS: Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan IV. DIRECT RENIN INHIBITOR: Aliskiren V. β ADRENERGIC BLOCKERS: Propranolol, Metoprolol, Atenolol, etc. VI. CALCIUM CHANNEL BLOCKERS: Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine , etc.

52. VII. β + α - ADRENERGIC BLOCKERS: Labetalol, Carvedilol VIII. α - ADRENERGIC BLOCKERS: Prazosin, Terazosin, Doxazosin, Phentolamine, Phenoxy benzamine IX. CENTRAL SYMPATHOLYTICS: Clonidine, Methyldopa X. VASODILATORS Arteriolar: Hydralazine, Minoxidil, Diazoxide Arteriolar + venous: Sodium nitroprusside XI. OTHERS: Adrenergic neurone blockers (Reserpine, Guanethidine, etc.), Ganglion blockers (Pentolinium, etc.)

53. Depending on chemical classification A C E inhibito rs Sulphydryl E.g : C a p to p r il D i c a rbo xy l a te E.g:Enalapril , Lisinopril Phosphate E .g: F o s in o p r il

54. ACE INHIBITORS NOTE: Reduce blood pressure (hypoxia to kidney or less oxygen supply) and lowered Na 2+ excretion induces the release of Renin

55. ADR: Dizziness, headache, Fatigue USES: Enalapril is an ACE inhibitor. Enalapril is used to treat high blood pressure (hypertension) in adults and children who are at least 1 month old. Enalapril is also used to treat congestive heart failure (CHF) ENALAPRIL CAPTOPRIL: ADR: Hypotension. Tachy cardia, chest pain, palpitation USES: Captopril is an ACE inhibitor. ACE stands for angiotensin converting enzyme. Captopril is used to treat high blood pressure (hypertension), congestive heart failure, kidney problems caused by diabetes, and to improve survival after a heart attack.

56. RAMIPRIL: It is a prodrug converted in to active metabolite Ramiprilate by hepatic biotransformation. USES: Ramipril ( Altace ) is an ACE inhibitor. Ramipril is used to treat high blood pressure (hypertension) or congestive heart failure, and to improve survival after a heart attack. Ramipril may also be used for purposes not listed in this medication guide. BENAZEPRIL USES: Benazepril is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Benazepril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow more easily. ADR: Nausea, vomiting, diarrhoea, dizziness

57. SAR of ACE INHIBITORS N- ring must contain carboxylic acid group to mimic the ‘C’ terminal carboxylic acid of ACE enzyme substrate to act as ACE inhibitor. The larger hydrophilic heterocyclic in the ‘N’ ring increases the potency and alter pharmacokinetic property. X- is usually methyl group (-CH2), mimic the side chain Alanine of ACE enzyme substrate to act as ACE inhibitor. The R group of ACE inhibitor binds to the cationic site (I.e. Zn++) of the angiotensin converting enzyme to act as ACE inhibitor with optimum potency.

58. ANGIOTENCIN RECEPTOR ANTAGONISTS Angiotensin II receptor antagonists overcome some disadvantages of ACE inhibitors that is degradation of Bradykinin ( contraction of smooth muscle and dilation of blood vessels) and cough. LOSARTAN: USES: Losartan (Cozaar) belongs to a group of drugs called angiotensin II receptor antagonists. It keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow. Losartan is used to treat high blood pressure (hypertension). ADR: Dizziness, upper respiratory infections, back pain, diarrhoea, fatigue, low blood sugar, Chest pain.

59. CANDESARTAN ADR: Cold or flu-like symptoms such as fever, cough, sneezing and running nose, severe throat pain, dizziness and back pain. USES: Candesartan is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Candesartan belongs to a class of drugs called angiotensin receptor blockers (ARBs). It works by relaxing blood vessels so blood can flow more easily

60. DIRECT RENIN INHIBITOR ADR: Dizziness, light headache, cough, diarrhoea, tiredness, kidney problems. USES: This medication is used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Aliskiren works by relaxing blood vessels so blood can flow more easily. It belongs to a class of drugs known as direct renin inhibitors. ALISKIREN

61. β - ADRENERGIC BLOCKERS SAR: The basic structure and side necessary for β- blocking activity because β- lockers are structurally similar to β-agonists. N, N- di substitution decreases the activity. In the side chain minimum two carbons of chain is necessary for β-blocking activity. Introduction of -OCH 2 group in between aromatic ring and ethylamine side chain provides β-blocking activity. Nitrogen atom should be 2 amine form to produce optimum β-blocking activity.

62. PROPRANOLOL USES: Propranolol is used to treat tremors, angina (chest pain), hypertension (high blood pressure), heart rhythm disorders, and other heart or circulatory conditions. It is also used to treat or prevent heart attack, and to reduce the severity and frequency of migraine headaches. ADR: Cold extremities, insomnia, fatigue and dizziness.

63. Dihydropyridine - Nifedipine, Nicardipine Phenylalkylamines - Verapamil Benzothiazepines - Diltiazem Diaminopropanol ether – Bepridil All the above groups are proved to be effective in the management of hypertension by blocking the movement of Calcium in to the muscle cells through specific ion channels (i.e. L-type of channel ) and their by block impulse formation to reduce myocardial contractility and peripheral vascular resistance which results in inhibition of hypertension, arrhythmias and angina pectoris. CALCIUM CHANNEL BLOCKERS

64. Dihydropyridine & SAR Name of the compound R1 R2 R3 X Amlodipine -CH 2 O(CH 2 ) 2 NH 2 -C 2 H 5 -CH 3 2-Cl Felodipine -CH 3 -C 2 H 5 -CH 3 2,3-Cl Nifedipine -CH 3 -CH 3 -CH 3 2-NO 2 Phenyl ring substitution at 4 th position optimises the activity. Substitution at para position to phenyl ring decreases the activity. 1,4-dihydro pyridine ring is essential for activity. Substitution at ‘N’ or oxidation or reduction of the decreases the activity or abolish the activity. The 3 rd and 5 th of ester group optimises the activity, any othe electron withdrawing substitution decreases the activity. All 1,4-dihydropyridines except Amlodipine have methyl group at C2 & C6 position enhance the activity.

65. AMLODIPINE USES: Amlodipine is a calcium channel blocker that dilates (widens) blood vessels and improves blood flow. Amlodipine is used to treat chest pain (angina) and other conditions caused by coronary artery disease. Amlodipine is also used to treat high blood pressure (hypertension). NIFEDIPINE ADR: Hypotension, peripheral oedema, fatigue, palpitation and tachycardia etc USES: Nifedipine is in a group of drugs called calcium channel blockers. It works by relaxing the muscles of your heart and blood vessels. Nifedipine is used to treat hypertension (high blood pressure) and angina (chest pain). Nifedipine may also be used for purposes not listed in this medication guide. ADR: Headache, peripheral oedema, fatigue etc

66. PHENYL ALKYL DERIVATIVES VERAPAMIL ADR: Bradycardia, CHF, Myocardial infraction, and atrio-ventricular block. USES: Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Verapamil belongs to a class of drugs known as calcium channel blockers. It works by relaxing blood vessels so blood can flow more easily. Verapamil is also used to prevent chest pain (angina).

67. β + α - ADRENERGIC BLOCKERS LABETOLOL 2-Hydroxy-5-[1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl]benzamide It is a competitive inhibitor of β1, β2, and α1 adrenergic receptor. ADR: Orthostatic hypotension, dizziness, and fatigue. USES: Uses. Labetalol is used with or without other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This medication is both an alpha blocker and beta blocker.

68. α - ADRENERGIC BLOCKERS PRAZOSIN ADR: Postural hypotension, syncope, palpitation and lack of energy. USES: Prazosin is used with or without other medications to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Prazosin belongs to a class of medications called alpha blockers. It works by relaxing and widening blood vessels so blood can flow more easily

69. Centrally acting sympatholytics Mechanism of action Methyldopa is an α2 adrenergic receptor agonist acts centrally by decreasing the sympathetic outflow which inturn lowers B.P. METHYL DOPA USES: This medication is used alone or with other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Methyldopa works by relaxing blood vessels so blood can flow more easily. ADR: Peripheral Edema, mental depression, anxiety and nightmares.

70. ANTIANGINAL DRUGS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

71. ANTIANGINAL DRUGS Definition: Antianginal drugs are those that prevent, abort or terminate attacks of angina pectoris. Antianginal drugs may relieve attacks of acute myocardial ischemia by increasing myocardial oxygen supply or by decreasing myocardial oxygen demand. CLASSIFICATION Based on mechanism of action and chemical structure they are classified as follows I. NITRATES 1. Short acting : Glyceryl trinitrate (GTN, Nitroglycerine ) 2. Long acting : Isosorbide dinitrate (short acting by sublingual route), Isosorbide, mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate II. β BLOCKERS: Propranolol, Metoprolol, Atenolol and others. III. CALCIUM CHANNEL BLOCKERS 1. Phenyl alkylamine : Verapamil 2. Benzothiazepine : Diltiazem 3. Dihydropyridines : Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine , Benidipine 4. Diamino propanol ether : Bepridil IV. POTASSIUM CHANNEL OPENER: Nicorandil V. OTHERS : Dipyridamole, Trimetazidine, Ranolazine, Ivabradine, Oxyphedrine

72. NITRATES/ ORGANIC NITRATES These are the organic nitrates of alcohols. MECHANISM OF ACTION: The organic nitrates produce their action either of the following ways. • Preload reduction: The vasodilating effect of organic nitrates on the veins leads to Peripheral pooling of blood → decreased venous return (preload reduction). • Afterload reduction: Nitrates also produce some arteriolar dilatation → slightly decrease total peripheral resistance or afterload on heart. • Redistribution of coronary flow: In the arterial tree, nitrates preferentially relax bigger conducting (angiographically visible) coronary arteries than arterioles or resistance vessels. Finally, the organic nitrates restore the balance between O 2 supply by venous dilation and oxygen demand by decreasing the myocardial work load.

73. NITROGLYCERIN or GLYCERYL TRINITRATE ADR: Facial flushing, dizziness, tachycardia ( heart rate over 100 beats per minute ), headache etc. USES: Anti-anginal drug. Nitroglycerin extended-release capsules are used to prevent chest pain (angina) in people with a certain heart condition (coronary artery disease). This medication belongs to a class of drugs known as nitrates. Angina occurs when the heart muscle is not getting enough blood. Synthesis:

74. ISOSORBIDE MONONITRATE USES: Isosorbide mononitrate is used to prevent chest pain (angina) in patients with a certain heart condition (coronary artery disease). This medication belongs to a class of drugs known as nitrates. It works by relaxing and widening blood vessels so blood can flow more easily to the heart. ISOSORBIDE DINITRATE USES: Isosorbide dinitrate is a nitrate that dilates (widens) blood vessels, making it easier for blood to flow through them and easier for the heart to pump. Isosorbide dinitrate is used to treat or prevent attacks of chest pain (angina). ADR: Hypotension, Facial flushing, dizziness, tachycardia, headache etc. ADR: Hypotension, Facial flushing, dizziness, tachycardia, headache etc.

75. ERYTHRITYL TETRANITRATE USES: t is a vasodilator with properties similar to nitroglycerin . It is usually used diluted with lactose or other suitable inert excipients, in order to minimise the risk of explosion; undiluted erythrityl tetranitrate can be exploded by percussion or excessive heat. It has a role as a vasodilator agent and an explosive. PENTAERYTHRITOL TETRANITRATE USES: Pentaerythritol tetranitrate (PETN) is an explosive used as the primary ingredient in detonating fuses and as a component in some plastic explosives. As a nitrate ester, PETN is structurally similar to Nitroglycerin in its pharmacological (vasodilatory) and explosive properties.

76. POTASSIUM CHANNEL OPENER These are the drugs that activates ATP-sensitive potassium channels in vascular smooth muscles. Opening of these channels hyperpolarizes the smooth muscles which closes voltage sensitive Ca +2 channels and decreases intracellular Ca +2 level this leads to relaxation and vasodilation . NICORANDIL USES: It is used to prevent or reduce painful signs (“angina pectoris”) of your heart disease. It is used in adults who cannot take heart medicines called “beta-blockers” or “calcium antagonists”. Nicorandil Tablets work by increasing the blood flow through the blood vessels of the heart 2-[(pyridin-3-ylcarbonyl)amino]ethyl nitrate ADR: Facial flushing, dizziness, nausea, headache, mouth ulcers, vomiting etc.

77. DIPYRIDAMOLE It is phosphodiesterase-3-inhibitor causes long acting and coronary vasodilator by increasing coronary blood flow via selective dilation of the coronary arteries. USES: Dipyridamole helps to prevent platelets in your blood from sticking together and forming a blood clot on or around an artificial heart valve. Dipyridamole is used to prevent blood clots after heart valve replacement surgery. Dipyridamole may also be used for other purposes not listed in this medication guide 2,2',2'',2'''-(4,8-di(piperidin-1-yl) pyrimido [5,4- d ]pyrimidine-2,6-diyl)bis( azanetriyl ) tetraethanol ADR: GI disturbance, dizziness, facial flushing, headache etc.

78. ANTIARRHYTHMIC DRUGS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

79. ANTIARRHYTHMIC DRUGS These are the drugs or agents which are used to prevent or correct irregularities of cardiac rhythm are known as Antiarrhythmic drugs. Arrhythmias is the disturbances in the heart rate, rhythm, impulse generation or conduction of electrical impulses responsible for membrane depolarization. These disturbances can lead to alterations in overall cardiac function that can be life threatening.

80. Classification: Based on their mechanism of action they are classified in to different types. Class I: Sodium Channel Blockers (Membrane Stabilizing Agents) - Procainamide, lidocaine, Quinidine, tocainide, lorcainide, phenytoin, propafenone, mexiletine, Disopyramide etc.  Class II: β-Adrenergic blockers - – Propranolol, acebutolol, esmolol, sotalol Class III: Potassium channel blockers (Repolarization prolongators)- Amiodarone, Defitilide, Ibutilide, bretylium. Class IV: calcium channel blockers - – Verapamil, diltiazem Miscellaneous – PSVT: Adenosine, Digoxin – AV block: Atropine

81. • Bind to and block Na+ channels (and K+ also) • Act on initial rapid depolarisation (slowing effect) • Local Anaesthetic (higher concentration): block nerve conduction • Do not alter resting membrane potential (Membrane Stabilisers) • At times, post repolarization refractoriness. • Bind preferentially to the open channel state • USE DEPENDENCE: The more the channel is in use, the more drug is bound Na+ channel blocker

82. The cardiac action potential. Phase 0—depolarization because of the opening of fast sodium channels. Potassium flux also decreases. Phase 1—partial repolarization because of a rapid decrease in sodium ion passage as fast sodium channels close. Phase 2—plateau phase in which the movement of calcium ions out of the cell, maintains depolarization. Phase 3—repolarization, sodium, and calcium channels all close and membrane potential returns to baseline. Phase 4—resting membrane potential (−90 mV), resulting from the activity of the Na+/K+ ATPase pump which creates a negative intracellular potential because of the exchange of three sodium ions for only two potassium ions.

83. QUINIDINE It is an alkaloid isolated from Cinchona bark. In this quinidine is compound of quinoline ring and bicyclic quinidine ring system are connected by hydroxy methylene bridge. ADR: Muscle weakness, nausea, vomiting, diarrhoea , cinchonism symptoms include impaired hearing, headache, blurred vision, dizziness, utricaria and skin reactions. USES: This medication is used to treat or prevent many types of irregular heartbeats (heart arrhythmias such as atrial fibrillation). Quinidine can greatly improve your ability to perform normal activities by decreasing the number of irregular heartbeats you have. 6-methoxy cinchonan-9-ol

84. PROCAINAMIDE USES: Used as antiarrhythmic drug. Procainamide is used to help keep the heart beating normally in people with certain heart rhythm disorders of the ventricles (the lower chambers of the heart that allow blood to flow out of the heart). Procainamide may also be used for purposes not listed in this medication guide. ADR: Severe hypotension, ventricular fibrillation, heart failure, agranulocytosis and psychosis.

85. LIDOCAINE or XYLOCAINE or LIGNOCAINE USES: Lidocaine, also known as lignocaine, is a medication used to numb tissue in a specific area (local anesthetic ). It is also used to treat ventricular tachycardia and to perform nerve blocks. TOCAINIDE USES: Tocainide affects the way that your heart beats. Tocainide is used to treat serious irregularity in heartbeat patterns. Tocainide may also be used for purposes other than those listed in this medication guide. ADR: Dizziness, drowsiness, confusion, respiratory depression, andconvulsion . It is a class I-b Antiarrhythmic drugs. N -(2,6-dimethylphenyl)alaninamide

86. Potassium channel blockers (Repolarization prolongators) Phase -III drugs are increasing the repolarization without altering the phase ‘0’ which increases the effective refractory period. USES: This medication is used to treat certain types of serious (possibly fatal) irregular heartbeat (such as persistent ventricular fibrillation/tachycardia). It is used to restore normal heart rhythm and maintain a regular, steady heartbeat. Amiodarone is known as an anti-arrhythmic drug. AMIODARONE It has a broad spectrum of activity and effective blockers of both Na + & K + channels. ADR : Blue-grey colour discoloration of skin, photosensitivity, peripheral neuropathy, myopathy, ataxia, metallic taste. (2-{4-[(2-butyl-1-benzofuran-3-yl)carbonyl]-2,6-diiodophenoxy}ethyl) diethylamine

87. BRETYLIUM USES: Bretylium blocks the release of noradrenaline from the peripheral sympathetic nervous system, and is used in emergency medicine, cardiology, and other specialties for the acute management of ventricular tachycardia and ventricular fibrillation. It is a class III antiarrhythmic drug.

88. ANTI-HYPERLIPIDAEMIC DRUGS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

89. ANTI-HYPERLIPIDAEMIC DRUGS Definition -: anti-hyperlipidaemic drugs are those which lower the level of lipids & lipoproteins in blood. They act either by reduce production of lipoprotein or by increasing their removal from blood. Main aim is to decrease plasma cholesterol Hyperlipidaemia is the term used to describe elevated plasma levels of lipids usually in the form of lipoprotein Lipoprotein consist of a central core of hydrophobic lipid (triglycerides or cholesteryl esters) enclosed in amore hydrophilic coat of polar substance

90. Classification Composition Primary function Chylomicrons Triglyceride TGs 99%, 1% protein Transport dietary TGs to adipose tissue & muscle VLDL newly synthesized TGs Lipid 90%, 10% protein Transport endogenous TGs to adipose tissue & muscle IDL intermediate between VLDL and LDL They are not usually detectable in the blood. LDL Lipid 80%, 20% protein Transport endogenous cholesterol from liver to tissues HDL Lipid 60%, 40% protein Collect cholesterol from the body's tissues, and take it back to the liver

91. S.No Class Examples 1 HMG CoA Reductase inhibitors Lovastatin, Simvastatin, Metastatin , Pravastatin, Fluvastatin, Atorvastatin, Pitavastatin , Rosuvastatin 2 Fibric acid derivatives Clofibrate, Fenofibrate, Gemfibrozil, Ciprofibrate, benzaffibrate , Fluvestatin . 3 Bile acid sequestrants Cholestyramine, Colestipol 4 LDL oxidation inhibitor Probucol 5 Pyridine derivatives Nicotinic acid, Nicotinamide 6 Cholesterol absorption inhibitors Ezetimibe 7 Miscellaneous agents β-Sitosterol, Dextrothyroxine   CLASSIFICATION

92. Mechanism:

93. SIMVASTATIN USES: Antihyper lipoprotenemic agent to treat cardiovascular diseases. Simvastatin is used along with a proper diet to help lower "bad"  cholesterol  and  fats  (such as LDL, triglycerides) and raise "good"  cholesterol  (HDL) in the blood. It belongs to a group of  drugs  known as "statins." It works by reducing the amount of  cholesterol  made by the liver. ADR: Headache, nausea, heart burn, and abdominal pain.

94. SAR for ALL HMGRIS Confirmation similarity between statin and HMG-CoA reductase enzyme All statins consist of two specific structural components a dihydroxy heptanoic acid and ring system with lipophilic substituents. The dihydroxy heptanoic acid essential to binds at active site of the enzyme. 3,5 dihydro carboxylate is essential for activity Lactone containing prodrugs require in vivo hydrolysis Eg. Lovastatin, Simvastatin Bicyclic ring could be replaced with other lipophilic rings, size and shape of it are important for activity.

95. FIBRIC ACID DERIVATIVES SAR: MOA: It works in a variety way Decrease plasma TGs levels more than C levels Fibrates lower blood triglyceride levels by reducing the liver's production of VLDL (the triglyceride-carrying particle that circulates in the blood) by activation of lipoprotein lipase and speeding up the removal of TGs from the blood. It is supported by PPAR-α. Fibrates also are modestly effective in increasing blood HDL cholesterol; however, fibrates are not much effective in lowering LDL cholesterol. Basic structure necessary for activity. Presence of Isobutyric acid essential for activity. Substitution at R1 chloro group or chlorine containing isopropyl ring produces an compound with significant activity. The R2 is mostly propyl group for producing active derivatives.

96. CLOFIBRATE USES: It is a drug of choice for the treatment of Type-III hyperlipoproteinemia. Clofibrate is used to lower high levels of  cholesterol  (a type of fat) in the blood. Clofibrate is especially good at lowering triglycerides and very-low-density lipoprotein (VLDL) (a form of  cholesterol ). Clofibrate may also be used for purposes other than those listed in this  medication  guide. Synthesis:

97. CHOLESTYRAMINE USES: Cholestyramine is used to lower high levels of cholesterol in the blood, especially low-density lipoprotein (LDL) ("bad" cholesterol). Cholestyramine powder is also used to treat  itching  caused by a blockage in the bile ducts of the gallbladder. BILE ACID SEQUESTRANTS It is a styrene co-polymer with divinylbenzene and quaternary ammonium functional group. MOA: The cation exchange resin simply binds with anionic bile acids, this form an insoluble complex which results in increase in the loss of faecal bile acid and prevent reabsorption in to liver. ADR: Constipation, skin rashes haemorrhoids .

98. LDL OXIDATION INHIBITOR USES: Probucol is a powerful  antioxidant drug  normally used to prevent vascular disease caused by the free radicals in the body. Probucol lowers serum  cholesterol  by increasing the fractional rate of low-density lipoprotein (LDL) catabolism in the final metabolic pathway for  cholesterol  elimination from the body PROBUCOL It is a most potent cholesterol lowering agent of a series of alkylidene dithiobisphenols .

99. PYRIDINE DERIVATIVES It is the only drug used to increase the HDL-C in higher proportion than any other drugs available in market. ADR: Vomiting, diarrhoea , peptic ulceration and jaundice. USES: Used to lower triglycerides, cholesterol and to enhance the HDL-C Nicotinic acid (also known as niacin) is vitamin B3, which occurs naturally in food. Used as a medicine, it can improve levels of blood fats (lipids) such as cholesterol and triglycerides. Nicotinic acid works by reducing the amount of 'bad' cholesterol and triglycerides made by the liver. NICOTINIC ACID

100. CHOLESTEROL ABSORPTION INHIBITORS MOA: It inhibits the absorption of cholesterol from the small intestine and decreases the amount of cholesterol normally available in the liver cells. ADR: Headache, diarrhoea , myalgia, hypersensitivity reactions, myopathy (disease of muscle fibres ) USES: Ezetimibe is used along with a low cholesterol/low fat diet and exercise to help lower cholesterol in the blood. Ezetimibe may be used alone or with other drugs (such as "statins" or fibrates). Ezetimibe works by reducing the amount of cholesterol your body absorbs from your diet. EZTIMIBE 1-(4-fluorophenyl)-3-[(3 S )-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one

101. β-SITOSTEROL USES: It is used to make medicine. Beta-sitosterol is most commonly used for lowering cholesterol levels and improving symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH). It is also used for other conditions, but there is no good scientific evidence to support its other uses. It is structurally similar to cholesterol except ethyl group on c-24 of its side chain. MOA: It inhibits the absorption of dietary cholesterol from the GIT. ADR: Diarrhoea , constipation, GI disturbance.

102. COAGULANTS & ANTICOAGULANTS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

103. COAGULANTS & ANTICOAGULANTS COAGULANTS: These are the drugs which are used to stop bleeding or promotes coagulation are known as coagulants. Fresh whole blood or plasma provide all the factors needed for coagulation and are the best therapy for deficiency of any clotting factor; also, they act immediately. Other drugs used to restore haemostasis. Haemostasis: The process of arrest of blood loss and blood coagulation, it is occurred by (1) vascular constriction (2) formation of a platelet plug (3) formation of a blood clot

104. There are thirteen coagulation factors

105. COAGULANTS

106. CLASSIFICATION: VITAMIN K Vitamin K 1 – Phytonadione (Phylloquinone) Vitamin K 3 (Synthetic) a. Fat soluble – Menadione, Acetomenaphthone b. Water soluble – Menadione sodium bisulfate , Menadione sodium diphosphate II. MISCELLANEOUS – Fibrinogen, Antihemophilic Factor, Desmopressin, Andrenochrome monosemicarbazone , Rutin , Ethamsylate

107. PHYTONADIONE Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat certain bleeding disorders. This includes in warfarin overdose, vitamin K deficiency, and obstructive jaundice. It is also recommended to prevent and treat vitamin K deficiency bleeding in infants. USES: Phytonadione is used to treat vitamin K deficiency, and to treat certain bleeding or blood-clotting problems caused by other medicines or medical conditions. Phytonadione may also be used for purposes not listed in this medication guide. MENADIONE USES: It is used as a nutritional supplement and for the treatment of hypoprothrombinemia. It has a role as a nutraceutical. Vitamin K is an essential fat-soluble vitamin that is important in maintaining normal coagulation, serving as a cofactor in the activation of several clotting factors and

108. ANTICOAGULANTS Anticoagulants, commonly known as blood thinners , are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time . Anticoagulants and antiplatelet drugs eliminate or reduce the risk of blood clots. They're often called blood thinners, but these medications don't really thin your blood. Instead, they help prevent and break up the dangerous blood clots that form in your blood vessels or heart. They are usually administered to patient with acute myocardial infraction and the one undergoing treatment for pulmonary and venous thrombosis.

109. Vitamin K anticoagulants: Coumadins : Warfarin, Acenocoumarol, Dicoumarol 1,3-inadanediones: Phenindione, Anisinedione II. Heparins and heparinoids: Heparinoids: Heparin, danaparoid Oligosaccharides: Fondaparinux, Idraparinux 3. LMWH (low molecular weight heparin): Dalteparin, Enoxaparin, Nadroparin, Tinzaparin. III. Direct thrombin inhibitors Bivalents: Bivalirudin, Desirudin, Lepirudin Univalent: Agratroban , Dabigatran, Melagatran, Ximelagatran IV. Direct factor Xa inhibitors: Apixaban, Betrixaban, Edoxaban , Otamixaban , Rivaroxaban.

110. Adverse effects: bruising more easily, bleeding that takes longer to stop, irritation, pain, redness, or sores at the injection site, allergic  reactions , such as hives, chills, and fever, increased liver enzymes on liver function test results. USES: Heparin  is an anticoagulant (blood thinner) that prevents the formation of blood clots.  Heparin  is used to treat and prevent blood clots caused by certain medical conditions or medical procedures. It is also used before surgery to reduce the risk of blood clots. HEPARIN Mechanism of action: Heparin  binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin, factor Xa and other proteases.

111. USES: It is a synthetic anticoagulant Warfarin is an anticoagulant (blood thinner). Warfarin reduces the formation of blood clots. Warfarin is used to treat or prevent blood clots in veins or arteries, which can reduce the risk of stroke, heart attack, or other serious conditions. It is also used as rodenticide. WARFARIN ADR: Hypersensitivity reaction, rash, alopecia and diarrhoea.

112. DICOUMAROL MOA: It is appeared to be act by interfering the function of Vit.K in the liver cell, which is a site for the synthesis of clotting factor including prothrombin. ADR: Haemolysis, haematochezia (passage of fresh blood through anus), menorrhagia and clotting factor disfunctions. USES: Often used along with heparin for treatment of deep vein thrombosis. Dicumarol is an coumarin-like compound found in sweet clover. It is used as an oral anticoagulant and acts by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors (prothrombin and factors VII, IX, and X).

113. 1,3-INADANEDIONES PHENINDIONE Synthesis: These are Oral anticoagulants and their mechanism of action is similar to that of Coumarin

114. DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Pharmacy,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.