Cardiovascular Agents PDF

Cardiovascular agent 1 Cardiovascular agents By the end of this chapter the student will be able to: Recognize the main practical points regarding the Pharmacophore, Structure activity relationship, metabolism, pharmacodynamics, mechanisms of action, clinical use, and...

Cardiovascular agent 1 Cardiovascular agents By the end of this chapter the student will be able to: Recognize the main practical points regarding the Pharmacophore, Structure activity relationship, metabolism, pharmacodynamics, mechanisms of action, clinical use, and adverse effects of the following drug groups:  Vasodilators  Antiarrhythmic drugs  Antihypertensive  Antihyperlipidemic  hypoglycemic  Diuretics 2 Cardiovascular agents Cardiovascular agents are medicines that are used to treat medical conditions associated with the heart or the circulatory system (blood vessels), such as arrhythmias, blood clots, coronary artery disease, high or low blood pressure, high cholesterol, heart failure, and stroke. 3 Cardiovascu lar agent These are drugs used for their action on the heart or other parts of the vascular system. They either modify the total output of the heart or the distribution of 4 These drugs are employed in treatment of: 1-Angina 2-Cardiac arrhythmias 3-Hyper lipidemias 4-Disorders of blood coagulation 5-Hypertension 5 Antianginal agent and vasodilators Angina pectoris is characterized by cardiac discomfort caused by inadequate blood supply to the tissue, its main symptom is sever constricting pain in the chest, to the left shoulder and down the arm. 6 Nitrovasodilators: ♦How do nitrovasodilators work? ♦ What are the unwanted side effects and problems? e. 7 ♦ Metabolised to NO  activate guanylate cyclase  increase in cGMP  fall in intracellular free calcium  vascular relaxation increase in venous capacitance  fall in central venous pressure  reduce preload  reduction in ventricular dimensions and cardiac output ♦ Side effect – headache due to dilatation of intracranial arteries Also problem with quickly developing tolerance that can lead to abnormal constriction of coronary arteries following withdrawal 8 Endogenous NO generated by the NO synthase from arginine 9 Also antianginal may act by reducing the work done by the heart so the oxygen demand is reduced. O2NO ONO2 ONO ONO2 amyl nitrite glyceryl trinitrate (nitroglycerin) O2NO H O O2NO ONO2 O O2NO ONO2 H ONO2 Isosorbide dinitrate Erythrityl tetranitrate O2NO ONO2 O2NO ONO2 pentaerythritol tetranitrate 10  Pharmacokinetics of Nitrate Esters Onset Duration of Action Metabolites (min) (min) Amyl nitrite 0.25 1 Nitroglycerin 2 30 Isosorbide dinitrate 3 60 Active Erythrityl tetranitrate 15 180 Pentaerythritol tetranitrate 20 330 Nitrate esters act fast! Think about the size of these molecules. They are rapidly metabolized in the liver (glutathione-nitrate reductase). Number of nitrate groups does not linearly correspond to potency Nitrate esters and possibility of explosion! Nitrovasodilators decrease the blood pressure of patients!! 11 Calcium antagonists: Stimulation of the cardiac cell initiates the process of excitation which has been related to ion fluxes through the cell membrane. Ca+2 play an important role in the regulation of many cellular processes. The entry of Ca+2 into the cytosol of the myocardial cells and the release of Ca+2 from intracellular storage sites are important for initiating contraction of the myocardium. Stimulus Ca+2 Cell membrane Ca+2 released from sarcoplasmic reticulum Troponin Ca+2 complex Proteins Actin + Myosin interaction 12 Muscle contraction  Three Classes of CCBs Chemical Type Chemical Names Brand Names Phenylalkylamine verapamil Calan, s Calna SR, Isoptin SR, Verelan Benzothiazepines diltiazem Cardizem CD, Dilacor XR 1,4- Nifedipine Adalat CC, Dihydropyridines Procardia XL nicardipine Cardene isradipine DynaCirc felodipine Plendil amlodipine Norvasc 13 Verapamil (Isoptin) Verapamil is a phenyl alkylamine Ca+2 channel antagonist. It binds to a specific site on the Ca+2 channels promoting antagonism. This effect result in vasodilatation, so verapamil is used in treatment of angina pectoris, arrhythmias and hypertension 14 Diltiazem Hydrochloride: Diltiazem undergoes several biotransformation, including deacetylation, oxidative O-demethylation and N- demethylation and conjugation of the phenolic metabolites. 15 16  Nifedipine: (Adalate) It is a 1,4-dihydopyridine derivative The nitro group is essential for its antianginal effect, but it is not a nitrate. It has potent peripheral vasodilator properties through the inhibition of Ca+2 channels in the vascular smooth muscle. nifedipine is more effective in patients whose anginal episodes are due to coronary vasospasm ,(why) also it is used to treat hypertension. 17 The metabolism of nifedipine: Metabolism of nifedipine is by 1- Aromatization oxidation by CYP450 2- Hydrolysis of the ester group by esterase enzyme 3- Benzylic oxidation by CYP450 4- Lactonization could be enzymatic or nonenzymatic 18 Antiarrythmic Drugs: Cardiac arrhythmias are caused by disturbance in the conduction of the impulse through the myocardial tissue or disorders of impulse formation or both. 19  Quinidine sulphate USP;- Procainamide Hydrochloride USP: (pronestyl) N-(2-Diethylaminoethyl)p- aminobenzamide It acts in a similar way to quindine but it bounds minimally to plasma protein and the plasma level appears 20-30 minutes after administration. Metabolism of procainamide occurs An alkaloid obtained from through the action of N-acetyl cinchona bark, it is the transferase and about 50 % of it is dextro diastereoisomer of excreted unchanged. quinine. Quindin reduces Synthesis of procainamide: the Na+ current by binding the open ion channels, which decrease the conduction velocity. 20  Synthesis of procainamide: O O H SO2Cl2 O2N COOH O 2N C-Cl + H2N-CH2CH2Cl O2N C - N-CH2CH2Cl P-nitrobenzoic acid C2 H 5 HN C 2H5 O H C2 H 5 O2N C - N-CH2CH2-N C2H 5 H 2/Pt O H C2H 5 H2N C - N-CH 2CH 2-N C 2H5 Procainamide 21 Lidocaine hydrochloride USP: (xylocaine) It is used as local anesthetic and the drug of choice for parenteral treatment of arrhythmias. It is effective for preventing and terminating ventricular arrhythmias. Lidocaine act by blocking the Na+ channels so causing a slowing down of the conduction time of the impulse through the heart. 22 Synthesis of Lignocaine: CH3 CH3 C2H 5 CH3 O O + HN O ClCH 2-C-Cl C2H 5 C2H5 NH2 NH-C-CH2Cl NH-C-CH2-N C2 H 5 CH3 CH3 CH3 Lignocaine 23 Antihypertensive Agents Drugs used to treat Hypertension 1- Ca+ channel blocker 2- Angiotensin Antagonists - Angiotensin- Converting Enzyme Inhibitors (ACE inhibitors) 3- Sympatholytics (SYMPATHETIC DEPRESSANTS 4- Direct - Acting Arteriolar Vasodilators 5- Diuretics 24 25 ACE cleaves two amino acids from its substrate to produce Ag-II. As a result, ACE is termed a "dipeptidyl" carboxypeptidase (i.e) it cleaves 2 amino acids. 26 By preventing the formation of Ag-II, ACE-I also cause a decrease in the production of aldosterone which produces hyperkalemia. ACE-I also inhibits degradation of bradykinin. This causes an elevation of bradykinins which is thought to be responsible for persistent dry cough and angioedema associated with ACE-I. About 10% of the patients using an ACE-I have dry cough. Angiotensin II is generated by two pathways: 1) rennin angiotensin system, and 2) chymases. 27  Schematic Model of Active Sites of Angiotensin Converting Enzyme Hypotherical Model of Active Sites on ACE + Auxiliary Zn++ Cationic H Binding Sites Site H3C O O- O- Substrate Binding O C H2C C C N C O H H3C O O- ACE-I (captopril -S H2C C C N C O Binding H 28 The three classes of marketed ACE-I include: 1) captopril analogs 2) enalapril analogs 3) phosphorous containing analogs. 4) They all have functional features that allow them to bind to the cationic binding site and the zinc binding site of ACE. The two interactions by ion-ion binding are essential for activity. 29 Review the SAR. All the drugs have one group that allows it to attach to the cationic binding site and another one that allows it to bind to the zinc binding site Additional auxiliary binding sites may present, and if they are accommodated, they will increase the effectiveness of ACEIs by enhancing the selectivity to ACE. Proline's carboxyl group is required for ion-ion binding to the cationic site on ACE. Captopril: have one group that allows it to attach to the cationic binding site and another one that allows it to bind to the zinc binding site Additional auxiliary binding sites may present, and if they are accommodated, they will increase the effectiveness of ACEIs by enhancing the selectivity to ACE. Proline's carboxyl group is required for ion-ion binding to the cationic site on ACE. The prototype compound's inhibitory action is increased by the methyl group. The addition of a mercapto group (-SH) resulted in a significant increase in inhibitory efficacy without a loss of selectivity. Enalapril: Cyclic amino acids for best activity. cyclic nature of proline to give steric hindrance to amide bond hydrolysis. methyl group for hydrophobic interaction. substitution of amino butyl group for increase oral bioavailability. Tetrahydroisoquinoline for more potent. Carbonyl oxygen give hydrogen bonding. Lisinopril: Even in the absence of an ester at the side chain carboxylic group, the aminobutyl group improves lisinopril oral bioavailability. Ramipril: is a drug supporter. The esterase must hydrolyze the molecule at the OCh2Ch3 to create a carboxylate. After that, the carboxylate combines with the positive Zn+2 to block the ACE enzyme. The COOH aids in orienting it with the enzyme. Ramipril has a similar structure to Trandolapril ACE Inhibitor, except it contains cyclopentane rather than cyclohexane. Imidapril: have one group that allows it to attach to the cationic binding site and another one that allows it to bind to the zinc binding site Additional auxiliary binding sites may present, and if they are accommodated, they will increase the effectiveness of ACEIs by enhancing the selectivity to ACE. Proline's carboxyl group is required for ion-ion binding to the cationic site on ACE. Lotensin: The OCh2Ch3 ring of Benazepril Hydrochloride must be metabolized in order to block the ACE Enzyme and generate Benazeprilat, the active component of the molecule. Hydrolysis is resistant to the bulky cyclic structures. The nitrogen inside the ring makes the heavy cyclic structure exceptionally difficult to break down, which may account for the drug's PK profile, which has a 24-hour duration of action. 30  Captopril Analogs Mercapto Propanoyl Proline H3C O OH 3 2 1 HS H2C C C N C O H 2-D-methyl, 3-mercapto propanoyl L-proline The pharmacophore is 2D-methyl, 3-mercapto propanoyl-L-proline.This designates a structure with a propanoyl (3 carbon structure with a keto group at the –C 1 position) attached to the proline at the amino terminal with the -C1 carbonyl and has a mercapto group at the –C 3 of the propanoyl. Further, the –C2 of the propanoyl has a methyl group. The carboxylic terminal of proline is essential for binding to the cationic site while the mercapto group is essential for binding to the zinc binding site. 31  Enalapril Analogs COOR2 COOR2 CH3 O R1 CH Ala Pro R1 CH NH CH C N COOH CH3 N-Carboxymethyl-L-alanyl-L-proline Ala = Alanine H2N CH COOH Pro = Proline N H COOH The pharmacophore is N-carboxymethyl-L-alanyl-L-proline.It has alanine and proline attached together by an amide bond. At the N- terminal of alanine, there is a methyl with a carboxylic group attached to it. the carboxylic terminal of proline is essential for binding to the cationic site while the second carboxylic group in the free form is essential for binding to the zinc binding site. Phenyl ethyl group in the S-configuration produced the best activity. 32 Enalpril maleate: (vasotec) It is a long action ACE inhibitor. It requires activation by hydrolysis of its ethyl ester. It has no side effects as those of captopril. Benazepril, Quinapril, Ramipril. 33  Phosphorous containing Analogs O O R1 P H2C C N COOH OR2 Phosphinylacetyl proline Fosinopril (Fovas) As with the captopril analogs, the carboxylic terminal of proline is essential for binding to the cationic site while the ionized –OH of the phosphinyl group is essential for binding to the zinc binding site. 34 Taste disturbance: Captopril because of HS group. Taste disturbances have been reported with various ACE inhibitors that do not contain the thiol radical. The ACE enzyme requires zinc to function. Because ACE inhibitors require zinc for reaction, even if they don't have thiol groups, the drug's suppression of ACE may modify the zinc of the ACE protein in salivary gland cells, altering taste. 35  Angiotensin II Receptor Blockers (ARB) The majority are analogs of the general pharmacophore above: 1-N-benzyl 2-butyl Imidazole Imidazole ring is required to mimic the His6 side chain of Ag-II. N N N N N HOOC N Acidic Group = COOH R Carboxylic Phenyltetrazole Phenyl Acid carboxylate Acidic group 1-N-benzyl 2 butyl imidazole 36 Losartan, Irbesartan, and Candesartan Cilexetil are a nonpeptide antagonist/blocker of one of the angiotensin receptors, the AT1 receptor, resulting in decreased presser effect. Cl N O O O N O CH3 O O CH3(CH2)3 CH2OH N N N N H3C O N Cadesartan Celixitil N N N N N N N N NH NH NH Losartan Irbesartan 37 Losartan is an analog of the general pharmacophore (1-N- benzyl 2-butyl Imidazole. The imidazole ring allows for better binding to Ag-II receptor (AT1). The phenyltetrazole acidic group contributes to binding to Ag-II receptor especially with the tetrazole being in the ortho position. Also, the tetrazole group increases metabolic stability, lipophilicity and oral bioavailability. Since there is no linker between the two phenyls, it has good oral activity. The 2-butyl group maintains activity. The methyl alcohol on the imidazole ring is also good for activity. Cl N CH3(CH2)3 CH2OH N N N N NH Losartan 38  Cl N CH3(CH2)3 CH2OH N N N N NH Losartan The parent structure is active but has a short half life (1.5-2.5 hr). The parent structure is oxidized to an active 5-carboxylic acid metabolite which is 10-40 times more potent than parent structure and has a longer half life (6-9 hr). This increases the duration of action and provides for once or twice a day dosing. 39 Some marketed products do not have (imidazole) it and other five membered heteroaromatic rings including pyrazole and pyrrole ring are acceptable. Also, one product, Valsartan has an open ring imidazole with a keto group that may serve to H- bind to the receptor. Cl N CH3(CH2)3 CH2OH N N N N NH Losartan 40 41 Anti hyperlipidemic agents Hyperlipidemia is the most prevalent indicator for susceptibility to atherosclerotic elevated plasma levels of lipids that are usually in the form of lipoproteins. Lipoproteins are macromolecules consisting of lipid substances (cholesterol, triglycerides) none covalently bound with protein and carbohydrate. The various lipoproteins found in plasma can be 1-Very low density lipoprotein (VLDL) 2-Intermediate density lipoprotein (IDL) 3-Low density lipoprotein ( LDL) 4-High density lipoprotein ( HDL) 5-Chylomicrons 42 Classification of Antihyperlipidemic Drugs Several different classes of drugs are used to treat hyperlipidemia. These classes differ not only in their mechanism of action but also in the type of lipid reduction and the magnitude of the reduction.  Drugs for hypercholesterolemia – Bile acid-binding resin – 3-hydroxy-3- methyglutaryl Co A (HMG-CoA) reductase inhibitor – Ezetimibe Drugs for reducing elevated TG and to raise HDL-C levels – Fibric acid derivatives – niacin 44 cholestyramine (Questran) is a non-absorbed bile acid sequestrant that is used a therapy of hyperlipidemia and for the pruritus of chronic liver disease and biliary obstruction. is a large, highly positively charged anion exchange resin that binds to negatively charged anions such as bile acids The binding of bile acids to cholestyramine creates an insoluble compound that cannot be reabsorbed and is thus excreted in the feces. Adverse effects Beceause they are not orally absorbed, they produce minimal systemic side effects Constipation Heartburn, nausea, belching, bloating – These adverse effects tend to disappear over time HMG-CoA Reductase Inhibitor (( Statin))  Target: HMG-CoA Reductase (HMGR) The enzyme that HO CH3 catalyzes the C conversion of HMG-CoA H2C CH2 C SCoA to mevanolate. C  O O O HMG-CoA 2NADPH This reaction is the HMG-CoA rate-determining step 2NADP+ Reductase + HSCoA in the synthetic HO pathway of CH3 cholesterole. C 3-hydroxy-3- H2C H2 CH2 C OH methylglutaryl-coenzyme A C  O O mevalonate (HMG-CoA) In 1976…….. metabolites isolated from a fungus (Penicillium citrinum) were found to reduce serum cholesterol levels in rats. This work was done by Akira Endo, Masao Kuroda and Yoshio Tsujita at the Fermentation Research Laboratories, Tokyo, Japan. Today, there are two classes of statins: Natural Statins: Lovastatin(mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor). Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol). Statins are competitive inhibitors of HMG-CoA reductase. They are bulky and “stuck” in the active site. This prevents the enzyme from binding with its 49 substrate, HMG-CoA.  HO O HO O O O O O O H3C H H O CH3 H3C H H CH3 H3C MEVASTATIN LOVASTATIN (MEVACOR) HO O HO COOH O OH O O O O H 3C CH3 H H3C H H CH3 CH3 HO SIMVASTATIN (ZOCOR) PRAVASTATIN (PRAVACHOL) SAR of HMG-CoA reductase inhibitors The structure should contains a. lactone ring (sensitive to stereochemistry of it, ability of ring to hydrolyzed, length of bridge) b. Bicyclic rings ( could be replaced with other lipophlic rings, size and shape of it are important for activity) c. Ethylene bridge between them Fibrates They are classified as analogues of isobutyric acid derivatives (essential for activity) SAR of Fabric acid derivatives Fabric acid They are classified as analogues of isobutyric acid derivatives (essential for activity)  CH3 CH3 CH3 O (CH2)3 C COOH Cl O C COOEt CH3 CH3 H 3C GEMFIBROSIL (LOPID) CLOFIBRATE (ATROMID-S) Cl CH3 iPrO2C C O CH3 O FENOFIBRATE (TRICOR) Fibrates are 2-phenoxy-2-methyl propanoic acid derivatives aromatic ring]-O-[spacer group]-C(CH3)2-CO-OH 54  SAR Fenofibrate gemfibrozil Fenofibrate contain ester (prodrug) Para-subtitution with Cl or Cl containing isopropyl ring increase half-lives. n-propyl spacer result in active drugs (gemfibrozil) Mechanism of Action = works in a variety ways Fibrates lower blood triglyceride levels by reducing the liver's production of VLDL (the triglyceride-carrying particle that circulates in the blood) and by speeding up the removal of TGs from the blood Fibrates also are modestly effective in increasing blood HDL cholesterol; however, fibrates are not effective in lowering LDL cholesterol. 56 Ezetimibe Approved in October 2002 Reduces serum LDL, TC, and TG and increases HDL Prevents the absorption of cholesterol from diet Useful in Type IIa, IIb, III, IV and V hyperlipidemias It acts in the intestinal wall to inhibit cholesterol through a novel mechanism with an as yet undiscovered target OH OH N F O F 57 Thyroid Hormones 58 Thyroid Hormones Thyroid hormones (THs) are essential for normal growth and development and stimulate metabolism in most tissues (adult brain is a conspicuous exception). 59 Thyroid Hormones THs increase mitochondrial oxidative phosphorylation and maintain amino acid and electrolyte transport into cells. They increase calorigenesis and oxygen consumption in most tissues. THs stimulate the synthesis of proteins that can be structural proteins or enzymes. They regulate carbohydrate metabolism, accelerating insulin degradation and increasing gluconeogenesis. Stimulation of lipid metabolism leads to a fall cholesterol concentration in plasma. arousal. 60  THs also increase the sensitivity of the cardiovascular and nervous system to catecholamines, the former leading to increases in heart rate and cardiac output, and the latter to increased The synthesis of these hormones requires the amino acid tyrosine and the trace mineral iodine. The production of these iodinated amino acids begins with the synthesis of thyroglobulin that is post translationally modified in a series of biochemically unique reactions. 61 Thyroid Hormones Within thyrocytes, iodide is oxidized to iodine. This reaction is catalyzed by enzyme thyroperoxidase (TPO) in the presence of hydrogen peroxide (H2O2). Iodine then binds to 3' position in the tyrosyl ring, a reaction yielding 3-monoiodotyrosine (MIT). A subsequent addition of another iodine to 5' position of the tyrosyl residue on MIT creates 3,5- diiodotyrosine (DIT). T4 is created by the condensation or coupling of two DIT molecules. Smaller amounts of DIT within the thyroid can also condense with MIT to form either T3 or rT3. All these biosynthetic processes within the thyroid gland are controlled by feedback mechanism within the hypothalamic-pituitary-thyroid axis. 62 Precursor molecule (Tyr) and intermediates (MIT, DIT) during thyroxine biosynthesis Schematic draw of condensation of DIT  Thyroid hormones: These drugs are used in case of thyroid gland deficiency as replacement therapy. T3= L- 3,3,5- triiodothyronine T4 = L- 3,5,3,5- tetraiodothyronine (thyroxine) SAR:- Contain 2 aromatic molecule (A and B) linked through hetero atom (O or S) the ring B contain amino acid side chain at least three carbons The ring A must be to perpendicular to ring B with 120. The ring B must be substituted in position 3,5 with halogen ((lipophilic group)) Iodine, the more lipophilic the more active the compound. The ring A must be substituted at 3 position by halogen, T3 contains three Iodine groups where T4 contains four Iodine groups so T4 is more active. Ring A must contain phenolic OH which is very important for binding to the receptor. T3,T4 function: Increase absorption of glucose from GIT. Stimulate synthesis of protein. Required for basal metabolism rate.  1. Levothyroxine sodium It is obtained from the thyroid gland of domesticated animals used for human food. It is also prepared synthetically It is use in treatment of decreased thyroid function. 68  2. Liothyronine sodium,USP: It has the same uses of levothyroxine, including: 1.Treatment of hypothyroidism ( metabolic in sufficiency) 2.Male infertility. 3.Certain gynecological disorders. 69 Anti thyroid drugs: When hyperthyroidism (excessive production of thyroid hormones) exists, the condition usually requires surgery, but before surgery the patient must be prepared preliminary abolition of the hyperthyroidism through the use of anti thyroid drugs. The thiourea and related compounds show an anti thyroid activity, but they are toxic. The more useful drug are 2- thiouracil derivatives and a closely related to 2- thioimidazloe derivatives. All of these drugs act by prevention of incorporation of iodine in thyroxin and triiodothyronine precursor. 70 A) 2-Thiouracil Methylthiouracil (Methiacil) 6-Methyl-2-uracil 71  Synthesis: O C2H5-C  NH 2 Drug S= C + NH2 O CH2CH2CH3 72 Synthesis: O O C2H5-C H-N  NH 2 S= C + S CH3 NH2 N O CH3 H O OH H-N N S CH 3 H- S CH3 N N H 73 Propylthiouracil (Propacil) This drug is useful in the treatment of hyperthyroidism; there is a lag time before it shows its action.Why? 74 B) 2-Mercaptoimidazole Methimazole Methimazole is more potent than propylthiourea but has the same side effects, so the patient should be under medical supervision (due to the agranulocytosis) as side effect. 75  Synthesis:- S N H3CO CH2NH2 + CH NH = C H3CO CH 2-NH H -H2O + S-H = H3CO H N H3CO =S H C C=S N CH 3 NHCH 3 CH3 H OH N -CH3 H 76 Carbimazole Advantage: 1.Longer duration of action. 2.Overcome the taste of drug. 77 Synthesis:- O N N N-C-OC 2H 5 O O SH + Cl-C-OC 2H5 S-C-OC2H5 S N N N CH 3 CH 3 CH 3 78 Synthetic Hypoglycemic Agents Sulfonylurea STRUCTURE ACTIVITY RELATIONSHIP (SAR) Best effect is with arylsulfonyl group in position l and an aliphatic (R2) group at the 3-position. Maximum activity when R2 is of 3-6 carbons it confers lipophillic properties to the molecule. If R2 is aryl group, the compound is rather toxic. The R1 group on aromatic ring influence duration of action as the difference between tolbutamide and chlopropamide. MODE OF ACTION The sulphonyl urea act by stimulating the release of insulin from the functioning β-cells of the intact pancreas. They have no significant effect on blood glucose, but they may have other action like inhibition of secretion of glucagons and action at the post receptor intracellular sites increase insulin activity. The sulfonyl urea compounds are used for diabetic patient whose disease had its onset in adult hood and not in juvenile's onset diabetic, why? Tolbutamide USP: (Orinase) 1-Butyl-3-(p-tolyl sulfonyl)-urea It is rapidly absorbed and the blood sugar reaches minimum after 5 to 8 hours. It is rapidly oxidized to: Chlorpropamide USP: Diabenese 1-[(p-chlorophenyl)-sulfonyl]3-propylurea It is more resistant to metabolism compared to tolbutamide so it has a much longer duration of action.  Acetohexamide: Possesses a ketone group that is rapidly reduced to the alcohol but this is more active than the parent compound and has a longer half-life. The 4 position on the hexane ring is also hydroxylated. Duration is similar to tolazamide.  Glipizide: (glucotrol) O O O S O N N N H H 1-cyclohexyl-3-[[(p-3- N H (methyl pyrazine H3 C N Glipizide carboxamide) ethyle] phenyl] sulfonyl urea. It is absorbed rapidly after oral administration it has a hypoglycemic effect that ranges from 12 to 24 hours. Are more potent on a per milligram basis Tend to produce fewer side effects. In addition, the pharmacokinetics of these second-generation agents allows for more effective once-a-day dosing, which enhances compliance.  Tolbutamide Chlorpropamide Acetohexamide CH3 O O O S O N N O H H O O O S N N N N H O H3C H H N H3C Glimepiride N H H3 C N Glipizide O O O S O N N H H Cl N H CH3 O Glyburide  Biguanides Several biguanidin derivatives are active as antihyperglycemic agents of which metformin and phenformin are of most interest.  Synthesis: Phenformin has the potential to cause lactic acidosis, the increase in blood lactic acid levels. NH NH H 2N-C C-NH2 + H2NCH2CH2 drug N H 2-Metformin (Glucophage) Metformin causes a small increase in peripheral lactate 1,1-dimethylbiguanid They are suitable for obese diabetic patient. C/I: Renal failure. Hepatic disorders. Cardiovascular disorders. Only metformin is available for clinical use.  Mode of action (MOA): They may act through inhibition of glucose absorption from GIT. inhibition of gluconeogensis Increase peripheral utilization of glucose Side effects: fatal lactic acidosis and its in phenformin more than in metformin.  THIAZOLINEDIONES H O N O O O S NH H3 C N S Pioglitazone O O O N N S NH CH3 Rosiglitazone O Does not increase insulin release like the sulfonylureas but increases the response to insulin. Example Pioglytazone (Actos) and rosiglitazone (Avandia).  -Glucosidase Inhibitors HO OH OH H3C O O O HO OH OH OH OH OH HO N O O HO HO HO H Acarbose Polysaccharides are broken down to smaller saccharides -Glucosidase breaks down more complex saccharides in the intestine such as tri− and disaccharides by splitting off a single sugar from the end These drugs, by mimicking the sugar structure, bind with a higher affinity than the natural substrate to the enzyme, inhibiting further breakdown of these saccharides This decreases the absorption of monosaccharides and decreases the postprandial peak in blood glucose. Thus most useful in patients with postprandial hyperglycemia. Note that monosaccharides already in the diet are not affected and so patients should avoid eating glucose, itself Unfortunately, these drugs can increase the amount of saccharides entering the colon, and can cause colonic distress, which includes diarrhea, flatulence, and cramping MEGLITINIDES O H3C Similar mechanism of O O OH action as the sulfonylureas without their toxicities N H Cl INCRETINS are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating. They also inhibit glucagon release from the alpha cells.  Diuretics A chemical agent that increases the rate of urine formation. Reabsorption of Na in the kidney results in the reabsorption of water. It follows that inhibition of Na reabsorption will result in diuresis. Because of this, the term diuretic has come to mean any agent that will inhibit the tubular absorption of sodium. Primary mechanism of most diuretics: direct inhibition of Na transport at one or more of the four major anatomical sites in the nephron, because Na transport at each of these location is unique, different rigid structural feature must be possessed to inhibit Na reabsorption.  Glomerulus r iole A r te e n t Afferent Arteriole e r Eff Juxta-glomerular apparatus (JGA) Proximal Convoluted Tubule Distal Convoluted Tubule Loop of Henle Collecting Duct r t ex Co la d u l M e  Diuretics can be classified by their electrolyte excretion patterns, they possess some combination of:  Natriuretic – enhanced sodium excretion  Chloruretic – enhanced chloride excretion  Saluretic – enhanced sodium chloride excretion  Kaliuretic – enhanced potassium excretion  Bicarbonaturetic – enhanced sodium bicarbonate excretion  Calciuretic – enhanced calcium excretion SULFANILAMIDE After its introduction for the NH2 treatment of bacterial infections, it was observed to produce a mild diuresis. It was shown that it induced this effect Through inhibition of renal Carbonic Anhydrase. SO2NH2 - but weakly , severe side effect. To improve the CA inhibitory property of sulfanilamide many sulfamoyl - containing compounds ( - SO2NH2 ) were synthesized and screened for their diuretic activity and their ability to inhibit CA. Two groups of CA inhibitors emerged: 1-Simple heterocyclic sulfonamides. 2- Metadisulfamoylbenzene derivatives. H2 O + CO2 (CA) H 2CO3 H + HCO3 The hydrogen ions (H+) formed is exchanged for Na+ in the renal tubules. Inhibition of (CA) reduces the (H+) formation, so the exchange for Na+ cannot take place. That is Na+ not reabsorbed and carries H2O with it. Acidosis occurs due to loss of HCO- 3 (which goes out with Na+) 100  HETEROCYCLIC SULFONAMIDES NH2 Sulfanilamide H2NO2S CH3 N N N N H2NO2S S NH C CH3 H2NO2S S NH C CH3 O O Acetazolamide Methazola ( Diamox ) mide (Neptazane  STRUCTURE- ACTIVITY RELATIONSHIPS -The prototype is Acetazolamide. N N The derivatives with the highest lipid / CH3 water partition H2NO2S S NH C coefficient and lowest O pKa have the greatest CA inhibitory and diuretic activity. The sulfamoyl group is essential The sulfamoyl nitrogen for the production of atom must remain diuresis unsubstituted to retain the activity.  Structure – activity relationships 1- The sulfamoyl group is absolutely essential for the in vitro carbonic anhydrase inhibitory activity. 2- The sulfamoyl nitrogen atom must remain unsubstituted to both in vivo and in vitro activities This feature explains why all of the antibacterial sulfonamide except sulfanilamide, are incapable of inhibiting carbonic anhydrase or exerting a diuresis. 3- Substitution of a methyl group on one of acetazolamido’s ring nitrogens yields methazolamide, a product that retains carbonic anhydrase inhibitory activity & even more potent. 4- Sulfamoyl group must be attached to a moiety that possess aromatic character. 103  Methazolamide, USP CH3 CH3 N N H2N S O N S O O N-(3-Methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)- ylidene)-acetamide Methazolamide is more potent carbonic anhydrase inhibitor than acetozolamide (the prototype), but is rarely used as diuretic. It is used in treatment of glaucoma, because it displays improved penetration into the eye. Diuretics 104  Metadisulfamoylbenzene derivatives SAR Substitution with an Maximal diuretic activity is amino group increases observed saluretic , but decrease CA inhibitory activity When this position is substituted with: Cl , Br , CF3 or NO2 SO2NH2 The sulfamoyl moiety can be replaced with a similarly electrophilic SO2NH2 An unsubstituted Group ( carbonyl , carbamoyl ) that may increase diuretic potency While sulfamoyl is of paramount decreasing CA inhibitory activity importance Cl Cl NH2 Cl H2NO2S SO2NH2 H2NO2S SO2NH2 Chloraminophena Dichlorphenamide mide ( Daranide ) The diuretics that act on site I may inhibit the reabsorption of 20% to 25% of the filtered sodium, but the other three sites may compensate reabsorbing most of the extra sodium presented to them. Thus the action of (CA) inhibitors may result in urinary lose 2%- 5% of the filtered load of sodium and up to 30% of the filtered load of bicarbonate which result in acidosis. Another side effect of (CA) inhibitors is hypokalemia due to renal loss of K+. Sulfonamide hypersensitivity reaction such as urticaria, drug fever and other allergic reaction might be seen with the use of such diuretics. 106 Site 2 diuretics: high ceiling or loop diuretics:- The diuretics of this class are of diverse chemical structures A) Organomercurials: They were the main diuretic therapy from 1926 to the early 1950s Limitations of the organomercurials They cannot be given orally because of poor and erratic absorption. After their parenteral administration there is a one- to two- hour lag in the onset of the diuresis. Their activity depend on the acid-base status of the individual (i.e., they are ineffective when the urine is alkaline), They are cardio- and nephro-toxic 107  1) 5-sulfamoyl-2-and-3-aminobenzoic acid derivatives:- The COOH group at position (1) is essential for activity. Sulfamoyl group in position (5) is prerequisite for optimal high-ceiling diuretic activity. X in the (4) position can be Cl or CF3 or a phenoxy ( ) or alkoxy, but the diuretic activity is better with Cl or CF3. Also the carboxylate moieties are thought to be responsible for Cl – excretion.108 Furosemide (Lasix):- 4-Chloro-N-furfuryl-5-sulfamoyl-anthranilic acid. Present as 20, 40, 80 mg tablet and as injectable form (10mg/ml) Furosemide has a rapid action and short duration (6-8 hr), it is a saliuretic 109  Preparation of Furosemide:- H Cl Cl Cl Cl Cl Cl CH2NH2 Cl N-CH2 ClSO3H NH3 O O COOH ClO3S COOH H2NO2S COOH H2NO2S COOH 110  Bumetanide (Burnix):- 3-(Butylamino)-4-phenoxy-5-salfamoyl benzoic acid Present as 0.5, 1.0 and 2.0 mg tablets. Bumetamide has the same uses as Furosamide. 111  CLINICAL USES OF LOOP DIURETICS EDEMA due to CHF, nephrotic syndrome or cirrhosis Acute heart failure with PULMONARY EDEMA HYPERCALCEMIA not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease) 112  Adverse Effects of Loop Diuretics similar to thiazides in many respects Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia Dehydration and postural hypotension Hypocalcemia (in contrast to thiazides) Hypersensitivity OTOTOXICITY (especially if given by rapid IV bolus) 113 3- Phenoxy acetic acids:- Ethacrynic acid USP (Edecrin) 2,3-Dichloro-4-(2-methylene-1-oxybutyl)phenoxy acetic acid. Ethacrynic acid has the same uses as furosemide and bumetemide, specially used for patients who are hypersensitive to sulfamoyl- containing drugs. 114  Phenoxyacetic acids Ethacrynic acid ( Edecrin ) Activating gp(-Cl,-CH3) occupy 3 position or 2&3 - Optimal diuretic activity is achieved when : Cl Cl O 3 2 CH3CH2 C O CH2 COOH 4 1 Alkyl subst. of H H 2 to 4 carbon An oxyacetic acid moiety atoms in length Is placed in the 1- occupy the position position α to On the benzene ring the carbonyl on A sulfhydryl reactive acryloyl moiety is the acryloyl located para to the oxyacetic group moiety. Hydrogen atoms occupy the terminal position of the C=C of the acryloyl moiety.  Cl Cl O H3CH2C O CH2 COOH H H RSH Cl Cl O H3CH2C H O COOH H S H R The acryloyl group selectively form an adduct with receptor (sodium/ potassium ATPase system) in the loop of Henle 116  Synthesis of Ethacrynic Acid: Cl Cl Cl Cl O Cl Cl O - + CH3CH2CH2-C-Cl O Na + ClCH2COOH OCH 2COOH CH2 - C OCH 2COOH AlCl3 CH2 CH3 CH2O CH3 HN CH3 Cl Cl Cl Cl O OH OCH2COOH C2H5 - C= C OCH2COOH C2H5 - CH - C CH2 CH2 N N CH3 CH3 117 Site 3 diuretics: - Thiazide and thiazide like diuretics: Include: chlorothiazide, hydrochlorothiazide (HCTZ), benzthiazide cyclothiazide, indapamide, chlorthalidone, bendroflumethizide, metolazone, etc 5 4 6 3 7 2 8 1 118 Structure activity relationship: Position 2 can tolerate small alkyl group such as CH3 Position 3 is extremely important for molecule modification, Substitution at this position play an important role in the potency and duration of action. Loss of the = bound increase the diuretics activity (3=4). Direct substitution on 4, 5, 8 position decrease the diuretic activity. Substitution with activating group at position 6 is essential, the best substituent Cl, Br, and CF3 and NO2 group. The sulfamoyl group is essential for diuretic activity. 119  Synthesis of Thiazaide and Hydrothiazaide: X NO2 X NH2 X NH2 Reduction 1- Chlorosulfonation 2- NH3 H2NO2S SO2 NH2 HCOOH HCHO/H X=Cl X=Cl H Cl N Cl N H2NO2S NH NH S H2NO2S S O O O O Chlorothiazaid Esidrex 120 Hydro chloro thiazide USP (Esidrix):- 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7- sulfonamide-1,1-dioxide. Present as 25, 50 and 100mg tablets used for treatment of edema associated with mild to moderate congestive heart failure, cirrhosis of the liver or nephritic syndrome. Also used in hypertension alone or in combination with other drugs. 121 Potassium-Sparing Diuretics They include amiloride, triamterene, and spironolactone. They are weak diuretics that exert their action mainly on the collecting ducts. Amiloride and triamterene act by blocking the Na+ channels in the luminal membrane of the principal cells of the cortical collecting ducts. This reduces the Na+ entry through the luminal membrane and hence the net reabsorption of NaCl. Spironolactone (Aldactone) is a competitive aldosterone antagonist at the cytosolic receptor level. 122 Spironolactone (aldoctone):- CH2OH Aldosterone CO HCO HO CH3 O It inhibits the reabsorption of 2% to 3% of the filtered load of sodium at site 4 by competitively inhibiting the action of aldosterone. Therefore it enhances the excretion of water, sodium and chloride. Spironolactone may be used as mild diuretic in edema in individuals with congestive heart failure or as antihypertensive. 123 1.Pyrazinoylguanidine :- (aminopyrazine) Amiloride hydrochloride USP :- (Midamor) It acts by plugging the sodium channel in the luminal membrane. In turn the driving force for potassium reaction is reduced or limited. It is mainly used in edema and as antihypertensive agent alone or in combination with hydrochlothaized. 124 Theophylline:- Theophylline is a xanthine alkaloids known to promote a weak diuresis by stimulation of cardiac function and by direct action on the nephron 125  Mannitol :- (osmotic diuretic) It causes a decrease in water reabsorption in the nephron units and promotes an osmotic diuresis generally without significant sodium excretion. Highly water soluble, not reabsorbed administered as hypertonic solution this cause water to pass from the body into tubule. 126 1. Circle the groups that are essential for such activity. Illustrate the effect of the chloride on the fenofibrate half- life. Cl CH3 iPrO2C C O CH3 O FENOFIBRATE (TRICOR) 2. Circle the groups that are essential for diuretic action. 3. Draw the structure of Tetraiodothronine (T 4).What is the effect of the removal of the para OH group 4. State the importance of the nitro group in Nifidipine..Cholestyramine Resin (Questran), have no systematic effects.5 127 6. Illustrate the reason(s) Meglitinide has similar mechanism of action as the sulfonylureas but without their toxicities. [2 marks] 7. Fibrates are used for reducing the elevated triglycerides and raising high density lipoproteins (HDL) levels. Circle the groups that are essential for such activity. Illustrate the effect of the chloride on the fenofibrate half-life. [4 marks] Cl CH3 iPrO2C C O CH3 O FENOFIBRATE (TRICOR) 128 Show the binding sites between the angiotensin converting enzyme and Captopril as substrate. [2 marks] CH3 O HS CH2 CH C N COO - 9. Methazolamide is more potent as carbonic anhydrase inhibitor than acetazolamide. Explain. [1 mark] Methazolamide Acetazolamide 9.1 Use the above structures to indicate the groups that are essential for diuretic activity. [2 marks] 9..2 The above carbonic anhydrase inhibitors are used for glaucoma and not for hypertension or edema. Explain. [1 mark] 129.Choose the best diuretic for the treatment of the followings cases. Explain your choice. ]marks 4[.Hypertension in patient allergic to sulfur containing drugs 5.1.Pulmonary edema 5.2.Heart failure in patient with hearing problems 5.3.Liver cirrhosis in patient with hypokalemia 5.4 Furosemide (1) Hydrochlorothiazide (2) Amiloride (3) Ethacrynic acid (4) 130 MCQ 1. Which of the following structural modifications will enhance therapeutic activity of structure 1? H O OH HOOC H2C C C N C O H 1 a. Changing the proline carboxylic group to a methyl. b. Removal of the carbonyl group. c. Replacing one of the –C2 hydrogen with a – CH3. d. Removal of the proline ring. 2. Compared to structure 2, structure 1 has O OH H3C H3C O OH O OH C H2C H2C C HN C C N C O HS H2C C C N C O H H H 2 1 a. less allergic reactions b. less taste disturbance c. a long duration of action d. a more allergic reactions 131 3. Procainamide reduces the Na+ current by binding the open ion channels, which decrease the conduction velocity. Its chemical name is a. N-(2-Diethylaminoethyl) p-aminobenzamide b. N-(2-Dipropylaminobutyl) m-aminobenzamide c. N-(5- Dipropylaminobutyl) m-aminobenzamide d. N-(5- Dipropylaminobutyl) o-aminobenzamide 4. Endogenous nitric oxide is generated by the NO synthase from amino acid a. aspargine b. arginine c. glycine d.glutamine 5. In nitro vasodilators, the Number of nitrate groups a. affect the level of LDL b. does not linearly correspond to potency c. correspond to potency d. increase the work of the heart 132 6. Diltiazem undergoes several biotransformation, including a. deacetylation, oxidative O-demethylation b. N- demethylation and conjugation of the phenolic metabolites c. opening of the thiazepine ring d. a & b 7. Furosemide is a loop diuretic. The carboxylate moieties are thought to be a. responsible for Cl – excretion b. essential for making urine alkaline c. responsible for Na+ excretion d. important for alkylation of the receptor 8. The drug shown below is a competitive inhibitor of aldosterone. It a. inhibits the reabsorption of 2% to 3% of the filtered load of sodium b. is a steroid with a lactone ring c. is a competitive aldosterone antagonist d. all of the above 133 9. Amiloride acts by plugging the sodium channel in the luminal membrane. It a. has a guanide group in its structure b.contains a piprazine ring in its structure c. has a pyrazine ring in its structure d. a & c 10. Ethacrynic acid is a site 2 diuretic. It is Cl Cl O 3 2 CH3CH2 C O CH2 COOH 4 1 H H a. phenoxy acetic acid derivatives b. phenoxy propanoic acid derivatives c. salicylic acid derivatives d. an acetate ester 134  11. Nitrate esters are compounds used for the treatment of angina pectoris. They a. are rapidly metabolized in the liver (glutathione-nitrate reductase) b. are metabolized to give nitric oxide which is essential for vasodilatation c. cause headache because of vasoconstriction d. a and b 12. Quinidine is an alkaloid used for cardiac arrhythmia. It a. is a sodium channel blocker b. is the dextro diastereoisomer of quinine c. decreases the conduction velocity d. all of the above 3. Structure that inhibits the enzyme HMG-CoA reductase (3- hydroxyl-3-methyle glutaryl CoA) should contain a. lactone ring, bicyclic rings and butyl chain between them b. benzene ring, lactone and propyl chain between them c. lactone ring, bicyclic rings and ethylene bridge between them d. pyrrol ring, bicyclic rings and ethylene bridge between them 135  14. Acarbose, α-Glucosidase inhibitor, hasHOa OH OH H3 C O O O HO OH OH OH OH OH HO N O O HO HO HO H a. Acarbose protein like structure b. sugar like structure c. monosaccharide structure d. disaccharide structure 15. Acetohexamide possess a ketone group and a cyclohexane ring. The a. ketone group is rapidly reduced to give more active hypoglycemic agent. b. ketone group is rapidly oxidized to give more active hypoglycemic agent. c. ketone group is rapidly oxidized to give less active hypoglycemic agent. d. cyclohexane ring is oxidized to give less polar hypoglycemic agent. 16. Nifidepine, is 1,4-dihydopyridine derivative. The nitro group is essential a. for production of nitric oxide b. for binding to the receptor c. to enhance metabolism d. to make the compound less polar 136 17. Carbimazole is useful in the treatment of hyperthyroidism, it NCH3 HN a. is urea derivative S b. blocks synthesis of T3 and T4 c. is thiourea derivative d. b and c 18. Bumetanide is more potent than furosemide because of the a. sulfamoyl group b. chloride group c. butyl chain d. butyl chain and the phenoxy group 19. The drug shown below is Chlorothiazide, 5 4 6 10 3 9 2 7 8 1 a. presence of the double bond is essential for diuretic activity b. direct substitution on 4, 5, 8 position increases the diuretic activity c. removal of chloride improve activity d. loss of the = bound increase the diuretics activity (3=4) 137  20. ACE inhibitors are associated with a persistent dry cough due to a.Ihibition of metabolism of bradykinin b.Accumulation of histamine c.Release of prostaglandin d.Release of thromboxane 21.tolbutamide has a short duration of action due to Its lipid solubility Rapid metabolism by benzylic oxidation Rapid metabolism by ω-oxidation Slow metabolism by sulfur reduction 22. meglitinide O H3C O O OH N H Cl Stimulate beta cell for insulin release Can be given to sulfur sensitive patients Less toxic than benzene sulfonyl urea Stimulate beta cell, cause less allergy and less toxicities 138  N N 23. in acetazolamide, the H2NO2S S NH C CH3 O sulfamoyl group is essential for diuretic action heterocyclic ring is essential for activity sulfamoyl group and acetamide group is essential for activity sulfamoyl group and heterocyclic group is essential for activity O N In the design of captopril the HS COOH a. COOH group is introduced in proline to enhance binding to the receptor cationic site b. SH group is introduced to enhance binding to the zinc site c. SH group is introduced to enhance binding to the cobalt ion in the ACE d. a and b 29. Losartan is an angiotensin II receptor blockers. The phenyl tetrazole group Cl N a. is the basic group required for activity CH3(CH2)3 CH2OH N b. is the acidic group essential for activity c. enhance potency and metabolic stability d. b and c N N N NH Losartan 139  30. Which of the following is thiazide derivatives a.Furosemide b.Spironolactone c.Acetazolamide d.Chlorothiazide 31. An angiotensin converting enzyme inhibitor have SH group and cause loss of taste is a. losartan b.captopril c. enalapril d.valsartan 32. Loop diuretic that is good for sulfur sensitive patients is a.Thiazaide b.Furosemide n-- butyl group c.Ethacrynic acid d.Bumetanide N N 33.Based on the following pharmacophore for angiotensin II antagonists, which of the following statements is true? R all marketed products have an imidazole ring Acidic group 1.A phenyl tetrazole or a –COOH can be substituted for the acidic group 2.A benzyl group is not necessary for activity 3.They are peptide antagonists 140 141