Lecture 1 - Hypertension_Diuretics PDF

Drugs and Diseases of the Cardiovascular/Renal Systems 1 Textbooks Foye’s Principles of Medicinal Chemistry, 7 th ed., Chapter 37 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12 th...

Drugs and Diseases of the Cardiovascular/Renal Systems 1 Textbooks Foye’s Principles of Medicinal Chemistry, 7 th ed., Chapter 37 Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12 th ed., Chapter 10 Some slides are courtesy of Dr. S. W. Zito  General Information Dr. Aaron Muth [email protected] Office: St. Albert Hall, Room B26 WebEx Room: https://sju.webex.com/meet/mutha Office hours: – Mondays and Thursdays from 10 am to 11:30 am – Or by appointment 2 Drugs for the Treatment of Hypertension 3  Overview of Antihypertensives Diuretics – Carbonic anhydrase inhibitors – High-ceiling or loop diuretics – Thiazides and thiazide-like diuretics – Potassium-sparing diuretics – Osmotic diuretics Angiotensin-converting enzyme inhibitors (ACEIs) Angiotensin II receptor antagonists (ARBs) Sympatholytics – β-adrenergic blocking agents – Centrally acting alpha-agonists – Adrenergic neuron blockers – α-adrenergic blockers Calcium-channel blockers (CCBs) Vasodilators 4  Diuretics Definition: An agent that increases the rate of urine formation, primarily by decreasing the reabsorption of Na + ions and their osmotic equivalent of water from the kidney tubules. Major Uses: – Mild hypertension – Treat edema caused by CHF – Treat edema cause by renal and liver disorders 5  Diuretics The main functions of the kidney are: 1. To regulate the volume and composition of body fluids 2. To maintain the pH of the body fluids 3. To eliminate the water-soluble metabolic nonelectrolytes 6  Diuretics The Nephron – Basic functional unit of the kidney. There are 2 million nephrons in the kidneys, each of which is made of 3 functional parts 1. Glomerulus enclosed in Bowman’s capsule 2. Renal tubule Proximal convoluted tubule (PCT) – 3 segments (S1, S2, S3) Loop of Henle – Descending limb (DLH) – Thick ascending limb (TALH) – Distal convoluted tubule (DCT) 3. Collecting tubule 7  Diuretics Classification of Diuretics based on their site of action – Proximal Convoluted Tubule (PCT) Carbonic anhydrase inhibitors – acetazolamide Osmotic diuretics – mannitol, urea – Thick Ascending Loop of Henle (TALH) High-ceiling or loop diuretics – Furosemide – Distal Convoluted Tubule (DCT) Thiazides and Thiazide-like diuretics – Hydrochlorothiazide – Collecting Duct (CD) Potassium-Sparing Diuretics - Spironolactone 8  Diuretics PCT Diuretics: Carbonic Anhydrase Inhibitors O H2N S NH2 O Sulfanilamide originally introduced as an antibacterial agent was observed to produce a mild diuresis. It was then discovered that it produced this effect by inhibiting the renal carbonic anhydrase enzyme Carbonic anhydrase catalyzes the hydration of CO2 to carbonic acid (also reverse dissociation). Carbonic acid gets ionized to form H+ and HCO3- CO2 + H2O H2CO3 H + HCO3 9  Diuretics Sulfanilamide was used as a lead compound and extensive SAR studies were conducted SAR studies showed that the sulfonamide N must be unsubstituted for diuretic activity O H2N S NH2 O Mechanism of inhibition of carbonic anhydrase is probably due to the similarity in structure between carbonic acid (H 2CO3) and the sulfamoyl group of sulfanilamide (SO2NH2), allowing competitive binding of the sulfonamide at the active site of carbonic anhydrase 10  Diuretics R 1 O C O H 4 1 O S N H 4 O O H H 3 3 2 2 Binding of carbonic anhydrase and sulfonamide at the hypothetical enzyme active site 11 12  Diuretics SAR studies using sulfanilamide as a lead compound led to two groups of carbonic anhydrase inhibitors: 1. Simple heterocyclic sulfonamides H2NO2S heteroaromatic ring NHR 2. Meta-disulfamoylbenzene derivatives 5 4 6 3 1 H2NO2S SO2NH2 2 13  Diuretics SAR of simple heterocyclic sulfonamides H3COCHN S SO2NH2 H3COCN S SO2NH2 N N N N H3C Acetazolamide Methazolamide (Diamox) (generic) NHCH2CH3 NHCH2CH3 SO2NH2 SO2NH2 H3C S H3CO(H2C)3 S O O O O Dorzolamide Brinzolamide (Azopt) (Truspot) H2NO2S heteroaromatic ring NHR 14  Diuretics Acetazolamide (Diamox®) S H3COCHN SO2NH2 N N – The sulfamoyl group is essential for inhibition of CA – The sulfamoyl nitrogen atom must remain unsubstituted to retain diuretic activity – Substitution of a methyl group on one of the ring nitrogens led to a more potent inhibitor of carbonic anhydrase (methazolamide) – Within a given series of heterocyclic sulfonamides, the derivatives with highest PC and the lowest pKa have the greatest CA-inhibitory activity 15 SAR of meta-disulfamoylbenzene derivatives meta-Disulfamoylbenzenes R2 R1 R3 H2N NH2 S S O O O O Cl Cl H2N Cl H2N NH2 H2N NH2 S S S S O O O O O O O O Dichlorophenamide Chloraminophenamide (Daranide) Precursor to the Thiazide Diuretics 16  Diuretics They can also be used to alkalinize the urine to increase the rate of excretion of noxious weak acids, or to maintain the solubility of certain endogenously produced weak acids (e.g. uric acid which has poor water solubility) Adverse effects – Metabolic acidosis – Hypokalemia – Sulfonamide-like hypersensitivity reactions (uticaria, drug fever, blood dyscrasias, etc.) 17  Diuretics DCT Diuretics: Thiazides and Thiazide-like Diuretics – These were developed from the study of meta-disulfamoylbenzenes as diuretics when an amide substituent was introduced at the ortho position of chloraminophenamide. This could be cyclized to give chlorothiazide leading to a new class of diuretics – 1,2,4-benzothiadiazine-1,1-dioxides – commonly referred to as thiazides – Cyclization with aldehydes or ketones in place of acylating agents leads to the corresponding dihydro derivatives - hydrothiazides O H Cl NH cyclized Cl N NH2 NH H2NO2S S H2NO2S S O O O O 3-chloro-4,5-disulfamoylformanilide 18  Diuretics Structure-Activity Relationships R N R1 6 5 4 3 2 7 8 1 N H2NO2S S R2 O O – For optimal activity 1. Sulfonamide group at position 7 is necessary (unsubstituted preferred) 2. At position 6, an electron withdrawing group (e.g., halogen or CF 3 is necessary) 19  Diuretics R N R1 6 5 4 3 2 7 8 1 N H2NO2S S R2 O O SAR continued 3. Substitution at positions 4, 5, or 8 decreases the activity 4. Saturation of 3,4 double bond increases the diuretic activity (~10-fold) 5. Lipophilic substitution at position 3 increases activity as well as the duration of action 6. Alkyl substitution at position 2 also increases the duration of action as well as decreases the polarity 7. Position 1 of the heterocyclic ring can be a sulfonyl or a carbonyl group…creating the class of Thiazide-like diuretic drugs (e.g., Quinazolinones) 20  Diuretics Products: A. Thiazide analogues (double bond between position 3 and 4) R N R1 6 5 4 3 2 7 8 1 N H2NO2S S R2 O O R R1 R2 Chlorothiazide (Diuril ®) -Cl H H Benzthiazide (Exna ®) -Cl -CH2SCH2O H 21  Diuretics Products (continued) B. Hydrothiazide analogues (no double bond between positions 3 and 4) H R N R1 N H2NO2S S R2 O O Hydrochlorothiazide (Hydrodiuril ®) -Cl H H Hydroflumethiazide (Saluron ®) -CF3 H H Bendroflumethiazide (Naturetin ®)-CF3 -CH2O H Trichlormethiazide (Naqua ®) -Cl -CH2Cl -CH3 Methyclothiazide (Enduron ®) -Cl -CH2Cl -CH3 Polythiazide (Renese ®) -Cl -CH2SCH2CF3 -CH3 22 Cyclothiazide (Anhydron ®) -Cl norbornene H  Diuretics Representatives from Thiazide-Like Diuretics Substituted meta-Disulfamoylbenzene Salicylanilide Cl Cl OH CH3 CH3 H N N H2NO2S S O H2NO2S CH3 O O O H3C Mefruside Xipamide (Baycaron) (Aquaphor, Diurexan) Benzhydrazides Cl Cl CH3 CH3 H H N N H2NO2S N H2NO2S N O O H3C Clopamide Indapamide (Aquex, Brinaldix) (Lozol) 23  Diuretics Representatives from Thiazide-like Diuretics Tetrahydroquinazolinones H H Cl N CH2CH3 Cl N CH3 NH N H2NO2S H2NO2S O O H3C Quinethazone Metolazone (Hydromox) (Diulo, Zaroxolyn) 1-Oxoisoindole Phthalmidine Cl Cl N OH H2NO2S H2NO2S O HN O Clorexolone Chlorthalidone 24 (Nefrolan) (Hygroton, Thalitone)  Diuretics Pharmacokinetics – Most thiazides and thiazide-like drugs are well absorbed orally (except chlorthiazide, 10% absorption) – They have rapid onset (1-2 hrs) and a peak effect between 3-6 hrs – Most drugs in this class are extensively protein bound – They achieve high luminal fluid concentrations by a combination of glomerular filtration and by OATS in the proximal tubule where they inhibit the Na+/Cl- co-transport system – Thiazides differ primarily in their potency and duration of action Difference in potency (reflected in their dosages) is determined by the lipophilicity of the substituent at position 3 The difference in duration of action is dictated by the degree of plasma binding as well as the lipophilicity of the molecule 25  Mechanism of action · Thiazides and thiazide-like diuretics block the reabsorption of the sodium ions in the distal convoluted tubule by blocking the Na+/Cl- cotransporter 26  Diuretics CD Diuretics: Potassium Sparing Diuretics – There are three chemically distinct diuretics which act at the CD Aldosterone antagonists (discussed in more detail for Heart Failure) Pteridines Aminopyrazines – The drugs in this category inhibit sodium ion reabsorption without promoting a urinary loss of potassium ions, and are therefore referred to as “potassium-sparing diuretics” 27  Diuretics b. Pteridines c. Aminopyrazines NH2 O NH2 Cl N Cl N N N NH2 H H2N N N NH2 H2N N NH2 Triamterene Amiloride HCl (Dyrenium) (Midamor) Triamterene and amiloride inhibit the sodium ion reabsorption at CD site, by a mechanism other than aldosterone antagonism (they “plug” the Na+ channels in the luminal membranes) 28  Diuretics Both triameterene and amiloride are weak organic bases, and they reach the luminal fluid by glomerular filtration and active tubular secretion (OCTS) The most serious side effect of these drugs is hyperkalemia, and therefore potassium supplements are contraindicated Triameterene is unique among K+ sparing diuretics in forming renal stones. It is not given to patients with impaired renal function Their primary use is in conjunction with site 2 or site 3 diuretic drugs to improve diuresis, and prevent excessive K+ loss 29  Calcium Channel Blockers Introduction – Role of calcium in muscle contraction Cytosolic Ca2+ binds to troponin C (cardiac) or calmodulin (smooth muscle) uncovering myosin binding sites on the actin molecule Subsequent interaction vs actin and myosin results in muscle contraction – Mechanism of calcium movement and storage 1. Receptor Operated Channel 2. Na+/Ca2+ exchange 3. Leak process 4. Potential Dependent Channel – a.k.a. voltage dependent – Site for Ca2+ channel blocker 5. ATP-driven Ca2+ pump 6. Mitochondria storage 7. Sacroplasmic reticulum storage – Sites 1 and 4 primary channels 30  Calcium Channel Blockers SAR of the calcium channel blockers – Chemical classificiation 1,4-dihydropyridines (nifedipine, 1,4-DHPs) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Diaminopropanol ethers (bepridil) – The 1,4-dihydropyridines are the majority – The others are actually the only examples of their class and thus have no SAR H H 3C N CH3 S N CH3 O O N H3CO2C CO2CH3 H3CO N CN N NO2 OO CH(CH3)2 H3CO CH2N(CH3)2 Nifedipine Verapamil Diltiazem Bepridil 31  Calcium Channel Blockers SAR of 1,4-DHPs – 4-phenyl necessary, pyridine, cycloalkyl NG – X: ortho and or meta substituents H Keeps rings perpendicular R1 N CH3 – 1,4-DHP is essential, pyridine, or piperidine NG 5 – R2 and R3 4 R2 R3 Esters optimize activity C3 and C5 are not equivalent, the C3-carbonyl is synplanar to the C2-C3 bond. The C5-carbonyl is antiperiplanar X – R1 Usually CH3 Amino ethanol ether (Amlodipine) enhances solubility (salt formation) and increases potency 32  Structure Challenge H H H H3C N CH3 H3 C N CH3 H2N N CH3 O H3CO2C CO2CH3 C2H5O2C CO2CH3 H3CO2C CO2CH3 NO2 Cl Cl Cl Nifedipine Felodipine Amlodipine H H H3 C N CH3 H3C N CH3 O O O CO2CH(CH3)2 CO2CH3 O O NO2 NO2 Nimodipine Nisoldipine H H H3C N CH3 H3C N CH3 CH3 O N O CO2CH3 CO2CH3 O N O O N NO2 Isradipine Nicardipine 33  Calcium Channel Blockers Physicochemical properties – All chemical classes are basic but 1,4-DHPs are less basic (except amlodipine and nicardipine…why?) At physiological pH 1,4-DHPs are unionized while the others are ionized Reason: the N in1,4-DHPs is conjugated to the esters – All are lipophilic (unionized form) with good oral bioavailability Within 1,4-DHPs, the lipophilicity is enhanced by larger esters and disubstituted phenyl rings – All except nifedipine contain at least one chiral carbon. However, they are used as racemic mixtures…impact upon activity not known The S (-) enantiomer of verapamil is more potent than the R (+) enantiomer – The cis arrangement of the acetyl ester and the phenyl ring is essential for diltiazem activity S O N OO CH2N(CH3)2 34  Calcium Channel Blockers Metabolism – All undergo extensive first pass metabolism H N-demethylation H3C N CH3 aromatized to pyridine 3A4; 10% activity inactive; grapefruit juice CH3 H3CO2C CO2CH3 H3CO N CN NO2 CH(CH3)2 H3CO Nifedipine Verapamil hydroxylation site hydrolysis N S 25-50% activity O N O N OO CH2N(CH3)2 Diltiazem Bepridil 35