Lesson 5.2. Antihypertensive Drugs

Descending Loop of Henle

Target of Osmotic Diuretics

hydroxyl groups (-OH)

Osmotic Diuretics are characterized by the presence of ____________________.

Mannitol

Osmotic Diuretic Drug

gold standard

Mannitol is the ______________ diuretic

Mannitol Structure

intraluminal osmotic pressure

Mechanism of Action of Osmotic Diuretics:

a. increases ______________________________

b. leading to more __________________ leading to more urine output.

a = ?

water in the tubule

Mechanism of Action of Osmotic Diuretics:

a. increases ______________________________

b. leading to more __________________ leading to more urine output.

b = ?

requires large doses for effectiveness

Disadvantage of Osmotic Diuretics

intracranial/intraocular pressure

Use of Osmotic Diuretics

Acetazolamide, Brinzolamide, Dorzolamide, Methazolamide

Drugs under Carbonic Anhydrase Inhibitors

C-5 position

SAR of Carbonic Anhydrase Inhibitors:

a. The ____________ must be unsubstituted for optimal activity.

b. The ________________ is essential for binding to the carbonic anhydrase enzyme.

c. The sulfamoyl group is attached to ____________________.

a = ?

sulfamoyl (-SO2 NH2) group

SAR of Carbonic Anhydrase Inhibitors:

a. The ____________ must be unsubstituted for optimal activity.

b. The ________________ is essential for binding to the carbonic anhydrase enzyme.

c. The sulfamoyl group is attached to ____________________.

b = ?

5-sided ring

SAR of Carbonic Anhydrase Inhibitors:

a. The ____________ must be unsubstituted for optimal activity.

b. The ________________ is essential for binding to the carbonic anhydrase enzyme.

c. The sulfamoyl group is attached to ____________________.

c = ?

Acetazolamide Structure

Brinzolamide Structure

Dorzolamide Structure

Methazolamide Structure

Proximal Convoluted Tubule

target of Carbonic Anhydrase Inhibitors

reabsorption of bicarbonate (HCO3)

MOA of Carbonic Anhydrase Inhibitors:

a. Inhibits carbonic anhydrase, so it blocks the ___________________________.

b. Leads to increased secretion of _______________________________, resulting in diuresis.

a = ?

Na, HCO3, and water

MOA of Carbonic Anhydrase Inhibitors:

a. Inhibits carbonic anhydrase, so it blocks the ___________________________.

b. Leads to increased secretion of _______________________________, resulting in diuresis.

b = ?

Glaucoma

Carbonic Anhydrase Inhibitors are useful in treating _______________ by reducing aqueous humor formation and intraocular pressure.

Hydrocholorothiazide, chlorothiazide

Drugs under Thiazides

Distal Convoluted Tubule

target of thiazides

benzothiadiazine

ring structure of thiazides

C3-C4 saturation

SAR of Thiazides:

a. ________________ increases activity by approximately 10-fold.

b. ________________ enhances diuretic potency and prolongs DOA.

c. ________________________________ essential for diuretic activity.

d. ________________ decreases polarity, leading to a longer DOA.

a = ?

C3 lipophilic substituent

SAR of Thiazides:

a. ________________ increases activity by approximately 10-fold.

b. ________________ enhances diuretic potency and prolongs DOA.

c. ________________________________ essential for diuretic activity.

d. ________________ decreases polarity, leading to a longer DOA.

b = ?

C6 EWG and C7 sulfonamide

SAR of Thiazides:

a. ________________ increases activity by approximately 10-fold.

b. ________________ enhances diuretic potency and prolongs DOA.

c. ________________________________ essential for diuretic activity.

d. ________________ decreases polarity, leading to a longer DOA.

c = ?

N2 substitution

SAR of Thiazides:

a. ________________ increases activity by approximately 10-fold.

b. ________________ enhances diuretic potency and prolongs DOA.

c. ________________________________ essential for diuretic activity.

d. ________________ decreases polarity, leading to a longer DOA.

d = ?

HTN (alone/combination), edema related to heart, liver, and renal diseases

Use of Thiazides

Na/Cl Cotransporter (NCC)

MOA of Thiazides:

a. Inhibits ____________________ which increases the release of these ions in the urine.

b. Decreases ____________________, leading to increased urinary excretion of these ions.

c. Reduces _________________ by enhancing its reabsorption in the DCT, which may cause hypercalcemia.

d. The resulting _________________________ can potentiate digoxin toxicity.

a = ?

reabsorption of K and Mg

MOA of Thiazides:

a. Inhibits ____________________ which increases the release of these ions in the urine.

b. Decreases ____________________, leading to increased urinary excretion of these ions.

c. Reduces _________________ by enhancing its reabsorption in the DCT, which may cause hypercalcemia.

d. The resulting _________________________ can potentiate digoxin toxicity.

b = ?

calcium excretion

MOA of Thiazides:

a. Inhibits ____________________ which increases the release of these ions in the urine.

b. Decreases ____________________, leading to increased urinary excretion of these ions.

c. Reduces _________________ by enhancing its reabsorption in the DCT, which may cause hypercalcemia.

d. The resulting _________________________ can potentiate digoxin toxicity.

c = ?

hypokalemia and hypomagnesia

MOA of Thiazides:

a. Inhibits ____________________ which increases the release of these ions in the urine.

b. Decreases ____________________, leading to increased urinary excretion of these ions.

c. Reduces _________________ by enhancing its reabsorption in the DCT, which may cause hypercalcemia.

d. The resulting _________________________ can potentiate digoxin toxicity.

d = ?

Hydrochlorothiazide Structure

Chlorothiazide Structure

Indapamide Structure

Thick Ascending Loop

Target of Loop Diuretics

Furosemide, Torsemide, Bumetanide, Ethacrynic Acid

Drugs of Loop Diuretics

thiazides

SAR of Loop Diuretics:

a. Sulfonamide-containing diuretics similar to ___________________.

b. known as _________________________.

c. has a _______________________.

a = ?

high-ceiling loop diuretics

SAR of Loop Diuretics:

a. Sulfonamide-containing diuretics similar to ___________________.

b. known as _________________________.

c. has a _______________________.

b = ?

fast onset, short DOA

SAR of Loop Diuretics:

a. Sulfonamide-containing diuretics similar to ___________________.

b. known as _________________________.

c. has a _______________________.

c = ?

Na/K/Cl cotransporter

MOA of Thiazides:

a. Inhibits ______________________

b. Leads to loss of ____________________________, which leads to diuresis

a = ?

Na, Cl, Ca, and Mg

MOA of Thiazides:

a. Inhibits ______________________

b. Leads to loss of ____________________________, which leads to diuresis

b = ?

pulmonary edema, HTN

Use of Loop Diuretics

Furosemide Structure

Bumetanide Structure

Torsemide Structure

Ethacrynic Acid Structure

Spirinolactone and Eplerenone

Potassium-sparring Diuretics (Hormone-derived) drugs

Amiloride and Triamterene

Potassium-sparring Diuretics (Synthetic) drugs

aldosterone

MOA of K-sparring Diuretics:

a. Hormone-Derived: inhibits _________________ leading to K retention and Na and H2O secretion

b. Synthetic: inhibits ___________________ in CD, leads to Na and H2O excretion and indirectly decrease K excretion.

a = ?

Epithelial Na co-transporter (ENaC)

MOA of K-sparring Diuretics:

a. Hormone-Derived: inhibits _________________ leading to K retention and Na and H2O secretion

b. Synthetic: inhibits ___________________ in CD, leads to Na and H2O excretion and indirectly decrease K excretion.

b = ?

steriodal

The _____________ structure of K-sparring diuretics may cause sex-related changes.

Spironolactone Structure

Eplerenone Structure

Amiloride Structure

Triamterene Structure

Nifedipine, Amlodipine, and Felodipine

Calcium Channel Blockers that are Dihydropyridines (DHP)

Diltiazem

Calcium Channel Blockers that are Benzothiazepine

Verapamil

Calcium Channel Blockers that are Phenylalkylamine

L-type Ca channel

MOA of Calcium Channel Blockers:

a. blocks ___________________ which decreases Ca influx, leading to vascular relaxation.

b. _________ promotes vasodilation without cardiac effects

c. _________ promotes vasodilation and reduces heart rate

a = ?

DHP

MOA of Calcium Channel Blockers:

a. blocks ___________________ which decreases Ca influx, leading to vascular relaxation.

b. _________ promotes vasodilation without cardiac effects

c. _________ promotes vasodilation and reduces heart rate

b = ?

Non-DHP

MOA of Calcium Channel Blockers:

a. blocks ___________________ which decreases Ca influx, leading to vascular relaxation.

b. _________ promotes vasodilation without cardiac effects

c. _________ promotes vasodilation and reduces heart rate

c = ?

IHD, HTN, Angina management

use of Calcium-Channel Blockers

para-position

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

a = ?

X can be an ortho- or meta-

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

b = ?

C2/C6

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

C = ?

Unsubstituted N1

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

d = ?

symmetrical esters

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

e.1. = ?

asymmetrical esters

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

e.2. = ?

phenyl ring

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

f.1. = ?

nonplanar alkyl/cycloalkyl group

SAR of Calcium Channel Blockers:

a. ______________ of the phenyl substituent must remain unsubstituted.

b. ______________ of the phenyl substituent are for optimal activity; if bulky is used, it will lock at a C4 perpendicular orientation.

c. 1,4 DHP can tolerate larger substitutions at ________________ for enhanced activity.

d. _______________ is essential for activity.

e. In C3/C5 position, 1.____________ optimize activity while 2. _______________ enhance selectivity.

f. In C4, 1._______________ is for optimal activity while 2.___________________ decrease activity.

f.2. = ?

Nifedipine Structure

Amlodipine Structure

Felodipine Structure

Nicardipine Structure

Diltiazem Structure

Verapamil Structure

RAAS Drugs

agents that act on the renin-angiotensin-aldosterone-system

Angiotensin-Converting Enzyme Inhibitor (ACE Inhibitor)

Most agents are prodrugs and are hydrolyzed to active from(-prils to-prilats).

Severe Dry Cough and Hyperkalemia

ADR of ACE Inhibitors

Enalapril, Captopril, Lisinopril, Fosinopril

Drugs under ACE Inhibitors

angiotensin I to angiotensin II

MOA of ACE Inhibitors:

a. blocks the conversion of _________________________.

b. inhibits metabolism of ______________= leads to vasodilation.

a = ?

bradykinin

MOA of ACE Inhibitors:

a. blocks the conversion of _________________________.

b. inhibits metabolism of ______________= leads to vasodilation.

b = ?

hydrolysis

Metabolism of ACE Inhibitors:

a. for activation

b. for Fosinopril

a = ?

glucuronidation

Metabolism of ACE Inhibitors:

a. for activation

b. for Fosinopril

b = ?

Captopril Structure

Captopril

fastest acting ACEI that may form dimers with cysteine

Lisinopril Structure

Lisinopril

excreted in the urine unchanged

Enalapril Structure

Enalapril

ester prodrug need activation and is excreted in the urine unchanged

Fosinopril Structure

Fosinopril

ester prodrug need activation and undergoes glucuronidation

-COOH

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. _____________ of carboxylate or phosphate results to prodrug structure.

a.1. = ?

large heterocyclic rings

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. Esterification of carboxylate or phosphate results to prodrug structure.

a.2. = ?

Zn binding

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. _____________ of carboxylate or phosphate results to prodrug structure.

b = ?

-SH

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. ______________ of carboxylate or phosphate results to prodrug structure.

b.1. = ?

X (-CH3)

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. ______________ of carboxylate or phosphate results to prodrug structure.

c = ?

Esterification

SAR of ACE Inhibitors:

a. N-ring:

1. must have _________ for binding at the ACE cationic sites

2. ________________________ = enhances potency

b. _________________ = essential for activity

1. __ are superiors in Zn-binding (but may cause skin rashes and loss of taste)

c. _____________ is useful for stereochemistry

d. ______________ of carboxylate or phosphate results to prodrug structure.

d = ?