Med Chem Spring Lec 6

Front 1

Approximately 98% of electrolytes and water filtered by the ____ is glomerulusis reabsorbed before leaving the ______ as urine

Back 1

glomerulusis reabsorbed before leaving the nephronas urine

Front 2

What are Diuretics? What do they increase

Back 2

Diuretics are chemicals that increase the rate of urine formation

Front 3

By increasing the urine flow rate, diuretic usage leads to increased what? Of what?

Back 3

leads to increased excretion of electrolytes (especially sodium and chloride ions) and water from the body without affecting protein, vitamin, glucose, or amino acid reabsorption.

Front 4

Diuretic drugs are used primarily to treat two medically important conditions, ____ and ___?

Back 4

edema and hypertension

Front 5

One key element in controlling blood pressure is what? What kind of drugs are related to this?

Back 5

sodium ion, and early antihypertensive effects of diuretics are related to increased salt and water excretion.

Front 6

The diuretics currently in use today (Table) are classified by what 4 components?

Back 6

by their chemical class (thiazides), mechanism of action (carbonic anhydrase inhibitors and osmotics), site of action (loop diuretics), or effects on urine contents (potassium-sparing diuretics

Front 7

Osmotic diuretics are what kind of solutes? Are they metabolized?

Back 7

are are nonreabsorbable solutes, and are not extensively metabolized.

Front 8

Once in the renal tubule, osmotic diuretics have a limited reabsorption because why?

Back 8

of their high water solubility

Front 9

When administered as a hypertonic (hyperosmolar) solution, these agents increase what?

Back 9

intraluminal osmotic pressure

Front 10

When administered as a hypertonic (hyperosmolar) solution, these agents increase intraluminal osmotic pressure, causing what to happen?

Back 10

causing water to pass from the body into the tubule.

Front 11

Osmotic diuretics increase what and what?

Back 11

the volume of urine and the excretion of water and almost all of the electrolytes.

Front 12

What is the agent most commonly used as an osmotic diuretic? What else is used?

Back 12

Mannitol

Sorbitol

Front 13

How are Mannitol and Sorbitol compounds prepared?

Back 13

by the electrolytic reduction of glucose or sucrose

Front 14

Mannitol is administered how?

Back 14

intravenously in solutions of 5 to 50% at a rate of administration that is adjusted to maintain the urinary output at 30 to 50 ml/hour

Front 15

Mannitol is filtered where? Where is it reabsorbed?

Back 15

glomerulus and is poorly reabsorbed by the kidney tubule

Front 16

The osmotic effect of mannitol in the tubule inhibits what? What can be maintained? What else is it used to reduce?

Back 16

inhibits the reabsorption of water, and the rate of urine flow can be maintained

also is used to reduce intracranial pressure by reducing cerebral intravascular volume.

Front 17

_______ is basically a bicyclic form of sorbitol that is used orally to cause a reduction in intraocular pressure in glaucoma cases

Back 17

Isosorbide

Front 18

Carbonic anhydrase inhibitors induce ____ by inhibiting the formation of what?

Back 18

induce diuresis by inhibiting the formation of carbonic acid within proximal and distal tubular cells to limit the number of hydrogen ions available to promote sodium reabsorption.

Front 19

With prolonged use of the carbonic anhydrase inhibitor diuretics, the urine becomes more ____ and the blood becomes more ___?

Back 19

alkaline

acidic

Front 20

When does , the carbonic anhydrase inhibitors lose their effectiveness as diuretics?

Back 20

When acidosis occurs

Front 21

_________ was the first of the carbonic anhydrase inhibitors to be introduced as an orallyeffective diuretic, with a diuretic effect that lasts approximately 8 to 12 hours .

Back 21

Acetazolamide

Front 22

The other three drugs are for oral treatment of glaucoma only, what are they?

Back 22

Dichlorphenamide

Ethoxzolamide

Methazolamide

Front 23

______ is a derivative of acetazolamide in which one of the active hydrogens has been replaced by a methyl group

Back 23

Methazolamide

Front 24

What does Methazolamide decrease? What does it permit?

Back 24

This decreases the polarity and permits a greater penetration into the ocular fluid,

Front 25

______ is another carbonic anhydrase inhibitor with properties and uses resembling those of acetazolamide.

Back 25

Ethoxzolamide

Front 26

_______ is a disulfonamide derivative that shares the same pharmacological properties and clinical uses as the previously discussed compounds?

Back 26

Dichlorphenamide

Front 27

The mechanism of action of the benzothiadiazine or thiazide diuretics is primarily related to their ability to inhibit what?

Back 27

inhibit the Na+/Cl- symporter located in the distal convoluted tubule

Front 28

These diuretics are actively secreted in the _____ and are carried to the ___ of ___ and to the ____ ____

Back 28

proximal tubule and are carried to the loop of Henle and to the distal tubule.

Front 29

These diuretics are actively secreted in the proximal tubule and are carried to the loop of Henle and to the distal tubule. The major site of action of these compounds is in the ___ ___?

Back 29

distal tubule

Front 30

The major site of action of these compounds is in the distal tubule, where these drugs compete for which binding site?

Back 30

chloride binding site of the Na+/Cl-
symporter

Front 31

The major site of action of these compounds is in the distal tubule, where these drugs compete for the chloride binding site of the Na+/Cl-
symporter and inhibit there absorption ____ and ____?

Back 31

of sodium and chloride ions

Front 32

The major site of action of these compounds is in the distal tubule, where these drugs compete for the chloride binding site of the Na+/Cl-
symporter and inhibit there absorption of sodium and chloride ions. For this reason, they are referred to as _______

Back 32

saluretics.

Front 33

The thiazide diuretics are weakly ___

Back 33

acidic

Front 34

Chlorothiazide is the simplest member of this series, having a pKa of what?

Back 34

6.7 and 9.5.

Front 35

. Chlorothiazide is the simplest member of this series, having a pKa of 6.7 and 9.5. The hydrogen atom at ____ is the most acidic

Back 35

N2

Front 36

Chlorothiazide is the simplest member of this series, having a pKa of 6.7 and 9.5. The hydrogen atom at N2 is the most acidic because why?

Back 36

the electron-withdrawing effects of the neighboring sulfone group.

Front 37

The hydrogen atom at N2 is the most acidic because of the electron-withdrawing effects of the neighboring sulfone group. The sulfonamide group that is sub-stituted at ____provides an additional point of acidity in the molecule but is less acidic than the N2 proton.

Back 37

c7

Front 38

The thiazide diuretics are weakly acidic. Chlorothiazide is the simplest member of this series, having a pKa of 6.7 and 9.5. The hydrogen atom at N2 is the most acidic because of the electron-withdrawing effects of the neighboring sulfone group. The sulfonamide group that is sub-stituted at C7 provides an additional point of acidity in the molecule but is less acidic than the N2 proton. These acidic protons make possible the fomation of a water-souble sodium salt that can be used to be administered how?

Back 38

intravenous administration of the diuretics.

Front 39

Thiazide SAR

An _____-_____ group is necessary at position _ for diuretic activity

Back 39

electron-withdrawing group

Front 40

Little diuretic activity is seen with a hydrogen atom at position 6, whereas compounds with a _____ or _____ substitution are highly active.

Back 40

chloro or trifluoromethyl

Front 41

Thiazide SAR

The _________-substituted diuretics are more lipid-soluble and have a longer duration of action than their ____-substituted analogues.

Back 41

trifluoromethyl

chloro

Front 42

Thiazide SAR

When electron-releasing groups, such as methyl or methoxyl, are placeda t position 6, the diuretic activity is markedly ____

Back 42

reduced

Front 43

Thiazide SAR

Replacement or removal of the sulfonamide group at position 7 yields compounds with _____or __ _____ activity

Back 43

little or no diuretic activity.

Front 44

Thiazide SAR

Saturation of the double bond to give a________produces a diuretic that is 10-fold more active than the unsaturated derivative

Back 44

3,4-dihydroderivative

Front 45

Thiazide SAR

Substitution with alipophilic group at position 3 gives a marked what to the potency?

Back 45

increase

Front 46

Thiazide SAR

Haloalkyl, benzyl, or thioether substitution at 3 increases what? What does it yield?

Back 46

the lipid solubility of the molecule and yields compounds with a longer duration of action

Front 47

Thiazide SAR

Alkyl substitution on the __ position also decreases the polarity and increases the duration of diuretic action.

Back 47

N2

Front 48

High-Ceiling (Loop) Diuretics

. Furosemide was the earliest discovered drug and may be regarded as a derivative of ___ or ___

Back 48

anthranilic acid or o-aminobenzoic acid

Front 49

Why is furosemide a stronger acid than the thiazide diuretics (pKa= 3.9).

Back 49

Because the molecule possesses a free carboxyl group

Front 50

The adrenal cortex secretes the mineralo corticoid called _____

Back 50

aldosterone

Front 51

The adrenal cortex secretes the mineralo corticoid called aldosterone, which promotes ____ and ____ retention and ____ and ____ excretion

Back 51

which promotes salt and water retention and potassium and hydrogen ion excretion.

Front 52

Other mineralocorticoids have an effect on the electrolytic balance of the body, but aldosterone is the most potent. Its ability to cause increased in what 2 components?

Back 52

cause increased reabsorption of sodium and chloride ion and increased potassium ion excretion is approximately 3,000-fold that of hydrocortisone

Front 53

A substance that antagonizes the effects of aldosterone could conceivably be a good diuretic drug. What is a good antagonist of this?

Back 53

Spironolactoneis such an antagonist.

Front 54

Spironolactoneis metabolized to ____, which is suspected to geneate most of the ___ _____ activity?

Back 54

canrenone, which is supected to generate most of the aldosterone antagonist activity.

Front 55

________interferes with the process of cationic exchange by blocking luminal sodium channels in the late distal convoluted tubule and collecting duct.

Back 55

Triamterene

Front 56

Triamterenei nterferes with the process of cationic exchange by blocking luminal sodium channels in the late distal convoluted tubule and collecting duct. Sodium channel inhibitors block the reabsorption of what and inhibit the secretion of what?

Back 56

of sodium ion and inhibit the secretion of potassium ion.

Front 57

Sodium channel inhibitors block the reabsorption of sodium ion and inhibit the secretion of potassium ion. Aldosterone is not antagonized by triamterene. The net result is increased what?

Back 57

sodium and chloride ion excretion in the urine and almost no potassium excretion.

Front 58

______ another potassium-sparing diuretic, is anaminopyrazine structurally related to Triamterene as an open-chain analogue.

Back 58

Amiloride,