Renal Drugs

UCL SCHOOL OF PHARMACY

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Structure/activity of key renal

drugs:

furosemide/ bendroflumethiazide

Dr Stephen Hilton


BRUNSWICK SQUARE Focus of the Lecture


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• Urinary system:

– Two kidneys

– Two ureters

– One bladder

– One urethra

– Each kidney has approximately one million

nephrons, which filter water and other

substances out of the blood to produce urine.

Renal Regulation


BRUNSWICK SQUARE The Nephron


BRUNSWICK SQUARE Mechanism of Action of Diuretics


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• Synthesized accidentally in an attempt to create more potent carbonic anhydrase inhibitors.

• They act by inhibiting sodium reabsorption at the cortex level, distal to the loop of Henle.

• They exert their effect from the luminal side of the nephron membrane thus, must be filtered to reach the site of action.

Thiazide and thiazide-like diuretics


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1. Mechanism

• Thiazide diuretics are absorbed from the

gastrointestinal (GI) tract and produce diuresis within

1—2 hours.

• They are secreted into the lumen of the proximal

tubule via an organic acid carrier.

• They exert effects only after reaching the lumen.

Thiazide diuretics


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Thiazides inhibit active reabsorption of sodium chloride (NaCl) in

the distal convoluted tubule by interfering with NCC (Na+—Cl-

cotransporter) a specific Na+/Cl- transport protein, resulting in the

net excretion of Na+ and an accompanying volume of water.

• These agents increase excretion of

» Cl-

» Na+

» K+

» at high doses, HCO3-

• They reduce excretion of calcium - Ca 2+.

Thiazide diuretics


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Thiazide diuretics can be derivatives of sulfonamides

(sulfonamide diuretics).

– Many also inhibit carbonic anhydrase, resulting in

diminished bicarbonate (HCO3-) reabsorption by the

proximal tubule.

Thiazide diuretics


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Therapeutic uses:

a) Thiazide diuretics are the preferred class of diuretic for

treatment of hypertension when renal function is

normal; they are often used in combination with other

antihypertensive agents to enhance their blood

pressure-lowering effects.

a) These agents reduce the formation of new calcium

stones in idiopathic hypercalciuria.

Thiazide diuretics


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c) Thiazide diuretics may be useful in patients with diabetes insipidus that is not responsive to antidiuretic hormone (ADH).

d) These agents are often used in combination with a potassium-sparing diuretic to manage:

– mild cardiac edema

– cirrhotic or nephrotic edema

– edema produced by hormone imbalances

– Ménière's disease (a disorder of the inner ear that can affect hearing and balance.)

Thiazide diuretics


BRUNSWICK SQUARE Thiazide diuretics

• Largest, most commonly prescribed class of diuretics

• Mechanism of action: to block Na+ reabsorption and

increase potassium and water excretion

• Primary use: to treat mild to moderate hypertension

– Also indicated to reduce edema associated with

heart, hepatic, and renal failure


BRUNSWICK SQUARE Thiazide development


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Chloramphenamide became a key intermediate in the

development of diuretics that lack the undesirable properties

of CA inhibitors

When chloramphenamide was treated with acylating agents,

cyclization resulted in the formation of thiazides. The use of

aldehydes or ketones in place of the acylating reagents

yielded the corresponding dihydro derivatives. The products

of these reactions became known as thiazides and

hydrothiazides, respectively.

The thiazides were the first orally effective saluretic agents

where diuretic activity was not influenced by the patient’s

acid-base status.



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They are generally medium potency diuretics.

The first thiazide in the market is chlorthiazide suffered poor GI absorption and low bioavailability.

Hydrochlorthiazide is the second member introduced to the market with higher bioavailability.

The main side effects are the possibility of inducing slight hyperglycemia and hyperlipidemia.



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• Thiazide like drugs don’t have true thiazide ring but share the same mechanism of action and chemically related.

• All members are available in oral forms except chlorthiazide ( oral and parentral): no clinical significance for their parentral forms.



BRUNSWICK SQUARE Thiazide and thiazide-like diuretics


BRUNSWICK SQUARE Thiazides – structure activity

1) The 2-position can tolerate small alkyl groups such as CH3. 2) Substituents in the 3-position determine the potency and duration of action of the thiazides. 3) Saturation of C-N bond between the 3 and 4 positions of the benzothiadiazine-1,1-dioxide nucleus increases the potency of this class of diuretics approximately 3-10 fold. 4) Direct substitution of the 4-, 5-, or 8-position with an alkyl group usually results in diminished diuretic activity, 5) Substitution of the 6-position with an activating group is essential for diuretic activity. The best substituent include Cl-, Br-, CF3-, and NO2- groups. 6) The sulfamoyl group in the 7-position is essential for diuretic activity.


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Physicochemical properties and SAR

N2 proton is acidic due to electron withdrawing effect

of sulphone group (pKa = 8.5). Sodium salt is water

soluble for i.v. administration.

Need electron withdrawing group at C6 (e.g. CF3) for

diuretic activity. CF3 substituent gives greater lipid

solubility and longer duration of action than Cl.

Loss of sulphonamide at C7 greatly reduced diuretic

activity. 3,4-dihydro derivatives 10x better diuretics

than unsaturated. Lipophilic group at C3 gives

increased potency.

Bendroflumethiazide


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ADME

Rapidly absorbed orally. Excreted primarily

unchanged into the urine

ADRs

Long-term use can cause hypokalaemia and

hypomagnesaemia.

Bendroflumethiazide


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Interactions

Increased risk of hyponatraemia with

carbamazepine. Enhances hypotensive effect of

other anti-hypertensives. Hypokalaemia may

increase toxicity of some anti-arrhythmics, risk of

arrhythmias with some anti-psychotics and beta-

blockers, and toxicity of cardiac glycosides.

Dosage form

2.5 mg o.m. Only tablet dosage form available.

Bendroflumethiazide


BRUNSWICK SQUARE Bendroflumethiazide


BRUNSWICK SQUARE Bendroflumethiazide retrosynthesis


BRUNSWICK SQUARE Bendroflumethiazide synthesis


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active in “loop” of Henle

Furosemide

Bumetanide

Torasemide

Ethacrynic acid

Loop diuretics - Furosemide


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edema: cardiac, pulmonary or renal

chronic renal failure or nephrosis

hypertension

hypercalcemia

acute and chronic hyperkalemia

Loop diuretics – Clinical use


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Mechanism:

• absorbed by the GI tract • eliminated by:

1. filtration 2. tubular secretion;

• some elimination occurs via the hepatic—biliary route.

• They are administered either orally or parenterally.

• Diuresis occurs within: – 5 minutes of intravenous (IV) administration – 30 minutes of oral administration.



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orally administered, rapid absorption

rapid onset of action

bound to plasma proteins: displaced by warfarin,

increase toxicity of cephalosporin antibiotics and lithium

additive toxicity with other ototoxic drugs

inhibitors of organic acid ion transport decrease potency (i.e.

probenecid, NSAID’s)

Loop diuretics - Pharmacokinetics


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Loop diuretics inhibit active NaCl reabsorption in the

thick ascending limb of the loop of Henle by inhibiting

NKCC2, a specific Na+/K+/2 Cl- cotransporter.

Because of the high capacity for NaCl reabsorption in

this segment, agents active at this site markedly

increase water and electrolyte excretion and are

referred to as high-ceiling diuretics.

These agents:

reduce reabsorption of Cl- and Na+ and increase K+, magnesium (Mg2+), and Ca2+ excretion.



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Furosemide is an acidic drug. It

contains a carboxylic acid

functional group that has a pKa

of 3.9.

Furosemide

The sulfonamide nitrogen is not basic as it does not have a lone pair of

electrons available to accept a proton

(sulfonamides are often weak acids).

The secondary amine is a very weak base

(lone pair is delocalised over the aromatic ring),

Does not behave as a base under physiological pH conditions


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Furosemide is an acidic drug. It

contains a carboxylic acid

functional group that has a pKa

of 3.9.

Furosemide

For an acidic drug, the higher the pH, (i.e. more basic)

the greater the proportion that will be deprotonated and

therefore negatively charged.

Acidic drugs are more soluble at high pHs, as a greater

proportion will be in the charged and highly polar form.

In dextrose saline at pH 4, approximately 50% of a dose

of furosemide will be protonated (-COOH) and 50%

deprotonated (-COO–).


BRUNSWICK SQUARE Furosemide Retrosynthesis


BRUNSWICK SQUARE Furosemide Synthesis


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Renal Drugs

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