Diuretics

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 Diuretics
Chemicals that increase the rate of urine formation and
Sodium excretion.

Are used to adjust the volume and/or composition of

body fluids in a variety of clinical situations, including
HTN, HF, renal failure, nephrotic syndrome, and cirrhosis

Kidney: make 0.5% of total body Wt; consume 7% of

total body oxygen

Nephron: basic urine forming unit

Constitutes: glomerulus & long tubular portion

RBF: 650ml/min, GFR = 125ml/min only 1ml/min of urine formed
 Proximal tubule
65% of filtered Na+ reabsorbed
Transport mechanisms: Na+H+-exchange, Na+-
phosphate , Na+-glucose, Na+-lactate, and Na+amino
acid cotransport
Na+H+- exchange is the primary mechanism (40%)
Highly permeable to water /isotonic re-absorption/
It is the site of organic acid transport (secretion)
Most of the K+ filtered is reabsorbed by proximal tubules.
Less diuretic potential
Several transport proteins mediate reabsorption
Compensatory reabsorption in the more distal portions
reduces the impact of diminished upstream Na+ recovery
Carbonic anhydrase-mediated Na+-H + exchange in
proximal convoluted tubule

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Loop of Henle
25% of filtered load of Na+ reabsorbed.
Thin descending limb (TDL): permeable to
water, permeability to NaCl & urea is low
Thick ascending limb (TAL): permeable to NaCl
but is impermeable to water
 Thick ascending limb (TAL):
25% of the filtered sodium is reabsorbed
Transport is mediated by Na+-K+-2Cl- cotransport
Little net K+ reabsorption occurs
Na+ reabsorbed by TAL increases as more is
delivered
Tubular fluid becomes dilute as it passes through
the TAL
Impermeable
to water
 Distal convoluted tubule (DCT)

5-8 % of filtered Na+ reabsorbed

/actively/
Reabsorption is mediated by Na+-
Cl- cotransport
Water permeability of the DCT is
regulated by antidiuretic hormone
(ADH, or vasopressin).
The main source of urinary K+ is
tubular secretion by DCT and
collecting ducts
There is a reciprocal relation between
the direction and magnitude of ca++
and Na+ transport
 Collecting duct
2 to 5% of filtered Na+ reabsorbed.

Electrolyte composition: modulated

by aldosterone

Water permeability: modulated

by ADH. In the absence of ADH, the

collecting ducts are essentially
impermeable to water.
 CLASSIFICATION
1. High efficacy diuretics :- loop diuretics

2. Medium efficacy diuretics:- Thiazide diuretics.

3. Weak or adjunctive diuretics

(a) Carbonic anhydrase inhibitors .Acetazolamide

(b) Potassium sparing diuretics

(i) Aldosterone antagonist: Spironolactone

(ii) Inhibitors of renal epithelial Na+ channel: Triamterene

(c) Osmotic diuretics :-Mannitol.

 I. loop Diuretics
Also called high ceiling diuretics,
high efficacy diuretics

Drugs: Furosemide, Torasemide,

Ethacrynic acid

Site of action: thick ascending limb

MoA: inhibit Na+-K+-2Cl- symport in

the thick ascending limb

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Pharmacological effects.
ed urinary excretion of Na+ & Cl-
ed excretion of Ca++ & Mg++
ed excretion of HCO3- & Phosphate
Furosemide
Some carbonic anhydrase inhibition activity
ed excretion of K+
Pharmacokinetics
All are orally effective (bioavailability 60-100%)
Highly protein bound: eliminated in the urine by
both glomerular filtration & tubular secretion
Elimination: metabolism and also renal as
unchanged 12
Adverse effects
Related to diuretic efficacy; otherwise are rare

Hypokalemia & /or ECFV depletion

Cardiac arrhythmias: Hypokalemia

Hypomagnesaemia, hypocalcaemia

Ototoxicity (inner ear electrolyte imbalance)

Hyperuricemia (2o gout),b/c it compete with uric acid in

excretion at PCT

Abnormalities in serum lipids: LDL & TGs; HDL

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Therapeutic use
Acute pulmonary edema

Chronic CHF, Hypertension

Edema of nephrotic syndrome

Edema of chronic renal failure

Facilitate excretion during poisoning, forced diuresis

Acute Hypercalcemia

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 II. Medium efficacy diuretics
Thiazide & Thiazide like diuretics,
benzothiazides.

Drugs:, Hydrochlorothiazide
Chlorothiazide, Indapamide

Site of action: distal convoluted tubule

MoA: inhibit Na+/Cl- symport system

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Pharmacological effects
Na+ & Cl- excretion and reducing Ca2+excretion

Also possess carbonic anhydrase inhibition activity

HCO3- & Phosphate excretion

excretion of K+

Reduce uric acid excretion

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Pharmacokinetics
All are well absorbed from GIT except chlorothiazide

Extensive plasma protein binding

Elimination mainly Renal as intact drug.

Reach their site of action: - secretion in the PT & by

glomerular filtration.

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Adverse Reaction
Vertigo, headache, NVD, blood dyscrasias
Photosensitivity, skin rashes
ECFV depletion, hyponatremia, hyperglycemia.
Hyperuricemia, Hypokalemia
se plasma LDL, total cholesterol & total TGs
Therapeutic uses
Edema associated with CHF, Hepatic cirrhosis,
Nephrotic syndrome, CRF, glomerulonephritis
Hypertension, Hypercalciuria (calcium stones)
Nephrogenic diabetes inspidus (reduce urine volume)

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 III. Weak diuretics
1. Carbonic anhydrase Inhibitors

Drugs: Acetazolamide,
Dichlorphenamide,
methazolamide, dorzolamide
Site of action: proximal tubule-
primary
Collecting duct secondary
MoA: Inhibition of Carbonic
Anhydrase activity.
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Pharmacological effects
Urinary excretion of HCO3- (35% of filtered load)

Increased urinary pH & metabolic acidosis

Excretion of 5% filtered Na+ & 70% of filtered K+

Increased phosphate excretion

Reduce intraocular pressure

Increase CO2 levels in peripheral tissue- reduce CO2

levels in expired gas

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Pharmacokinetics
All are orally effective

Protein binding moderately high

Distributed to site of action: glomerular filtration &

proximal tubular secretion

Eliminated as unchanged or as metabolites in urine

Adverse effects
Drowsiness, Skin toxicity, bone marrow toxicity

Metabolic acidosis, urinary alkalinization.

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Therapeutic uses
Rarely used as diuretics

Urinary alkalinization

Uric acid, cystine, and other weak acids are most easily
reabsorbed from acidic urine.

Therefore, renal excretion of cystine (in cystinuria) and

other weak acids can be enhanced by increasing urinary
pH with carbonic anhydrase inhibitors.

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 Glaucoma
The most common indication
The reduction of aqueous humor formation decreases
the intraocular pressure.
Oral : Acetazolamide 250 mg 14 times daily
Dichlorphenamide 50 mg 13 times daily
Methazolamide 50100 mg 23 times daily
Topically: dorzolamide and brinzolamide

Metabolic alkalosis
Acute Mountain Sickness
Epilepsy
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 2. Osmotic Diuretics
Drugs: Mannitol, Urea, Glycerin, Isosorbide
Site of action -Nephron segments which are freely
permeable to water

MoA and Properties

Water soluble and are hence freely filtered
Insoluble in lipids and hence are poorly reabsorbed
Pharmacologically inert, undergoes limited
reabsorption
Inhibits water and electrolyte reabsorption/ increase
the osmolarity of tubular fluid 24
Pharmacokinetics
Glycerin & Isosorbide: orally effective

Mannitol & urea: orally ineffective (hence IV.)

Elimination:

Renal: Isosorbide, urea, Mannitol

Metabolism: glycerin, Mannitol (- 10%)

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Adverse effects
Headache, nausea, vomiting
Dehydration
Pain (urea)
Hyperglycemia (glycerin)

Therapeutic uses
Treatment & prevention:- acute glaucoma & Cerebral
edema (ed ICP)

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III. Potassium Sparing Diuretics
a) Renal epithelial Na+ channel inhibitor

b) Aldosterone antagonists: Spironolactone

a)Renal epithelial Na+

channel (ENaC) inhibitor
Drugs: Triameterene,amiloride

MoA: inhibition of renal epithelial

Na+ channels

Site of action: collecting duct system

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Pharmacological effect:
Mild in Na+ & Cl- excretion (2% of filtered Na+ )
ed excretion of H+ & K+

Pharmacokinetics
Orally effective with bioavailability of 10-60%
Moderately protein bound: enter the lumen via filtration &
secretion in the PT.
Elimination metabolism: bile & urine (intact & metabolite)

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Adverse effects
Nausea, Vomiting, headache, photosensitivity, cramps,
hyperkalemia, hyperglycemia.

Therapeutic use
Combination with other diuretics

Decrease the Kaluretic effect of other diuretics

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b) Aldosterone antagonists

Drug: Spironolactone,
eplerenone

MoA: inhibit the binding of

aldosterone to Mineralocorticoid

Receptors.

Site of action: collecting

duct system

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Pharmacological effects
Similar to ENaC inhibitors

Pharmacokinetics
Partially absorbed from GIT

Extensive hepatic 1st pass: short half life

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Adverse effects

Hyperkalemia, metabolic acidosis: in Patients with

liver disease

Drowsiness, lethargy, headache

Gynecomastia, impotence

Diarrhea, gastritis (PUD)

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Therapeutic uses
Combined with other diuretics (to decrease K+
excretion)

Primary hyper- aldosteronism (adrenal adenoma,

hyperplasia)

Secondary hyper- aldosteronism (2o to CHF, CRF)

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 Type Example Sites of Action

Osmotic agents Mannitol Proximal tubule

Descending loop
Collecting duct
Carbonic Acetazolamide Proximal tubule
anydrase inhib.
Thiazides Hydrochlorothia Distal convoluted
tubule
zide
Loop diuretic Ethacrynic acid Loop of Henle

Furosemide
K+ - sparing Spironolactone Collecting tubule
Amiloride
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Drugs used for treatments
of Urinary Tract Infection

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 Introduction
Second most common infection following respiratory
infections
Young women are particularly susceptible, 40% of all
women will suffer at least one UTI at some point.
Infection in men occurs less frequently until the age of 50,
when incidence in men and women is similar.
Classification
According to anatomic site of involvement:
Lower tract infection: cystitis, urethritis, prostatitis
Upper tract infection: pyelonephritis, involving the kidneys
 Classification
According to Degree
1-Uncomplicated
Occur in individuals who lack structural or functional
abnormalities in the UT that interfere with the normal flow of
urine.
Mostly in healthy females of childbearing age
2-Complicated
predisposing lesion of the UT such as congenital
abnormality or distortion of the UT, a stone, a catheter,
prostatic hypertrophy, obstruction, or neurological deficit
All can interfere with the normal flow of urine and urinary
tract defenses.
 Treatment with antimicrobials aims to eradicate the bacteria causing
infection.
The chosen antimicrobials depend on extent of infection (uncomplicated or
complicated), common local pathogens, and resistance patterns.
Drugs commonly recommended for simple UTIs include:
Trimethoprim-sulfamethoxazole (3-5 days )
Inhibition of microbial DNA synthesis by inhibiting the folic acid synthesis
Fluoroquinolones : (Norfloxacin) (3-5 days )
Inhibition of microbial DNA synthesis by blocking DNA gyrase and
topoisomerase IV needed for successful DNA replication and
transcription.
Nitrofurantoin
The mechanism is not fully understood, but it directly causes
selective damage to microbial DNA.
Penicillin : Amoxicillin
Inhibition of cell wall synthesis
 Acute uncomplicated upper UTI can be treatments
same antibiotics but the period of treatment should be
extend for 7-10 days

N.B

1 .In sever case antibiotics should be given parenterally

for the first 48-72 hour

2.In sever case addition of amonoglycosides like

Gentamycin could be considered
Oral treatment regimens for acute uncomplicated cystitis

Agent Normal dosage Side effects, cautions

Ciprofloxacin 250 mg bid for 3 d Drowsiness; increases theophylline levels; avoid in
pregnancy; avoid divalent and trivalent cations;
Fosfomycin 3-g single dose Increased incidence of diarrhea and nausea and
increased relapse rate
Gatifloxacin 200 mg/d for 3 d Avoid in pregnancy; avoid divalent and trivalent
cations
Levofloxacin 250 mg/d for 3 d Avoid in pregnancy; avoid divalent and trivalent
cations
Nitrofurantoin 100 mg bid for 7 d Idiosyncratic pulmonary fibrosis; avoid in patients
with estimated monohydrate/ creatinine clearance <
Nitrofurantoin 100 mg qid for 7 d 60 mL/min

Norfloxacin 400 mg bid for 3 d Avoid in pregnancy; avoid divalent and trivalent
cations
Ofloxacin 200 mg bid for 3 d Avoid in pregnancy; avoid divalent and trivalent
cations
Trimethoprim 100 mg bid for 3 d Nausea
Trimethoprim- 1 double-strength Nausea; rash;
sulfamethoxazole tablet bid for 3 d
 Complicated UTI

Accurate urine culture and susceptibility is necessary to target

the pathogen
Treatment duration at least 10-14 days
Severely ill patients
Should be hospitalized and treated with IV Abs
Use broad spectrum directed at bacteremia or sepsis
Drugs commonly recommended complicated UTI include
Treatment of acute pyelonephritis

Agent Normal dosage

Ceftriaxone 1 g/d, IV
or
Cefotaxime Aminoglycoside 1 g q8h, IV
Ciprofloxacin 400 mg q12h, IV
500 mg bid, PO
Gentamicin 1.5 mg/kg q8h or 5 mg/kg q24h, IV

Ampicillin 1 g q6h, IV

Levofloxacin 500 mg/d, PO or IV

If gram-positive organisms seen on Gram stain:
Ampicillin/sulbactam 1.5 g q6h, IV

Aminoglycoside
Trimethoprim- 10 mg/kg/d in 2 - 4 divided doses, IV or 1 or 2 double-strength
sulfamethoxazole* tablets bid, PO
 Fungal Infection
Many patients with a long-term catheter will have colonization of
their bladder with Candida species or, rarely, other fungi.
Treatment
The catheter should be removed, since this will result in cure in
some patients.
If C.albicans infection, then oral fluconazole, 100 mg/d, should
be prescribed for a 2- to 5-days
IV fluconazole should be reserved for patients without the ability
to take oral medications or in those with ileus or bowel
obstruction.
MOA :- Blocks fungal P450 enzymes and interferes with ergosterol synthesis
Non- albicans Candida species, including C.parapsilosis,
C.glabrata, and C. krusei, are becoming more common.
The Tx should be either low-dose IV amphotericin B (0.1
mg/kg/d) or continuous amphotericin B bladder irrigation.
Both regimens are effective when given for 2 to 5 days
MOA :- Forms pores in fungal membranes - Loss of intracellular contents
through pores is fungicidal broad spectrum of action