NAFRIALDI, MD, PhD

Department of Pharmacology
Faculty of Medicine
Universitas Indonesia

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 Introduction
 Nephron is the functional unit of the kidney
 There are about 1000 000 nephron in each
kidney
 Process of urine formation:
◦ Filtration by glomerulus
◦ Reabsorption by tubules
◦ Secretion by tubules
 Glomeruli receive 25% of cardiac output
◦ Filtration rate: 100-120 ml/minute
 Tubules:
◦ Reabsorption of 99% of glomerular filtrate  thus
only + 1 ml/min. excreted as urine

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 Proximal tubuls:
◦ Reabsorption of 65% Na+
◦ Permeable to water  isotonic urine
 Loop of Henle
◦ Thick decending limb: most active water
reabsorption
◦ Thin ascending limb
◦ Thick ascending limb:
 Reabsorption of Na+,
 Water impermeable  diluting segment
 Distal tubules :
◦ Na+ reabsorption

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 DIURETIC DRUGS
 DRUG THAT CAN INDUCE THE INCREASE OF
URINE VOLUME
 Main Indications:
◦ Hypertension
◦ Congestive heart failure
◦ Other conditions with water retention:
 Edema, Ascites
◦ Others :
 Cerebral edema, Glaucoma, Etc ...

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 Drug Site of Action Mechanism
1.Osmotic Diuretic 1. Proximal tubules Inhibition of water and Na+
2. Loop of Henle reabsorption
3. Collecting duct

2. Carbonic Proximal tubules Inhibition of bicarbonate

Anhydrase reabsorption
Inhibitor (CA-I)
3. Thiazides Early distal tubule Inhibition of Na+, Cl-
cotransport
4. Loop Diuretic Loop of Henle Inhibition of Na+, K+, Cl-
(thick ascending limb) cotransport
5. Potassium Late distal tubule Inhibition of Na+ reabsorption
sparing diuretics Collecting duct and K+ secretion

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Example: Mannitol
 Properties of osmotic diuretics:
 Mechanism of Action:
◦ increases osmotic pressure in tubular lumen 
prevent reabsorption of electrolytes and water
 water excretion ↑
 Almost all electrolytes are excreted: Na+, K+,
Ca++, Mg++, HCO3-, phosphate

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Pharmacokinetics
 Mannitol is not absorbed from GI tract 
should be administered intravenously
 Metabolism:
◦ mannitol 20% metabolized
 Excretion: renal

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Indications
 Brain edema
 mannitol is given before and after brain surgery
 Glaucoma (rare)
 Disequilibrium syndrome after hemodialysis
 Prophylaxis of ATN (acute tubular necrosis)
due to contrast media, surgery, and trauma.

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 Osmotic Diuretics

Adverse Effects
• Initial increase of plasma volume (due to relatively
large volume of mannitol)  potentially
dangerous in heart failure and lung edema
• Hyponatremia  headache, nausea, vomitus
• Hypovolemia
• Hypersensitivity reaction
• Vein thrombosis, pain if extravasation (urea)

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Contraindications
 Renal failure with anuria
 Lung edema
 Dehydration
 Intracranial hemorrhage, except before
craniotomy

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 CARBONIC ANHYDRASE INHIBITOR

(Acetazolamide, Dichlorphenamide, Metazolamide)

Mechanism of Action
• In tubular cell, CA-I inhibits conversion of CO2 +
H2O  HCO3- + H+
• In tubular lumen, CA-I inhibits conversion of HCO3-
 H2O + CO2
• Na-H exchange is inhibited  Na is combined with
HCO3-  NaHCO3  then, excreted in urine along
with H2O
• In the eye: CA-I inhibits formation of aqueos humor
 decrease intraocular pressure
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 Indications of CA-I
• Glaucoma (mainly)
• Treatment of metabolic alkalosis
• CNS:
• Anti epilepsi, limited usage
• acute mountain sickness
• Familial periodic paralysis
• Urinary alkalinization: preventing uric acid
and cystine stones
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Adverse effects
 Metabolic acidosis
 Renal stones (phosphate and calcium
stone)
 Drowsiness, paresthesia, disorientation
Contraindication
 Liver cirrhosis (CA-I inhibits conversion
of NH3 to NH4)  NH3 increased 
hepatic encephalopathy
 Renal failure (↑ risk of metabolic
acidosis)

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 Hydrochlorothiazide (HCT), Chlorothiazide,
Bendroflumethiazide, Clortalidone, Metolazone, Indapamide

 Main indication: antihypertension

 Mechanism of Actions
◦ Thiazides are secreted by proximal tubules but
works in distal convoluted tubules
◦ Inhibit Na+-Cl- symporter from the lumen to
tubular cells  increase Na+, Cl- excretion (and
water)
◦ Some thiazides have weak CA-I effect

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THIAZIDES

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 Increases Na+ and Cl- excretion, (also K+
and Mg2+)
  AE: Hypo Na, Hypo K, Hypo Mg
 Inhibits uric acid secretion
  AE: hyper uricemia and gout
 Decreases Ca2+ excretion  tends to
increase plasma Ca2+  Delays
osteoporotic process

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Other adverse effects:
 Hyperglycemia and hypercholesterolemia  not
very suitable for DM and dyslipidemia (although
not contraindicated)
 (Indapamid has less effects on lipid and
uric acid)
 Sexual dysfunction

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 Hypertension (single drug or in
combination)
 Heart failure (chronic, mild)
 Edema (loop diuretic is preferable)
 Diabetes insipidus (mainly nephrogenic)
 Idiopathic hypercalciuria

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 Due to hypokalemia, thiazide may increase
the risk for arrhythmia when combined with
digitalis, quinidine and other anti arrhythmias
 NSAIDs reduce the efficacy of thiazide
 Thiazides reduce the efficacy oral anti
diabetics

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Furosemide, torasemide, bumetanide, ethacrynic acid
 Site
of action: thick ascending limb of Ansa
Henle
 Mechanism:
 Loop diuretic is excreted into the lumen
 Inhibits Na+-K+-2Cl- symporter (reabsorption) 
increases the excretion of Na+, K+, Cl- and water
 Ca2+ and Mg2+ are excreted as well.

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Mechanism of Action of Loop Diuretic

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 Congestive heart failure (first line drug)
 Acute pulmonary edema
 Other conditions with water retention: edema
due to renal failure, nephrotic syndrome,
ascites
 Hypercalcemia
 Severe hypertension
 Force diuresis during drug/chemical
intoxication (drug that excreted through the
kidney in active form)

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 Hypo-K, hypo-Na
 metabolic alkalosis,
 hypercholesterolemia, hyperuricemia,
hyperglycemia
 Hypocalcemia (opposite to thiazides)
 Ototoxicity (especially ethacrynic acid if given
by rapid IV bolus)
 Increasesthe risk of arrhythmia when
combined w/ digitalis, quinidine and other
anti arrhythmias
 Concomitant use w/ aminoglycoside or
cisplatin increases the risk of nephrotoxicity
and ototoxicity
 NSAIDs reduce the effects of diuretics

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Site of action: late distal tubule and collecting duct
It works by two mechanisms:
1. Na+ channel inhibitors (amiloride, triamterene)
 Inhibit Na+ reabsorption  Na+ excretion
 Reduce K+ secretion  K+ retention
2. Aldosterone antagonist (spironolactone,
eplerenone)
◦ Aldosterone induces Na+ reabsorption and K+ excretion
◦ Spironolactone and eplerenone block aldosterone
receptors  thus, Na+ is excreted but K+ is retained

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 Potassium sparing diuretics have a weak
diuretic action
 Usually used in combination w/ other
diuretic:
 Potentiation with other diuretics
 Prevent hypokalemia due to thiazide or loop
diuretic
 Longterm use of spironolactone for
prevention of myocardial remodeling
(hypertrophy and fibrosis)

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 Hyperkalemia
 Anti androgenic effect (gynecomastia,
decrease of libido, impotency, menstrual
dysturbance): spironolactone
 Megaloblastic anemia : Triamteren (a folate
antagonist)

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INDICATIONS
 Antihypertension:
 In combination w/ other anti hypertensions
 To increase the effect and to prevent
hypokalemia of other diuretics
 Heart
failure: prevention of cardiac
remodelling

Contraindications /Precautions
 Conditions that prone to hyperkalemia:
 Renal failure
 Concomitant use with ACE-inhibitor, ARB, NSAID,
K+ supplementation (except in hypokalemic
condition)
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 Blockers of Renin-Angiotensin System
◦ ACE-Inhibitors
◦ Angiotensin Receptor Blockers
 Calcium Channel Blockers
 Beta Adrenergic Blockers

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 ACE-inhibitor and ARB
Angiotensinogen ACE-inhibitor

Angiotensin I Bradykinin

ARB ACE

Angiotensin II Inactive
peptide

AT1 receptor AT2 receptor

•Vasoconstriction •Vasodilatation
•Aldosterone secretion •Nitric oxide secretion
•Vascular/cardiac •Anti remodelling
remodelling
•Sympathetic stimulation

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 ACE-inhibitors
Drugs Prodrug/ Active form Hepatic Eliminati Daily
active Metabolism on Dosing
Captopril Active - + Kidney 2-3 x

Lisinopril Active - - Kidney OD

Perindopril Prodrug Perindoprilat + Kidney OD

Enalapril Prodrug Enalaprilat + Kidney OD/ 2x

Ramipril Prodrug Ramiprilat + Kidney OD/ 2x

Quinapril Prodrug Quinaprilat + Kidney OD/ 2x

Silazapril Prodrug Silazaprilat + Kidney OD

Benazepril Prodrug Benazeprilat + Kidney OD/ 2x

Fosinopril Prodrug Fosinoprilat + Kidney + OD

bilier

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 ACE-inhibitor and ARB
 D.O.C for HT with compelling indications or
metabolic problems
 ACE-Inhibition:
◦ AngII  : vasodilatation  BP 
: aldosterone   Na+ and water
retention 
◦ Bradykinin  (with ACE-I)  vasodilatation
 Clinical use:
◦ First line drug for mild, moderate and severe HT
◦ HT with CVDs (heart failure, post MCI, stroke)
◦ Hypertensive crisis
◦ HT in diabetes, dyslipidemia, and DM nephropathy
◦ Longterm use: cardioprotective, vasculoprotective
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 Adverse effects:
◦ Dry cough (10-20%)
◦ Angio udem, skin rash, dysgeusia
◦ Hypotension (first dose phenomen)
◦ Risk of Hyperkalemia:
 In renal failure
 If combined with K+ Sparing Diuretics or NSAID
◦ Embryotoxic
 Contraindication
◦ Pregnancy
◦ Lactation  risk of renal failure in the fetus
◦ Bilateral stenosis of Renal artery or unilateral
stenosis in single kidney
◦ Hyperkalemia

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 Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan

 Mechanism of action:
◦ Blockade of Ang II (AT1) receptor.
◦  Vasodilatation
◦  Aldosterone 
◦  Decreasing Ang II-mediated sympathetic activation
◦  Prevents vascular and cardiac hypertrophy (vasculo-
and cardio protective)
 Side effects  ACE-I, except:
◦ No dry cough
◦ No angio-edema
 Indications and contraindications = ACE-I

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 Mechanism: inhibition of b1 receptors
◦ Heart  decreases cardiac output
◦ Juxtaglomerular cells  decreases renin secretion
 Clinical use:
◦ Antihypertension
 Mild to moderate hypertension
 Hypertension with CAD
 Hypertension with tachycardia
◦ Anti arrhythmia
◦ Coronary heart diseases

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 Adverse effects
 Bronchospasm
 Bradycardia
 Decrease sexual function … impotency
 Peripheral vascular disturbances
(coldness of the legs/hands)
 Unfavorable effect on lipid profile
 Masking hypoglycemic symptoms (in
patient during anti diabetic treatment)
 Decrease renal function

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 Contraindications
◦ Asthma, COPD
◦ Peripheral vascular disease (claudicatio
intermittent, Reynaud disease)
◦ 2nd and 3rd degree AV block
◦ Sick sinus syndrome

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Mechanism: Inhibition of Ca++ influx
◦ Blood vessels  vasodilatation
◦ Heart  negative inotropic,
dromotropic and chronotropic

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1. Dihydropyridine (DHP):
◦ (nifedipine, amlodipine, nicardipine, felodipine,
lasidipine, nitrendipine, lecarnidipine)
◦ Vasculo selective:  Predominant vasodilatory
effect, but minimal cardiac effects
2. Non dihydropyridine: Verapamil, DIltiazem
◦ More cardioselective:
◦  Decreases myocardial contractility and conduction
◦  not recomanded in the presence of heart failure

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 Pharmacokinetics:
◦ Nifedipine:
 Rapid oral absorpton  rapid BP 
 Short T1/2  needs 3-4 x daily dosing
◦ Amlodipine:
 Slow absorption
 Long half life  once daily
 Extensive first pass metabolism (all CCB)
 Extensive hepatic metabolism (>90%): all
CCB  precaution in liver failure
 Minimal renal excretion  relatively save for
renal failure

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INDICATIONS
◦ Hypertension:
 dihydropiridine (amlodipine), verapamil,
(diltiazem: rare)
◦ Note: Short acting Nifedipin is not recommanded
for maintenance therapy of HT
◦ Hypertensive crisis: nicardipine iv,
nifedipine sublingual (no more
recomanded)
◦ Arrhythmia: verapamil, diltiazem

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 Nifedipine:
◦ Hipotension  risk of myocardial and cerebral
ischemia
◦ Tachycardia
◦ Headache, flushing, peripheral edema
 Verapamil, diltiazem:
◦ Bradicardia, constipation
Contraindication
◦ Heart failure (except amlodipine)
◦ Precaution in liver cirrhosis
◦ (Relatively safe in renal failure)

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Vasopresin, Arginine vasopressin (AVP),
Desmopressin (DDAVP, 1-deamino-8D-
arginine vasopressin)

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Mechanisms of Action
• Works on ascending limb of Henle’s loop
and collecting ducts
• 2 kind of receptors:
– V1: vascular smooth muscle 
vasoconstriction
– V2: kidney  increase water permeability of
tubular epithelium  water reabsorption

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Indications
• Neurogenic Diabetes Insipidus (central type)
(not for nephrogenic DI)
• DI due to head trauma or brain surgery
• GI bleeding due to portal hypertension:
vasoconstriction  reducing mesenteric blood
flow
• Von Willebrand disease (DDAVP stimulate
secretion of vWF in endothelial cells)

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Kinetics
• Not to be administered orally (rapid
degradation by trypsin)
• Administration: im, iv, sc, intranasal
• Half-life of ADH: 17-35 minutes
• Desmopresin (DDAVP): long half-life 
effective until 48-96 h after intranasal
administration.

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Adverse Effects

• Hypertension
• Abdominal colic due to increased peristalsis
• Coronary vasoconstriction  angina pectoris

Preparation:
– Pitressin for injection
– Vasopresin tanat for IM injection
– Intranasal powder
– Lipresin (lisine-vasopresin) nasal spray
– Desmopresin acetate (DDAVP): nasal drop

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