DIURETICS

Ion movement in the nephron

2

LA PLUS
GRANDE PARTIE
DE Na FILTRE Late distal tubule (or
EST REABSORBEE connecting tubule) is
AU NIVEAU DU responsive to
TP(65-70%) Aldosterone

• 25% of filtered solutes

are reabsorbed !!! Collecting duct is
• Poorly water permeable responsive to
• Presence of macula vasopressin (or
densa
ADH)
 Principles of diuretic action
4

 Diuretics are drugs that increase the rate of urine flow

 NaCl in the body is the major determinant of extracellular fluid volume
 Diuretics increase the rate of excretion of
 Na+ (natriuresis)
 An accompanying anion, usually Cl- (saluresis)

 Clinical goal of diuretics :  extracellular fluid volume by  total-body

NaCl content.
 Diuretics not only alter the excretion of Na+ but also may modify renal
handling of
 Other cations e.g., K+, H+, Ca2+, and Mg2+
 Anions e.g., Cl-, HCO3-, and H2PO4 -
 uric acid
 Principles of diuretic action
 Diuretic braking = phénomène de tolérance (suite à une administration prolongée du diurétique)
 A sustained imbalance between dietary Na+ intake and Na+ loss is incompatible with life.
A net positive Na+ balance would result in volume overload with pulmonary edema, and
 a net negative Na+ balance would result in volume depletion and cardiovascular collapse.
 Continued diuretic administration causes a sustained net deficit in total-body Na+but the time
course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line
with Na+ intake, a phenomenon known as diuretic braking
 MOA :
 Sympathetic nervous system,
 Activation of the RAAS,
 Decreased arterial blood pressure (which reduces pressure natriuresis),
 Renal epithelial cell hypertrophy,
 Increased renal epithelial transporter expression,
 Alterations in natriuretic hormones such as atrial natriuretic peptide(facteur natriuretique atriale)

 Mechanisms of action of diuretics

 Non specific: osmotic diuretics
 Specific : all others (targets include enzymes, transport proteins, hormone receptors, or ion channels
that function in renal tubular sodium reabsorption)
Classification of diuretics
 No basis for classification
 Site of action (loop diuretics)
 Chemical structure (thiazide diuretics)
 Effects on K+ excretion (K+-sparing diuretics).

 According to the mechanism of action

 Inhibitors of Carbonic anhydrase (CA)
 Osmotic diuretics
 Inhibitors of Na+-K+-2Cl– symport = loop diuretics
 Inhibitors of Na+-Cl– symport = thiazide diuretics
 Inhibitors of renal epithelial Na+ channels
 Antagonists of mineralocorticoid receptors = aldosterone
antagonist
 On distingue trois
catégories principales
de diurétiques en
fonction des sites
d’action au niveau du
tubule rénal :
 Ceux qui inhibent la
réabsorption du sodium
au niveau de la branche
ascendante de l’anse de
Henlé (diurétiques de
l’anse) : ils inhibent le co-
transport Na+, K+ et Cl-.
 Ceux qui inhibent la
réabsorption de sodium
au niveau du tube
contourné distal : les
thiazides et apparentés
 Ceux qui inhibent la
réabsorption de sodium
au niveau du tube
contourné distal et
surtout du tube
collecteur (diurétiques
distaux).
 Certains de ceux-ci sont
des inhibiteurs
compétitifs de
l’aldostérone.
 L’amplitude de leur effet
La natriurèse induite dépendra donc du niveau
de concentration
est très importante plasmatique de
8 l’aldostérone
 Table 25–1 Excretory Effects of Diureticsa
Diuretic Mechanism CATIONS ANIONS URIC ACID
(Primary site of action) Na+ K+ H+b Ca2+ Mg2+ Cl– HCO3– H2PO4– Acute Chronic
Inhibitors of CA (proximal tubule) + ++ – NC V (+) ++ ++ I –
Osmotic diuretics (loop of Henle) ++ + I + ++ + + + + I
Inhibitors of Na+-K+-2Cl– symport
++ ++ + ++ ++ ++ +c +c + –
(thick ascending limb)
Inhibitors of Na+-Cl– symport
+ ++ + V(–) V(+) + +c +c + –
(distal convoluted tubule)
Inhibitors of renal epithelial Na+
channels (late distal tubule, + – – – – + (+) NC I –
collecting duct)
Antagonists of mineralocorticoid
receptors (late distal tubule, + – – I – + (+) I I –
collecting duct)
aExcept for uric acid, changes are for acute effects of diuretics in the absence of significant volume depletion,
which would trigger complex physiological adjustments. bH+, titratable acid and NH4+. cIn general, these
effects are restricted to those individual agents that inhibit carbonic anhydrase. However, there are notable
exceptions in which symport inhibitors increase bicarbonate and phosphate (e.g., metolazone, bumetanide).
++, +, (+),–, NC, V, V(+), V(–) and I indicate marked increase, mild to moderate increase, slight increase,
decrease, no change, variable effect, variable increase, variable decrease, and insufficient data, respectively.
For cations and anions, the indicated effects refer to absolute changes in fractional excretion.
9
 ANTI HYPERTENSIVE DRUGS
1INHIBITORS OF CARBONIC ANHYDRASE:

 Acetazolamide : DIAMOX
 Dorzolamide : TRUSOPT
 Brinzolamide : AZOPT
Mechanism of action :
Carbonic anhydrase (CA) is located in
proximal tubular epithelial cells in
the luminal membrane and in the
cytoplasm.
CA plays a key role in NaHCO3
reabsorption and acid secretion
Luminal CA

H2CO3 CO2 + H2O URINE SANG

Epithelial cell CA
 1INHIBITORS OF CARBONIC ANHYDRASE:
 Na + - H+ antiporter transport H+ into
tubular lumen in exchange for Na+
 H+ reacts with HCO3-H2CO3
 CA decomposes H2CO3CO2 +H2O
in the tubular lumen
 CA catalyzes CO2 + H2 OH2CO3 in
the epithelial cell.
 Continued operation of antiporter
Na+-H+ maintain in the cell low H+
concentrationso H2CO3 ionizes
spontaneously H+ + HCO3-
 HCO3- is transported by symporter
Na+- HCO3- in the interstitial space.
 Net effect of CA is to transport HCO3-
from the lumen tubular to interstitial
space followed by movement of water
ICA inhibit both CA
 ANTI HYPERTENSIVE DRUGS
1INHIBITORS OF CARBONIC ANHYDRASE

 CA inhibition results in
 The excretion of Na+, K+ and water
 Little or no effect on Ca++ & Mg++
 Urinary alkalosis ( HCO3-)

 Effects on urinary excretion:

 ICA increase HCO3- urinary excretion
 Increase urinary pH =8 and induce urinary alkalosis & metabolic
acidosis
 Small increase in Cl– excretion occurs
 increased delivery of Cl- and Na+ to the loop of Henle which
reabsorbed most Cl- and a portion of Na+
 Increased excretion of K+secondary to increased delivery of Na+ to
distal nephron
 HCO3- is the major anion excreted along with Na+ and K+
Carbonic anhydrase inhibitors (CAI)
 Other actions : Carbonic anhydrase is present in a number
of extrarenal tissues
 Eye
 CA mediates formation of large amounts of HCO3– in aqueous humor
 CAI decreases the rate of formation of aqueous humor 
intraocular pressure
 CNS
 CAI induce drowsiness, paresthesias & anticonvulsant effect (direct
effect + metabolic acidosis)

 Toxicity
 Sulfonamides : bone marrow depression, skin toxicity,
sulfonamide-like renal lesions, and allergic reactions
 induction or worsening hepatic encephalopathy
 worsening of metabolic or respiratory acidosis
 reduction of the urinary excretion rate of weak organic bases
ANTI HYPERTENSIVE DRUGS
1INHIBITORS OF CARBONIC ANHYDRASE

 Diuretic : monotherapy  efficacy is low & combination

potentiates efficacy (but metabolic acidosis)
 Glaucoma :major indication TRUSOPT & AZOPT
 Treatment of epilepsy : DIAMOX
 Prevention of mountain sickness or high-altitude illness :
related may be to metabolic acidosis induced by DIAMOX
 Correcting metabolic alkalosis
 Osmotic diuretics
15

 Mannitol (IV); glycerin (po) ; urea (IV)

 Nonspecific mechanism of action & Relatively inert pharmacologically
 In plasma :  osmotic pressure of the plasma  attract water from interstitial
and transcellular fluids   cerebral edema & intracranial pressure
 In the eye : attract water from ocular fluids into the circulation   intraocular
volume & pressure (used in acute glaucoma)
 In kidneys : ( urinary excretion of all electrolytes)
 Direct effect :
 Freely filtered at the glomerulus  limited reabsorption by the renal tubule 
osmotic effect in the tubules
 Osmotically attracts and retains water as it moves through the nephron and into the
urine   tubular Na concentration and the concentration gradient between the
tubular fluid and cells  retards Na reabsorption
 Marked ability to inhibit Mg2+ reabsorption  specific mechanism ?
 Indirect effect : extraction of intracellular water→expansion of extracellular fluid
volume   blood viscosity & inhibition of renin release   RBF
Osmotic diuretics
 Toxicity
 Extraction of water to plasma  hyponatremia  common adverse effects:
headache, nausea, and vomiting.
 Extraction of water from intra- to extra-cellular compartments  expansion of
extracellular fluid  pulmonary edema in heart failure patients
 Loss of water in excess of electrolytes  hypernatremia and dehydration
 Urea may cause thrombosis or pain if extravasation occurs
 Glycerin  hyperglycemia

 Indications
 Acute glaucoma (all agents) ;
 Cerebral edema (mannitol & urea)
 Treatment of dialysis disequilibrium syndrome :
 Hemodialysis  fast removal of solutes from the extracellular fluid   osmolality
in extracellular fluids  water moves from the extra-into the intracellular
compartment  hypotension and CNS symptoms (headache, nausea, muscle
cramps, restlessness, CNS depression, and convulsions).
 Osmotic diuretics increase the osmolality of the extracellular fluid compartment and
thereby shift water back into the extracellular compartment.
 Inhibitors of Na+-K+-2Cl- Symport
(Loop Diuretics or high-ceiling diuretics)
17

 Agents
 Sulfonamides
 Furosemide LASIX
 Bumetanide BURINEX
 Ethacrynic acid
 Sulfonylurea : Torsemide
 site of action : AL(ascending
limb)
 Mechanism of action
 Loop diuretics inhibit the activity of the
Na+-K+-2Cl- symporter in the thick
ascending limb of the loop of Henle
resulting in
 Profound increase in urinary Na+
and Cl- excretion
 Increase in Ca++ , Mg++ , K+ , and
H+ excretion The most potent diuretics
 Inhibitors of Na+-K+-2Cl- Symport
(Loop Diuretics or high-ceiling diuretics)
 High-ceiling diuretics :Although the proximal tubule reabsorbs ~65% of filtered Na+,
diuretics acting only in the proximal tubule have limited efficacy because the thick
ascending limb has a great reabsorptive capacity and reabsorbs most of the rejectate
from the proximal tubule
 Effects on urinary excretion
 Excessive amounts  dehydration & electrolyte depletion
 Furosemide  weak CAI   urinary excretion of HCO3– and phosphate
 Uric acid :
 Acute administration   uric acid excretion
 Chronic administration  hyperuricemia

 Effects on renal hemodynamics

  RBF via PG (?)  NSAIDs  RBF & diuretic effect
  salt transport into the macula densa   renin release

 Other effects
 Furosemide : direct vascular effects
  systemic venous capacitance   left ventricular filling pressure
 Inhibitors of Na+-K+-2Cl- Symport
(Loop Diuretics or high-ceiling diuretics)
 PK
 Extensive binding to plasma proteins  limited glomerular filtration
 Secreted efficiently by the organic acid transport system in the
proximal tubule
 Short elimination t1/2→post diuretic Na+ retention" overcome by
restricting dietary Na+ intake or by more frequent administration of the
loop diuretic

DRUG RELATIVE POTENCY ORAL AVAILABILITY t1/2 (HOURS) ROUTE OF ELIMINATION

Furosemide 1 ~60% ~1.5 ~65% R,
LASIX ~35% M
Bumetanide 40 ~80% ~0.8 ~62% R
BURINEX ~38% M
Ethacrynic acid 0.7 ~100% ~1 ~67% R
~33% M

Torsemide 3 ~80% ~3.5 ~20% R,

~80% M
Inhibitors of Na+-K+-2Cl- Symport
(Loop Diuretics or high-ceiling diuretics)
 Toxicity
 Electrolytes disturbances:
 Hyponatremia and/or extracellular fluid volume depletion associated with
hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in
patients with liver disease: hepatic encephalopathy
 Hypochloremic alkalosis due to increase K+ , and H+ excretion

 Hypokalemia (may induce cardiac arrhythmias, particularly in patients taking cardiac

glycosides),
 Hypomagnesemia (a risk factor for cardiac arrhythmias) and hypocalcemia (rarely
leading to tetany)

 Ototoxicity: (hearing impairment, deafness, vertigo)

 Hearing impairment and deafness are usually, but not always, reversible.
 Ototoxicity occurs most frequently with rapid IV administration (IV>>> po)
 Primarily with ethacrynic acid

 Metablic effects : hyperuricemia, hyperglycemia ,  LDL & TG and HDL

 GI disturbances, bone marrow depression, and skin rashes, photosensitivity,
paresthesias
Inhibitors of Na+-K+-2Cl- Symport
(Loop Diuretics or high-ceiling diuretics)
 Drug interactions
 Aminoglycosides, carboplatin, paclitaxel and several other agents
(synergism of ototoxicity)
 Anticoagulants (increased anticoagulant activity)
 Digitalis glycosides (increased digitalis-induced arrhythmias)
 Lithium (increased plasma levels of lithium)
 Propranolol (increased plasma levels of propranolol)
 Sulfonylureas (hyperglycemia)
 Cisplatin (increased risk of diuretic-induced ototoxicity)
 NSAIDs (blunted diuretic response and salicylate toxicity when
given with high doses of salicylates)
 Probenecid (blunted diuretic response) Thiazide diuretics
(synergism of diuretic activity of both drugs leading to profound
diuresis)
 Amphotericin B (increased potential for nephrotoxicity and
toxicity and intensification of electrolyte imbalance)
ANTI HYPERTENSIVE DRUGS
3 INHIBITORS OF Na+-K+-2Cl- SYMPORTER

 Therapeutic uses :
 Acute pulmonary edema
 Hypertension but their short t½ render them less useful
than thiazide diuretics
 Edema of nephrotic syndrome : LDs the most active

 Edema and ascites of liver cirrhosis

 Edema associated with chronic kidney disease

 DIURETICS
4 - INHIBITORS OF Na+- Cl- SYMPORTER
 Agents :
 Benzothiazides : sulfonamides
 Hydrochlorothiazide ESIDREX
 Chlorthalidone HYGROTON
 Indapamide FLUDEX
 Chlorothiazide ,
Trichlormethiazide, Metolazone
, Quinethazone
 unlike CAIs (primarily increase
NaHCO3 excretion ) they
predominantly increase NaCl
excretion
 Site of action :
 distal convulated tubule which
expresses Na+ - Cl- symporter
Diuretics
4- INHIBITORS OF Na+- Cl- SYMPORTER
 Mechanism of action
 Inhibition of Na+- Cl- symport in the
distal convoluted tubule
 Moderate  in Na+ and Cl-
excretion
  excretion of K + & H+
  excretion of Mg++
  in Ca++ reabsorption
 Uric acid : short term :  excretion
and long term :  excretion

 Long duration of action ! (12-14h)

Natriuretic effect (5%)

is less important than that of LDs
 Inhibitors of Na+- Cl- symport
(Thiazide Diuretics)
 Pharmacokinetics
 Oral administration  good bioavailability
 Variable PP binding
 Secreted into the proximal tubule by the organic acid
secretory pathway
RELATIVE ORAL t1/2 (HOURS) ROUTE OF
DRUG
POTENCY AVAILABILITY ELIMINATION
Hydrochlorothiazide
1 ~70% ~2.5 R
(ESIDREX)
~65% R,
Chlorthalidone
1 ~65% ~47 ~10% B,
(HYGROTON)
~25% U
Indapamide (FLUDEX) 20 ~93% ~14 M

R, renal excretion of intact drug; M, metabolism; B, excretion of intact drug into bile; U, unknown pathway of
elimination
 Inhibitors of Na+- Cl- symport
26
(Thiazide Diuretics)
 Adverse effects
 Electrolyte disturbances
 Hyponatremia, hypochloremic alkalosis
 hypokalemia, hypercalcemia, Mg deficiency
 Hyperuricemia
 Metabolic effects
 Hyperglycemia
  plasma levels of LDL cholesterol, total cholesterol, and total triglycerides
 CNS and GI disturbances (not common)
 Hematological and dermatological disorders

 Drug interactions:
  effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas and
insulin
  the effects of anesthetics, digitalis glycosides, lithium, loop diuretics, and vitamin D
 Diuretic effect of thiazides may be reduced by NSAIDs and bile acid sequestrants
 Potentially lethal drug interaction with : quinidine: thiazide induced hypokalemia
increases the risk of quinidine-induced torsades de pointes (polymorphic ventricular
tachycardia ).
Inhibitors of Na+- Cl- symport
(Thiazide Diuretics)
 Therapeutic uses
 Treatment of edema associated with
 Heart disease(congestive heart failure),
 Liver disease(hepatic cirrhosis),
 Renal disease(nephrotic syndrome, chronic renal failure, and acute
glomerulonephritis)
 Most are ineffective when the GFR is <30-40 mL/min (except
indapamide)

 Hypertension
 Monotherapy or combination therapy
 Advantages :
 Can be administered QD
 Do not require dose titration,
 Have few contraindications
 Have additive or synergistic effects when combined with other
classes of antihypertensive agents
DIURETICS
5- INHIBITORS OF Na+CHANNELS (K+ sparing
diuretics)
Agents : Triamterene and Amiloride
 MAO :
 Inhibits Na+ channels in late distal tubule
and collecting duct
 mildly ↑ of Na+ and Cl- excretion.
 ↓ K+, Ca2+, Mg2+, H+ excretion
 Pharmacokinetics
 Oral administration
 Amiloride : urinary excretion of intact drug
 Triamterene : metabolized extensively to an
active metabolite which is excreted in urine
 transported by the organic base secretory
mechanism in proximal tubule

used essentially for their antikaliuretic effects to

offset the hypokaliemic effect of other diuretics
 ANTI HYPERTENSIVE DRUGS
5 INHIBITORS OF Na+ CHANNELS

 Toxicity
 Hyperkalemia :
 Contraindicated in patients with hyperkalemia, as well as in patients at
increased risk of developing hyperkalemia
 renal failure,
 Coadministration of other K+-sparing diuretics, ACE I, NSAIDs
 Patients taking K+ supplements
 CNS , GI, skin rush
 Triamterene:
 reduces glucose tolerance,
 photosensitization
 It is a weak anti folic Megaloblastosis in cirrhotic patient
 N,V, leg cramps and dizziness
Amiloride:
 N,V, diarrhea and vomiting
 ANTI HYPERTENSIVE DRUGS
5 INHIBITORS OF Na+ CHANNELS
 Therapeutic uses
 Seldom used as sole agents
 Amiloride blocks Li transport into collecting
tubule:use to treat lithium induced nephrogenic
diabetes insipidus
 Associated with LDs to counteract their hypokalemia
effects of thiazide & loop diuretics :
Amiloride +hydrochlorothiazide= MODURETIC
Amiloride +hydrochlorothiazide +timolol =
MODUCREN
DIURETICS
6 -ANTAGONISTS OF MINERALOCORTICOID RECEPTORS

Introduction
 MRs :
 Located in late distal tubule and collecting duct
 have high affinity for aldosterone.
 Mineralocorticoids bind to MRs :
 cause salt and water retention
 increase K+ and H+ excretion
 Specific antagonist of MRs:
 effects depend on endogenous aldosterone level :higher aldosterone level
greater MR antagonists effects on urinary excretion.
 Effects on urinary excretion are similar to those of Na channels inhibitors:
 Agents :
 Spironolactone ALDACTONE
 Canrenone: active metabolite of spironolactone
 Eplerenone
ANTI HYPERTENSIVE DRUGS
6 -ANTAGONISTS OF MINERALOCORTICOID RECEPTORS

 Aldosterone binds to MRs  MR-

Aldosterone(MR-A)
 Translocation of MR-A into nucleus
 Binding of MR-A to specific DNA
sequences
 regulates expression of multiple gene
AIPs (aldosterone induced proteins ).
 The results is enhanced transepithelial
NaCl transport and increase K+ and
H+ secretion into tubular lumen
 Spironolactone and other
antagonists inhibit competitively the
binding of aldosterone to MRs.:
they block biological effects of
aldosterone: ALDOSTERONE
ANTAGONIST
 MR- antagonist complex does not
induce synthesis of AIP
 Potassium sparing diuretics
Aldosterone receptors antagonists
34

 Mineralocorticoids cause retention of salt and water and increase the

excretion of K+ and H+ by binding to specific mineralocorticoid receptors.

1, Activation of membrane-bound Na+ channels;

2, Redistribution of Na+ channels from cytosol to
membrane;
3, De novo synthesis of Na+ channels;
4, Activation of membrane-bound Na+, K+-ATPase;
5, Redistribution of Na+,K+-ATPase from cytosol to
membrane;
6, De novo synthesis of Na+,K+-ATPase;
7, Changes in permeability of tight junctions;
8, Increased mitochondrial production of ATP.

BL and LM indicate basolateral and luminal membranes,

respectively. AIP, aldosterone-induced proteins; ALDO,
aldosterone; MR, mineralocorticoid receptor; CH, ion channel
Potassium sparing diuretics Mineralocorticoid
receptor antagonists Aldosterone antagonists
 Are the only diuretics that do not require access to the tubular lumen to
induce diuresis

 Effects on urinary excretion are very similar to those induced by renal

epithelial Na+-channel inhibitors
 Main difference : MR antagonists effects depend on endogenous
aldosterone level
other effects:
 Spironolactone has affinity to progesterone and androgen receptors

 gynecomastia,
 impotence
 menstrual irregularities
 Elperenone has low affinity to these receptors due to the presence of
9,11epoxyde group
 High spironolactone concentrations interfere with steroid biosynthesis by
inhibiting steroid hydroxylases
 ANTI HYPERTENSIVE DRUGS
6 ANTAGONISTS OF MINERALOCORTICOID RECEPTORS

Pharmacokinetic:
 Spironolactone :
 absorbed partially (~65%),
 extensively metabolized( hepatic first passage)
 active metabolite : canrenone
 undergoes enterohepatic recirculation
 Highly protein bound , t½= 1,6h9h in cirrhotic patient
 Eplerenone:
 Has good oral availability
 metabolism by CYP3A4 to inactive metabolites
 t½= 5h
 DIURETICS
6 ANTAGONISTS OF MINERALOCORTICOID RECEPTORS
 Toxicity: hyperkalemia
 Therapeutic uses
 Spironolatone :
Edema & hypertension :Co
 Gynecomastia,impotence,
administered with thiazide or
hirsutism, menstrual irregularities.
LDs :ALDACTAZIDE
 CNS: drowsiness, ataxia,
 Hypertension due to primary
confusion, headache
hyperaldosteronism
 Breast cancer with chronic
 Refractory edema associated
administration
with secondary aldosteronism
 GI: diarrhea, gastritis, gastric
 Spironolactone ,diuretic of
bleeding, and peptic ulcers
choice in hepatic cirrhosis
 Eplerenone
 Eplerenone effective and safe
low incidence of gynecomastia antihypertensive drug
hyperkalemia
VASODILATORS
ANTI HYPERTENSIVE DRUGS
VASODILATORS / HYDRALAZINE
Pharmacological effects
 Directly relaxes arteriolar smooth muscle by lowering intracellular Ca2+
 Does not relax venous smooth muscle  no postural hypotension
 Hydralazine induced vasodilation stimulates sympathetic nervous system:
 Tachycardia, contractility,
  plasma renin activity , fluid retention counteract antihypertensive
effect
 Induces tachyphylaxis
 Decrease in blood pressure is associated with a selective decrease in
vascular resistance in the coronary, cerebral, and renal circulations, with a
smaller effect in skin and muscle.
 MOA:
 inhibition of IP3 induced release of Ca from intracellular storage,
 opening high conductance Ca2+ activated K+
channelhyperpolarisation relaxation
 Hydralazine
 Pharmacokinetics
 Hydralazine is N-acetylated in the bowel and/or the liver. : fast & low acetylators
 Oral bioavailability low : 16% in fast acetylators and 35% in slow acetylators
 Extra hepatic metabolism  metabolite with longer t½ but not active
 The t1/2 of hydralazine is 1 hour but the duration of the hypotensive effect of
hydralazine can last as long as 12 hours.
 Adverse effects
 2 types of adverse effects:
 Due to the pharmacological effects:
 headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and
angina pectoris
 The second type of adverse effect is caused by immunological reactions
 Lupus syndrome is the most common.

 Serum sickness, hemolytic anemia, vasculitis, and rapidly progressive

glomerulonephritis.
ANTI HYPERTENSIVE DRUGS
VASIDILATOR: MINOXIDIL

 Prodrug  minoxidil N -O sulfate

 Minoxidil sulfate activates ATP modulated K+ channels: by opening K+ channels
in smooth muscle  permits k+ efflux  hyperpolarisation and relaxation
 Arteriolar vasodilation.
 Increases BF to skin, GIT, heart & less to CNS
 Toxicity:
 retention of salt and water due to renin and aldosterone secretion (loop
diuretics)
 activation of sympathetic system : in heart rate, contractility myocardial O2
consumption myocardial ischemia in patients with coronary disease (
blockers, ACEIs)
 hypertrichosis : Growth of hair on the face, back, arms, and legs and is
particularly offensive to women, consequence of K+ channel activation
 Therapeutic uses:
 Treatment of severe hypertension.
 Should never be used alone combined to diuretics , beta blockers
 Topical preparation REGAIN for male baldness, loss hair : can cause measurable
cardiovascular effects in some individuals.
ANTI HYPERTENSIVE DRUGS
VAODILATOR: NITROPRUSSIDE

NITROPRUSSIDE:
 Unstable product that decompose under alkaline conditions and when exposed to
light( protected from light, IV infusion )
 Dilates arterioles & venules

 Vasodilator acting by releasing NO by enzymatic and non enzymatic pathways

 NO activates the guanylyl cyclase–cyclic GMP–PKG pathway, leading to

vasodilation
 Unlike nitroglycerine ,tolerance does not develop
 Metabolism:

 Onset of action=30 sec

 Reduction followed by release of cyanide then NO
 Cyanide is further metabolized by liver rhodanase to form thiocyanate t½= 3D
 Toxicity :

 excessive vasodilation and hypotension

 accumulation of cyanide severe lactic acidosis
 Use to treat hypertension in emergency