Parmacology of Renal System by Birhanu Geta

Pharmacology of Renal System
Pharmacology of Renal System 1

Out line
Introduction: function of the renal system
Tubular ion & fluid transport mechanisms
Drugs involved in the renal system;
Diuretics
Antibiotics
Urinary antiseptics

Objectives
 @ the end of this session you will be able to;
Explain the function of renal system
Identify tubular ion & fluid transport MCZs
Determine d/t classes of diuretics with their PK & PD
Explain drugs used in the management of UTI

Introduction
 The Renal System
The kidneys are major organs of urine formation
Regulate the ionic composition, volume & pH of
urine/body fluid by three major processes;
Urine formation = glomerular filtration - tubular
reabsorption + active tubular secretion

Function of Renal System
Excretory function: metabolic wastes, drugs, toxins, NTs,
water soluble metabolites, hormones
Regulatory function:
Water/fluid/ balance: diluting & concentrating urine
Electrolyte balance: K+, Na+, Ca2+, Mg2+, Cl-, Pi-
Acid base balance: H+, HCO3
-
Endocrine function: EPO, renin, PGs
Metabolic function: activation of Vit-D, gluconeogenesis

Urine formation
 An important interplay b/n RBF & nephron function
 CO  RBF  RPF  GFR  tubular flow  urine
CO = HR  SV
= 72 beats (strokes)/minute  70 mL/beat(stroke)
= 5040 mL/minute
5 Liters/minute

RBF to both kidneys = 20-25% of CO
Out of 5 Liters; 20% = 1 L/minute
In the 1 L blood; 40% (400 mL) are cells & 60% (600
mL) is plasma
Cells (RBCs, WBCs, platelets) do not filtered, simply
circulate through the blood vessels

Out of 600 mL plasma 20% (120 mL/min) filtered in the
glomeruli in both kidneys (60 mL/min/kidney) as it is
passing in the glomerular capillaries i.e GFR
Out of 120 mL:
65% of fluid is reabsorbed in the PCT
10-15% of fluid is reabsorbed in the thin ascending loop
of Henle (water permeable site)
Water permeability of the collecting tubule system is ADH
dependent
Finally 1 mL/minute urine is produced

Diuretics
Diuretic: the Greek ‘diouretikos’ - to promote urine
An agent that increases urine volume
A natriuretic: increase in renal sodium excretion
Aquaretic increases excretion of solute-free water
Not directly natriuretic; osmotics & ADH antagonists
B/c natriuretics almost always also ↑water excretion &
usually called diuretics

Diuretics increase renal excretion of salt & water
Principally used to remove excess ECF from the body
180 liters of fluid is filtered from the glomerulus into the
nephron per day
The normal urine out put is 1-5 liters per day
The remaining is reabsorbed in d/t areas of nephron

Renal Tubule Transport Mechanisms
 Proximal Tubule: PCT
85% of filtered NaHCO3, 66% of filtered NaCl & 100% of the
filtered glucose, amino acids & other organic solutes are
reabsorbed via specific transport systems
65% of filtered K+ reabsorbed via the paracellular pathway
≈80% of Pi (H2PO4
-/HPO4
2-) reabsorbed via Na+/Pi co-
transporters then via controlled leak pathways to the blood

Phosphate transport is regulated by parathyroid hormone
60% of H2O is reabsorbed passively; via a transcellular
pathway (AQP1) & a paracellular pathway (claudin-2)
Loose tight junctions make the proximal tubule water
permeable
The osmolarity of tubular fluid is isotonic

NaHCO3 & NaCl: important solutes for diuretic action
NHE3 (luminal): initiate the reabsorption of NaHCO3
Na+ enter to the cell in exchange for a H+
Na+/K+-ATPase (basolateral) pumps the reabsorbed Na+
into the interstitium in order to maintain a low intracellular
Na+ concentration

H+ secreted into the lumen combines with HCO3
- to form
H2CO3, w/c is rapidly dehydrated to CO2 & H2O by CA
CO2 produced by dehydration of H2CO3 enters the
proximal tubule cell by simple diffusion, where it is then
rehydrated back to H2CO3, facilitated by intracellular CA

After dissociation of H2CO3, the H+ is available for
transport by the NHE3 & the HCO3
- is transported out of
the cell by a basolateral membrane transporter
Bicarbonate reabsorption by the proximal tubule is thus
dependent on carbonic anhydrase activity

Since HCO3
- & organic solutes have been largely removed from
the tubular fluid in the late proximal tubule, the residual
luminal fluid contains predominantly NaCl
Under these conditions, Na+ reabsorption continues, but the
H+ secreted by the NHE3 can no longer bind to HCO3
-
Free H+ causes luminal pH to fall, activating Cl-/base exchanger
The net effect of parallel Na+/H+ exchange & Cl-/base
exchange is NaCl reabsorption
As yet, there are no diuretic agents that are known to act on
this conjoint process

Organic acid secretory systems;
Located in the middle third of the straight part of the
proximal tubule (S2 segment)
Secrete a variety of organic acids (uric acid, NSAIDs,
diuretics, antibiotics, etc) into the lumen
Diuretics must be secreted for their action
Organic base secretory systems (creatinine, choline, etc)
are also present, in the early (S1) & middle (S2) segments
of the proximal tubule

Dehydration
Rehydration

Loop of Henle
 Thin descending limb:
Urea recycling via UTA2
Permeable to solutes
Water permeable (osmotic forces in the hypertonic
medullary interstitium)
 The thin ascending limb:
Water impermeable but is permeable to some solutes

 The thick ascending limb (TAL):
Impermeable to water: diluting segment
Actively reabsorbs NaCl (about 25% of the filtered Na+);
Na+/K+2Cl- cotransporter (luminal): electrically neutral
(Two cations & two anions are cotransported)
3Na+ pumped out of the cell & 2K+ transported in to the
cell via NA+/K+-ATPase & Cl- transported out of the cell in
the basolateral side via Cl- transporter

Excess K+ accumulation within the cell → back diffusion of this
K+ into the tubular lumen (ROMK)
Causes a lumen-positive electrical potential
Provides the driving force (repelled from the lumen) for
reabsorption of cations (Mg2+, Ca2+) via the paracellular
pathway
Contribute to medullary hypertonicity;
Play an important role in concentration of urine by the
collecting duct

Distal Convoluted Tubule: DCT
About 10% of the filtered NaCl is reabsorbed via
electrically neutral Na+/Cl--cotransporter
Relatively impermeable to water & NaCl reabsorption
further dilutes the tubular fluid
B/c K+ does not recycle across the apical membrane, no
lumen-positive potential develops

DCT…
Ca2+ & Mg2+ are not driven out of the tubular lumen by
electrical forces
Instead, Ca2+ actively reabsorbed by the DCT epithelial
cell via an apical Ca2+ channel & basolateral Na+/Ca2+
exchanger
This process is regulated by PTH

Collecting Tubule System
Connects the DCT to the renal pelvis & the ureter
Consists of several sequential tubular segments:
The connecting tubule, the collecting tubule &
The collecting duct (formed by the connection of two or
more collecting tubules): UTA1 & UTA3 in the IMCD
A segment of the nephron containing several distinct cell
types
Responsible for only 2-5% of NaCl reabsorption

Collecting System…
The final site of NaCl reabsorption, so responsible for;
Tight regulation of body fluid volume &
Determining the final Na+ concentration of the urine
Where aldosterone exerts a significant influence
Most important site of K+ secretion
Virtually all diuretic induced changes in K+ balance occur

The mechanism of NaCl reabsorption is distinct
Principal cells: major sites of Na+, K+ & water transport
Intercalated cells (α, β): primary sites of H+ (α cells) or
bicarbonate (β cells) secretion
The α & β intercalated cells are very similar,
Except that the membrane locations of the H+-ATPase &
Cl-/HCO3
- exchanger are reversed

 Principal cell membranes;
No apical cotransport systems for Na+ & other ions
Exhibit separate ion channels for Na+ & K+
Since these channels exclude anions, transport of Na+ or
K+ leads to a net mov’t of charge across the membrane
B/c Na+ entry into the principal cell predominates over K+
secretion into the lumen, a 10-50 mV lumen –ve electrical
potential develops

Na+ that enters the principal cell from the tubular fluid is
then transported back to the blood via the basolateral
Na+/K+-ATPase
The 10-50 mV lumen negative electrical potential drives
the transport of Cl- back to the blood via the paracellular
pathway & draws K+ out of cells through the apical
membrane K+ channel

Important r/ship:
↑Na+ delivery to this segment → ↑secretion of K+
If Na+ is delivered to the collecting system with an anion
that cannot be reabsorbed as readily as Cl- (e.g, HCO3
-),
the lumen -ve potential is ↑ed & K+ secretion is enhanced
In addition, enhanced aldosterone secretion due to
volume depletion, is the basis for most diuretic-induced K+
wasting: adenosine antagonists violate this principle

Aldosterone
➲Regulates the reabsorption of Na+ via the ENaC & its
coupled secretion of K+
➲Via its action on gene transcription, ↑es the activity of
both apical membrane channels & the basolateral Na+/K+-
ATPase
➲⇒an ↑in the transepithelial electrical potential & a
dramatic ↑in both Na+ reabsorption & K+ secretion

Principal cells also contain a regulated system of water
channels
ADH/AVP controls the permeability of these cells to water
by regulating the insertion of pre-formed water channels
(AQP2) into the apical membrane
In the absence of ADH, the collecting tubule (& duct) is
impermeable to water & dilute urine is produced
ADH by acting on V2, markedly ↑es water permeability →
formation of a more concentrated urine

ADH also stimulates the insertion of UT1 (UT-A, UTA-1)
molecules into the apical membranes of collecting duct
cells in the medulla
Urea concentration in the medulla plays an important role
maintaining the high osmolarity of the medulla & in the
concentration of urine

Prostaglandins
Five PG subtypes (PGE2, PGI2, PGD2, PGF2α & TXA2 are
synthesized in the kidney & have receptors in this organ
PGE2 (acting on EP1, EP3 & possibly EP2) has been shown to
play a role in the activity of certain diuretics
PGE2 blunts Na+ reabsorption in the TAL of Henle’s loop &
ADH-mediated water transport in collecting tubules
Contribute to the diuretic efficacy of loop diuretics
Blockade of PG synthesis with NSAIDs ↓loop diuretic activity

How diuretics work?
Inhibit specific membrane transport proteins in renal
tubular epithelial cells
Osmotic effects that prevent water reabsorption
Inhibit enzymes (CAI), or
Interfere with hormone receptors in renal epithelial cells
(vaptans, or vasopressin antagonists)

Classification of Diuretics
Carbonic anhydrase inhibitors
Adenosine A1-receptor antagonists
Loop (high ceiling) diuretics
Benzothiadiazides & thiazide-like diuretics
Potassium-sparing diuretics
Aquaretics: osmotic diuretics, ADH antagonists

Carbonic Anhydrase Inhibitors: CAIs
 Acetazolamide, Brinzolamide, Dichlorphenamide,
Dorzolamide, Methazolamide
CA: present in kidney (PCT, collecting duct), eye, CNS,
RBCs, pancreas, gastric mucosa
Predominate in the epithelial cells of the PCT (type-II;
cytosolic & type-IV; membrane associated)

 MOA:
Inhibit CA located intracellularly (type-II) & on the apical
membrane (type-IV) of the PCT
CA activity in the PCT regulates the reabsorption of ≈20-
25% of the filtered load of Na+ as NaHCO3
>99% of the CA must be inhibited for a diuretic response

 CAIs: not efficacious (only 2-5% Na+ is excreted)
HCO3
- depletion → ↑ed NaCl reabsorption by the
remainder of the nephron
HCO3
- loss cause metabolic acidosis that stimulates CA
Dev’t of tolerance
CA independent HCO3
- reabsorption

Pharmacokinetics of CAIs
Well absorbed after PO
Onset: 30’; ↑in urine pH from the HCO3
- diuresis
Peak: 2 hrs
DOA: 12 hrs
Excretion: via kidney (by secretion in the proximal tubule
S2 segment by OAT)
Dose must be reduced in renal insufficiency

Clinical indications
Glaucoma (closed & open angle): 500 mg PO/IV, followed
by 125-250 mg PO q4hr, 250 mg-1 g PO/IV QD/BID/QID
Topicals: dorzolamide, brinzolamide with no systemic
effects
Urinary alkalinization: acetazolamide
Metabolic alkalosis due to excess use of diuretics in CHF
or that may appear in the correction of respiratory
acidosis: acetazolamide

Acute altitude sickness: 500 mg-1 g/day PO BID
By ↓ing CSF formation & by ↓ing the pH of the CSF &
brain, acetazolamide can ↑ventilation & diminish Sxs of
mountain sickness
Drug induced or CHF-associated edema;
250-375 mg (5 mg/kg) PO/IV QD

Familial periodic paralysis (hypokalemic), sleep apnea
Epilepsy/seizure (adjuvant): 8-30 mg/kg/day PO QD/BID
B/c of metabolic/CSF acidosis
Severe hyperphosphatemia (adjuvant): ↑phosphate
excretion
In pts with CSF leakage (caused tumor or head trauma,
but often idiopathic); by ↓CSF formation & ICP

Other uses:
Rx of dural ectasia in individuals with Marfan syndrome,
of sleep apnea & of idiopathic intracranial hypertension:
off-label
To correct a metabolic alkalosis, especially one caused by
diuretic-induced ↑in H+ excretion

Adverse Effects
Hyperchloremic metabolic acidosis
Renal stones: calcium phosphate insoluble at alkaline pH
Renal K+ wasting:
↑Na+ & HCO3
- delivery to collecting tubule → ↑lumen -ve
potential in that segment → ↑K+ secretion by K+ channels
↑H2O delivery to collecting tubule → flushes secreted K+
→ further ↑K+ secretion
Use KCl or K+ sparing diuretic

Adverse Effects…
Drowsiness & paresthesias at high dose of Acetazolamide
 Caution: CAIs may accumulate in pts with renal failure →
CNS toxicity

 Contraindications:
Hypersensitivity reactions: fever, rashes, bone marrow
suppression & interstitial nephritis
Liver cirrhosis:
CAI-induced alkalinization ↓es urinary excretion of NH4
+
(by converting it to rapidly reabsorbed NH3) & → dev’t of
hyperammonemia & hepatic encephalopathy

Adenosine
A1 receptor is found on the pre-glomerular afferent
arteriole, the PCT & most other tubule segments
Adenosine affect ion transport in the PCT, the medullary
TAL & collecting tubules; e.g, ↑es proximal reabsorption of
Na+ via ↑NHE3 activity, inhibit NHE3 at very high conce.?
In addition, via A1 on the afferent arteriole, reduces blood
flow to the glomerulus (GFR) & is also the key signaling
molecule in the process of tubuloglomerular feedback

Adenosine A1-receptor antagonists
MOA: interfere with the activation of NHE3 in the PCT &
the adenosine-mediated enhancement of collecting tubule
K+ secretion
Avoid the diuretic effects of K+ wasting & decreased GFR
resulting from tubuloglomerular feedback (TGF)
Caffeine & theophylline: weak diuretics b/c of modest &
nonspecific inhibition of adenosine receptors
Under dev’t: Aventri [BG9928], SLV320 & BG9719

Loop Diuretics
Sulfonamide derivatives: Furosemide, Bumetanide
Phenoxyacetic acid derivative: Ethacrynic acid
Sulfonylurea: Torsemide
 MOA: inhibit luminal Na+-K+-2Cl- cotransporter in the TAL
☞Filtered or secreted to the lumen for their diuretic action
↑Na+, Cl- & H2O delivery to collecting tubule →↑K+ excretion
Diminish the lumen +ve potential that comes from K+
recycling →↑in Mg2+ & Ca2+ excretion

Prolonged use → hypomagnesemia in some pts but not
hypocalcemia b/c vit-D induced intestinal absorption &
PTH induced renal reabsorption of Ca2+ can be ↑ed
If given with saline infusion: ↑Ca2+ excretion (for Rx of
hypercalcemia)
If not given with saline infusion, due to severe natriuresis
& high water loss the pt becomes severely dehydrated

Due to ↑Na+ delivery to the collecting tubule →↑H+
secretion to the lumen & HCO3
- reabsorption by the
intercalated cells
Since these cells have carbonic anhydrase to regulate
acid-base balance

 Induce expression of COX-2 → ↑production of PGE2, PGI2
PGE2, inhibits salt transport in the TAL & thus participates
in the renal actions of loop diuretics
PGI2: increases renal blood flow, stimulates renin release
Both furosemide & ethacrynic acid ↓pulmonary congestion &
left ventricular filling pressures in acute left ventricular failure
before a measurable ↑in urinary output occurs due to short-
lived venodilation by PGI2Pharmacology of Renal System 63

Also produce arterial vasodilation but due to their short DOA,
not widely used to treat hypertension
NSAIDs (e.g, indomethacin), interfere with the actions of
loops & significant in pts with nephrotic syndrome or
hepatic cirrhosis
 Have weak CA inhibition (sulfonamides) → ↑urinary
excretion of HCO3
- & phosphate
 Uric acid excretion: ↑ed (acutely), ↓ed (chronically due to
competition at OAT) Pharmacology of Renal System 64

 Block TGF by inhibiting salt transport into the macula
densa,
So that the macula densa no longer can detect NaCl
concentration in the tubular fluid
Unlike CAIs, loop diuretics do not ↓GFR by activating TGF
 Highly efficacious (high ceiling) b/c:
 25% of the filtered Na+ is reabsorbed
Nephron segments past the TAL do not possess the
reabsorptive capacity

Pharmacokinetics
 Absorption: Furosemide
BA: 47-64% (PO)
Onset: 30-60’(PO/SL); 30’ IM; 5’ IV
Peak effect: <15’(IV); 1-2 hr(PO/SL)
DOA: 2hr (IV); 6-8 hr(PO)
Distribution: protein bound: 91-99%, Vd: 0.2 L/kg

Eliminated by the kidney by glomerular filtration & tubular
secretion
Since they act on the luminal side of the tubule, their
diuretic activity correlates with their secretion by the
proximal tubule
Half-life depends on renal function
NSAIDs or probenecid ↓secretion of loop diuretics
(compete for weak acid secretion in the proximal tubule)

Edematous conditions:
Acute pulmonary edema, CHF, nephrotic syndrome & liver
cirrhosis
Acute hypercalcemia
Hyperkalemia
ARF: the rate of urine flow & enhance K+ excretion in ARF
Anion overdose: Br-, F-, I- w/c are reabsorbed in the TAL

Adverse Effects
Hypokalemic metabolic alkalosis:
Since they ↑Na+ delivery to the collecting tubule →↑ed
secretion of K+ & H+ by the duct
Dehydration (↑Na+ & water excretion) → activation of
RAAS → release of aldosterone → further ↑ed secretion of
K+ & H+
Reversed by K+ replacement & correction of hypovolemia

Ototoxicity: in high doses & renal impairment, loop
diuretics also inhibit electrolyte transport in many tissues
Na+-K+-2Cl-1: is necessary for establishing K+-rich
endolymph that bathes part of the cochlea, an organ
necessary for hearing
Hearing can be affected especially if used in conjunction
with aminoglycosides
Vestibular function is less likely to be affected

Hyperuricemia & precipitate attacks of gout
Due to competition for secretion
Rx: using lower doses to avoid dev’t of hypovolemia
Hypomagnesemia in chronic use in pts with dietary Mg2+
deficiency may predispose to arrhythmia
Rx: oral magnesium preparations
Acute hypovolemia, hypotension & cardiac arrhythmia

 Contraindication:
Hypersensitivity reaction:
Furosemide, bumetanide & torsemide may exhibit allergic
cross-reactivity in pts, sensitive to other sulfonamides
Less common with ethacrynic acid

 Thiazide diuretics: prototype is HCTZ
Were discovered in 1957, as a result of efforts to
synthesize more potent CAIs
But, inhibit NaCl reabsorption, rather than NaHCO3
-
Chlorthalidone (the parent) retain significant CA inhibitory
activity
Like CAIs & three loop diuretics, all thiazides have an
unsubstituted sulfonamide groupPharmacology of Renal System 75

Mechanism of Action
 Block Na+-Cl- co-transporter in the luminal side of the DCT
Inhibit Na+ & Cl- reabsorption, max natriuresis 5-8%
Enhance Ca2+ reabsorption
Due to effects in both the PCT & DCT
In the PCT: thiazide-induced volume depletion →↑Na+ &
passive Ca2+ reabsorption

In the DCT: lowering of intracellular Na+ by thiazide-
induced blockade of Na+ entry enhances Na+/Ca2+
exchange in the basolateral membrane
Rarely cause hypercalcemia

Enhance renal PGs production
Inhibited by NSAIDs under certain conditions
Arterial vasodilation occurs during long-term use of
thiazides (K+-channel openers, ↓Na+ load in vessel wall &
inhibit Ca2+ influx) at lower doses than needed for diuresis

Pharmacokinetics
All thiazides can be administered orally
Chlorothiazide not very lipid-soluble & must be given in
large doses
The only thiazide available for parenteral administration
Well absorbed from the gut and extensively metabolized
in the liver with differences in their metabolism

Mainly secreted via the PCT organic acid secretory system
& compete with the secretion of uric acid
Has longer duration than loop diuretics
Less effective in renal failure (GFR < 20 ml/min) except
metolazone

Hypertension
Heart failure
Nephrolithiasis due to idiopathic hypercalciuria
Nephrogenic diabetes insipidus: polyuria & polydipsia

Adverse effects
☠Hypokalemic metabolic alkalosis & hyperuricemia
☠Impaired carbohydrate tolerance
Due to both impaired insulin release & reduced sensitivity
Thiazides stimulate ATP-sensitive K+ channels & cause
hyperpolarization of beta cells → inhibiting insulin release
Exacerbated by hypokalemia; may be partially reversed
with correction of hypokalemia

☠Hyperlipidemia: 5-15% ↑in total cholesterol, LDLs
Return toward base line after prolonged use
☠Hyponatremia: caused by;
Hypovolemia-induced elevation of ADH
Reduction in the diluting capacity of the kidney
Increased thirst
Prevented by ↓the dose or limiting water intake

 Other Toxicities
☠Weakness, fatigability & paresthesias
☠Impotence: related to volume depletion
 Contraindications
☠Allergic reactions: sulfonamides
☠Overuse in hepatic cirrhosis, borderline renal failure, or
heart failure

Potassium-sparing Diuretics
 Aldosterone antagonists: spironolactone, eplerenone
Action depends on the presence of aldosterone
 ENaC blockers: amiloride, triamterene
Both groups produce Na+ (2-3% of filtered Na+) & water
loss accompanied by preservation of plasma K+ by
reduction of Na+/K+ exchange
Combined with thiazides or loop diruretics, to reduce or
eliminate the hypokalemia

Pharmacokinetics
Route of administration: orally
Spironolactone: metabolized in the wall of the gut & liver to
canrenone
Has slow onset (6 wks)
Triamterene, metabolized extensively in the liver → short t1/2
(must be given frequently)
Elimination: renal excretion (active form & metabolites)
Amiloride: not metabolized (secreted into PCT), no frequent
administration
Onset of triamterene & amiloride is rapidPharmacology of Renal System 88

Primary hyperaldosteronism (Conn’s syndrome, ectopic
ACTH production)
Secondary hyperaldosteronism caused by CHF, hepatic
cirrhosis & nephrotic syndrome
Combined with thiazides or loop diuretics
Liddle’s syndrome: amiloride but not spironolactone
Antiandrogenic uses (female hirsutism)

Adverse effects
Hyperkalemia: should not be given with agents that blunt
RAAS; β blockers, NSAIDs, aliskiren, ACEIs/ARBs
Hyperchloremic metabolic acidosis
Inhibiting H+ secretion in parallel with K+secretion
Gynecomastia, impotence & BPH: spironolactone
Kidney stones: Triamterene slightly soluble in urine
 Contraindications
Patients with chronic renal insufficiency
Patients with severe liver impairmentPharmacology of Renal System 90

Osmotic Diuretics
Mannitol, Glycerin, Isosorbide, Sorbitol, Urea
Filtered at the glomerulus but not reabsorbed from the
renal tubule
Limit passive tubular water reabsorption at the PCT &
descending limb (water permeable sites) → diuresis
Water loss is accompanied by a variable natriuresis

 After IV administration mannitol ↑ECF: extracting fluid
from the cell (fluid shift) results in;
↑Renal blood flow by;
↓Viscosity of blood
Inhibition of RAAS as ECF ↑ed
↓Sympathetic tone no activation of α1
➨Diuresis

Pharmacokinetics
Mannitol: not given PO rather IV
Poorly absorbed in the GIT → osmotic diarrhea rather
than diuresis
Not metabolized & excreted by glomerular filtration within
30-60’, without reabsorption or secretion
Caution: in pts with even mild renal insufficiency

To increase urine volume with limited effect on electrolyte
or acid-base balance as postoperative, after accidents, or
hemolysis; to remove renal toxins
To ↓ICP in ABI, hemorrhagic strock
To ↓IOP before ophthalmologic procedures

Adverse Effects
Extracellular volume expansion (prior to diuresis)
Dehydration & hypernatremia: excessive use with no
adequate rehydration
Hyperkalemia:
As water is extracted from cells, intracellular K+ conce.
rises → cellular losses & hyperkalemia

Hyponatremia: in pts with severe renal impairment,
mannitol can’t be excreted & retained in blood
This causes osmotic extraction of water from cells →
hyponatremia
Attention to serum ion composition & fluid balance

ADH Antagonists
ADH: octapeptide produced in the hypothalamus
Medical conditions (CHF, SIADH) stimulate ADH secretion
→ water retention
Pts with CHF who are on diuretics frequently develop
hyponatremia secondary to excessive ADH secretion
Ethanol, water: inhibit ADH secretion from hypothalamus

 ADH receptors: V1 (V1a, V1b) & V2
V1: expressed in the vasculature & CNS
V2: expressed specifically in the kidney
Non specific agents: Lithium & demeclocycline
Now replaced by vaptans due to ADR (renal failure)

Conivaptan (available in IV): act on both V1a & V2
Orals (tolvaptan, lixivaptan & satavaptan): V2 selective
Tolvaptan: FDA-approved, very effective for hyponatremia
Lixivaptan & satavaptan: under clinical dev’t
t1/2 of conivaptan & demeclocycline: 5-10 hrs, tolvaptan
12-24 hrs

Syndrome of Inappropriate ADH Secretion
If water restriction is not successful
Other causes of elevated ADH
Thirst: IV conivaptan is effective by blocking V1a
Autosomal dominant polycystic kidney disease
Cyst dev’t in polycystic kidney disease is mediated
through cAMP
ADH is a major stimulus for cAMP production in the
kidney via V2: tolvaptanPharmacology of Renal System 103

Adverse Effects
Nephrogenic diabetes insipidus: caused by Li+
Can be treated with thiazides & amiloride
HCTZ causes ↑ed osmolality in the inner medulla (papilla)
& a partial correction of the Li+-induced reduction in
aquaporin-2 expression
Amiloride blocks Li+ entry into collecting duct cells &
reverses Li+-induced polyuria

Acute renal failure: Li+ & demeclocycline
Chronic interstitial nephritis: in long-term Li+ therapy
Hypotension & elevation in liver function tests: tolvaptan

Diuretic resistance
Failure to achieve therapeutically desired reduction in
edema despite a full dose of diuretic
The mechanisms of diuretic resistance are complex &
differ from patient to patient
Three suggested mechanisms are;
Rebound Na+ retention: that occur during diuretic action
Post-diuretic effect: short term NaCl retention
Braking phenomenon: ↑ Na+ retention chronically

 Rebound Na+ retention:
After administration of loop diuretics, Na+ absorption is
blocked at the loop of Henle, leading to a pronounced
reabsorption of Na+ at the distal sites of the nephron
This reabsorption may be sufficient to nullify the effects
of the prior blockage

 Post diuretic effect:
A compensatory Na+ retention process that begins as the
diuretic action wanes
The body has compensated by absorbing more Na+,
partially nullifying the effect of the drug
 Diuretic braking:
A ↓in a pt’s response to a diuretic after receiving the first
dose or
The magnitude of response to each administered dose of
diuretic declines with timePharmacology of Renal System 109

Management of diuretic resistance
Attenuating neurohormonal compensation: ACEIs/ARBs,
β-blockers & spironolactone
Improving contractility with inotropes (heart failure)
Regulating dietary fluid & Na+ intake; bed rest, avoiding
NSAIDs
Sequential diuretic blockade: (loop + thiazide) diuretics &
Continuous infusion loop diuretic therapy (CILT)

Diuretic abuse/doping/
In sports: athletics; box, weight lifting…
As masking agents: WADA
To regulate body mass:
Eating disorders: anorexia nervosa, bulimia nervosa

Antimicrobial Agents in the Treatment
of
Urinary Tract Infections

Commonly used antimicrobial agents in the treatment of UTIs

Nitrofurantoin:
Activity: bactericidal
Spectrum: active against G+ve & G-ve bacteria;
Escherichia.coli,
Staphylococcus saprophyticus, Coagulase negative
staphylococci, S.aureus, Streptococcus agalactiae,
Enterococcus faecalis, Citrobacter, Bacillus subtilis

MOA: Nitrofurantoin is reduced by bacterial flavoproteins
(nitrofuran reductase) to reactive intermediates which
inactivate or alter bacterial ribosomal proteins, DNA,
respiration, pyruvate metabolism & other macromolecules
Commonly used in pregnancy to treat UTIs (category B)
Poor tissue penetration & low blood levels (rather
concentrated in urine)
Not recommended for the Rx of pyelonephritis, prostatitis
& intra-abdominal abscess

Fosfomycin (Phosphonomycin)
Is phosphoenolpyruvate (PEP) analog
Enter the cell through the glycerophosphate transporter
Activity: bactericidal
Spectrum: active against G+ve & G-ve bacteria;
Escherichia.coli (ESBL-producing),
Enterococcus faecalis, Citrobacter, Proteus

MOA: inhibits bacterial cell wall biogenesis by inactivating
[alkylating an active site cysteine residue (Cys115) in
E.coli enzyme];
The enzyme UDP-N-acetylglucosamine-3-enolpyruvyl
transferase, also known as MurA
MurA, catalyzes the ligation of PEP to the 3’-OH group of
UDP-N-acetylglucosamine (the committed step in
peptidoglycan biosynthesis)Pharmacology of Renal System 121

Overview of outpatient antimicrobial therapy for lower tract infections in adults

Evidence-based empirical treatment of UTIs & prostatitis

Parmacology of Renal System by Birhanu Geta

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Parmacology of Renal System by Birhanu Geta

Similar to Parmacology of Renal System by Birhanu Geta (20)

More from Addis Ababa University

More from Addis Ababa University (12)

Recently uploaded

Recently uploaded (20)

Parmacology of Renal System by Birhanu Geta

Editor's Notes