Basic Renal Pharmacology

Jarir Atthobari
Dept. Pharmacology and Toxicology
Faculty of Medicine, Gadjah Mada
University
Yogyakarta

Renal Pharmacology
Kidneys:
Represent 0.5% of total body

weight, but receive ~25% of the

total arterial blood pumped by the
heart
Each contains from one to two
million nephron:

The glomerulus
The proximal convoluted
tubule
The loop of Henle
The distal convoluted
tubule

Normal Kidney Function

1. Extra Cellular Fluid Volume control
2. Electrolyte balance
3. Waste product excretion
4. Drug and hormone

elimination/metabolism
5. Blood pressure regulation
6. Regulation of hematocrit
7. regulation of calcium/phosphate
balance (vitamin D3 metabolism)

Renal process
Glomerular
Filtration
Tubular Reabsorption

Tubulus Secretion
In 24 hours the kidneys reclaim:

~ 1,300 g of NaCl
~ 400 g NaHCO3
~ 180 g glucose
almost all of the 180 L of water that entered the

Mechanism of renal transport

process

Renal Pharmacology
Blood enters the glomerulus

under pressure
This causes water, small
molecules (but not macro
molecules like proteins) and
ions to filter through the
capillary walls into the
Bowman's capsule
This fluid is called nephric filtrate

Not much different from interstitial fluid

Nephric filtrate collects within the Bowman's capsule
and flows into the proximal tubule

GFR
GFR rate = 120 ml/min

Plasma filtrate is composed of

fluids and soluble constituents

Substances normally not filtered included cell,

plasma proteins or substances bound to them,
lipids and another macromolecules

Renal Pharmacology
In proximal tubule, all of the

glucose and amino acids, >90%

of the uric acid, and ~60% of
inorganic salts are reabsorbed
by active transport (AT)
AT of Na+ out of the proximal
tubule is controlled by
angiotensin II.
As these solutes are removed from the nephric filtrate,

a large volume of the water follows them by osmosis:

8085% of the 180 liters deposited in the Bowman's
capsules in 24 hours

Renal Pharmacology
As the fluid flows into the

descending segment of the

loop of Henle, water continues
to leave by osmosis because
the interstitial fluid is very
hypertonic:
This is caused by the active transport of Na+
out of the tubular fluid as it moves up the
ascending segment of the loop of Henle
In the distal tubules, more sodium is reclaimed by
active transport, and still more water follows by
osmosis.

Drug process in human body

Drug enter to body
1

Absorption (input)

Drugs in plasma

Distribution

Drug in tissue
3

Metabolism
Metabolite

Metabolite drugs in
urine, feces, and bile

Elimination (output)

Drugs excretion
Important in determining both the duration
of drug action and rate of drug elimination.
A process whereby drugs are transferred
from the internal to the external
environment (kidney, lungs, biliary system
and GI)
Kidney is the primary organ for drugs
excretion, especially for those that are
water soluble and not volatile

Drugs excretion
Chemically
Chemically unchanged
unchanged or
or
metabolite
metabolite
Vascular
Vascular wall
wall structure
structure glomerular
glomerular
capillaries
capillaries
Drugs
Drugs
Molecular
Molecular weight
weight (MW)
(MW)
<5000
<5000

Renal Excretion
Glomerular
Filtration
Active tubular
secretion
Passive Tubular
reabsorption

Glomerular filtration

primary urine

Glomerular filtration
of drug

final urine

concentration drug
in tubule

Glomerular filtration
Restricting to compounds having relatively
large MW.
Selective filtration is important to prevent
filtration of plasma protein (albumin)
Free drug in the plasma water (unbound to
plasma protein or formed elements for
blood) and ionized will be filtered
Adequate hydrostatic pressure of blood (BP)

Drug Clearance
Factors that affect GFR
also can influence the rate of drug clearance

Inflammation
Inflammation

Congestive
Congestive Heart
Heart Failure
Failure

Neonates
Neonates

Antihypertensive
Antihypertensive

Elderly
Elderly

Organic
Organic disease
disease

Proximal Tubular Secretion

Active tubular secretion
Epithelia proximal
tubules into tubular
fluid via energyconsuming transport
system limited
capacity
When several
substrates present
simultaneously
competition for carrier

Proximal renal tubule

Carrier-mediated tubular secretion add

drug to the tubular fluid.

Transporters (P-glycoprotein) glucuronides,

sulfates, and glutathione adducts)
Adenosine triphosphate (ATP)-binding cassette
(ABC) transporters selective for organic
cationic drugs

Membrane transporters, mainly located in

the distal renal tubule, also are responsible

for any active reabsorption of drug from the
tubular lumen back into the systemic
circulation.

primary urine

Glomerular filtration
of drug

final urine

concentration drug
in tubule

Distal Tubular Reabsorption

Passive diffusion
Reabsorption dependent
upon urinary pH or degree
of dissociation (pKa)
Raising or lowering pH and
pKa will influenced
reabsorption. Lower pH and
pKa more drug will be reabsorb

Tubular reabsorption:
Effect of urine pH and pKa
Many
Many drugs
drugs are
are weak
weak acids
acids and
and weak
weak
bases
bases (weak
(weak dissociated
dissociated into
into ions
ions in
in
solution),
solution), therefore
therefore urine
urine pH
pH (range
(range 4-7.5)
4-7.5)
modulates
modulates rate
rate of
of reabsorption
reabsorption
Acidic
Acidic condition
condition suppress
suppress ionization
ionization of
of
weak
weak acids
acids and
and increase
increase fraction
fraction unionized
unionized

leading
leading increased
increased reabsorption
reabsorption and
and
reduced
reduced renal
renal clearance.
clearance. In
In contrast
contrast acidic
acidic
increase
increase the
the renal
renal clearance
clearance of
of weak
weak
bases.

This plot of cumulative excretion of drug in urine vs.

time demonstrates the a weak base of drug
(barbiturate)

Acidic urine
%
drugs
excrete
d

Alkaline
urine

TIME

Hydrophilic vs. Lipophilic

Hydrophilic
drug

Lipophilic
Lipophilic
Lipophilic
drug
drug
drug
No metabolismSlow metabolismRapid metabolism

Endogenous substances in the

kidney (vasodilator promote
diuresis)
1. Dopamine stimulates alpha, beta and dopamine
receptors and
increases renal blood flow;
increases glomerular filtration rate; main effect is to
increase renal blood flow; increases Na+ excretion
2. Prostaglandins PGE2 and PGI2 increase renal blood
flow, promote diuresis and natriuresis. Complications of
prostaglandin inhibition with non-steroidal antiinflammatory drugs: acute renal failure, hyperkalemia.
3. Kinins (Bradykinin) potent vasodilator, may promote
prostaglandin synthesis and nitric oxide release.
Increases cGMP and cAMP formation.

Endogenous substances in the

kidney (vasoconstrictor)
1. Thromboxane A2 Formed in the kidney during
pathophysiologic conditions (e.g., obstruction of
a
ureter). PGE2 and PGI2 are released to
counteract
the vasoconstriction.
2. Norepinephrine.
3. Angiotensin II - potent vasoconstrictor.

Diuretics

Loop
Thiazide
Aldosterone antagonist
Osmotic

Tubule transport systems and sites of action of diuretics

Renal Pharmacology
Diuretics:
Loop diuretics (= high ceiling diuretics):

Strong, but brief diuresis (within 1 hr, lasts ~ 4hrs)

Used for moderate to severe fluid retention and hypertension
Most potent diuretics available
Act by inhibiting the Na+/K+/2Cl- symporter in the ascending limb in the
loop of Henle
Major side effects: loss of K+ (and Ca++ and Mg++)

Furosemide
Bumetanide
Torasemide

Renal Pharmacology
Diuretics:
Thiazide diuretics:

Used for mild to moderate hypertension, mild heart failure,

Medium potency diuretics
Act by inhibiting the Na+/Cl- symporter in the distal convoluted tube
Major side effects: loss of K+ (and Mg++, but not Ca++)

Hydrochlorothiazide
Benzthiazide
Cyclothiazide

Renal Pharmacology
Diuretics:
Carbonic anhydrase inhibitors:
Azetazolamide
Can trigger metabolic acidosis
Not in use as diuretic anymore
Primary indications is glaucoma
(prevents production of aequous
humor)

Dorzolamide
CA-inhibitors are sulfonamides =>
cross-allergenic with antibiotics etc.

Renal Pharmacology
Major side effects of these diuretics :
Hypokalemia, hyponatremia, hypochloremia
Hypotension and dehydration
Interaction with Cardiac Glycosides

=> Potassium can be given orally or IV

or

Potassium-sparing diuretics:
Often used in combination with high-ceiling

diuretics or thiazides due to potassium-sparing

effects
Produce little diuresis on their own

Renal Pharmacology
Diuretics:
Potassium-sparing diuretics:
Act on the distal portion of the distal tube (where Na+ is exchanged for
K+)
Aldosterone promotes reabsorption of Na+ in exchange for K+
(transcriptionally upregulates the Na+/K+ pump and sodium channels)

Spironolactone
Aldosterone receptor antagonist
Onset of action requires several days
Amiloride; Trimterene
Block sodium channels
Quick onset

Aldosterone

Spironolactone

Renal Pharmacology
Diuretics:
Osmotic diuretics:
Small, non-reabsorbable molecules that inhibit passive
reabsorption of water
Predominantly increase water excretion without
significantly increasing Na+ excretion => limited use
Used to prevent renal failure, reduction of intracranial
pressure
(does not cross blood-brain barrier => water is pulled out of
the brain into the blood)
Mannitol
Only given IV can crystallize (=> given with filter needle
or in-line filter)

A Schematic Portrayal of the Three Major Physiological Pathways Regulating Renin Release.

Clinical Implication of renal excretion

The
The rate
rate of
of urinary
urinary drug
drug excretion
excretion will
will depend
depend
on
on the
the drugs
drugs volume
volume distribution,
distribution, its
its degree
degree
protein
protein binding
binding and
and the
the following
following renal
renal
condition:
condition:
Glomerular
Glomerularfiltration
filtrationrate
rate
Tubular
Tubularfluid
fluidpH
pH
Extent
Extentof
ofback-diffusion
back-diffusionof
ofthe
theunionized
unionizedform
form
Extent
Extentof
ofactive
activetubular
tubularsecretion
secretionof
ofcompound
compound
Possibly,
Possibly, extent
extentof
ofactive
activetubular
tubularreabsorption
reabsorption

Clinical Implication of renal excretion

For
For many
many drugs,
drugs, the
the duration
duration and
and intensity
intensity of
of
pharmacological
pharmacological effect
effect will
will be
be influenced
influenced of
of by
by the
the
status
status of
of renal
renal function.
function.
Ultimately,
Ultimately, whether
whether or
or not
not dosage
dosage adjustment
adjustment
(prolongation
(prolongation of
of dosing
dosing interval,
interval, reduction
reduction dose
dose or
or
both)
both) becomes
becomes necessary
necessary will
will depend
depend on
on an
an
assessment
assessment of
of the
the degree
degree renal
renal dysfunction,
dysfunction, the
the
percentage
percentage of
of drug
drug cleared
cleared by
by kidney,
kidney, and
and
potential
potential drug
drug toxicity,
toxicity, especially
especially ifif renal
renal function
function
is
is reduced.
reduced.