FARMAKOTERAPI TERAPAN

Tujuan Perkuliahan
Farmakoterapi Terapan
• Memahami dan mengevaluasi regimentasi dosis
untuk setiap kasus khusus pada farmakoterapi
sistem syaraf; sistem renal dan kardivaskular;
sistem pencernaan dan pernafasan; sistem
hormon dan endokrin; penyakit infeksi; kanker;
patofisiologi dan pemilihan obat untuk masing-
masing penyakit; dan evaluasi penggunaan
beberapa obat pada beberapa kasus.
RENAL ANATOMY AND
PHYSYOLOGY
Renal Circulation
 Kapsul Bowman Tubulus proksimal
Glomerulus

Korteks Lengkunga
ginjal n Henle
menaik
Lengkunga
Medula n Henle Duktus
ginjal menurun pengumpul

Lengkungan Ke ureter
Henle

Kapiler
Pertubular
Diagram Unit Fungsional Ginjal Terkecil
Nephron
Macula Densa

Glomerulus
Glomerular Capillaries
Nephron
Epithelial Cell
 Renal system – important points
• Kidneys have excellent blood
supply: 0.5% total body
weight but ~20% of CO.
• Kidneys process plasma
portion of blood by removing
substances from it, and in a
few cases, by adding
substances to it.
• Works with cardiovascular
system (and others!) in
integrated manner
RENAL FUNCTION
• Along the
nephron, sodium
ions are
reabsorbed by
two mechanisms:
– Cation
exchange
– Chloride ion
transport
 The functional unit of the kidney: the
nephron
• Total of about 2.5 million in the
2 kidneys.
• Each nephron consists of 2
functional components:
– The tubular component
(contains what will
eventually become urine)
– The vascular component
(blood supply)
• The mechanisms by which
kidneys perform their functions
depends upon the relationship
between these two
components.
 Functions of the kidneys
• Regulation of H2O and inorganic ion balance – most important
function!
• Removal of metabolic waste products from blood and excretion
in urine.
• In kidney disease, build-up of waste serious, but not a bad as
ECF volume and composition disturbances.
• Removal of foreign chemicals in the blood (e.g. drugs) and
excretion in urine.
• Gluconeogenesis
• Endocrine functions (e.g. renin, erythropoetin, 1,25-
dihydroxyvitamin D)
 The three basic renal processes
• Glomerular filtration
• Tubular reabsorption
• Tubular secretion

Excretion
• GFR is very high: ~180l/day.
Lots of opportunity to precisely
regulate ECF composition and
get (menyingkirkan) rid of
unwanted substances.

• N.B. it is the ECF that is being

regulated, NOT the urine.
 Glomerular filtration
• GFR controlled by diameters
of afferent and efferent
arterioles
• Sympathetic vasoconstrictor
nerves
• ADH and RAAS also have an
effect on GFR.
• Autoregulation maintains
blood supply and so maintains
GFR. Also prevents high
pressure surges damaging
kidneys.
• Unique system of upstream
and downstream arterioles.

• Remember: high hydrostatic pressure (PGC) at glomerular capillaries is due to short, wide
afferent arteriole (low R to flow) and the long, narrow efferent arteriole (high R).
 GFR depends on diameters of afferent and efferent arterioles
Glomerulus

Afferent arteriole Efferent arteriole

GFR GFR
Glomerular filtrate

Eff. Art. Aff. Art. Eff. Art.

Aff. Art.
constriction constriction dilatation
dilatation

Prostaglandins, Angiotensin II Ang II (high dose), Angiotensin II

Kinins, Dopamine (low dose) Noradrenaline (Symp blockade
(low dose), ANP, nerves), Endothelin,
NO ADH, Prost. Blockade)
 Peritubular reabsorption
• Peritubular capillaries provide
nutrients for tubules and retrieve
the fluid the tubules reabsorb.
• Oncotic P is greater than
hydrostatic P in these capillaries,
so therefore get reabsorption
NOT filtration.
• Must occur since we filter
180l/day, but only excrete 1-
2l/day of urine.
• Reabsorb 99% H2O, 100%
glucose, 99.5% Na+ and 50%
urea. Most of this occurs at
proximal convoluted tubule.
 RENAL TRANSPORT SYSTEMS
• Lots of transporter proteins for
different molecules/ions so they
can be reabsorbed.
• They all have maximum
transport (TM) capacities where
transport saturates i.e.
10mmol/l for glucose.
• Over this value, you excrete the
excess in urine, so can be useful
sign of disease either in kidneys
or other systems.
• Amino acids also have a high
TM value because you try and
preserve as much of these
useful nutrients as possible.
 Na+ absorption
• Na+ absorbed by active transport
mechanisms, NOT by TM mechanism.
Basolateral ATPases establish a
gradient across the tubule wall.
• Proximal tubule is very permeable to
Na+, so ions flow down gradient,
across membranes.
• Microvilli create large surface area for
absorption.
• Electrical gradient created also draws
Cl- across.
• H2O follows Na+ due to osmotic force.
• Means fluid left in tubule is
concentrated.
 Glucose handling
• Glucose absorption
also relies upon the
Na+ gradient.
• Most reabsorbed in
proximal tubule.
• At apical membrane,
needs Na+/glucose
cotransporter (SGLT)
• Crosses basolateral
membrane via glucose
transporters (GLUT’s),
which do not rely upon
Na+.
EPITHELIAL
TRANSPORT
THERAPIES
MECHANISM
OF ACTION
 Osmotic Diuretics
• Filtered by glomerulus but not reabsorbed by
renal tubules, creating osmotic gradient.
• Stimulate urine flow, producing mild diuresis
with no electrolyte imbalance.
• Treatment for anuria and oligouria
• Adverse effects include nausea, dizziness, headache,
and chills. Mannitol is contraindicated in patients with
edema from cardiovascular insufficiency, pulmonary
edema, or intracranial bleeding.
OSMOTIC DIURETICS
 Osmotic Diuretics
• Common Drugs:
– Glycerin (oral)
– Isosorbide (oral)
– Mannitol (Osmitrol) IV
• Acute renal failure or cardiovascular surgeries
• Cerebral edema and glaucoma
• Increase flow to help excrete toxic substance
CARBONIC ANHYDRASE INHIBITORS:
MECHANISM OF ACTION
• The enzyme carbonic anhydrase helps to make
H+ ions available for exchange with sodium and water in
the proximal tubules.

• CAIs block the action of carbonic anhydrase, thus

preventing the exchange of H+ ions with sodium
and water.
Asetozolamida:
ASETOZOLAMIDA
 Sulfonamida tanpa aktivitas Lumen Darah
antibakteria H2O + CO2 H2O + CO2 CO2
 Efek utama menghambat karbonik
anhidrase pada sel-sel epitel tubulus Karb-anhidrase
proksimal, ..\..\RENAL-ANATOMI- H2CO3
FISIOLOGI\RENAL ANIMASI\ACID H2CO3
BASE\88no2anim-700x347[1].swf
 KAnh mengkatalisis CO2 dan H2O HCO3- H+ H+ HCO3-
H+ dan HCO3 Na+
Na+ Na+
• Penurunan kemampuan untuk
menukar Na+ untuk H+ dgn
Sel epitel tubulus
adanya asetozolamida diuresis proksimal ginjal
ringan, sementra itu HCO3-
ditahan dalam lumen shg pH urin
naik
• Hilangnya HCO3-  asidosis
metabolisme hiperkloremik dan Sekresi urin Sekresi urin 
penurunan kemampuan diuresis
stlh bbp hari pengobatan Na+, K+, HCO3-
 Kurang poten jika dibanding diuretik Volume urin
tiazida atau loop diuretics
 Carbonic Anhydrase Inhibitors
• Increase sodium and water excretion by
inhibiting carbonic anhydrase:
– No hydrogen ions to exchange for sodium ions
– Decreased sodium reabsorption
– Sodium ions and increased water excreted in urine
– Increased loss of potassium in urine
– Decreased bicarbonate in blood (acidosis)
 Carbonic Anhydrase Inhibitors
• Used in the treatment of CHF or drug- induced edema
• Reduce pressure with glaucoma (stop production of
aqueous humor)
• Useful in the treatment of epilepsy (acidosis)
• Adverse effects:
– Drowsiness
– Headache
– GI distress
– Acidosis
 CARBONIC ANHYDRASE INHIBITORS
• Common Drugs:
– Acetazolamide
(Diamox)
– Methazolamide
Osmotics/Carbonic Anhydrase Inhibitors

25-38
Na-K-2Cl SYMPORT INHIBITORS
Also Called:
•Loop Diuretics
•High Ceiling Diuretics
Ethacrynic
Furosemide
(LASIX)
Acid
(EDECRIN)

Bumetanide Torsemide
(BUMEX) (DEMADEX)
(Bartter’s Syndrome)
 Na-Cl SYMPORT INHIBITORS

Also Called:
•Thiazide Diuretics
•Thiazide-Like Diuretics

Hydrochlorothiazide Chlorthalidone
(HYDRODIURIL) (HYGROTON)

Chlorothiazide Metolazone
(DIURIL) (ZAROXOLYN)
• Thiazides, due to their inhibition of the Na+-Cl-
symport system, increase sodium and chloride
excretion.(renal synport diagram)
• By increasing the sodium load at the distal renal
tubule,thiazide indirectly increases potassium
excretion via the sodium/ potassium exchange
mechanism.
• Thiazide diuretics, when used in the management of
hypertension, is administered in combination with a
potassium-sparing drug. Reduction in the amount of
potassium loss can be achieved by:
• Using potassium sparing drugs block Na+ channels in
the late distal tubule and collecting duct (Amiloride
(Midamor)& Triamterene (Dyrenium))
(Gitelman’s Syndrome)
Na CHANNEL INHIBITORS

Also Called:
•K-Sparing Diuretics

Triamterene
(DYRENIUM)

Amiloride
(MIDAMOR)
• Amiloride and probably triamterene blocks sodium
channels in the luminal membrane in the late distal
tubule and collecting duct.
• Such action inhibits the normal movement of Na+ into
the cell.
• Since K+ secretion in in the late distal tubule and
collecting duct.are driven by the electrochemical
gradient generated by Na+ reabsorption, K+ (and
H+) transport into the urine is reduced.
• By reducing the net negative luminal charge,
amiloride/triamterene administration help conserve
potassium. Therefore, they are called "potassium
sparing".
(Liddle’s Syndrome)
Triamterene
 Triamterene directly blocks the
epithelial sodium channel (ENaC)
on the lumen side of the kidney
collecting tubule. Other diuretics
cause a decrease in the sodium
concentration of the forming
urine due to the entry of sodium
into the cell via the ENaC, and
the concomitant exit of
potassium from the principal cell
into the forming urine. Blocking
ENaC prevents this from
happening.
 Amiloride works in the same
way. Sodium channel blockers
directly inhibit the entry of
sodium into the sodium channe
GENERIC NAME: triamterene and hydrochlorothiazide
(HCTZ); BRAND NAMES: Maxzide, Dyazide
• DRUG CLASS AND MECHANISM:
Triamterene/hydrochlorothiazide is an oral diuretic
(water pill) that is used for treating high blood pressure
(hypertension) and edema (water accumulation). It is a
combination of two different diuretics. The FDA
approved triamterene/hydrochlorothiazide in December
1965.
• Triamterene (trade name Dyrenium) is a potassium-
sparing diuretic used in combination with thiazide
diuretics for the treatment of hypertension and edema.
In combination with hydrochlorothiazide, it is marketed
under the names Maxzide and Dyazide
 Common side effects
• May include a depletion of sodium, folic acid and calcium,
nausea, vomiting, diarrhea, headache, dizziness, fatigue, and
dry mouth. Serious side effects may include heart palpitations,
tingling/numbness, fever, chills, sore throat, rash, and back
pain. Triamterene can also cause kidney stones through direct
crystallization or by seeding calcium oxalate stones.
Triamterene is best avoided in patients with chronic kidney
disease due to the possibility of hyperkalemia. People using
this drug should use salt substitute cautiously.[2]
• Triamterene may impart a blue fluorescent color to the urine.[
MINERALOCORTICOID RECEPTOR
ANTAGONISTS

Also Called:
•K-Sparing Diuretics
•Aldosterone Antagonists
http://www.pharmacology2000.com/Cardio/antihyper/antihype2.htm

Spironolactone
(ALDACTONE)
Eplerenone
(INSPRA)
• Spironolactone is an antagonist of mineralocorticoid
receptors (aldosterone antagonist)
• Normally, aldosterone interactions with
mineralocorticoid receptors result in synthesis of
aldosterone-induced proteins (AIPs).
– These proteins appear to increase the number or
activity of Na+ channels with an attendant increase
in Na+ conductance.
– Increased Na+ conductance (with inward movement
of Na+) results in a net negative luminal charge
favoring K+ loss.
• Antagonism of the interaction between aldosterone
and its receptor by spironolactone conserves K+
(potassium sparing).
(Syndrome of Apparent MC excess)
(Licorice: Glycyrrhizic Acid)
ADH Antagonist
Vasopressin - ADH
• Demeclocycline (marketed as Declomycin,
Declostatin, and Ledermycin) is a tetracycline
antibiotic derived from a strain of
Streptomyces aureofaciens
• It is not completely understood why
demeclocycline impairs the action of
antidiuretic hormone, but is thought to block
the binding of the hormone from its receptor
Na-K-2Cl SYMPORT INHIBITORS

Also Called:
•Loop Diuretics
•High Ceiling Diuretics

Ethacrynic
Furosemide
Acid

Bumetanide Torsemide
 THERAPEUTIC EFFECTS
Increase Na Excretion Treatment for
to 25% of Filtered Load Severe Edema

Treatment for
Increase Urine Volume
Oliguric ARF

Treatment for
Increase Ca Excretion
Hypercalcemia

Impair Free Water Treatment for

Reabsorption Hyponatremia

Treatment for
Increase Venous
Pulmonary
Capacitance
Edema
 ADVERSE EFFECTS
Profound ECFV
Depletion Hypocalcemia

Hypokalemia
Ototoxicity

Metabolic
Alkalosis Hyperuricemia

Hypomagnesemia Hyperglycemia
 OTHER EFFECTS

Release PGs Block TGF

Increase &
Increase Renin
Redistribute
Release
RBF
 Na-Cl SYMPORT INHIBITORS

Also Called:
•Thiazide Diuretics
•Thiazide-Like Diuretics

Hydrochlorothiazide Chlorthalidone

Chlorothiazide Metolazone
 THERAPEUTIC EFFECTS
Increase Na Excretion
to 5% of Filtered Load

Treatment for Treatment for

Treatment for
Hypertension Nephrogenic
Mild Edema
Diabetes
Insipidus

Treatment for
Decrease Ca Excretion Calcium
Nephrolithiasis
 ADVERSE EFFECTS
ECFV Hypercalcemia
Depletion

Hypokalemia Hyponatremia

Metabolic Hyperuricemia
Alkalosis

Hypomagnesemia Hyperglycemia

Impotence Increased LDL

(Renal Cell Carcinoma??)

Na CHANNEL INHIBITORS

Also Called:
•K-Sparing Diuretics

Triamterene

Amiloride
 THERAPEUTIC EFFECTS
Enhance Natriuresis Used in
Caused by Other Diuretics Combination with
Loop &
Thiazide
Prevent Hypokalemia
Diuretics

Block Na Channels

Treatment for
Treatment for
Lithium-Induced
Liddle’s
Diabetes
Syndrome
Insipidus
 ADVERSE EFFECTS
Triamterene
Amiloride
Hyperkalemia
Hyperkalemia

Renal Stones

Interstitial
Nephritis

Megaloblastosis
MINERALOCORTICOID RECEPTOR
ANTAGONISTS

Also Called:
•K-Sparing Diuretics
•Aldosterone Antagonists

Spironolactone

Eplerenone
 THERAPEUTIC EFFECTS

Enhances Natriuresis Used in

Caused by Other Diuretics Combination with
Loop &
Thiazide
Prevents Hypokalemia
Diuretics

Blocks Aldosterone

Treatment for Treatment for

Primary Hyper- Heart Failure
aldosteronism Treatment for
Treatment for
Edema of Liver
Hypertension
Cirrhosis
 ADVERSE EFFECTS
Gastritis
Hyperkalemia

Metabolic Peptic Ulcers

Acidosis

Impotence Deepening of
Voice

CNS Side
Effects
Hirsutism

Gynecomastia Menstrual
Irregularities
 RATIONALE FOR LOW SODIUM DIET

A low sodium diet attenuates postdiuretic

sodium retention, thereby lowering diuretic
requirements!!

Major Problem is Compliance

 IMPORTANT DRUG INTERACTIONS

NSAIDS
Salt Diminished
Decongestants Diuretic
Probenecid Response

ACE Inhibitors
Beta-Blockers Hyperkalemia-
K Supplements Induced by K-Sparing
K-Sparing Diuretics Diuretics
Heparin

Ototoxic Drugs Enhanced Ototoxicity

of Loop Diuretic
 Chronic Moderate Cirrhosis
Renal Nephrotic Mild CHF
Syndrome or
Failure Severe Spironolactone:
CHF Titrate up to 400 mg/d Cr
as needed. Cl
>
CrCl< 50
50
Add
Add
Loop Diuretic: Titrate Single Daily Dose up to Ceiling Dose as Needed
Thiazide:
Drop Thiazide
50 to 100 mg/d HCTZ

Loop Diuretic: Increase Frequency of Ceiling Dose as Needed:

Furosemide, up to 3X daily; Bumetanide, up to 4X daily; Torsemide, up to 2X daily

Add
K+-Sparing Diuretic: Thiazide Diuretic:
If CrCl > 75 & urinary [Na]:[K] ratio is < 1 CrCl > 50, use 25 to 50 mg/d HCTZ
(Note: May add K-Sparing Diuretic to Loop Add CrCl 20 to 50, use 50 to 100 mg/d HCTZ
and/or Thiazide Diuretic at Any Point in Algorithm CrCl < 20, use 100 to 200 mg/d HCTZ
for K+ Homeostasis.)

While Maintaining Other Diuretics, Switch Loop Agent to Continuous Infusion

 Pustaka
• Dipiro, J.T., Talbert, RI., and Yen, G.C., 1997, Pharmacotherapy:A
Pathophysiologic Approach, 3rd. ed., Appleton & Lange, Stamford.
• Herfindal, E.T., and Gourley, D.R., 2000, Text-book of Therapeutics,
Drug and Disease Management, 7th. ed., Lippincot & Williams,
Philadelphia
• O Graddy, F., Lambert, H.P., Finch, R.G., and Greenwood, D.,
1997,Antibiotic and Chemo-therapy : Anti-infective agents and their
use in therapy, 7th. Ed., Churchill, Livingstone.
• Schwinghammer, T.L., 2002, Pharmacotherapy Casebook: A Patient
Focused Approach, 5th. Ed., McGraw-Hill Companies, New York.
• McPhee, S., Lingappa, V.R., Ganong, W.F., Lange J.D.,
2000,Pathophysiology of Disease : An Introduction to Clinical
Medicine, 3rd Ed., McGraw-Hill, New York.
• Koda-Kimble, A.M., Lee Young, L., Kradjan, W.A., Guglielmo,
B.J.,2005,Applied therapeutics : The Clinical Use of Drugs, Eighth
Ed., Lippincot William & Wilkins, Philadelphia.