Pharmacological Properties

A. Spironolactone
Mechanism of Action
Spironolactone is a synthetic steroid that acts as a potassium-sparing diuretic. It prevent
+
K secretion by competitively antagonizing the effects of aldosterone in collecting tubules. It
inhibits the effect of aldosterone by direct pharmacologic antagonism of mineralocorticoid
receptors.
Pharmacokinetic
- Absorption: fairly rapidly absorbed from the gastrointestinal tract. Food increases the
bioavailability of unmetabolized spironolactone by almost 100%.
- Distribution: Spironolactone and its metabolites are more than 90% bound to plasma
proteins.
- Metabolism: substantial inactivation occur in the liver
- Excretion: The metabolites are excreted primarily in the urine and secondarily in bile.
Pharmacodynamic
Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts.
Potassium absorption (and K+ secretion) at this site is regulated by aldosterone.
Spironolactone bind to mineralocorticoid receptors and blunt aldosterone activity. The actions
of the aldosterone antagonists depend on renal prostaglandin production. The K +-sparing
diuretics can be inhibited by NSAIDs under certain conditions.
Adverse Effect
Toxicity may induce
- Hyperkalemia
- Hyperchloremic metabolic acidosis
- Gynecomastia
Drug Interaction
Concomitant use of agents that blunt the RAAS such as beta blockers, ACE inhibitors, and
ARBs increase the likelihood of hyperkalemia.
Indication and Use
Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or
hyperaldosteronism, due either to primary hypersecretion (Conns syndrome, ectopic
adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by HF,
hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective
intravascular volume). In the setting of enhanced mineralocorticoid secretion and excessive
delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics
may be used in this setting to blunt the K + secretory response.
Contraindication
- Patients with chronic renal insufficiency: they are especially vulnerable to hyperkalemia
and should rarely be treated with these diuretics
- Oral K+ administration should be discontinued if K+ sparing diuretics are administered
- Simultaneous use of agents that blunt the RAAS as stated above
- Patients with liver disease may have impaired metabolism, so dosing must be carefully
adjusted

B. Furosemide
Mechanism of Action

Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending limb of the loop
of Henle, this in turn will inhibit water reabsorption in the nephron. This is achieved through
competitive inhibition at the chloride binding site on the cotransporter, thus preventing the
transport of sodium from the lumen. Consequently, the lumen becomes more hypertonic while
the interstitium becomes less hypertonic, which in turn diminishes the osmotic gradient for
water reabsorption.
Pharmacokinetic
- Absorption: rapidly absorbed
- Distribution: 95% bound to plasma proteins
- Metabolism: only a small amount is hepatically metabolized
- Excretion: they are eliminated by the kidney, by glomerular filtration and tubular
secretion.
Pharmacodynamic
Loop diuretics inhibit NKCC2, the luminal Na +/K+/2Cl- transporter in the thick ascending
limb of the loop of Henle. By inhibiting this transporter, the loop diuretics reduce the
reabsorption of NaCl and also diminish the lumen-positive potential that comes from K +
recycling. This positive potential that comes from K + recycling. This positive potential normally
drives divalent cation reabsorption in the TAL, and by reducing this potential, loop diuretics
can cause an increase in Mg2+ and Ca2+ excretion.
Loop diuretics have also been shown to induce expression of COX-2. At least PGE 2 inhibits
salt transport in the TAL and thus participates in the renal actions of loop diuretics. Loop
agents also have direct effects on blood flow through several vascular beds. Furosemide
increases renal blood flow via prostaglandin actions on kidney vasculature and also reduce
pulmonary congestion and left ventricular filling pressures in HF.
Adverse Effect
Toxicity may induce
- Hypokalemic metabolic alkalosis
- Ototoxicity
- Hyperuricemia
- Hypomagnesemia
Other adverse effect
- Allergic reaction such as skin rash, eosinophilia, and interstitial nephritis
- Cross-reaction to allergy with other sulfonamides
Drug Interaction
Simultaneous administration of NSAIDS or probenecid may reduce loop diuretic secretion.
Other ototoxic agents such as aminoglycoside may increase risk of ototoxicity.
Indication and Use
The most important indications for the use of the loop diuretics include acute pulmonary
edema, other edematous conditions, and acute hypercalcemia. Other indications include
hyperkalemia, acute renal failure, and anion overdose.
Contraindication
- Patients who are sensitive to other sulfonamides
- Overzealous use of any diuretics in hepatic cirrhosis, borderline renal failure, or HF

C. Interferon
Interferons are host cytokines that exert complex antiviral, immunomodulatory, and
antiproliferative actions. Interferon appears to function by induction of intracellular signals
following binding to specific cell membrane receptors, resulting in inhibition of viral
penetration, translation, transcription, protein processing, maturation, and release, as well as

increased host expression of major histocompatibility complex antigens, enhanced phagocytic

activity of macrophages, and augmentation of the proliferation and survival of cytotoxic T
cells.
interferons are filtered at the glomerulus and undergo rapid proteolytic degradation
during tubular reabsorption, such that detection in the systemic circulation is negligible. Liver
metabolism and subsequent biliary excretion are considered minor pathways.
The adverse effects of interferon include a flu-like syndrome (ie, headache, fevers, chills,
myalgias, and malaise) that typically occurs within 6 hours after dosing; this syndrome occurs
during the first week of therapy and tends to resolve upon continued administration. Transient
hepatic enzyme elevations may occur in the first 812 weeks of therapy and appear to be
more common. Potential adverse effects during chronic therapy include neurotoxicities (mood
disorders, depression, somnolence, confusion, and seizures), myelosuppression, profound
fatigue, weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss,
retinopathy, pneumonitis, and possibly cardiotoxicity. Induction of autoantibodies may occur,
causing exacerbation or unmasking of autoimmune disease (particularly thyroiditis).
Contraindications to interferon therapy include hepatic decompensation, autoimmune
disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric
disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and
cytopenia.
Potential drug-drug interactions include increased theophylline and methadone levels. Coadministration with didanosine is not recommended because of a risk of hepatic failure and
co-administration with zidovudine may exacerbate cytopenias.

Laboratory Exams
Serology
Hepatitis A
- Antibody to hepatitis A (anti-HAV) appears early in the course of the illness.
- Both IgM and IgG anti-HAV are detectable in serum soon after the onset.
- Peak titers of IgM anti-HAV occur during the first week of clinical disease and disappear
within 36 months.
- Detection of IgM anti-HAV is an excellent test for diagnosing acute hepatitis A.
- Titers of IgG anti-HAV rise after 1 month of the disease and may persist for years.
- IgG anti-HAV (in the absence of IgM anti-HAV) indicates previous exposure to HAV,
noninfectivity, and immunity.

Hepatitis B

HBsAg: the appearance of this antigen in serum is the first evidence of infection and
persist throughout the clinical illness. Persistence of HBsAg more than 6 months after the
acute illness signifies chronic hepatitis B.
Anti-HBs: specific antibody to HbsAg (anti-HBs) appears in most individuals after
clearance of HBsAg and after successful vaccination against hepatitis B. Disappearance
of HBsAg and the appearance of anti-HBs signal recovery from HBV infection,
noninfectivity, and immunity.
Anti-HBc: IgM anti-HBc indicates a diagnosis of acute hepatitis B. It can persis for 3-6
months and sometimes longer. IgM anti-HBc may also reappear during flares of previously
inactive chronic hepatitis B.
HBeAg: HBeAg is a secretory form of HBcAg that appears in serum during the incubation
period shortly after the detection of HBsAg. HBeAg indicates viral replication and
infectivity. Persistence beyond 3 months indicates an increased likelihood of chronic
hepatitis B. Its disappearance is often followed by the appearance of anti-HBe, generally
signifying diminished viral replication and decreased infectivity.
HBV DNA: the presence of HBV DNA in serum generally parallels the presence of HBeAg,
although HBV DNA is a more sensitive and precise marker of viral replication and
infectivity.

Hepatitis C
Antibodies to HCV (anti-HCV) is detected by an enzyme immunoassay (EIA). Limitations of
the EIA include moderate sensitivity for the diagnosis of acute hepatitis C in the ocurse
and low specificity in some presons with elevated gamma-globulin levels.
Anti-HCV in serum may be confirmed by a recombinant immunoblot assay (RIBA)
HCV RNA may also be detected using PCR

Hepatitis D
The diagnosis of hepatitis D is made by detection of anti-HDV, HDAg, or HDV RNA in
serum.

Hepatitis E
The diagnosis of acute hepatitis E is done by testing for IgM anti-HEV ins erum
HEV RNA may be detected in the serum using PCR

Blood
a. Leukocyte
Generally: neutropenia and lymphopenia are transient and are followed by a relative
lymphocytosis. Atypical lymphocytes are common during the acute phase.
- Hepatitis A: normal to low, especially in preicteric phase; large atypical lymphocytes may
occasionally be seen.
b. Coagulation Factors
Generally: measurement of the prothrombin time (PT) is important in patients with acute viral
hepatitis. A prolonged value may reflect a severe hepatic synthetic defect, signifying
extensive hepatocellular necrosis, and indicate a worse prognosis.
c. Protein
Generally: a fall in serum albumin is uncommon in uncomplicated acute viral hepatitis. A
diffuse but mild elevation of the gamma globulin fraction is common during acute viral
hepatitis. Serum IgG an IgM levels are elevated in about one third of patients.

Urinalysis
Generally: a slight microscopic hematuria and minimal proteinuria has been noted. The color
of the urine is also observed.
- Hepatitis A: mild proteinuria is common; bilirubinuria often precedes the appearance of
jaundice.

Stool Examination
Generally: mild and transient steatorrhea has been noted. In fecal specimen the color of the
feces is noted.
- Hepatitis A: PCR can detect HAV in stool, but it is rarely used outside of research; stools
may be acholic during onset of jaundice