Piretanide
Pharmacokinetics
Piretanide has been reported to be almost completely ab-
sorbed following oral administration, it is extensively bound
to plasma proteins, and is reported to have a half-life of about
1 hour.
Adverse Effects
As for Frusemide which are listed below. Muscle cramps have been reported
following high doses of piretanide.
ADVERSE REACTIONS:
Adverse reactions are categorized below by organ system and listed by decreasing
severity.
GASTROINTESTINAL SYSTEM REACTIONS
1. pancreatitis 5. cramping
2. jaundice (intrahepatic 6. diarrhea
cholestatic jaundice) 7. constipation
3. anorexia 8. nausea
4. oral and gastric 9. vomiting
irritation
SYSTEMIC HYPERSENSITIVITY REACTIONS
1. systemic vasculitis
2. interstitial nephritis
CENTRAL NERVOUS SYSTEM REACTIONS
1. tinnitus and 4. dizziness
hearing loss 5. headache
2. paresthesias 6. blurred vision
3. vertigo 7. xanthopsia
HEMATOLOGIC REACTIONS
1. aplastic anemia (rare) 4. hemolytic anemia
2. thrombocytopenia 5. leukopenia
3. agranulocytosis (rare) 6. anemia
DERMATOLOGIC- HYPERSENSITIVITY REACTIONS
1. exfoliative dermatitis 5. urticaria
2. erythema multiforme 6. rash
3. purpura 7. pruritus
4. photosensitivity
CARDIOVASCULAR REACTION
Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or
narcotics.
OTHER REACTIONS
1. hyperglycemia 6. restlessness
2. glycosuria 7. urinary bladder spasm
3. hyperuricemia 8. thrombophlebitis
4. muscle spasm 9. fever
5. weakness
Whenever adverse reactions are moderate or severe, Lasix(R) dosage should be
reduced or therapy withdrawn.
Precautions
Piretanide's precautions and contra-indications which are de-
pendent on its effects on fluid and electrolyte balance are sim-
ilar to those of the thiazide diuretics, see
Hydrochlorothiazide record below. Patients with impaired micturi-
tion or prostatic hyperplasia may develop retention of urine
with piretanide.
PRECAUTIONS:
General
All patients receiving diuretic therapy should be observed for evidence of fluid
or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and
hypokalemia. Serum and urine electrolyte determinations are particularly
important when the patient is vomiting excessively or receiving parenteral
fluids. Warning signs or symptoms of fluid and electrolyte imbalance,
irrespective of cause, include dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis
is present or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to
hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or
exaggerate the response of the heart to the toxic effects of digitalis (e.g.,
increased ventricular irritability). Hypokalemia may be avoided or treated by
use of potassium sparing diuretics or potassium supplements such as foods with a
high potassium content.
Although any chloride deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances (as in liver disease
or renal disease), chloride replacement may be required in the treatment of
metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather;
appropriate therapy is water restriction, rather than administration of salt,
except in rare instances when the hyponatremia is life threatening. In actual
salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or acute gout may be precipitated in certain patients
receiving thiazides.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents
may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent
diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post-
sympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or
discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause
intermittent and slight elevation of serum calcium in the absence of known
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy.
Laboratory Tests
Periodic determination of serum electrolytes to detect possible electrolyte
imbalance should be done at appropriate intervals.
Drug Interactions
When given concurrently the following drugs may interact with thiazide
diuretics.
Alcohol, Barbiturates, Or Narcotics--potentiation of orthostatic hypotension may
occur.
Antidiabetic Drugs--(oral agents and insulin)--dosage adjustment of the
antidiabetic drug may be required.
Other Antihypertensive Drugs--additive effect or potentiation.
Cholestyramine And Colestipol Resins--Absorption of hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its
absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH--intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (e.g., Norepinephrine)--possible decreased response to pressor
amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine)--possible
increased responsiveness to the muscle relaxant.
Lithium--generally should not be given with diuretics. Diuretic agents reduce
the renal clearance of lithium and add a high risk of lithium toxicity. Refer to
the package insert for lithium preparations before use of such preparations with
ESIDREX.
Non-Steroidal Anti-Inflammatory Drugs--In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when ESIDREX and non-steroidal anti-inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Drug/Laboratory Test Interactions
Thiazides should be discontinued before carrying out tests for parathyroid
function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year feeding studies in mice and rats conducted under the auspices of the
National Toxicology Program (NTP) uncovered no evidence of a carcinogenic
potential of hydrochlorothiazide in female mice (at doses of up to approximately
600 mg/kg/day) or in male and female rats (at doses of up to approximately 100
mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity
in male mice.
Hydrochlorothiazide was not genotoxic In Vitro in the Ames mutagenicity assay of
Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and
in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or In Vivo
in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow
chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive
test results were obtained only in the In Vitro CHO Sister Chromatid Exchange
(clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using
concentrations of hydrochlorothiazide from 43 to 1300 mcgm/mL, and in the
Aspergillus Nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of
either sex in studies wherein these species were exposed, via their diet, to
doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout
gestation.
Pregnancy
Teratogenic Effects--Pregnancy Category B: Studies in which hydrochlorothiazide
was orally administered to pregnant mice and rats during their respective
periods of major organogenesis at doses up to 3000 and 1000 mg
hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well- controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: Thiazides cross the placental barrier and appear in cord
blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and
possibly other adverse reactions that have occurred in adults.
Nursing Mothers
Thiazides are excreted in breast milk. Because of the potential for serious
adverse reactions in nursing infants, a decision should be made whether to
discontinue nursing or to discontinue hydrochlorothiazide, taking into account
the importance of the drug to the mother.
Interactions
As for Frusemide which are listed below
DRUG INTERACTIONS
Lasix(R) may increase the ototoxic potential of aminoglycoside antibiotics,
especially in the presence of impaired renal function. Except in life-
threatening situations, avoid this combination.
Lasix(R) should not be used concomitantly with ethacrynic acid because of the
possibility of ototoxicity. Patients receiving high doses of salicylates
concomitantly with Lasix(R), as in rheumatic disease, may experience salicylate
toxicity at lower doses because of competitive renal excretory sites.
Lasix(R) has a tendency to antagonize the skeletal muscle relaxing effect of
tubocurarine and may potentiate the action of succinylcholine.
Lithium generally should not be given with diuretics because they reduce
lithium's renal clearance and add a high risk of lithium toxicity.
Lasix(R) may add to or potentiate the therapeutic effect of other
antihypertensive drugs. Potentiation occurs with ganglionic or peripheral
adrenergic blocking drugs.
Lasix(R) may decrease arterial responsiveness to norepinephrine. However,
norepinephrine may still be used effectively.
Simultaneous administration of sucralfate and Lasix(R) tablets may reduce the
natriuretic and antihypertensive effects of Lasix(R). Patients receiving both
drugs should be observed closely to determine if the desired diuretic and/or
antihypertensive effect of Lasix(R) is achieved. The intake of Lasix(R) and
sucralfate should be separated by at least two hours.
One study in six subjects demonstrated that the combination of FRUSEMIDE and
acetylsalicylic acid temporarily reduced creatinine clearance in patients with
chronic renal insufficiency. There are case reports of patients who developed
increased BUN, serum creatinine and serum potassium levels, and weight gain when
FRUSEMIDE was used in conjunction with NSAIDs.
Literature reports indicate that coadministration of indomethacin may reduce the
natriuretic and antihypertensive effects of Lasix(R) (FRUSEMIDE) in some
patients by inhibiting prostaglandin synthesis. Indomethacin may also affect
plasma renin levels, aldosterone excretion, and renin profile evaluation.
Patients receiving both indomethacin and Lasix(R) should be observed closely to
determine if the desired diuretic and/or antihypertensive effect of Lasix(R) is
achieved.
Pharmacokinetics
Piretanide has been reported to be almost completely ab-
sorbed following oral administration, it is extensively bound
to plasma proteins, and is reported to have a half-life of about
1 hour.
Uses and Administration
Piretanide is a loop diuretic with actions and uses similar to
those of frusemide . In the treatment of hypertension
it is given in a usual dose of 6 to 12 mg daily by
mouth. The sodium salt is given by injection.