DESCRIPTION
Nizatidine is a histamine H2-receptor antagonist. Chemically, it is N-[2-[[[2-[(dimethylamino)methyl]-4-thizolyl]methyl]thio]ethyl-N'-methyl-2-nitro-1,1-ethenediamine.
The structural formula is as follows:
Nizatidine has the empirical formula C12H21N5O2S2 representing a molecular weight of 331.46. It is an off-white to buff crystalline solid that is soluble in water. Nizatidine has a bitter taste and mild sulfur-like odor. Each capsule contains for oral administration gelatin, colloidal silicon dioxide, sodium starch glycolate, titanium dioxide, yellow iron oxide, red iron oxide, sicomet-85 black iron oxide, magnesium stearate, povidone (K:25), sodium lauryl sulphate, talc and 150 mg (0.45 mmol) or 300 mg (0.91 mmol) of nizatidine.
CLINICAL PHARMACOLOGY
Nizatidine is a competitive, reversible inhibitor of histamine, at the histamine H2-receptors, particularly those in the gastric parietal cells.
Antisecretory Activity
1. Effects on Acid Secretion
Nizatidine significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Nizatidine also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1).
Table 1: Effect of Oral Nizatidine on Gastric Acid Secretion
|
|
Time After Dose (h) |
% Inhibition of Gastric Acid Output by Dose (mg) |
|
20 to 50 |
75 |
100 |
150 |
300 |
|
Nocturnal |
Up to 10 |
57 |
|
73 |
|
90 |
|
Betazole |
Up to 3 |
|
93 |
|
100 |
99 |
|
Pentagastrin |
Up to 6 |
|
25 |
|
64 |
67 |
|
Meal |
Up to 4 |
41 |
64 |
|
98 |
97 |
|
Caffeine |
Up to 3 |
|
73 |
|
85 |
96 |
2. Effects on Other Gastrointestinal Secretions – Pepsin
Oral administration of 75 to 300 mg of nizatidine did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions.
Intrinsic factor
Oral administration of 75 to 300 mg of nizatidine increased betazole-stimulated secretion of intrinsic factor.
Serum gastrin
Nizatidine had no effect on basal serum gastrin. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of nizatidine.
3. Other Pharmacologic Actions
a. Hormones: Nizatidine was not shown to affect the serum concentrations of gonadotropins, prolactin, growth hormone, antidiuretic hormone, cortisol, triiodothyronine, thyroxin, testosterone, 5α-dihydrotestosterone, androstenedione, or estradiol.
b. Nizatidine had no demonstrable antiandrogenic action.
4. Pharmacokinetics
The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800 mcg/L for a 150 mg dose and 1,400 to 3,600 mcg/L for a 300 mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1,000 mcg/L is equivalent to 3 μmol/L; a dose of 300 mg is equivalent to 905 μmoles. Plasma concentrations 12 hours after administration are less than 10 mcg/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Nizatidine exhibits dose proportionality over the recommended dose range.
The oral bioavailability of nizatidine is unaffected by concomitant ingestion of propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of nizatidine by about 10%. With food, the AUC and Cmax increase by approximately 10%.
In humans, less than 7% of an oral dose is metabolized as N2-monodesmethylnizatidine, an H2-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose).
More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces.
Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of nizatidine should be reduced in proportion to the severity of dysfunction (see DOSAGE AND ADMINISTRATION).
Approximately 35% of nizatidine is bound to plasma protein, mainly to α1-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro.
Clinical Trials
1. Active Duodenal Ulcer
In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of nizatidine, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness.
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