Cimetidine

CIMETIDINE- cimetidine tablet, film coated
Teva Pharmaceuticals USA, Inc.

DESCRIPTION

Cimetidine is a histamine H₂ -receptor antagonist. Chemically it is N” -cyano-N -methyl-N’ -[2-[[(5-methyl-1H -imidazol-4-yl)methyl]thio]-ethyl], guanidine.

The molecular formula for cimetidine is C₁₀ H₁₆ N₆ S; and the molecular weight is 252.35. The structural formula for cimetidine is:

Solubility Characteristics

Cimetidine is soluble in alcohol, slightly soluble in water, very slightly soluble in chloroform and insoluble in ether.

Each tablet, for oral administration, contains 300 mg, 400 mg, or 800 mg cimetidine, USP. In addition, each tablet contains the following inactive ingredients: corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and sodium starch glycolate. The coating for the tablets contains: carnauba wax, hypromellose, polyethylene glycol, polysorbate 80, talc, titanium dioxide, and triethyl citrate. The coating for the 300 mg and 400 mg tablets also contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, and FD&C Yellow No. 6 Aluminum Lake.

CLINICAL PHARMACOLOGY

Cimetidine competitively inhibits the action of histamine at the histamine H₂ receptors of the parietal cells and thus is a histamine H₂ -receptor antagonist.

Cimetidine is not an anticholinergic agent. Studies have shown that cimetidine inhibits both daytime and nocturnal basal gastric acid secretion. Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.

Antisecretory Activity

1) Acid Secretion

Nocturnal

Cimetidine 800 mg orally at bedtime reduces mean hourly H⁺ activity by greater than 85% over an eight-hour period in duodenal ulcer patients, with no effect on daytime acid secretion. Cimetidine 1600 mg orally at bedtime produces 100% inhibition of mean hourly H⁺ activity over an eight-hour period in duodenal ulcer patients, but also reduces H⁺ activity by 35% for an additional five hours into the following morning. Cimetidine 400 mg twice daily and 300 mg four times daily decrease nocturnal acid secretion in a dose-related manner, i.e., 47% to 83% over a six- to eight-hour period and 54% over a nine-hour period, respectively.

Food stimulated

During the first hour after a standard experimental meal, oral cimetidine 300 mg inhibited gastric acid secretion in duodenal ulcer patients by at least 50%. During the subsequent two hours cimetidine inhibited gastric acid secretion by at least 75%.

The effect of a 300 mg breakfast dose of cimetidine continued for at least four hours and there was partial suppression of the rise in gastric acid secretion following the luncheon meal in duodenal ulcer patients. This suppression of gastric output was enhanced and could be maintained by another 300 mg dose of cimetidine given with lunch.

In another study, cimetidine 300 mg given with the meal increased gastric pH as compared with placebo.

Table 1. Mean Gastric pH

	Cimetidine	Placebo
1 hour	3.5	2.6
2 hours	3.1	1.6
3 hours	3.8	1.9
4 hours	6.1	2.2

24-Hour mean H⁺ activity

Cimetidine 800 mg at bedtime, 400 mg twice daily and 200 mg four times daily all provide a similar, moderate (less than 60%) level of 24-hour acid suppression. However, the 800 mg at bedtime regimen exerts its entire effect on nocturnal acid, and does not affect daytime gastric physiology.

Chemically stimulated

Oral cimetidine significantly inhibited gastric acid secretion stimulated by betazole (an isomer of histamine), pentagastrin, caffeine and insulin as follows:

Table 2

Stimulant	Stimulant Dose	Cimetidine	% Inhibition
Betazole	1.5 mg/kg (sc)	300 mg (po)	85% at 2 ½ hours
Pentagastrin	6 mcg/kg/hr (iv)	100 mg/hr (iv)	60% at 1 hour
Caffeine	5 mg/kg/hr (iv)	300 mg (po)	100% at 1 hour
Insulin	0.03 units/kg/hr (iv)	100 mg/hr (iv)	82% at 1 hour

When food and betazole were used to stimulate secretion, inhibition of hydrogen ion concentration usually ranged from 45 to 75% and the inhibition of volume ranged from 30 to 65%.

2) Pepsin

Oral cimetidine 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice.

3) Intrinsic Factor

Intrinsic factor secretion was studied with betazole as a stimulant. Oral cimetidine 300 mg inhibited the rise in intrinsic factor concentration produced by betazole, but some intrinsic factor was secreted at all times.

Other

Lower Esophageal Sphincter Pressure and Gastric Emptying

Cimetidine has no effect on lower esophageal sphincter (LES) pressure or the rate of gastric emptying.

Pharmacokinetics

Cimetidine is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of cimetidine is approximately 2 hours. Blood concentrations remain above that required to provide 80% inhibition of basal gastric acid secretion for 4 to 5 hours following a dose of 300 mg.

The principal route of excretion of cimetidine is the urine. Following oral administration, the drug is extensively metabolized, the sulfoxide being the major metabolite. Following a single oral dose, 48% of the drug is recovered from the urine after 24 hours as the parent compound.