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Pharmacology & Chemistry
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RANITIDINE ORAL
Pharmacology & Chemistry
Chemistry and Stability
from AHFS DITM
Chemistry
Ranitidine is a histamine H2-receptor antagonist. Unlike the earlier histamine H2-receptor antagonists, burimamide and
metiamide, which are not commercially available, and cimetidine, ranitidine contains an aminoalkyl-substituted furan ring
rather than an imidazole ring.
Ranitidine hydrochloride has solubilities of 660 mg/mL in water and 190 mg/mL in alcohol. The drug has pKas of 8.2 and
2.7.g Ranitidine hydrochloride occurs as a white to pale yellow granular substance having a slightly bitter taste and sulfurlikeodor.
Ranitidine hydrochloride is commercially available for oral administration as conventional and effervescent tablets,
effervescent granules, capsules, and solution. Each effervescent tablet or packet of effervescent granules containing 150 mg of
ranitidine provides 7.96 or 7.55 mEq of sodium, respectively.
Ranitidine hydrochloride injection is a clear, colorless to yellow, sterile solution of the drug in water for injection,
Ranitidine hydrochloride injection and the commercially available injection of the drug in 0.45% sodium chloride have a pH
of 6.7—7.3. The latter preparation has a calculated osmolarity of approximately 180 mOsm/L. Each 50 mL of the
commercially available IV infusion solution of the drug in 0.45% sodium chloride provides 5.1 mEq ofsodium.
Potency of ranitidine hydrochloride preparations and dosage of the drug generally are expressed in terms of the base. Each
168 mg of ranitidine hydrochloride is approximately equivalent to 150 mg of ranitidine.
Ranitidine bismuth citrate occurs as a white to off-white amorphous powder.ij The drug is readily soluble in water.
Ranitidine bismuth citrate is commercially available for oral administration as 400-mg tablets; each tablet contains
approximately 162mg of ranitidine, 128 mg of trivalent bismuth, and 110 mg ofcitrate.
Stability
Ranitidine hydrochloride tablets or capsules should be stored at 15—30 or 2—25°C, respectively, in tight, light-resistant containers in a dry
place; the cap should be replaced securely each time the container is opened. The oral solution should be stored in a tight, light-resistant
container at 4—25°C. g USP states that the oral solution should be stored below 25°C and freezing should be avoided. The effervescent
tablets or granules should be stored at 2—30°C in tight, light-resistant containers. Ranitidine hydrochloride injection and the commercially
available injection of the drug in 0.45% sodium chloride should be stored below 30°Cfe (preferably at 4—30°C) and 2—25°C, respectively,
and protected from light; freezing of the injections should be avoided. Brief exposure to temperatures up to 40°C will not adversely affect
stability of the injections; in addition, darkening of the undiluted injection will not affect potency.
Ranitidine bismuth citrate tablets should be stored at 2—30°C in a dry place and should be protected from light; the cap should be replaced
securely each time the container is opened. Commercially available ranitidine bismuth citrate tablets have an expiration date of 2 years
following the date of manufacture.
Ranitidine hydrochloride injection is stable for up to 48 hours at room temperature when added to or diluted with most IV solutions (e.g.,
0.9% sodium chloride, 5 or 10% dextrose, lactated Ringer's, 5% sodium bicarbonate). The commercially available IVinfusion solution of the
drug in 0.45% sodium chloride is provided in containers fabricated from a specially formulated, nonplasticized, thermoplastic copolyester
(CR3). Water can permeate from inside the container into the overwrap in amounts insufficient to substantially affect the solution. Solutions in
contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection;
however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers. Additives should
not be introduced into the injection container of the commercially available diluted solution of the drug. The commercially available IV
infusion solution of the drug in 0.45% sodium chloride is stable through the expiration date noted on the container when stored as
Pharmacology & Chemistry
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recommended. When the pharmacy bulk package is used, infusion solutions of ranitidine hydrochloride should be prepared within 24 hours
afterthe vial is first entered; any drug remaining in the bulk package after this period should be discarded.
Pharmacology
from AHFS DITM
GI Effects
Ranitidine competitively inhibits the action of histamine on the H2 receptors of parietal cells, reducing gastric acid secretion under daytime
and nocturnal basal conditions and also when stimulated by food, insulin, amino acids, histamine, or pentagastrin. Ranitidine has been
shown to be 3—13 times as potent on a molar basis as cimetidine in inhibiting stimulated gastric acid secretion.
Basal, nocturnal, and betazole-stimulated gastric acid secretion appear to beinhibited to a greater extent than are meal- and pentagastrinstimulated gastric acid secretion following a given dose of ranitidine. Following oral administration of 150 mg of ranitidine, 95% of
basal gastric acid secretion is inhibited for up to 4 hours, 92% of nocturnal gastric acid secretion is inhibited for up to 13 hours, and
99% of betazole-stimulated gastric acid secretion is inhibited for up to 3 hours. Following oral administration of 150 mg of ranitidine,
72% of pentagastrin-stimulated gastric acid secretion is inhibited for up to 5 hours and 79% of meal-stimulated gastric acid secretion is
inhibited for up to 3 hours. In one study, hydrogen ion secretion was reduced by 29, 50, and 70% and volume of gastric secretion was
reduced by 21,37, and 47% following oral administration of 20,40, and 80 mg of ranitidine, respectively. Following treatment with 80
mg of ranitidine in another study, 85% of the gastric acid samples obtained from individuals with duodenal ulcers had a pH greater than
3 and 71% of these samples had a pH greater than 5 for up to 12 hours after administration of the drug; 92% of pretreatment gastric
acid samples had a pH lessthan 2.
Following IV administration of 20,60, and 100 mg of ranitidine, 93, 99, and 99% of betazole-stimulated gastric acid secretion is
inhibited, respectively, for up to 2 hours and 47,66, and 77% of pentagastrin-stimulated gastric acid secretion is inhibited, respectively,
for up to 3 hours.
Ranitidine indirectly causes a dose-dependent reduction in pepsin secretion by decreasing the volume of gastric acid secretion, The drug
appears to have little, if any, effect on gastric secretion of mucus, gastric intrinsic factor secretion, or fasting and postprandial serum
gastrin concentrations. Ranitidine may protect the gastric mucosa from bleeding and the irritant effects caused by certain drugs (e.g.,
aspirin, nonsteroidal anti-inflammatory agents).
The manufacturers state that ranitidine does not reduce serum calcium concentration in individuals with hypercalcemia and is not an
anticholinergic agent. In one in vitro study, ranitidine appeared to inhibit human erythrocyte acetylcholinesterase and plasma
pseudocholinesterase; however, in another study in vivo, ranitidine did not inhibit cholinesterases. Ranitidine inconsistently increases
lower esophageal sphincter pressure; however, the drug may have some therapeutic value in the inhibition of acid gastroesophageal
reflux, Although ranitidine has been shown to delay gastric emptying, the clinical importance of this effect is not known.
Endocrine and Gonadal Effects
Ranitidine generally has been shown to have little, if any, effect on serum prolactin concentration in healthy individuals or in those with
clinically diagnosed duodenal ulcers.8 In one study, IV administration of 50 or 100 mg of ranitidine did not substantially alter basal
prolactin secretion; however, an increase in serum prolactin concentration occurred following IV administration of 200 or 300 mg. The
increase in serum prolactin caused by IV administration of 300 mg of ranitidine was comparable to that observed following IV
administration of 200 mg ofcimetidine. (See Cautions: Adverse Effects).
Ranitidine has been shown to have little, if any, effect on serum concentrations of testosterone, luteinizing hormone (LH),B folliclestimulating hormone (FSH), thyrotropin (TSH), cortisol, aldosterone, growth hormone (GH), progesterone, or estradiol. In onestudy,
Pharmacology & Chemistry
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basal serum concentrations of thyroxine (T4) and serum concentrations of T4 40 minutes after protirelin stimulation were decreased
slightly during ranitidine therapy, while basal and protirelin-stimulated serum concentrations of triiodothyronine (T3) and reverse
triiodothyronine (rT3) were not altered by ranitidine therapy, Ranitidine therapy has also been shown to have little, if any, effect on sperm
count, motility, or morphology; penile erection; sexual arousal; or ejaculation. (See Cautions: Adverse Effects.) Ranitidine may possibly
inhibit vasopressin release; the clinical importance of this effect is not fully understood.
Ranitidine does not appear to alter mean fasting blood glucose concentration or mean daily insulin requirement in patients with type 1
(insulin-dependent) diabetes mellitus; sensitivity of the serum glucose concentration to IV infusion of insulin alsodoes not appear to be
affected by prolonged (4 weeks) ranitidine therapy.
Other Effects
Although cimetidine and ranitidine have been reported to reduce hepatic blood flow in some studies, other studies have not confirmed
this finding. Unlike cimetidine, ranitidine does not inhibit hepatic metabolism of antipyrine. Although ranitidine affects the cytochrome
P-450 enzyme system in the liver, the drug appears to interact with the enzyme system differently than does cimetidine. (See Drug
Interactions: Effects on Hepatic Clearance of Drugs.)
Secretin- and cholecystokinin-induced pancreatic secretion volume and bicarbonate and protein secretion do not appear to be altered by
IV infusion ofranitidine. Ranitidine increases nitrate-reducing bacterial flora in the GI tract; however, the clinical importance of this
effect is not known.
Pharmacokinetics
from AHFS DITM
Absorption
Ranitidine is rapidly absorbed from the GI tract following oral administration and from parenteral sites following IM injection;
however, following oral aclministration, the drug undergoes extensive first-pass metabolism. (See Pharmacokinetics: Elimination.)
After ingestion, ranitidine bismuth citrate dissociates in intragastric fluid to ranitidine and soluble and insoluble forms of bismuth. The
absolute bioavailability of orally administered ranitidine has been reported to be about 50%; similar oral bioavailability of the drug has
been reported in children 3.5—16 years of age. The oral solution, capsules, effervescent tablets, and effervescent granules of ranitidine
hydrochloride have been shown to be bioequivalent to conventional tablets of the drug. Following oral administration, area under the
plasma concentration-time curve may besubstantially increased in geriatric individuals compared with younger adults. Following IM
administration, the absolute bioavailability of ranitidine is 90—100%.
Following oral administration of 150-mg doses of ranitidine hydrochloride, mean peak serum ranitidine concentrations of 372—545
ng/mL occur within 2—3 hours and may be positively correlated with age in adults. Following oral administration of single doses of the
drug in one study, peak serum concentrations were biphasic in some individuals with an initial peak occurring at 0.5—1.5 hours after
administration and a second peak occurring about 3 hours after administration, Following IM administration of a single 50-mg dose of
ranitidine hydrochloride, mean peak serum ranitidine concentrations of 576 ng/mL occur within 15 minutes.
Following oral administration of a single 400-mg dose of ranitidine bismuth citrate in healthy individuals, mean peak plasma ranitidine
concentrations of 455 ng/mL occurred at 0.5—5 hours. The rate and extent of ranitidine absorption following administration of
ranitidine bismuth citrate increased proportionally with increasing doses up to 1.6 g. Ranitidine plasma concentrations showed no
evidence of accumulation during a 28-day dosing period.
Oral absorption of bismuth is variable; mucosal penetration and absorption of bismuth from ranitidine bismuth citrate is not affected by
the degree of gastritis, the presence of Helicobacter pylorit or an active ulcer. Following a 400-mg dose of ranitidine bismuth citrate,
peak plasma bismuth concentration average 3.3 ng/mL at 15—60 minutes. The rate and extent of bismuth absorption from ranitidine
bismuth citrate does not increase with increasing doses up to 800 mg, but increases more than proportionally with higher doses.
Pharmacology & Chemistry
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Administration of 800 mg of ranitidine bismuth citrate 30 minutes after a meal decreases the rate and extent of bismuth absorption by
50 and 25%, respectively, compared with administration 30 minutes prior to a meal. The absorption of bismuth from an 800-mg dose of
ranitidine bismuth citrate was increased when gastric pH exceeded 6, which resulted from administration 3 hours previously of an 800mg dose of the drug.
The manufacturer states that there are no differences in the extent of bismuth absorption according to body weight; however, peak
plasma bismuth concentrations in healthy females and males are different. No evidence of differences in the pharmacokinetics of
bismuth according to race has been found based on trough concentrations observed in clinical studies.
Small amounts of bismuth accumulate in plasma during twice-daily dosing with ranitidine bismuth citrate. Following administration of
ranitidine bismuth citrate 800 mg twice daily (twice the recommended daily dose) for 28 days, the median peak plasma bismuth
concentration on day 28 was 6.3 ng/mL; peak plasma bismuth concentrations did not exceed 20 ng/mL at any time during the 28-day
period in any patient. Median peak and trough plasma bismuth concentrations were 105 and 68% of predicted steady-state peak and
trough concentrations, respectively, on day 28.11 In a study in which ranitidine bismuth citrate 400 mg twice daily was administered for
12 weeks (3 times the recommended duration of therapy for active duodenal ulcer), trough bismuth concentrations did not exceed
predicted accumulation in any patient; median trough plasma bismuth concentrations were 2.8 ng/mL at week 12.
Absorption and mean peak plasma concentration of ranitidine are not substantially decreased by concomitant administration of food or
low-potency antacids (neutralizing capacity of 10—15 mEq of hydrochloric acid per 10 mL); however, concomitant administration of
higher potency antacids may decrease absorption of ranitidine. (See Drug Interactions: Food and Antacids.) Concomitant administration
of propantheline appears to increase peak serum concentrations of ranitidine. (See Drug Interactions: Propantheline Bromide.)
The manufacturers state that serum ranitidine concentrations necessary to inhibit 50% of pentagastrin-stimulated gastric acid secretion
(IC50) are estimated to be 36—94 ng/mL. However, the manufacturers state that a consistent relationship between serum ranitidine
concentrations and a given dose or given therapeutic effect of acid inhibition does not appear to exist. Following administration of a
single 150-mg oral or 50-mg IM or IV dose, serum ranitidine concentrations remain in the IC50 range for up to 12 hours and 6—8 hours,
respectively. Following chronic oral administration of 150 mg of ranitidine twice daily, trough serum concentrations range between
53—57 ng/mL. In one study following intraduodenal administration of ranitidine in individuals with duodenal ulcers, the IC50 of the drug
was estimated to be 100 ng/mL. Substantial inhibition of gastric acid secretion reportedly continues for about 9.5 hours after ingestion of
a single 150-mg dose of the drug.
Distribution
Ranitidine is widely distributed throughout the body and is 10—19% protein bound. The apparent volume of distribution of ranitidine
is reported to be 1.7 (1.2—1.9) L/kg. The apparent volume of distribution in children 3.5—16 years of age is reported to be 2.3—2.5
L/kg (range: 1.1—3.7 L/kg).
Following oral administration, ranitidine is distributed into CSF. In one study in patients undergoing diagnostic lumbar puncture, CSF
concentrations of 0.01—0.04 ug/mL were achieved 2—6 hours after a dose following 6 days of oral ranitidine 150 mg twice daily. In
individuals with uninflamed meninges, CSF ranitidine concentrations are reported to be approximately 3—5% of concurrent peak
serum concentrations.
Ranitidine is distributed into milk; concentrations in milk reportedly range from 25—100% of concurrent serum concentrations.
Elimination
The elimination half-life of ranitidine in adults averages 1.7—3.2 hours and may be positively correlated with age in adults. The halflife of ranitidine following administration of ranitidine bismuth citrate is reported to be 2.8—3.1 hours. The elimination half-life is
prolonged in patients with renal impairment 8 In children 3.5—16 years of age, the elimination half-life averages 1.8—2 hours (range:
Pharmacology & Chemistry
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1.4—2.9 hours). In one study following oral administration of a single 150-mg dose of ranitidine in patients with creatinine clearances
averaging 27.2 mL/minute, the terminal elimination half-life of ranitidine was 8.7 hours; a correlation between the degree of
impairment and the elimination half-life of the drug was not apparent. However, in another study in patients with GFRs (as determined
by inulin clearance) ranging from 3—69 mL/minute per 1.73 m , ranitidine clearance was shown to correlate with GFR and elimination
half-life of ranitidine was correlated with degree of renal impairment. 8 In a study in patients with creatinine clearances of 0.5—34
mL/minute, the elimination half-life ranged from 3—10 hours following IV administration of a single 50-mg dose. The manufacturers
state that following oral administration of 150 mg of ranitidine twice daily for 4 weeks in patients with renal impairment, mean serum
ranitidine concentrations were higher after 24 hours than the concentration observed 12 hours after the same dosage in patients with
normal renal function. The half-life of ranitidine reportedly is prolonged to about 6 hours in geriatric individuals following oral
administration of a 100-mg dose of the drug.
Following administration of ranitidine bismuth citrate, elimination of bismuth is polyexponential with a terminal elimination half-life of
11—28 days. The renal clearance of bismuth averages 30—60 mL/minute, indicating net tubular secretion. Followingadministration of
ranitidine bismuth citrate, less than 1% of the amount of bismuth in the dose is recovered from urine. Up to 28% of the bismuth in a
dose of ranitidine bismuth citrate was recovered in feces during a 6-day period following the dose. A minor portion of the bismuth in a
dose of ranitidine bismuth citrate is excreted in bile.
Ranitidine is metabolized in the liver to ranitidine TV-oxide, desmethyl ranitidine, and ranitidine S-oxide. Orally administered ranitidine
undergoes extensive metabolism on first pass through the liver. Following oral administration of ranitidine to individuals with cirrhosis,
the manufacturers state that there are minor but clinically unimportant alterations in the half-life, distribution, clearance, and
bioavailability of ranitidine. Peak serum ranitidine concentrations in patients with cirrhosis appear to be higher than those in healthy
individuals because of reduced first-pass metabolism of the drug and resultant increased bioavailability; bioavailability of ranitidine
appears to average 70% following oral administration in patients with cirrhosis.
Ranitidine is excreted principally in urine via glomerular filtration and tubular secretion. The majority of urinary excretion of ranitidine
occurs within the first 6 hours after administration. The portion of an orally administered dose that is excreted unchanged in urine is
dose dependent; however, approximately 16—36% of an orally administered dose is excreted unchanged in urine within 24 hours.
Approximately 4,1—2, and 1% are excreted in urine as ranitidine TV-oxide, desmethyl ranitidine, and ranitidine S-oxide, respectively,
within 24 hours. The remainder of the administered dose is eliminated in feces, apparently via biliary excretion.
Approximately 70% of an IV dose of ranitidine is excreted in urine as unchanged drug.
Renal clearance of ranitidine in healthy individuals is reported to average 410—530 mL/minute. In one study following oral
administration of 100-mg doses of ranitidine in healthy adults, plasma, renal, and hepatic clearances of the drug were reportedto be 20.8,
5.6, and 16.4 mL/minute per kg, respectively. Plasma clearance of ranitidine appears to be decreased in patients with renal dysfunction.
In one study following IV administration of a single 50-mg dose of the drug in patients with creatinine clearances of 0.5—34
mL/minute, plasma clearance of the drug correlated with creatinine clearance and ranged from 1.7—10.9 mL/minute per kg. Plasma
clearance appears to be reduced in geriatric patients and in patients with cirrhosis, Plasma bismuthconcentrations in geriatric patients
and patients with renal impairment receiving ranitidine bismuth citrate may be elevated as a result of decreased renal elimination in
these patients.
Ranitidine is removed by hemodiarysis. The amount of ranitidine removed during hemodialysis depends on several factors (e.g., type
of coil used, dialysis flow rate); however, preliminary evidence indicates that a single 6-hour period of hemodialysis removes about
10% of a 120-mg dose of ranitidine into the dialysat.
Pharmacology & Chemistry
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