A Comprehensive Monograph on Cimetidine (DB00501)

Introduction: A Paradigm of Rational Drug Design

Cimetidine's Place in Medical History: The Pre- and Post-Cimetidine Eras of Ulcer Therapy

Prior to the mid-1970s, peptic ulcer disease was a formidable and often life-threatening condition. Management was largely palliative, relying on bland diets and rudimentary antacids, with severe cases frequently culminating in invasive and debilitating surgeries like vagotomy or partial gastrectomy.[1] The introduction of cimetidine, marketed under the brand name Tagamet, represented a watershed moment in gastroenterology and pharmacology. Developed by a team at Smith Kline & French (SKF) in the United Kingdom, the drug entered commercial use in 1976 and was approved in the United States in 1979, fundamentally transforming the treatment of acid-related disorders.[3] So profound was its impact that many clinicians and medical historians now delineate the history of ulcer therapy into two distinct epochs: the era before cimetidine and the era after.[4] This single molecule shifted the therapeutic paradigm from surgical intervention to effective medical management, alleviating suffering for millions and earning a place on the World Health Organization's list of essential medicines.[4]

The Scientific Journey: From Histamine Theory to the First H2-Receptor Antagonist

The development of cimetidine stands as a landmark achievement in the history of pharmaceutical science, not merely for its therapeutic success but for the methodology that produced it. It is one of the earliest and most celebrated examples of rational drug design, a process where a therapeutic agent is logically engineered based on a deep understanding of pathophysiology and molecular targets, rather than being discovered through serendipity or mass screening.[1]

The project, initiated at SKF in 1964, was predicated on a bold and controversial hypothesis. The research team, led by luminaries such as Sir James Black, C. Robin Ganellin, and Graham J. Durant, proposed that histamine was the principal final mediator of gastric acid secretion.[1] This theory was met with skepticism, primarily because existing antihistamines—now known as H1-receptor antagonists—had demonstrated no effect on acid production, leading many to discount histamine's role in the stomach.[6] The SKF team theorized the existence of a second, undiscovered subtype of histamine receptor, which they termed the H2 receptor, located on gastric parietal cells.[6]

Embarking on a project with a theoretical target and no lead compound was an unprecedented and high-risk endeavor.[6] The team began their work using the endogenous agonist, histamine, as their chemical scaffold. Their objective was to systematically modify its structure to create an analogue that would bind to the hypothetical H2 receptor with high affinity but would fail to elicit a response, thereby acting as a competitive antagonist.[1] After eight years of painstaking medicinal chemistry, the team synthesized burimamide, the first-ever H2-receptor antagonist. While not orally active, its existence validated the H2 receptor theory and proved the concept.[5] Further refinement led to metiamide, a more potent compound that showed promise in clinical trials but was associated with safety concerns, specifically agranulocytosis, linked to its thiourea group.[5] This final challenge prompted the replacement of the thiourea with a structurally similar but non-toxic cyanoguanidine group, yielding the final, successful molecule: cimetidine.[6] This journey, from a speculative hypothesis to a revolutionary medicine, underscores the power of a targeted, mechanism-based approach to drug discovery and the scientific fortitude required to pursue a novel biological pathway against prevailing dogma.[5]

The success of cimetidine was far more than a therapeutic breakthrough; it was a methodological revolution that reverberated throughout the pharmaceutical industry. By validating the principles of rational drug design, it provided a powerful proof-of-concept that a profound understanding of a biological target could be leveraged to engineer a novel drug from first principles. This stood in stark contrast to the prevailing models of discovery, which often relied on modifying existing drugs or screening vast libraries of natural and synthetic compounds. The triumph of the cimetidine program likely catalyzed a strategic shift in research and development investment across the industry, steering resources toward target-based discovery and away from less efficient random screening. This paradigm, which prioritizes understanding the molecular underpinnings of disease, now dominates modern drug development. Consequently, cimetidine's enduring legacy is twofold: it is remembered not only as the first effective anti-ulcer drug but also as a catalyst that helped usher in a more scientific, logical, and efficient era of pharmaceutical innovation.

Physicochemical Characteristics and Pharmaceutical Formulations

Chemical Identity and Structure

• Drug Name: Cimetidine [7]
• Type: Small Molecule [7]
• CAS Number: 51481-61-9 [7]
• DrugBank ID: DB00501 [7]
• Molecular Formula: C10​H16​N6​S [8]
• Molecular Weight: 252.34 g·mol⁻¹ [3]
• IUPAC Name: 1-cyano-2-methyl-3-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine [3]
• Chemical Structure: Cimetidine is a synthetic organic compound belonging to the class of guanidines. It features an imidazole ring, making it a structural analogue of histamine, and a polar cyanoguanidine group.[10]
• SMILES: CN\C(NCCSCC1=C(C)NC=N1)=N\C#N [9]
• InChI: InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14) [9]
• InChIKey: AQIXAKUUQRKLND-UHFFFAOYSA-N [9]

Physical and Chemical Properties

Cimetidine presents as a white to off-white crystalline powder, which may be odorless or possess a faint, characteristic odor.[13] It exhibits a melting point within the range of 139°C to 144°C.[13] Its solubility profile is characterized by being sparingly or slightly soluble in water (approximately 0.5 g/100 mL at 20°C), soluble in alcohols such as ethanol and methanol, and practically insoluble in non-polar organic solvents like methylene chloride and diethyl ether.[13] As a basic compound, it readily dissolves in dilute mineral acids to form salts.[13] An important characteristic for formulation and manufacturing is that cimetidine exists in at least three distinct polymorphic forms.[15] The reported pKa of the compound is 6.80.[13]

Available Formulations and Excipients

Cimetidine is available in a variety of formulations to suit different clinical needs, including both prescription and over-the-counter (OTC) products.

• Oral Formulations:
• Tablets: Available in multiple strengths, commonly 200 mg (OTC), 300 mg, 400 mg, and 800 mg (prescription).[16]
• Oral Solution: Typically formulated as cimetidine hydrochloride to improve solubility, with common concentrations of 300 mg/5 mL and 200 mg/5 mL.[12]
• Parenteral Formulations:
• Injection: For intramuscular (IM) or intravenous (IV) administration, solutions are available at concentrations such as 150 mg/mL or 200 mg/mL.[16] Premixed, single-dose plastic containers for IV infusion (e.g., 300 mg of cimetidine in a sodium chloride solution) are also manufactured, facilitating administration in hospital settings.[20]
• Brand Names: The most widely recognized brand name is Tagamet, with Tagamet HB designating the OTC formulation.[3] A multitude of other trade names are used globally, including Acinil, Dyspamet, and Ulhys.[8]
• Excipients: Pharmaceutical formulations of cimetidine contain various inactive ingredients necessary for stability, palatability, and manufacturing. For instance, the oral solution may contain ethanol (2.8%), preservatives like methylparaben and propylparaben, sweeteners such as saccharin and sorbitol, and coloring agents like FD&C Yellow No. 6 (also known as Sunset Yellow E110).[12] The presence of these excipients is clinically relevant, as some, like Sunset Yellow, can cause allergic reactions, particularly in individuals with aspirin sensitivity.[18]

A consolidated summary of cimetidine's core identifiers is essential for precise database searching, cross-referencing scientific literature, and understanding its fundamental molecular characteristics.

Property	Value	Source(s)
Generic Name	Cimetidine	7
DrugBank ID	DB00501	7
CAS Number	51481-61-9	7
Type	Small Molecule	7
Molecular Formula	C10​H16​N6​S	8
Molecular Weight	252.34 g·mol⁻¹	3
IUPAC Name	1-cyano-2-methyl-3-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine	3
SMILES	CN\C(NCCSCC1=C(C)NC=N1)=N\C#N	9
InChIKey	AQIXAKUUQRKLND-UHFFFAOYSA-N	9
Appearance	White to off-white crystalline powder	13
Melting Point	139-144 °C	13
Water Solubility	Sparingly soluble (0.5 g/100 mL at 20 °C)	13

In-Depth Pharmacological Profile

Pharmacodynamics: Mechanisms of Action

The pharmacodynamic profile of cimetidine is complex, characterized by a highly specific primary mechanism responsible for its therapeutic effects and several significant secondary mechanisms that account for its side effects and extensive drug interaction profile.

Primary Mechanism: Competitive Antagonism at the Histamine H2 Receptor

Cimetidine's principal therapeutic action is as a selective, competitive histamine H2-receptor antagonist.[3] It functions as a structural analogue of histamine, enabling it to bind to H2 receptors located on the basolateral membrane of gastric parietal cells.[7] By competitively inhibiting the binding of endogenous histamine, cimetidine effectively blocks the primary signal for gastric acid production.[7] This antagonism leads to a marked reduction in basal (fasting) and nocturnal gastric acid secretion, as well as a blunted response to stimuli such as food, caffeine, and insulin.[7] The ultimate effect is a decrease in the volume of gastric juice, its hydrogen ion concentration (acidity), and the total output of gastric acid. Additionally, cimetidine has been shown to inhibit the output of pepsin and gastrin.[7] The binding affinity of cimetidine for the human H2 receptor has been quantified, with a dissociation constant (

Kd​) of 42 nM, indicating potent binding to its target.[3]

Cytochrome P450 Inhibition: A Clinically Defining Characteristic

A defining feature of cimetidine's pharmacology, and the source of its most significant clinical limitations, is its activity as a potent, broad-spectrum inhibitor of the hepatic cytochrome P450 (CYP) enzyme system.[3] This property distinguishes it sharply from later-generation H2-receptor antagonists like ranitidine and famotidine, which exhibit much weaker affinity for these enzymes.[24]

Cimetidine inhibits a wide array of clinically important CYP isoenzymes, most notably CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Its inhibitory effect is particularly pronounced for CYP1A2, CYP2D6, and CYP3A4, for which it is classified as a moderate inhibitor.[3] The primary mechanism of this inhibition is reversible and competitive. The cimetidine molecule, via a lone pair of electrons on a nitrogen atom in its imidazole ring, binds directly to the heme-iron prosthetic group at the active site of the CYP enzyme. This physical occupation of the active site prevents the enzyme from binding to and metabolizing other drug substrates.[3]

Further research has revealed a more complex interaction. There is evidence for mechanism-based ("suicide") irreversible inhibition of CYP2D6.[3] Moreover, studies suggest that cimetidine is metabolized by CYP enzymes to form a stable metabolite-intermediate (MI) complex, which remains tightly bound to the enzyme and inactivates it.[26] This MI complex formation helps to explain a long-standing pharmacological puzzle: the observation that the concentrations of cimetidine required to inhibit CYP enzymes in vitro are 100- to 1000-fold higher than the plasma concentrations that produce significant inhibition in vivo.[26] The formation of this high-affinity inhibitory complex in vivo accounts for its potent effect at therapeutic concentrations.

Secondary Mechanisms: Antiandrogenic and Immunomodulatory Effects

Beyond its effects on gastric acid and drug metabolism, cimetidine possesses other distinct pharmacological activities.

• Antiandrogenic Effects: At high therapeutic doses, cimetidine exhibits weak but clinically significant antiandrogenic activity.[3] This effect is multifactorial. Firstly, it acts as a direct, competitive antagonist at the androgen receptor (AR), competing with testosterone and dihydrotestosterone (DHT) for binding. Its affinity for the AR is very low (dissociation constant, Ki​, of 140 μM), but at high concentrations, this antagonism can become relevant.[3] Secondly, through its inhibition of CYP450 enzymes involved in steroid metabolism, cimetidine can inhibit the 2-hydroxylation of estradiol, leading to a relative increase in circulating estrogen levels.[3] Finally, there are reports of cimetidine stimulating prolactin secretion, which can further contribute to endocrine side effects.[3] This combination of AR blockade, increased estrogenic tone, and potential hyperprolactinemia is the basis for adverse effects such as gynecomastia, decreased libido, and erectile dysfunction observed with high-dose or long-term therapy.[3]
• Immunomodulatory Effects: Cimetidine has demonstrated notable immunomodulatory properties that are independent of its effects on gastric acid. Histamine, acting via H2 receptors present on various immune cells (such as T-lymphocytes), can exert an immunosuppressive effect. By blocking these receptors, cimetidine can reverse this suppression and enhance cell-mediated immunity.[28] Specifically, it has been shown to block histamine's ability to stimulate suppressor T-lymphocyte activity and to inhibit the function of Natural Killer (NK) cells and the production of interleukin-2 (IL-2).[28] One study demonstrated that cimetidine could inhibit the production of the immunosuppressive cytokine IL-10 while restoring the secretion of the immunostimulatory cytokine IL-12 in dendritic cells.[8] These immunomodulatory actions are believed to be the mechanistic foundation for cimetidine's observed efficacy in off-label uses, such as the treatment of viral warts and its investigational role as an adjunct in cancer therapy.[22]

Pharmacokinetics: The Journey Through the Body

The disposition of cimetidine in the body is characterized by rapid absorption, wide distribution, limited metabolism, and prompt renal elimination.

Absorption and Bioavailability

Following oral administration, cimetidine is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations (Tmax​) typically occurring within 45 to 90 minutes.[3] The absolute oral bioavailability is consistently in the range of 60% to 70% in healthy individuals.[3] In patients with active peptic ulcer disease, bioavailability can be slightly higher, reaching up to 70%, though it may also be more variable in this population.[7]

Distribution and Protein Binding

Cimetidine is widely distributed throughout the body's tissues.[3] The apparent volume of distribution (

Vd​) is approximately 1.0 L/kg in adults, indicating that the drug distributes well beyond the plasma volume into tissues.[3] In pediatric populations, the volume of distribution is larger, ranging from 1.2 to 2.1 L/kg.[3] Critically, cimetidine is capable of crossing the blood-brain barrier, a pharmacokinetic property that underlies its potential to cause central nervous system (CNS) side effects.[3] Plasma protein binding is low, reported at 13% to 25%, and is not considered to be a significant factor in its pharmacokinetics or potential for displacement-based drug interactions.[3]

Hepatic Metabolism and Metabolites

While a substantial portion of a cimetidine dose is eliminated unchanged, it does undergo partial hepatic metabolism.[3] Both cytochrome P450 enzymes and flavin-containing monooxygenases have been implicated in its biotransformation.[7] The primary metabolic pathway is oxidation of the sulfur atom in the side chain to form the major metabolite, cimetidine sulfoxide.[3] A minor metabolite, hydroxymethyl cimetidine, is also formed.[7] The extent of metabolism is greater following oral administration compared to parenteral administration, due to first-pass hepatic effects.[17]

Renal Excretion and Elimination Kinetics

The primary route of elimination for cimetidine and its metabolites is renal excretion into the urine.[3] After a single oral dose, approximately 48% of the drug is recovered in the urine as the unchanged parent compound over 24 hours.[17] The elimination half-life (

t1/2​) in adults with normal renal function is rapid, approximately 2 hours (123 minutes).[3] The half-life is significantly prolonged in neonates (around 3.6 hours) and in patients with renal impairment.[30] The total systemic clearance of cimetidine is high, in the range of 500-600 mL/min, reflecting efficient renal elimination.[7] Following a standard therapeutic dose, blood concentrations remain sufficient to inhibit gastric acid secretion for a duration of 4 to 8 hours.[3]

A summary of these pharmacokinetic parameters provides a quantitative foundation for understanding cimetidine's clinical behavior and for designing appropriate dosing regimens.

Parameter	Value	Notes and Source(s)
Bioavailability (Oral)	60-70%	Can be higher and more variable in patients with peptic ulcer disease. 3
Time to Peak (Tmax)	45-90 minutes	17
Plasma Protein Binding	13-25%	Considered pharmacologically insignificant. 3
Volume of Distribution (Vd)	~1.0 L/kg (Adults) 1.2-2.1 L/kg (Children)	Widely distributed; crosses the blood-brain barrier. 3
Elimination Half-life (t1/2)	~2 hours (Adults) ~3.6 hours (Neonates)	Prolonged in renal impairment. 3
Systemic Clearance	500-600 mL/min	7
Primary Route of Elimination	Renal (Urine)	~48% of an oral dose is excreted unchanged in 24 hours. 7
Major Metabolites	Cimetidine sulfoxide, Hydroxymethyl cimetidine	3

The complete pharmacological profile of cimetidine presents a compelling duality that has defined its clinical history. On one hand, its primary mechanism of H2-receptor blockade was a revolutionary therapeutic innovation, offering the first effective medical treatment for peptic ulcer disease. On the other hand, its potent and non-selective inhibition of the cytochrome P450 system represents a significant clinical liability. This "off-target" effect is not therapeutically beneficial but is the root cause of a vast and complex web of drug-drug interactions. The subsequent development of H2-receptor antagonists with less CYP affinity (e.g., ranitidine, famotidine) and, more importantly, the introduction of the pharmacologically distinct and more efficacious proton pump inhibitors (PPIs), provided clinicians with alternatives that lacked this extensive interaction profile. This progression illustrates a fundamental principle in pharmacology and drug development: the pursuit of target selectivity. A drug's unintended or "off-target" effects can be as clinically consequential as its intended mechanism. The gradual decline in cimetidine's clinical use was not due to a failure of efficacy but rather to a lack of safety and predictability in the context of polypharmacy, which is increasingly the norm in modern medicine. Thus, cimetidine serves as a classic and invaluable case study on the critical importance of molecular selectivity in drug design.

Clinical Efficacy and Therapeutic Applications

Approved Indications and Clinical Evidence

Cimetidine is approved for the treatment and prevention of several acid-related disorders of the upper gastrointestinal tract.

Peptic Ulcer Disease (Duodenal and Gastric)

Cimetidine is indicated for the short-term treatment of active duodenal ulcers and active benign gastric ulcers.[3] Clinical trials have demonstrated its efficacy in promoting ulcer healing. For duodenal ulcers, treatment with an 800 mg dose administered at bedtime results in healing rates of approximately 80% after four weeks of therapy and 89% after six weeks.[17] For patients who have healed, cimetidine is also approved for long-term maintenance therapy at a reduced dosage (e.g., 400 mg at bedtime) to prevent the recurrence of duodenal ulcers.[7]

Gastroesophageal Reflux Disease (GERD)

The drug is used for the symptomatic management of GERD and for the short-term treatment (up to 12 weeks) of erosive esophagitis that has been confirmed by endoscopy.[7] By reducing gastric acidity, cimetidine decreases the erosive potential of refluxate on the esophageal mucosa, providing symptomatic relief and promoting healing of esophageal lesions.

Pathological Hypersecretory Conditions

Cimetidine is an effective therapy for managing pathological hypersecretory conditions, which are characterized by excessive production of gastric acid. These include Zollinger-Ellison Syndrome (caused by a gastrin-secreting tumor), systemic mastocytosis, and multiple endocrine adenomas.[3] In these conditions, higher doses of cimetidine are often required to control acid output adequately.

Over-the-Counter (OTC) Use for Dyspepsia and Heartburn

Lower-strength formulations of cimetidine are available over-the-counter for the self-treatment and prevention of heartburn, acid indigestion, and sour stomach.[3] It provides relief from symptoms caused by the consumption of certain foods and beverages.

Other Approved Uses

Cimetidine is also indicated for the prophylaxis of stress-induced ulcers in critically ill, hospitalized patients.[22] Additionally, it has niche approvals for use as an adjunctive therapy in the management of malabsorption in children with cystic fibrosis and for the treatment and prevention of gastrointestinal lesions and symptoms associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).[7]

Off-Label and Investigational Applications

Beyond its approved indications, cimetidine has been explored for a diverse range of off-label applications, largely leveraging its immunomodulatory and enzyme-inhibiting properties.

Role in Dermatology: Verruca (Warts) and Urticaria

One of the most established off-label uses of cimetidine is in dermatology for the treatment of viral warts (verruca vulgaris), which are caused by the human papillomavirus (HPV).[22] It has been reported to be effective in cases of recalcitrant or widespread warts in both adults and children, including immunocompromised patients such as pediatric heart transplant recipients.[22] This application often requires higher doses and longer treatment durations than those used for acid suppression.[29] The mechanism is believed to be related to the drug's immunomodulatory effects, enhancing the host's cell-mediated immune response against the virus. Cimetidine is also used off-label for the management of chronic urticaria (hives) and associated pruritus (itching).[32]

Adjunctive Therapy in Oncology

There is a body of research investigating cimetidine as a potential adjunctive therapy in oncology, particularly in colorectal cancer.[29] It is not considered a standalone cancer treatment but may confer benefits when used alongside conventional therapies like chemotherapy.[29] The proposed mechanisms are twofold:

1. Immunomodulation: By blocking H2 receptors on suppressor T-cells, cimetidine may counteract histamine-induced immune suppression, thereby augmenting the body's natural anti-tumor immune response.[28]
2. Anti-metastatic Effects: Cimetidine has been shown to inhibit the expression of E-selectin on endothelial cells. E-selectin is an adhesion molecule that cancer cells use to attach to the blood vessel wall during the process of metastasis. By blocking this interaction, cimetidine may help to prevent the spread of cancer cells. This effect appears to be most pronounced in patients with colorectal tumors that express high levels of the E-selectin ligands sialyl Lewis-X and sialyl Lewis-A, where cimetidine use has been associated with improved survival rates.[3]

Other Investigational Uses

Cimetidine is sometimes used off-label for the prevention of aspiration pneumonia in patients undergoing anesthesia, as reducing gastric acid volume and increasing pH can lessen the severity of lung injury if aspiration occurs.[32] There is also a theoretical, though unproven, benefit in the management of paracetamol (acetaminophen) overdose. By inhibiting the CYP enzymes (CYP1A2, CYP2E1, CYP3A4) responsible for converting paracetamol into its toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), cimetidine could potentially reduce the extent of liver injury.[3] Finally, its well-characterized profile as a CYP inhibitor has made it a useful tool in clinical pharmacology, where it is often used in Phase 1 drug-drug interaction studies to probe the metabolic pathways of new investigational drugs, such as gepotidacin and dexpramipexole.[35]

The broad spectrum of cimetidine's off-label applications, particularly in fields as disparate as dermatology and oncology, strongly indicates that its pharmacological activity is more complex than simple gastric acid suppression. While its approved indications are all directly linked to its primary mechanism of H2-receptor blockade in the stomach, its off-label uses are not. The treatment of viral warts and its potential as an anti-cancer adjunct cannot be explained by a reduction in stomach acidity. The unifying mechanism that logically connects these seemingly unrelated applications is its immunomodulatory effect. An enhanced cell-mediated immune response provides a plausible explanation for its ability to help the body clear the HPV virus and to augment the anti-tumor immune surveillance. This realization recasts cimetidine as a candidate for drug repositioning. Although its primary market in gastroenterology has been largely eroded by newer, superior agents, its secondary pharmacological effects present new and compelling avenues for research and clinical application. This serves as a powerful example of how a well-characterized older drug can find new therapeutic life when its "off-target" mechanisms are systematically investigated, highlighting the potential value that may lie dormant within the existing pharmacopeia.

Clinical Practice: Dosing, Administration, and Monitoring

Dosing Regimens by Indication (Adults)

The dosage of cimetidine varies significantly depending on the indication, severity of the condition, and whether it is being used for treatment or prophylaxis.

• Active Duodenal Ulcer: The standard treatment regimens are 800 mg orally once daily at bedtime, 400 mg orally twice daily, or 300 mg orally four times daily with meals and at bedtime. The typical duration of therapy is four to eight weeks.[12]
• Duodenal Ulcer Maintenance: For prophylaxis against recurrence, a reduced dose of 400 mg orally once daily at bedtime is recommended.[12]
• Active Benign Gastric Ulcer: Recommended dosing is 800 mg orally once daily at bedtime or 300 mg orally four times daily. Treatment should continue for at least six to eight weeks.[12]
• Erosive GERD: Higher doses are generally required. The recommended regimen is 800 mg orally twice daily or 400 mg orally four times daily for up to 12 weeks.[12]
• Pathological Hypersecretory Conditions: The initial dose is typically 300 mg orally four times daily with meals and at bedtime. The dose must be titrated based on patient response, and daily doses may be increased up to a maximum of 2400 mg.[19]
• OTC Heartburn (Self-Medication): For immediate relief of symptoms, the dose is 200 mg orally with a glass of water. To prevent symptoms, 200 mg can be taken up to 30 minutes before consuming food or beverages known to cause heartburn. The maximum daily OTC dose is 400 mg (two tablets), and self-treatment should not exceed 14 consecutive days without medical consultation.[32]

Administration Guidelines

Proper administration is crucial for ensuring efficacy and minimizing adverse effects.

• Oral Administration: Tablets should be swallowed with a glass of water.[37] For heartburn prevention, the dose should be timed 30 minutes prior to a meal.[22] While concomitant antacids can be used for rapid pain relief, their administration should be separated from oral cimetidine by at least two hours, as antacids can interfere with cimetidine's absorption.[12]
• Parenteral (IV/IM) Administration: Cimetidine can be administered via intramuscular injection or intravenously, typically every 6 to 8 hours in a hospital setting.[19] When given as an intravenous push (direct injection), it is critical that the injection be administered slowly, over a period of at least 5 minutes. Rapid IV administration has been associated with serious cardiovascular adverse effects, including hypotension, cardiac arrhythmias, and cardiac arrest.[19]

Special Populations: Dosage Adjustments

Dosage adjustments are required for specific patient populations to account for differences in drug clearance and susceptibility to adverse effects.

• Pediatric Patients: The use of cimetidine in children is not extensively studied and should be reserved for situations where the anticipated benefit clearly outweighs the potential risk. When used, doses are based on body weight, typically ranging from 20 to 40 mg/kg/day, administered in divided doses every 6 hours. Neonates require lower doses (5-20 mg/kg/day) and less frequent administration (every 8 to 12 hours) due to immature renal function.[16]
• Geriatric Patients: Elderly patients are more susceptible to the CNS side effects of cimetidine, particularly confusion and delirium. Therefore, it should be used with caution, typically at lower doses. It is generally recommended to avoid cimetidine in elderly patients who have, or are at high risk of, delirium.[16]
• Renal Impairment: As cimetidine is primarily eliminated by the kidneys, dosage reduction is mandatory in patients with renal impairment to prevent drug accumulation and toxicity. The degree of dose reduction is based on creatinine clearance (CrCl):
• CrCl 30-50 mL/min: 200 mg every 6 hours (800 mg/day).[18]
• CrCl 15-30 mL/min: 200 mg every 8 hours (600 mg/day).[18]
• CrCl <15 mL/min: 200 mg every 12 hours (400 mg/day). A common recommendation for severe impairment (CrCl <30 mL/min) is 300 mg orally every 12 hours.[16]
• Hepatic Impairment: Cimetidine should be used with caution in patients with severe hepatic impairment, as it undergoes some liver metabolism. Dose reduction may be necessary.[19]

A consolidated table provides a practical reference for clinicians to ensure appropriate dosing across various clinical scenarios.

Indication	Patient Population	Recommended Oral Dose	Recommended Parenteral Dose	Dosage Adjustments & Notes
Active Duodenal Ulcer	Adult	800 mg qHS; or 400 mg BID; or 300 mg QID	300 mg IV/IM q6-8h	Duration: 4-8 weeks.
Duodenal Ulcer Maintenance	Adult	400 mg qHS	N/A	Long-term use.
Active Benign Gastric Ulcer	Adult	800 mg qHS; or 300 mg QID	300 mg IV/IM q6-8h	Duration: 6-8 weeks. Exclude malignancy first.
Erosive GERD	Adult	800 mg BID; or 400 mg QID	300 mg IV/IM q6-8h	Duration: Up to 12 weeks.
Pathological Hypersecretion	Adult	300 mg QID, titrate up to 2400 mg/day	Titrated dose, may exceed 2 g/day	Dose adjusted based on acid output.
OTC Heartburn	Adult	200 mg PRN for relief; 200 mg 30 min before meal for prevention	N/A	Max: 400 mg/day. Max duration: 14 days.
Pediatrics	Neonate Infant/Child	5-20 mg/kg/day divided q8-12h 20-40 mg/kg/day divided q6h	Dose based on weight and age.	Use only if benefit outweighs risk.
Renal Impairment	CrCl <30 mL/min	300 mg q12h	Dose adjustment required.	Monitor for CNS side effects.
Geriatrics	Elderly (>65 years)	Use lower end of dosing range.	Use with caution.	High risk of confusion; avoid if delirium risk.

Comprehensive Safety Analysis and Risk Management

Profile of Adverse Drug Reactions

While cimetidine is generally well-tolerated, particularly with short-term, low-dose use, it is associated with a range of adverse effects, some of which are unique among its class due to its specific pharmacological properties.[29]

• Common and Mild Side Effects: The most frequently reported adverse effects are mild and often transient. These include headache, diarrhea, dizziness, drowsiness, constipation, and myalgia (muscle pain).[3]
• Significant Adverse Events:
• Central Nervous System (CNS) Effects: Due to its ability to cross the blood-brain barrier, cimetidine can cause a spectrum of CNS adverse effects. Reversible mental confusion, agitation, psychosis, depression, anxiety, disorientation, and hallucinations have been reported.[38] These effects are rare in the general population but occur more frequently in elderly patients, the critically ill, and individuals with pre-existing renal or hepatic impairment, where drug accumulation is more likely.[22]
• Endocrine System Effects: Cimetidine's antiandrogenic properties are responsible for its characteristic endocrine side effects. Gynecomastia (painful breast enlargement in males) and reversible impotence can occur, particularly with high doses (e.g., >5 g/day) or prolonged therapy.[3] While the incidence at standard ulcer-healing doses is low (less than 1%), it can be substantially higher in patients receiving high-dose therapy for conditions like Zollinger-Ellison syndrome.[3] Galactorrhea has also been reported, likely related to increased prolactin levels.[22]
• Cardiovascular Effects: Adverse cardiovascular events are primarily associated with rapid intravenous administration. Bolus injections have been linked to hypotension, bradycardia, and, in rare cases, cardiac arrest.[19]
• Hepatic and Renal Effects: Cimetidine can cause transient elevations in serum aminotransferases.[3] Clinically significant hepatotoxicity is rare.[38] It can also cause a benign and reversible increase in serum creatinine. This is not due to a true decrease in glomerular filtration rate (GFR) but rather to competitive inhibition of the active tubular secretion of creatinine in the kidneys.[22] Rare cases of acute interstitial nephritis, an allergic reaction in the kidneys, have also been reported.[38]
• Hematologic Effects: Rare instances of blood dyscrasias, including agranulocytosis, thrombocytopenia, and aplastic anemia, have been associated with cimetidine use, although establishing a definitive causal link is often complicated by concomitant diseases and medications.[38]
• Vitamin B12 Deficiency: Long-term therapy (defined as two years or more) with acid-suppressing agents, including cimetidine, can lead to malabsorption of dietary vitamin B12. Gastric acid is required to cleave B12 from food proteins, and in a state of hypochlorhydria, this process is impaired, potentially leading to a deficiency over time.[22]

Drug-Drug Interactions: A Critical Review

The extensive and clinically significant drug-drug interaction profile of cimetidine is its single greatest liability and the primary reason for its decline in use relative to other acid-suppressing agents.

The Central Role of CYP450 Inhibition

The vast majority of cimetidine's pharmacokinetic interactions stem from its potent, reversible inhibition of a broad range of cytochrome P450 isoenzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.[3] By binding to these enzymes, cimetidine competitively inhibits the metabolism of numerous co-administered drugs that are substrates for these pathways. This inhibition leads to decreased clearance, elevated plasma concentrations, and a prolonged half-life of the affected drug, thereby increasing the risk of concentration-dependent toxicity.[7]

Other Interaction Mechanisms

In addition to CYP inhibition, cimetidine can interact via two other mechanisms:

• Altered Gastric pH: By raising the intragastric pH, cimetidine can decrease the dissolution and absorption of drugs that require an acidic environment for optimal bioavailability. Examples include the antifungal agent ketoconazole and certain formulations of iron salts.[16]
• Inhibition of Renal Tubular Secretion: Cimetidine can compete for active transport via the organic cation transporter in the renal tubules. This can inhibit the renal excretion of other cationic drugs that share this pathway, such as procainamide and metformin, leading to increased plasma levels.[3]

Recommendations for Clinical Management

Given the high potential for interactions, extreme caution must be exercised when prescribing cimetidine to patients on other medications, particularly those with a narrow therapeutic index. Management strategies include:

• Avoiding the combination whenever possible.
• Selecting an alternative acid-suppressing agent with a lower interaction potential, such as famotidine or a proton pump inhibitor.
• If co-administration is unavoidable, empirically reducing the dose of the affected drug.
• Implementing intensive clinical and/or laboratory monitoring (e.g., monitoring INR for warfarin, serum drug levels for theophylline or phenytoin, or ECG for QT-prolonging drugs).[44]

The following table summarizes some of the most clinically significant drug interactions with cimetidine, organized by therapeutic class.

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Anticoagulants (e.g., Warfarin, Acenocoumarol)	Inhibition of CYP2C9 and other CYPs	Increased plasma levels of the anticoagulant, leading to an elevated INR and a significantly increased risk of major bleeding.	Avoid combination. If unavoidable, perform frequent INR monitoring and make aggressive warfarin dose adjustments. Consider an alternative H2RA or PPI.	21
Antiarrhythmics (e.g., Amiodarone, Lidocaine, Procainamide, Quinidine)	Inhibition of CYP3A4 (Amiodarone, Lidocaine) and renal tubular secretion (Procainamide)	Increased plasma levels, leading to an increased risk of proarrhythmia, CNS toxicity (Lidocaine), and other adverse effects.	Avoid combination. These agents have a narrow therapeutic index, and the risk of toxicity is high.	19
Anticonvulsants (e.g., Phenytoin, Carbamazepine)	Inhibition of CYP2C9/2C19 (Phenytoin) and CYP3A4 (Carbamazepine)	Increased plasma levels, leading to a high risk of concentration-dependent toxicity (e.g., nystagmus, ataxia, confusion).	Avoid combination. If necessary, monitor serum drug levels closely and adjust the anticonvulsant dose.	21
Benzodiazepines (e.g., Diazepam, Alprazolam, Midazolam)	Inhibition of CYP3A4	Increased plasma levels and prolonged half-life, leading to excessive and prolonged sedation, respiratory depression, and psychomotor impairment.	Avoid combination, especially with midazolam and alprazolam. Consider benzodiazepines not metabolized by CYP3A4 (e.g., lorazepam).	21
Theophylline	Inhibition of CYP1A2	Markedly increased theophylline levels, leading to a high risk of life-threatening toxicity (e.g., seizures, cardiac arrhythmias).	Combination is contraindicated or requires extreme caution with therapeutic drug monitoring and significant dose reduction of theophylline.	21
SSRIs (e.g., Citalopram)	Inhibition of CYP2C19, 2D6, 3A4	Increased citalopram levels, leading to a dose-dependent risk of QT interval prolongation and Torsades de Pointes.	Citalopram dose should not exceed 20 mg/day when co-administered. Monitor ECG and electrolytes. Advise patient on symptoms of arrhythmia.	45
Beta-Blockers (e.g., Propranolol, Metoprolol)	Inhibition of CYP2D6	Increased plasma levels, leading to an increased risk of excessive beta-blockade (bradycardia, hypotension).	Monitor heart rate and blood pressure. A dose reduction of the beta-blocker may be necessary.	21
Immunosuppressants (e.g., Cyclosporine)	Inhibition of CYP3A4	Increased cyclosporine levels, leading to an increased risk of nephrotoxicity and other serious adverse effects.	Avoid combination. Requires intensive therapeutic drug monitoring of cyclosporine levels.	16

Contraindications, Warnings, and Precautions

• Contraindications: Cimetidine is absolutely contraindicated in patients with a known history of hypersensitivity to the drug or any of its excipients. Cross-sensitivity with other H2-receptor antagonists may occur.[19]
• Warnings:
• Masking of Gastric Malignancy: A critical warning is that the symptomatic relief provided by cimetidine can mask the symptoms of an underlying gastric malignancy. It is imperative to exclude the presence of cancer through endoscopy and biopsy before initiating therapy, particularly in older patients with new-onset dyspepsia or in those with a diagnosed gastric ulcer.[30]
• Precautions:
• OTC Use: Patients self-medicating with OTC cimetidine should be advised to seek medical attention if their heartburn persists for more than 14 days, worsens, or is accompanied by alarm symptoms such as dysphagia (difficulty swallowing), odynophagia (painful swallowing), vomiting blood, or passing bloody or black, tarry stools.[30]
• Renal and Hepatic Impairment: Use with caution and at reduced doses in patients with renal or hepatic impairment due to the risk of drug accumulation and increased susceptibility to adverse effects, especially CNS disturbances.[30]

Conclusion: The Legacy and Current Standing of Cimetidine

Summary of Cimetidine's Therapeutic Profile

Cimetidine occupies a seminal position in the history of pharmacology. As the first-in-class H2-receptor antagonist, it provided an effective, non-surgical treatment for acid-related gastrointestinal disorders, most notably peptic ulcer disease. Its development stands as a triumphant validation of the principles of rational drug design, demonstrating that a deep understanding of pathophysiology could lead to the logical creation of a novel therapeutic agent. Its efficacy in reducing gastric acid secretion is well-established. However, this therapeutic benefit is inextricably linked to a challenging safety profile. Cimetidine's clinical utility is significantly constrained by its potent, broad-spectrum inhibition of the cytochrome P450 enzyme system, which creates a high propensity for clinically significant drug-drug interactions. This, combined with a risk of CNS and endocrine side effects, particularly in vulnerable populations, defines its therapeutic limitations.

Cimetidine in the Context of Modern Gastroenterology

In contemporary clinical practice, cimetidine is no longer considered a first-line agent for most of its original indications. The landscape of acid suppression therapy has evolved significantly since its introduction. It has been largely superseded by second-generation H2-receptor antagonists (e.g., famotidine, nizatidine) that possess a much cleaner drug interaction profile, and more profoundly, by the therapeutically superior and more potent class of proton pump inhibitors (PPIs) like omeprazole and lansoprazole.[3] The primary clinical niches for cimetidine today are as a low-cost generic option in patients taking no interacting medications, for specific off-label uses, or as a tool in clinical pharmacology research.

Future Directions and Unresolved Questions

While its role in gastroenterology has diminished, the most compelling future for cimetidine may lie in the exploration of its secondary pharmacological properties. Its well-documented immunomodulatory effects present intriguing possibilities for drug repositioning. Further rigorous clinical investigation is warranted to definitively establish its efficacy and role as an adjunctive therapy in oncology—particularly for preventing metastasis in certain cancer types—and in the management of viral dermatological conditions like recalcitrant warts. These avenues represent a potential second life for a historic drug, transforming it from a landmark of the past into a tool for future therapeutic innovation. The story of cimetidine thus continues to evolve, serving as a powerful and enduring lesson on the complex, multifaceted nature of drug action and the potential for established medicines to find new purpose.

Works cited

1. Tagamet Discovery of Histamine H2-receptor Antagonists - American Chemical Society, accessed August 28, 2025, https://www.acs.org/education/whatischemistry/landmarks/cimetidinetagamet.html
2. Graham J. Durant - Cimetidine - National Inventors Hall of Fame®, accessed August 28, 2025, https://www.invent.org/inductees/graham-j-durant
3. Cimetidine - Wikipedia, accessed August 28, 2025, https://en.wikipedia.org/wiki/Cimetidine
4. Charon Robin Ganellin - National Inventors Hall of Fame®, accessed August 28, 2025, https://www.invent.org/inductees/charon-robin-ganellin
5. The development of cimetidine: 1964-1976. A human story - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/7806839/
6. RATIONAL DESIGN OF CIMETIDINE, accessed August 28, 2025, https://uomustansiriyah.edu.iq/media/lectures/4/4_2018_12_13!06_06_15_PM.pdf
7. Cimetidine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 28, 2025, https://go.drugbank.com/drugs/DB00501
8. Cimetidine | CAS 51481-61-9 | SCBT - Santa Cruz Biotechnology, accessed August 28, 2025, https://www.scbt.com/p/cimetidine-51481-61-9
9. 3D structure for Cimetidine (DB00501) | DrugBank Online, accessed August 28, 2025, https://go.drugbank.com/structures/small_molecule_drugs/DB00501
10. Cimetidine | C10H16N6S | CID 2756 - PubChem, accessed August 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Cimetidine
11. cimetidine (CHEBI:3699) - EMBL-EBI, accessed August 28, 2025, https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:3699
12. Cimetidine: Package Insert / Prescribing Information - Drugs.com, accessed August 28, 2025, https://www.drugs.com/pro/cimetidine.html
13. Cimetidine | 51481-61-9 - ChemicalBook, accessed August 28, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4229414.htm
14. Cimetidine 51481-61-9 | TCI AMERICA - TCI Chemicals, accessed August 28, 2025, https://www.tcichemicals.com/CA/en/p/C1252
15. Cimetidine (Cimetidinum), accessed August 28, 2025, https://cdn.who.int/media/docs/default-source/medicines/pharmacopoeia/omitted-monographs/cimetidine.pdf?sfvrsn=22a8255d_5
16. Tagamet HB (cimetidine) dosing, indications, interactions, adverse effects, and more, accessed August 28, 2025, https://reference.medscape.com/drug/tagamet-cimetidine-341984
17. CIMETIDINE TABLETS, USP - DailyMed, accessed August 28, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9fde45b1-b40c-4374-81ad-f2bf1015950b
18. Cimetidine 200mg/5ml Oral Solution - Summary of Product Characteristics (SmPC) - (emc), accessed August 28, 2025, https://www.medicines.org.uk/emc/product/1734/smpc
19. Cimetidine injection USP 200mg/mL - SUMMARY OF PRODUCT CHARACTERISTICS, accessed August 28, 2025, http://www.efda.gov.et/wp-content/uploads/2024/06/Cimetidine-injection-USP-200mg-per-mL_-Humanwell-Pharmaceutical-Ethiopia-PLC.pdf
20. Cimetidine - Pharmaceutical Drugs - NCBI Bookshelf, accessed August 28, 2025, https://www.ncbi.nlm.nih.gov/books/NBK526181/
21. Cimetidine (Tagamet): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 28, 2025, https://www.webmd.com/drugs/2/drug-7035/tagamet-oral/details
22. Cimetidine - StatPearls - NCBI Bookshelf, accessed August 28, 2025, https://www.ncbi.nlm.nih.gov/books/NBK544255/
23. Cimetidine hydrochloride | DrugBank Online, accessed August 28, 2025, https://go.drugbank.com/salts/DBSALT000287
24. Clinical relevance of cimetidine drug interactions - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/1524698/
25. Drug Interactions of H2-Receptor Antagonists Involving Cytochrome P450 (CYPs) Enzymes: from the Laboratory to the Clinic, accessed August 28, 2025, http://neuron.mefst.hr/docs/CMJ/issues/1999/40/3/10411963.pdf
26. Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/8689952/
27. EFFECT OF CIMETIDINE ON HEPATIC CYTOCHROME P450: EVIDENCE FOR FORMATION OF A METABOLITE-INTERMEDIATE COMPLEX - CiteSeerX, accessed August 28, 2025, https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=65885c6ac05bb1b8735836f396901d2700f30a0a
28. Definition of cimetidine - NCI Drug Dictionary, accessed August 28, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cimetidine
29. Cimetidine's Off-Label Uses: From Warts to Cancer Treatment Adjuncts - Pharmacy Planet, accessed August 28, 2025, https://www.pharmacyplanet.com/blog/post/cimetidines-off-label-uses-from-warts-to-cancer-treatment-adjuncts
30. Cimetidine | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 28, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5629/Cimetidine
31. Cimetidine: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed August 28, 2025, https://www.medcentral.com/drugs/monograph/11210-382256/cimetidine-oral
32. Cimetidine: MedlinePlus Drug Information, accessed August 28, 2025, https://medlineplus.gov/druginfo/meds/a682256.html
33. medlineplus.gov, accessed August 28, 2025, https://medlineplus.gov/druginfo/meds/a682256.html#:~:text=Cimetidine%20is%20also%20used%20sometimes,prevent%20aspiration%20pneumonia%20during%20anesthesia.
34. Cimetidine and Other H2 Blockers - CancerChoices, accessed August 28, 2025, https://cancerchoices.org/therapy/cimetidine/
35. Cimetidine Completed Phase 1 Trials for Bacterial Infections Treatment | DrugBank Online, accessed August 28, 2025, https://go.drugbank.com/drugs/DB00501/clinical_trials?conditions=DBCOND0027917&phase=1&purpose=treatment&status=completed
36. Cimetidine Completed Phase 1 Trials for Amyotrophic Lateral Sclerosis (ALS) Treatment, accessed August 28, 2025, https://go.drugbank.com/drugs/DB00501/clinical_trials?conditions=DBCOND0029898&phase=1&purpose=treatment&status=completed
37. Cimetidine Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 28, 2025, https://www.drugs.com/dosage/cimetidine.html
38. Cimetidine: II. Adverse reactions and patterns of use - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/6753681/
39. 8 Cimetidine Side Effects You Should Know About - GoodRx, accessed August 28, 2025, https://www.goodrx.com/cimetidine/cimetidine-side-effects
40. Cimetidine: Uses & Side Effects - Cleveland Clinic, accessed August 28, 2025, https://my.clevelandclinic.org/health/drugs/18309-cimetidine-tablets
41. www.goodrx.com, accessed August 28, 2025, https://www.goodrx.com/cimetidine/cimetidine-side-effects#:~:text=Although%20it's%20usually%20well%20tolerated,and%20joint%20and%20muscle%20pain.
42. Cimetidine Uses, Side Effects & Warnings - Drugs.com, accessed August 28, 2025, https://www.drugs.com/mtm/cimetidine.html
43. Cimetidine (Tagamet): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 28, 2025, https://www.webmd.com/drugs/2/drug-11210/cimetidine-oral/details
44. What is Cimetidine used for? - Patsnap Synapse, accessed August 28, 2025, https://synapse.patsnap.com/article/what-is-cimetidine-used-for
45. Cimetidine and citalopram Interactions - Drugs.com, accessed August 28, 2025, https://www.drugs.com/drug-interactions/cimetidine-with-citalopram-669-0-679-0.html?professional=1
46. Drug Interaction Report: cimetidine, hydroxychloroquine - Drugs.com, accessed August 28, 2025, https://www.drugs.com/interactions-check.php?drug_list=669-0,1298-0&professional=1