An Expert Report on Tromethamine (DB03754): Properties, Clinical Applications as an Alkalizing Agent, and Role as a Pharmaceutical Salt

Executive Summary

Tromethamine, also known by the synonyms Tris and THAM, is a small organic molecule with a multifaceted and distinct dual identity in the fields of medicine and pharmacology. This report provides a comprehensive analysis of Tromethamine (DrugBank ID: DB03754), meticulously differentiating its two primary roles to prevent the critical misattribution of pharmacological properties.

First, Tromethamine functions as an active pharmaceutical ingredient (API) in the form of an intravenous solution, commercially known as THAM. In this capacity, it is a potent, physiologically optimized alkalizing agent indicated for the prevention and correction of severe metabolic acidosis in specific, acute clinical settings such as cardiac bypass surgery and cardiac arrest.[1] Its mechanism as a proton acceptor that does not generate carbon dioxide offers a significant therapeutic advantage over sodium bicarbonate in patients with compromised respiratory function.[4] However, its use is confined to critical care environments due to a high-risk profile that includes potential respiratory depression, hypoglycemia, and severe tissue necrosis upon extravasation.[5]

Second, and more ubiquitously in modern pharmaceuticals, Tromethamine serves as a chemically vital but pharmacologically inert excipient. It is widely used to form a salt with an acidic active drug, a common strategy to enhance the drug's solubility, stability, and bioavailability.[7] The most prominent example is Ketorolac Tromethamine, a potent nonsteroidal anti-inflammatory drug (NSAID).[10] A significant portion of publicly available data and safety warnings associated with the term "Tromethamine" pertains to the severe, life-threatening adverse effects of the Ketorolac moiety, including gastrointestinal bleeding, cardiovascular events, and renal failure.

A primary objective of this report is to perform a critical disambiguation. By presenting a detailed profile of Tromethamine as the API in THAM and contrasting it with a comprehensive case study of its role in Ketorolac Tromethamine, this analysis aims to provide clinicians, pharmacists, and researchers with the clarity required to ensure patient safety. Understanding this distinction is paramount to correctly assessing the unique risk-benefit profile of each therapeutic entity and avoiding dangerous clinical misconceptions.

Identification and Physicochemical Properties of Tromethamine

A thorough understanding of Tromethamine's pharmacology begins with its fundamental chemical and physical identity. These properties not only define its behavior in solution and in biological systems but also explain its utility as both a therapeutic agent and a versatile chemical in broader scientific applications.

Nomenclature and Chemical Identifiers

The molecule is known by several names across different disciplines, reflecting its widespread use in clinical, research, and industrial settings.

• Common Names: The most frequently used names are Tromethamine, Tris(hydroxymethyl)aminomethane, Tris, THAM, and Trometamol.[2] "THAM" is commonly used in the medical context for the active drug formulation, while "Tris" is prevalent in biochemistry and molecular biology laboratory settings.
• Systematic (IUPAC) Name: 2-Amino-2-(hydroxymethyl)propane-1,3-diol.[2]
• Key Identifiers:
• CAS Number: 77-86-1 [2]
• DrugBank ID: DB03754 [1]
• FDA UNII (Unique Ingredient Identifier): 023C2WHX2V [2]
• ATC (Anatomical Therapeutic Chemical) Codes: B05XX02 (Other i.v. solution additives), B05BB03 (Solutions affecting the electrolyte balance) [1]
• InChIKey: LENZDBCJOHFCAS-UHFFFAOYSA-N [2]

Chemical Structure and Formula

Tromethamine is a structurally simple yet functionally versatile organic compound.

• Chemical Formula: C4​H11​NO3​.[1]
• Molecular Weight: The average molecular weight is consistently reported as 121.135 to 121.14 g·mol⁻¹.[2] The monoisotopic mass is 121.073893223.[2]
• Structural Description: It is classified as an organic amine proton acceptor and belongs to the chemical class of 1,2-aminoalcohols.[2] Its structure consists of a central carbon atom bonded to a primary amine group ( –NH2​) and three hydroxymethyl groups (–CH2​OH).[7] This unique arrangement of a basic amine and three polar hydroxyl groups is responsible for its high water solubility and its buffering capacity. Industrially, it is prepared through the condensation of nitromethane with formaldehyde, followed by hydrogenation of the resulting intermediate, (HOCH2)3CNO2.[9]

Physical and Chemical Properties

The distinct physical and chemical characteristics of Tromethamine are fundamental to its function as both a biological buffer and a pharmaceutical excipient. These properties are consolidated in Table 1.

• Appearance: Under standard conditions, Tromethamine is a white crystalline solid or powder.[7]
• Solubility: It exhibits high aqueous solubility, with values reported as 550 g/L at 25°C and up to 695 mg/mL.[2] This property is essential for its formulation as a high-concentration intravenous solution. It is slightly soluble in ethanol and very slightly soluble in ethyl acetate.[7]
• Stability: The compound is generally stable, non-volatile, and described as almost non-hygroscopic, although some sources note it as hygroscopic.[7] It is incompatible with strong bases and strong oxidizing agents and should be protected from moisture.[11]
• Buffering Capacity (pKa): The pKa is a critical parameter defining its buffering range. At room temperature (25°C), its pKa is approximately 8.1, making it an excellent buffer for biochemical applications which often require a pH between 7.0 and 9.0.[9] Critically, this value is temperature-dependent. At physiological body temperature (37°C), the pK shifts to 7.8.[5] This shift is not a minor detail; it is the cornerstone of its clinical efficacy. The bicarbonate buffer system, the body's primary defense against pH changes, has a pKa of 6.1. A buffer is most effective at a pH close to its pKa. With a pK of 7.8, Tromethamine is a significantly more powerful and efficient buffer than bicarbonate within the physiological blood pH range of ~7.35 to 7.45. This physicochemical property explains its potency as a therapeutic agent in severe acidaemia, where it can resist pH changes with a greater capacity than the body's overwhelmed natural systems.[5]
• pH of Solution: An aqueous solution of Tromethamine is alkaline. A 5% solution has a pH in the range of 10.0 to 11.5, while the therapeutic 0.3 M injection solution is adjusted with acetic acid to a pH of approximately 8.6.[3] This alkalinity necessitates careful administration into large veins to prevent tissue irritation.[6]

Table 1: Consolidated Physicochemical Properties of Tromethamine

Property	Value	Source(s)
CAS Number	77-86-1	2
Molecular Formula	C4​H11​NO3​	1
Average Molecular Weight	121.14 g·mol⁻¹	12
Appearance	White crystalline powder	7
Melting Point	167–172 °C	11
Boiling Point	219–220 °C (at 10 mmHg)	11
pKa (conjugate acid)	8.1 (at 25 °C); 7.8 (at 37 °C)	5
pH (5% aqueous solution)	10.0–11.5	7
Water Solubility	550 g/L (at 25 °C)	11
logP	-2.1 to -2.7	2
Hydrogen Bond Donors	4	2
Hydrogen Bond Acceptors	4	2
Polar Surface Area	86.71A˚2	2

Non-Pharmaceutical Applications

To provide a complete profile of the molecule, it is essential to recognize its extensive utility beyond medicine. This broad application underscores its chemical stability and well-characterized properties.

• Biotechnology and Research: Tromethamine, universally known as "Tris" in this context, is a cornerstone of modern molecular biology. Its pKa of ~8.1 at room temperature makes it the buffer of choice for countless applications involving nucleic acids and proteins.[9] It is a key component of widely used electrophoresis buffers like TAE (Tris-acetate-EDTA) and TBE (Tris-borate-EDTA) for separating DNA and RNA fragments.[11] It is also used to maintain pH stability in PCR detection systems, in protein crystallization experiments, and to increase the permeability of cell membranes for experimental purposes.[7]
• Industrial and Cosmetics: In the cosmetics industry, Tromethamine functions as a pH buffer, emulsifier, solubilizer, and humectant, and is often used as a replacement for triethanolamine.[7] In the chemical industry, it serves as an additive in coatings and paints to improve stability and smoothness.[7]

Tromethamine as an Active Pharmaceutical Ingredient (API): THAM

When used as a therapeutic agent, Tromethamine is administered intravenously as a 0.3 M solution, commonly referred to by the brand name THAM. Its clinical role is highly specialized, serving as a potent alkalizing agent for the treatment of severe metabolic acidosis in specific, life-threatening situations. Its pharmacology, efficacy, and safety profile are distinct and should not be confused with its role as an excipient in other drug formulations.

Clinical Pharmacology

The clinical effects of THAM are a direct result of its unique chemical properties, which allow it to function as a powerful and physiologically optimized buffer.

Mechanism of Action

Tromethamine's primary mechanism is that of a proton acceptor. As a biologically inert organic amine, it actively binds free hydrogen ions (H+) from the bloodstream and interstitial fluid.[4] Its action is twofold and provides a key advantage over sodium bicarbonate:

1. Buffering of Metabolic and Carbonic Acids: THAM buffers both fixed metabolic acids (e.g., lactic acid, ketoacids) and, importantly, carbonic acid (H2​CO3​).[3] By accepting a proton, it effectively generates bicarbonate ( HCO3−​), thus supplementing the body's main buffering system.[5]
2. CO2-Sparing Effect: The administration of sodium bicarbonate (NaHCO3​) for acidosis results in the formation of carbonic acid, which rapidly dissociates into water and carbon dioxide (CO2​), as shown by the equation H++HCO3−​↔H2​CO3​↔H2​O+CO2​. This increases the body's CO2​ load, which must be eliminated by the lungs. In patients with respiratory failure or inadequate ventilation, this can paradoxically worsen intracellular and central nervous system acidosis.[16] Tromethamine, in contrast, directly binds protons and also reacts with CO2​, leading to a decrease in the partial pressure of arterial carbon dioxide (PaCO2).[5] This makes it a superior choice in clinical scenarios of mixed metabolic and respiratory acidosis where ventilation is compromised.[14]

Additionally, THAM acts as an osmotic diuretic, increasing urine flow, urinary pH, and promoting the renal excretion of fixed acids, electrolytes, and carbon dioxide.[3]

Pharmacodynamics

The pharmacodynamic effects of THAM are centered on the rapid correction of acidaemia and its systemic consequences. Its pKa of 7.8 at 37°C makes it a more efficient buffer than bicarbonate (pKa 6.1) in the physiological pH range, allowing for a more potent and immediate effect on blood pH.[5]

The decision to use THAM instead of the more conventional sodium bicarbonate is a critical clinical judgment based on their differing pharmacodynamic profiles. While both are alkalizing agents, their effects on electrolytes and respiration are distinct. Sodium bicarbonate administration increases the body's sodium load and can cause or worsen hypokalemia. Conversely, THAM does not contain sodium and may even lower serum sodium levels, while its effect on potassium is generally neutral, although hypokalemia can occur as a secondary effect of correcting acidosis.[16] This makes THAM a potentially favorable option in hypernatremic patients. However, THAM carries its own unique and significant risks. Large or rapidly administered doses can lead to profound hypoglycemia, particularly in neonates, and can cause respiratory depression.[5] This depression occurs because the rapid increase in blood pH and decrease in PaCO2 reduces the primary chemical drive for respiration at the brainstem. This complex risk-benefit profile positions THAM not as a first-line therapy, but as a specialized tool for specific, severe clinical situations where the risks of sodium bicarbonate (e.g., hypercapnia, hypernatremia) are deemed greater.

Table 2: Comparison of Tromethamine (THAM) and Sodium Bicarbonate for Metabolic Acidosis

Feature	Tromethamine (THAM)	Sodium Bicarbonate
Mechanism	Proton (H+) acceptor	Bicarbonate (HCO3−​) donor
pKa at 37°C	7.8 (more efficient at physiological pH)	6.1 (less efficient at physiological pH)
CO2 Generation	Decreases or does not generate CO2​	Generates CO2​
Primary Site of Action	Extracellular and intracellular	Primarily extracellular
Effect on Serum Na+	Decreases or no change	Increases
Effect on Serum K+	Generally no direct effect; may cause hypokalemia secondary to pH correction	Decreases (can cause hypokalemia)
Primary Route of Elimination	Renal (as protonated form)	Respiratory (as CO2​) and renal

Data compiled from sources.[5]

Pharmacokinetics

The pharmacokinetic profile of THAM is straightforward, reflecting its administration route and lack of metabolism.

• Absorption: As it is administered exclusively via the intravenous route, absorption is immediate and bioavailability is 100%.[3]
• Distribution: THAM distributes rapidly throughout the extracellular fluid. A key feature is that a significant portion (approximately 30% at a pH of 7.4) remains unionized.[3] This non-ionized fraction is lipid-soluble enough to slowly cross cell membranes, allowing it to penetrate the intracellular space and buffer intracellular acidosis. This is a notable advantage over bicarbonate, which is an ion and remains largely in the extracellular compartment. The exceptions to this intracellular penetration are erythrocytes and hepatocytes.[5]
• Metabolism: Tromethamine is a biologically inert compound and is not known to be metabolized by the body.[21]
• Excretion: The drug is rapidly and efficiently eliminated by the kidneys. More than 75% of an administered dose is excreted in the urine within eight hours, with excretion continuing for up to three days.[4] It is excreted in its protonated form, meaning it continues to carry excess acid out of the body. The renal clearance rate of Tromethamine is reported to be slightly greater than that of creatinine, indicating some degree of active secretion may occur in addition to glomerular filtration.[5]

Clinical Applications and Efficacy

The use of THAM is reserved for severe acidosis where conventional therapies are insufficient or contraindicated.

Approved Indications

The U.S. Food and Drug Administration (FDA) has approved Tromethamine injection for the prevention and correction of metabolic acidosis in specific, acute scenarios.[1] These indications include:

• Metabolic Acidosis Associated with Cardiac Bypass Surgery: It is used to correct acidosis that may occur during or immediately after cardiac bypass procedures.[4]
• Correction of Acidity of Stored Blood: Acid-citrate-dextrose (ACD) preserved blood becomes increasingly acidic during storage. THAM is added directly to this blood when it is used to prime a pump-oxygenator for cardiac surgery, thereby preventing the patient from receiving a large initial acid load.[4]
• Metabolic Acidosis Associated with Cardiac Arrest: Severe acidosis is a common consequence of cardiac arrest and can hinder resuscitation efforts. THAM can be administered to correct this acidosis and has been shown to help restore cardiac response to standard resuscitative measures when they have failed alone.[23]

Off-Label and Investigational Uses

Beyond its approved indications, THAM has been investigated and used in other critical care settings.

• Increased Intracranial Pressure (ICP): There is a growing body of evidence supporting the use of THAM to control elevated ICP in patients with traumatic brain injury (TBI) and malignant ischemic stroke.[5] Cerebral injury often leads to localized lactic acidosis, which contributes to cerebral edema and high ICP. THAM is thought to work by buffering this local acidosis and by causing cerebral vasoconstriction through a reduction in PaCO2, thereby lowering cerebral blood volume and ICP.[18] A systematic review concluded there is Oxford level 2b, GRADE B evidence for its efficacy in reducing ICP.[27] Clinical case reports suggest that early administration of THAM may reduce the need for more aggressive and higher-risk therapies such as therapeutic hypothermia and high-dose sedatives or paralytics.[26]
• Salicylate or Barbiturate Intoxication: While older literature cites THAM as a potential treatment for acidosis resulting from drug intoxication, its role is now considered limited and complex.[5] The standard of care for severe salicylate poisoning involves supportive measures, urinary alkalinization with sodium bicarbonate to enhance renal excretion, and hemodialysis for severe cases.[28] Notably, THAM is specifically contraindicated in neonates with salicylate intoxication.[4] Its use in adults is not a primary therapy and would only be considered in highly specific circumstances by a toxicologist.
• Other Potential Uses: THAM has also been used in the management of diabetic ketoacidosis, renal acidosis, during liver transplantation, and for the chemical dissolution (chemolysis) of certain types of renal calculi.[5]

Dosage and Administration

The administration of THAM requires meticulous attention to dosing calculations and infusion technique to maximize efficacy and minimize its significant risks.

Dosing Regimens

Dosage must be highly individualized based on the patient's weight, the severity of acidosis, and ongoing clinical and laboratory monitoring. The goal is to correct the acid-base derangement and raise blood pH to the normal range (7.35 to 7.45) without causing overtreatment and alkalosis.[24]

• General Dosing Formula: The most widely cited method for estimating the initial dose is based on the patient's base deficit, determined from blood gas analysis using a Siggaard-Andersen nomogram. The formula is: Dose(mLof0.3MTHAM)=BodyWeight(kg)×BaseDeficit(mEq/L)×1.1 The factor of 1.1 accounts for the distribution of the buffer in the extracellular fluid and a slight reduction in buffering capacity due to the acetic acid used to adjust the solution's pH.4
• Specific Indications (Adults):
• Cardiac Bypass Surgery: A typical single dose is 500 mL (150 mEq), though up to 1000 mL may be needed in severe cases. The maximum recommended dose is 500 mg/kg administered over a period of not less than one hour.[24]
• Cardiac Arrest: If the chest is open, 2 to 6 g (62 to 185 mL of 0.3 M solution) is injected directly into the ventricular cavity. If the chest is closed, 3.6 to 10.8 g (111 to 333 mL of 0.3 M solution) is injected into a large peripheral vein.[24] It must not be injected into the cardiac muscle.[4]
• Pediatric Dosing:
• For metabolic acidosis associated with respiratory distress syndrome (RDS) in neonates and infants, an initial dose of 1 mL/kg for each pH unit below 7.4 is suggested.[4]

Administration Guidelines

Proper administration technique is critical to prevent serious local complications.

• Route: THAM is administered by slow intravenous infusion.[3] Rapid infusion should be avoided as it increases the risk of hypoglycemia and respiratory depression.[4]
• Vascular Access: Due to the solution's high alkalinity (pH ~8.6), it is a potent chemical irritant. It must be infused through a large needle or an indwelling catheter placed securely within the largest available vein (e.g., a large antecubital vein) to ensure rapid dilution and minimize contact with the vessel wall.[3]
• Extravasation Warning: Perivascular infiltration (extravasation) is a serious complication that can cause severe inflammation, chemical phlebitis, venospasm, and ultimately tissue necrosis and sloughing.[3] The infusion site must be monitored closely.
• Monitoring: Continuous and vigilant monitoring is mandatory during THAM therapy. This includes frequent determinations of blood pH, PaCO2, electrolytes (especially potassium), and blood glucose levels, as well as urinary output.[5]

Safety Profile of THAM

The potent therapeutic effects of THAM are balanced by a profile of serious potential adverse effects that limit its use to critical care settings where patients can be closely monitored.

Adverse Effects

• Respiratory: The most significant systemic risk is respiratory depression. This is a direct consequence of its mechanism of action—the rapid increase in blood pH and decrease in PaCO2 can suppress the central respiratory drive. The risk is highest in patients with pre-existing chronic hypoventilation or those receiving other respiratory depressant medications.[3]
• Metabolic: Hypoglycemia can occur, especially in premature and full-term neonates, and with rapid or large-dose infusions in adults.[5] Hyperkalemia has been cited as a potential risk, though other data suggest THAM does not directly alter potassium levels.[16]
• Local and Vascular: As noted, extravasation is a major concern, leading to severe tissue damage.[5] Even with proper placement, chemical phlebitis and venospasm can occur.[6]
• Hepatic: In neonates, infusion of THAM via low-lying umbilical venous catheters has been associated with hepatocellular necrosis.[6]
• General: Overhydration and solute overload from the infused volume can lead to dilution of serum electrolytes, congested states, or pulmonary edema.[6] Fever and infection at the injection site are also possible.

Contraindications and Precautions

• Absolute Contraindications: THAM is contraindicated in patients with uremia (high levels of urea in the blood) and anuria (inability to produce urine), as the drug is entirely dependent on renal excretion for elimination.[4]
• Contraindications in Neonates: In addition to the above, it is specifically contraindicated in neonates with chronic respiratory acidosis and salicylate intoxication.[4]
• Precautions: Extreme caution is necessary in patients with any degree of renal impairment.[6] If THAM is used in a patient with co-existing respiratory acidosis, mechanical ventilatory support is strongly recommended to manage ventilation and PaCO2 levels.[3]

Drug and Disease Interactions

• Drug Interactions: Specific drug interaction data for Tromethamine as an API is limited. An increase in the serum concentration of the antiarrhythmic drug Flecainide has been reported.[2] As an alkalinizing agent, it may theoretically decrease the excretion of basic drugs (e.g., amphetamines, quinidine) and increase the excretion of acidic drugs.[4] A comprehensive drug interaction database identifies 33 potential interactions, primarily classified as moderate or minor in severity.[37]
• Disease Interactions: The primary disease interactions involve conditions that would be exacerbated by the drug's properties. These include renal dysfunction (impaired clearance), conditions with altered CO2 tension or ventilation (risk of respiratory depression), existing acid/base imbalances (risk of overcorrection to alkalosis), and disorders of glucose metabolism (risk of hypoglycemia).[37]

Overdose Management

• Symptoms: Overdose is a direct extension of the drug's therapeutic effects and is caused by too-rapid administration or excessive dosage. Symptoms include metabolic alkalosis, hypoglycemia, overhydration, and solute overload.[39] Signs may include a rapid heart rate, confusion, weakness, or seizure.[36]
• Management: There is no specific antidote. Treatment is supportive and symptomatic. The infusion must be discontinued immediately, and the patient's clinical status, including acid-base balance, electrolytes, and glucose, must be evaluated. Appropriate countermeasures should be instituted to correct the specific derangements.[39]

Tromethamine as a Pharmaceutical Excipient and Salt

While Tromethamine has a niche but important role as an active therapeutic agent, its most widespread and common use in modern medicine is as a pharmaceutical excipient. In this context, it is chemically vital for drug formulation but is considered pharmacologically inert. A failure to recognize this distinction can lead to a dangerous misinterpretation of drug safety profiles, an issue best illustrated by the case of Ketorolac Tromethamine.

Rationale for Use in Drug Formulation

In pharmaceutical development, many active drug molecules are acidic in nature, which can limit their water solubility, stability, or suitability for certain dosage forms. A common and effective formulation strategy is to react the acidic drug with a basic compound to form a salt. Tromethamine, with its primary amine group, is a biologically compatible organic base that is frequently used for this purpose.[9]

Forming a tromethamine salt of an acidic API can confer several advantages:

• Enhanced Aqueous Solubility: The salt form is often many times more soluble in water than the free acid form of the drug. This is critical for developing stable, high-concentration liquid formulations, especially for intravenous injection.[7]
• Improved Stability: The salt form can be more chemically stable than the parent drug, leading to a longer shelf life.
• Modified Bioavailability: By improving solubility and dissolution rate, the salt form can lead to faster and more consistent absorption of the active drug after administration.

In these formulations, the Tromethamine moiety serves a purely pharmaceutical function. The amount present is stoichiometric to the active drug and is far below the doses required to exert any of its own systemic buffering or diuretic effects.

Case Study: Ketorolac Tromethamine (NSAID)

The case of Ketorolac Tromethamine provides the most critical and illustrative example of the need to differentiate the properties of an active drug from its salt-forming counter-ion.

Introduction and Disambiguation

It must be unequivocally stated that the pharmacological activity, clinical indications, and extensive safety warnings detailed in this section are attributable entirely to the KETOROLAC moiety. Tromethamine is present only to form the water-soluble salt that allows Ketorolac to be formulated as an injection.[9] The severe risks of gastrointestinal bleeding, cardiovascular events, and renal toxicity are well-established class effects of nonsteroidal anti-inflammatory drugs (NSAIDs), and specifically of Ketorolac. Attributing these effects to Tromethamine is a pharmacological error with serious implications for patient safety. This case study is presented to provide a clear, evidence-based separation of the two entities.

Clinical Pharmacology and Indications of Ketorolac

• Mechanism of Action: Ketorolac is a potent, non-selective NSAID. Its mechanism involves the inhibition of the cyclooxygenase (COX) enzymes, COX-1 and COX-2. By blocking these enzymes, Ketorolac prevents the conversion of arachidonic acid into prostaglandins, which are key mediators of pain, inflammation, and fever.[40] The desired analgesic and anti-inflammatory effects are primarily due to COX-2 inhibition, while the inhibition of the constitutively active COX-1 enzyme in gastric mucosa and platelets is responsible for its most serious gastrointestinal and bleeding risks.[40] The biological activity is associated with the S-enantiomer of the racemic mixture.[40] Ketorolac possesses no sedative or anxiolytic properties.[41]
• Indications: Ketorolac Tromethamine is indicated for the short-term (total duration not to exceed 5 days) management of moderately severe acute pain that requires analgesia at the opioid level.[10] Its use is typically initiated with an intravenous (IV) or intramuscular (IM) injection in a postoperative setting, with oral tablets used only as continuation therapy if necessary.[10] It is explicitly not indicated for minor or chronic painful conditions.[10]
• Off-Label Use: Despite not being FDA-approved for this purpose, Ketorolac is frequently used off-label as an abortive therapy for acute migraine headaches, often administered as an injection in emergency departments.[46]

Pharmacokinetics (ADME) of Ketorolac

The pharmacokinetic profile of Ketorolac is characterized by rapid absorption, high protein binding, and renal elimination.

• Absorption: Ketorolac is rapidly and completely absorbed following both oral and IM administration. The bioavailability of the oral and IM forms is equivalent to that of an IV bolus.[40] Peak plasma concentrations ( Cmax​) are reached within approximately 30 to 60 minutes after IM or oral dosing.[40] Food can delay the rate of absorption but does not affect the overall extent.[40]
• Distribution: Ketorolac is highly bound (>99%) to plasma proteins, primarily albumin.[40] It has a small mean apparent volume of distribution ( Vβ​) of approximately 13 liters, indicating that it does not distribute extensively into tissues and remains largely within the vascular and extracellular compartments.[41]
• Metabolism: The drug is extensively metabolized in the liver. The primary metabolic pathways are hydroxylation to form p-hydroxyketorolac (an inactive metabolite) and conjugation with glucuronic acid.[40]
• Excretion: Elimination is primarily renal. Approximately 92% of a dose is recovered in the urine, with about 60% as unchanged Ketorolac and 40% as metabolites. A small fraction (~6%) is eliminated in the feces.[40] Ketorolac is administered as a racemate, and the enantiomers have different clearance rates. The pharmacologically active S-enantiomer has a half-life of approximately 2.5 hours, while the R-enantiomer has a half-life of about 5 hours. Consequently, the S-enantiomer is cleared about twice as fast.[40] The overall half-life of the racemate is in the range of 5 to 6 hours.[43]

Table 3: Key Pharmacokinetic Parameters of Ketorolac by Route of Administration in Adults

Parameter	30 mg IV Bolus	30 mg IM	10 mg Oral
Bioavailability	100%	100%	100%
Tmax (minutes)	~2.9	~44	~44
Cmax (mcg/mL)	~4.65	~2.42	~0.87
Volume of Distribution (Vβ​)	~0.210 L/kg	~0.175 L/kg	~0.175 L/kg
Plasma Protein Binding	>99%	>99%	>99%
Half-life (racemate)	~5-6 hours	~5-6 hours	~5-6 hours
Primary Elimination	Renal (~92%)	Renal (~92%)	Renal (~92%)

Data compiled from sources.[40]

Safety Profile of Ketorolac

The use of Ketorolac is limited by a severe safety profile, which has led to multiple FDA-issued boxed warnings. These warnings highlight risks that are far greater than those associated with over-the-counter NSAIDs like ibuprofen.

Table 4: Summary of Boxed Warnings and Major Adverse Effects of Ketorolac Tromethamine

Risk Category	Key Warning Summary	Absolute Contraindications
Gastrointestinal	Can cause serious and potentially fatal peptic ulcers, gastrointestinal bleeding, and perforation at any time during use, without warning symptoms. Risk increases with dose and duration.	Active peptic ulcer disease; recent or history of GI bleeding/perforation.
Cardiovascular	Increased risk of serious and potentially fatal cardiovascular thrombotic events, including myocardial infarction (MI) and stroke. Risk may occur early in treatment and increase with duration.	Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
Renal	Can lead to acute renal failure. Risk is increased in volume-depleted patients, the elderly, and those with pre-existing renal impairment.	Advanced renal impairment; patients at risk for renal failure due to volume depletion.
Bleeding	Inhibits platelet function, increasing the risk of bleeding.	Suspected or confirmed cerebrovascular bleeding; hemorrhagic diathesis; incomplete hemostasis; high risk of bleeding; prophylactic use before major surgery.
General Use	Total duration of use (all formulations combined) must not exceed 5 days. Not for minor or chronic pain. Concomitant use with other NSAIDs or aspirin is contraindicated due to cumulative risk.	Hypersensitivity to ketorolac, aspirin, or other NSAIDs; use during labor and delivery; neuraxial (epidural/intrathecal) administration.

Data compiled from sources.[10]

• Common Adverse Effects: The most frequently reported adverse effects (incidence >10%) are headache, nausea, dyspepsia, and abdominal pain.[10] Other common effects (1-10%) include dizziness, drowsiness, edema, hypertension, increased bleeding time, injection site pain, rash, and tinnitus.[10]
• Drug Interactions: Ketorolac interacts with hundreds of medications. The most critical interactions involve an increased risk of bleeding when combined with anticoagulants (e.g., warfarin, heparin) or other antiplatelet agents.[55] Concomitant use with other NSAIDs or aspirin is contraindicated.[10] It can reduce the efficacy of diuretics and antihypertensives (e.g., ACE inhibitors) and increase the toxicity of drugs like methotrexate, lithium, and cyclosporine.[57]

Other Pharmaceutical Formulations

The use of Tromethamine as a salt-forming agent is not limited to Ketorolac. Its utility is demonstrated across various therapeutic classes, further cementing its role as a key excipient in pharmaceutical formulation. Examples include:

• Carboprost Tromethamine (Hemabate): A synthetic prostaglandin analogue used to control postpartum hemorrhage by stimulating uterine contractions.[59]
• Fosfomycin Tromethamine (Monurol): An oral antibiotic used for the treatment of acute uncomplicated urinary tract infections.[62]
• Fostemsavir Tromethamine (Rukobia): An antiretroviral drug used in combination therapy for multi-drug resistant HIV-1 infection.[64]
• Dinoprost Tromethamine: A prostaglandin used in veterinary medicine for luteolysis (regression of the corpus luteum) in cattle, sows, and mares.[66]

Use in Special Populations

The clinical use and safety considerations for both Tromethamine (THAM) and Ketorolac Tromethamine differ significantly across special patient populations, including pregnant or lactating women, children, and the elderly.

Pregnancy and Lactation

• Tromethamine (THAM): The safety of THAM in pregnancy has not been established. It is assigned FDA Pregnancy Category C, indicating that animal reproduction studies have not been conducted and there are no adequate and well-controlled studies in humans. Therefore, it should be administered to a pregnant woman only if clearly needed.[6] It is not known whether Tromethamine is excreted in human milk, and caution is recommended if it is administered to a nursing mother.[6]
• Ketorolac Tromethamine: The use of Ketorolac is subject to severe restrictions in pregnancy and lactation. It is contraindicated during labor and delivery because its prostaglandin-inhibiting effect may adversely affect fetal circulation (e.g., premature closure of the ductus arteriosus) and inhibit uterine contractions, increasing the risk of uterine hemorrhage.[43] Use of NSAIDs, including Ketorolac, at or after 20 weeks of gestation may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.[68] Although studies have shown that levels of Ketorolac in breast milk are low after oral administration, the manufacturer contraindicates its use during breastfeeding. This is due to the drug's potent antiplatelet activity and the potential risk of causing gastrointestinal bleeding and other adverse effects in the nursing infant.[40]

Pediatric Use

• Tromethamine (THAM): The safety and effectiveness of THAM in pediatric patients are not based on formal clinical trials but on over 30 years of clinical experience documented in medical literature.[6] It has been used to treat severe metabolic acidosis in neonates and infants, particularly in cases with concurrent respiratory acidosis, because it does not raise PaCO2 like bicarbonate does.[6] However, due to its osmotic effects and the significant risk of causing hypoglycemia in premature and full-term neonates, sodium bicarbonate is often the preferred agent for treating acidosis associated with Respiratory Distress Syndrome (RDS).[6] Specific pediatric dosing formulas based on weight and base deficit or pH are available.[4] THAM is contraindicated in neonates with chronic respiratory acidosis and salicylate intoxication.[4]
• Ketorolac Tromethamine: Ketorolac is not approved by the FDA for use in pediatric patients under the age of 16.[10] While some off-label dosing information for children aged 2-16 years exists in reference materials (e.g., single dose of 0.5 mg/kg IV/IM), any use in this population must be determined and closely supervised by a physician due to the high risk of severe adverse effects.[72]

Geriatric Use

• Tromethamine (THAM): Clinical studies of THAM did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. However, general guidance recommends that dose selection for an elderly patient should be cautious, typically starting at the low end of the dosing range.[6] This caution reflects the greater frequency of decreased hepatic, renal, or cardiac function in this population. Since Tromethamine is substantially excreted by the kidney, the risk of toxic reactions is greater in patients with impaired renal function, a common condition in the elderly. Monitoring of renal function may be useful.[6]
• Ketorolac Tromethamine: Elderly patients are at a significantly increased risk for serious adverse effects from Ketorolac, and its use requires extreme caution and modified dosing. They are more sensitive to the dose-related adverse effects of NSAIDs, particularly serious gastrointestinal bleeding, ulceration, and perforation.[43] The risk of renal and cardiovascular complications is also elevated.[73] Consequently, the maximum daily dose for patients aged 65 or older is reduced by 50% compared to younger adults: the total daily dose should not exceed 60 mg for IV or IM administration (vs. 120 mg) and 40 mg for oral administration.[10] The guiding principle is to use the lowest effective dose for the shortest possible duration, with the total treatment period never exceeding 5 days.[74]

Regulatory Status and Approval History

The regulatory pathways and market availability of products containing Tromethamine reflect its dual role as both a niche API and a common excipient.

United States (FDA)

• THAM (Tromethamine Injection): The original New Drug Application (NDA 013025) for Tham Solution, held by Hospira, Inc., was approved on December 16, 1965, for the prevention and correction of metabolic acidosis.[75] The product has faced periods of discontinuation by manufacturers; for instance, Pfizer notified the FDA of its discontinuation in February 2018.[17] However, in July 2019, the FDA officially determined that THAM Solution was not withdrawn from sale for reasons of safety or effectiveness. This crucial determination allows the FDA to approve Abbreviated New Drug Applications (ANDAs) from other manufacturers, ensuring that generic versions of this medically necessary product can remain available.[75] Generic tromethamine injection solutions are currently marketed in the U.S..[76]
• Ketorolac Tromethamine: Numerous formulations containing Ketorolac Tromethamine have been approved by the FDA, highlighting the success of Tromethamine as a salt-forming agent.
• Injectable Solution: The original Reference Listed Drug (RLD) was Toradol, from Roche Palo Alto.[45] Following its success, many generic versions have received ANDA approval, including those from Alembic Pharma (approved November 2022) and Cycle Pharmaceuticals (approved September 2017).[45]
• Oral Tablets: An ANDA for Ketorolac Tromethamine tablets from Lemmon Company was approved on May 16, 1997.[78]
• Ophthalmic Solution: Acuvail (ketorolac tromethamine 0.45%) was first approved on July 22, 2009, for the treatment of pain and inflammation following cataract surgery.[79]
• Nasal Spray: Sprix (ketorolac tromethamine) nasal spray was first approved on May 14, 2010, for the short-term management of moderate to severe pain.[80]

European Union (EMA)

• The European Medicines Agency (EMA) has authorized several medicinal products that utilize Tromethamine as a salt-forming excipient. A notable example is Rukobia, which contains fostemsavir tromethamine, an antiretroviral medication for HIV-1.[64] The EMA also recognizes fosfomycin tromethamine as a critical antibiotic.[62]
• In the United Kingdom (which follows harmonized European standards), the Summary of Product Characteristics (SmPC) for Ketorolac Trometamol injection specifies its indication for the short-term management (maximum of two days) of moderate to severe acute post-operative pain. Treatment must be initiated in a hospital setting.[81]
• The provided documentation does not contain evidence of a centrally authorized, standalone THAM-like product for metabolic acidosis by the EMA, although clinical literature from Europe indicates its use and comparison with sodium bicarbonate in ICU settings.[20]

Australia (TGA)

• The Therapeutic Goods Administration (TGA) maintains the Australian Register of Therapeutic Goods (ARTG), which lists products approved for supply in Australia.
• The ARTG includes multiple products containing Ketorolac Trometamol. For example, TORADOL 30mg/1mL injection ampoule is listed with ARTG ID 34357, first registered on April 2, 1992.[84] Its approved indication is for the short-term (not to exceed five days) management of moderately severe acute pain following surgical procedures.[85] Several generic versions are also available, though some have been discontinued for commercial reasons.[87]
• Other drugs utilizing Tromethamine as a salt are also registered, such as Hemabate (carboprost trometamol) for postpartum hemorrhage and Monurol (fosfomycin trometamol) for urinary tract infections.[61]
• Similar to the EMA, the provided materials do not indicate the registration of a standalone THAM solution for metabolic acidosis with the TGA.[88]

Conclusion and Expert Insights

This comprehensive analysis of Tromethamine (DB03754) reveals a molecule of profound duality, whose identity in pharmacology is split between two distinct and non-interchangeable roles. On one hand, as the active ingredient in THAM solution, it is a potent, physiologically superior buffering agent for severe metabolic acidosis. Its unique CO2-sparing mechanism and ability to penetrate intracellularly provide clear advantages over sodium bicarbonate in select critical care scenarios, particularly those involving respiratory compromise. However, this efficacy is counterbalanced by a significant risk profile, including respiratory depression and severe local tissue toxicity, which rightfully relegates its use to a niche, high-acuity environment under the supervision of specialists.

On the other hand, and far more pervasively, Tromethamine functions as a foundational tool in pharmaceutical formulation. As a salt-forming excipient, it is chemically indispensable for enabling the solubility, stability, and delivery of numerous acidic active drugs, from the NSAID Ketorolac to antibiotics like Fosfomycin and antiretrovirals like Fostemsavir. In this role, it is pharmacologically inert, serving as a silent partner to the active moiety.

The central and most critical conclusion of this report is the imperative to prevent the "pharmacological identity theft" of Tromethamine. The sheer volume of safety data, including multiple FDA-issued boxed warnings, associated with Ketorolac Tromethamine creates a significant potential for confusion. A healthcare professional or researcher who fails to distinguish the salt from the API could erroneously attribute the life-threatening risks of Ketorolac—gastrointestinal perforation, myocardial infarction, stroke—to the Tromethamine molecule itself. This misconception could lead to an inaccurate assessment of the risks of using THAM solution, potentially withholding a life-saving therapy, or conversely, underestimating the true dangers of Ketorolac.

Therefore, it is recommended that clinicians, pharmacists, and all healthcare providers maintain a rigorous conceptual separation:

1. Tromethamine (THAM) is a high-risk, high-reward alkalizing agent for specific, severe acidosis. Its risks are respiratory depression, hypoglycemia, and tissue necrosis.
2. ** Tromethamine** is a salt formulation where the safety profile is dictated entirely by the active drug.

Failure to uphold this distinction represents a tangible risk to patient safety. This report serves as a definitive resource to establish and reinforce this critical clarity, ensuring that Tromethamine, in both its forms, is understood and utilized with the precision and caution that modern medicine demands.

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