Description
Ketorolac tromethamine is a nonsteroidal antiinflammatory agent that exhibits analgesic
and antipyretic activity. The compound is effective in the management of moderate to
severe postoperative pain. It is, however, the first of this type of agent to be
administered parenterally as an analgesic and is specifically indicated for intramuscular
injection. Ketorolac represents a useful alternative to the narcotic analgesics due to its
lack of abuse potential.
Description
Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) and a non-selective COX inhibitor (IC
50 = 20 nM for both COX-1 and COX-2). It prevents increases in paw swelling, increases paw withdrawal latency in a hot-plate test, and decreases prostaglandin E
2 (PGE
2) levels in paw tissue in a mouse model of carrageenan-induced inflammation when administered at a dose of 30 mg/kg. Ketorolac is a racemic mixture containing the active (S)-ketorolac and inactive (R)-ketorolac enantiomers. Formulations containing ketorolac have been used to manage postoperative pain and as ophthalmic solutions to treat ocular pain and inflammation.
Chemical Properties
A carboxylic acid derivative nonsteroidal antiinflammatory agent, ketorolac tromethamine occurs as an off-white crystalline powder with a pKa of 3.54 (in water). More than 500 mg are soluble in one mL of water at room temperature. The commercially available injection is a clear, slightly yellow solution with a pH of 6.9 – 7.9. Sodium chloride is added to make the solution isotonic. Ketorolac tromethamine may also be known as RS-37619-00- 31-3; many trade names are available.
Chemical Properties
Off-White to Pale Yellow Solid
Uses
Ketorolac is used primarily for its analgesic effects for short-term treatment of mild to moderate pain in dogs and rodents. The duration of analgesic effect in dogs is about 8 – 12 hours, but because of the availability of approved, safer NSAIDs for dogs, its use is questionable.
Uses
Analgesic;Cyclooxygenase Inhibitor
Uses
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
Indications
Ketorolac tromethamine is a pyrrolol-pyrrole nonsteroidal anti- inflammatory agent that inhibits prostaglandin formation. Prostaglandins mediate inflammation within the eye by disrupting the blood-aqueous barrier, inducing vasodilation and increasing intraocular pressure. Prostaglandins may also cause iris sphincter constriction (miosis) independent of cholinergic mechanisms. Ketorolac tromethamine is marketed for use before cataract extraction in human patients (to prevent miosis during surgery) and for control of post surgical inflammation, especially following cataract surgery. It is also approved for management of conjunctivitis associated with seasonal allergy in people. In veterinary medicine, ketorolac tromethamine is primarily used to control surgical or nonsurgical uveitis particularly in cases with concurrent corneal bacterial infection or ulceration when topical corticosteroids are contraindicated. It is also used in diabetic patients, especially smaller patients, adversely affected by systemic uptake of topically applied corticosteroids. Nonsteroidal agents like ketorolac tromethamine can be combined with topical steroids in patients with severe uveal inflammation.
Definition
ChEBI: An organoammonium salt resulting from the mixture of equimolar amounts of ketorolac and tromethamine (tris). It has potent non-sedating analgesic and moderate anti-inflammatory effects. It is used in the short-term management of post-operative pain, and in
eye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis.
Manufacturing Process
Preparation of 2-bromo-4-chloro-N-methyl-N-phenylbutanamide
4-Chlorobutanoyl chloride (62 g, 440 mmol) and phosphorus tribromide (3 g)
were added to a distillation flask, and heated to 90°C. Bromine (77.5 g, 485
mmol) was added over eight hours, with the solution being allowed to
decolorize between additions. After the addition was complete, and the
solution decolorized, a vacuum was slowly applied, and the acid gases and
phosphorus tribromide scrubbed. Unreacted starting material was distilled at
98-100°C/22 mm Hg, and the temperature slowly increased to 105°C, where
a mixture of 2-bromo-4-chlorobutanoyl chloride and 2-bromo-4-
chlorobutanoyl bromide began to distill. Pure 2-bromo-4-chlorobutanoyl
bromide distilled at approximately 108°C. The combined yield of 2-bromo-4-
chlorobutanoyl chloride and 2-bromo-4-chlorobutanoyl bromide was 100.5 g,
with a bromide/chloride ratio of approximately 6:1. The mixture of 2-bromo-
4-chlorobutanoyl bromide and chloride is directly usable in the preparation of
the butanamide, if desired, or may be separated and either component used.
2-Bromo-4-chlorobutanoyl bromide (300 mmol) was added to a solution of Nmethylaniline (320 mmol) and triethylamine (330 mmol) in toluene (340 mL).
The reaction was exothermic, and the mixture was cooled to maintain the
temperature at about 40°C. After the addition was complete, the resulting
mixture was stirred for 30 minutes, 150 mL water was added, and the mixture
was stirred further. The aqueous and organic phases were separated, and the
organic phase was washed with 5% hydrochloric acid and with water. The
toluene was evaporated completely under vacuum to yield 86.3 g 2-bromo-4-
chloro-N-methyl-N-phenylbutanamide (98% yield, approximately 95-96%
pure).
A solution of methylmagnesium chloride in butyl diglyme (4.0 L, 2.8 M, 11.2
mol, 2.8 equivalents with respect to 2-bromo-4-chloro-N-methyl-Nphenylbutanamide) was added to a 12 L 4-necked round bottom flask fitted
with a mechanical stirrer and two 1 L addition funnels, under a nitrogen
atmosphere. 2-Bromo-4-chloro-N-methyl-N-phenyl-butanamide (3.98 mol)
was added to the first addition flask, and pyrrole (3.04 equivalents with
respect to 2-bromo-4-chloro-N-methyl-N-phenyl-butanamide) was added to
the second. The pyrrole was slowly added to the methylmagnesium
chloride/butyl diglyme solution at 45-50°C over 3 hours. The resulting viscous
mixture was cooled to 25°C and stirred for 30 min. 2-Bromo-4-chloro-Nmethyl-N-phenylbutanamide was added to the resulting mixture over a period
of 2 hours at 25-30°C, and the resulting solution was stirred for another 3
hours.
The dark colored reaction mixture was transferred into 5.76 mol 2 N
hydrochloric acid with rapid stirring for 1 hour. The aqueous phase was
removed, and 0.8 L 15 weight % ammonium chloride in water was added to
the organic phase. The resulting mixture was stirred at 35-40°C for 10 min,
the aqueous phase then removed, and hexanes (2.4 L) added. The resulting
suspension was cooled to -20°C and maintained at that temperature for a few
minutes. The precipitate was filtered in a 300 mL sintered glass funnel and
washed with hexanes (1 L). Drying of the solid under vacuum at 25-30°C
yielded 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide (81% yield).
A solution of 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide in toluene
was added dropwise at 85°C over 40 min to 1 hour to a stirred suspension of
ALIQUAT 336 (phase transfer catalyst, 2 mol % with respect to
pyrrolylbutanamide) and granular sodium hydroxide (3 equivalents) in toluene
(50 mL). After the addition was complete, the suspension was stirred under a
nitrogen atmosphere at a temperature of 85°C for 30 min, then cooled to
35°C. Cooled water (200 mL) was rapidly added to the mixture and stirred for
15 min at 25°C. The solution was rinsed with water and the layers were
separated. The organic layer was washed with water, then distilled under
atmospheric pressure to recover the toluene and water. The resultant solution
was cooled to 50°C and allowed to crystallize after the addition of hexane and
a seed crystal. The suspension was cooled to 5°C and stirred for 15 minutes.
The resultant precipitate was filtered, washed with 100 mL of hexane, and
dried under vacuum at 25°C to yield approximately 38 g (63%) N-methyl-Nphenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide. This solid was recrystallized
from toluene to yield colorless crystals of N-methyl-N-phenyl-2,3-dihydro-1Hpyrrolizine-1-carboxamide, melting point 112-112.5°C.
Benzoyl chloride (4.3 mol) was added dropwise to a rapidly stirring mixture of
piperidine (4.3 mol), sodium hydroxide (4.7 mol), toluene (1 L), and water
(1.7 L) over a period of 70 min. After the addition was complete, the mixture
was stirred at 25°C for one hour. The organic and aqueous phases were
separated, and the organic phase was washed with 2 N hydrochloric acid,
concentrated by rotary evaporation, and distilled under vacuum to yield
benzoylpiperidine as a colorless liquid which crystallized on standing (95%
yield, boiling point 169-171°C).
N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (480 mmol) and
toluene (100 mL) were added to a mixture of benzoylpiperidine (1.05 eq.) and
phosphorus oxychloride (0.96 eq.), which had been stirred at 25°C for 1 hour.
An additional 100 mL toluene was added. The suspension was heated to at
40-45°C for 4 hours. The resulting syrup was transferred into a rapidly stirring
solution of sodium hydroxide (4.5 mol), piperidine (1.0 mL), and water (650
mL) at 25-35°C and the mixture was stirred for 1 hour. A mixture of toluene
(100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was added
to the reaction flask, and the reaction mixture was stirred at 25°C for 1 hour.
The suspension was then heated to 75°C and the layers were separated. The
organic layer was cooled to 60°C and hexane (100 mL) was slowly added, and
the solution slowly stirred and cooled to -15°C. The precipitate was filtered,
washed with toluene/hexane (2:1) and then with hexane, and dried under
vacuum at 25°C to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1Hpyrrolizine-1-carboxamide (83.5% yield).
Preparation of ketorolac tromethamine.
A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-
1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80
mL methanol was refluxed for 5 hours. The mixture was cooled to room
temperature, stirred under nitrogen for sixteen hours, and then diluted with
80 mL of water. The mixture was extracted with toluene, and the aqueous and
organic phases were separated. The aqueous phase was acidified with 6 N
hydrochloric acid. The resulting precipitate was extracted with
dichloromethane. The combined extract was treated with activated clay
decolorizing agent (4.5 g) for 30 minutes, filtered, and concentrated byatmospheric distillation. Hexane was added and the mixture allowed to cool to
0-5°C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
(ketorolac) was collected by filtration, washed with 100 mL of
hexane/dichloromethane (7:3), and dried at 60°C under vacuum, to yield
ketorolac (83.4% yield), melting point 152-162°C. Ketorolac (25 g) and 11.9
g tromethamine were dissolved in 175 mL methanol. The solution was filtered
and the filter washed with 40 mL methanol. The resulting solution was
concentrated by vacuum distillation. Ethylacetate was added to precipitate the
ketorolac tromethamine; and the solution was cooled to room temperature for
two hours, cooled further to 0°C, and filtered. The precipitate was washed
with ethyl acetate/methanol (4:1) and dried under vacuum at a temperature
of 65°C, to yield ketorolac tromethamine (95% yield).
brand name
Acular (Allergan); Toradol (Roche);Toradol IM.
Therapeutic Function
Analgesic, Antiinflammatory
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards. Ketorolac Tromethamine belongs to the class of non-steroidal anti-inflammatory drugs, and its mode of action involves the inhibition of the bodily synthesis of prostagladins. It exhibits anti-inflammatory, antipyretic and analgesic effects.
Biochem/physiol Actions
Ketorolac is a non-steroidal agent that possesses moderate anti-inflammatory activity and is also a potent analgesic. It shows superior analgesic efficacy to that of the opioid analgesics like morphine in patients with moderate to severe postsurgical pain. It inhibits prostaglandin synthesis and platelet aggregation induced by arachidonic acid and collagen. It is a dual COX-1/COX-2 inhibitor.
Pharmacology
Like other NSAIDs, ketorolac exhibits analgesic, antiinflammatory, and antipyretic activity probably through its inhibition of cyclooxygenase with resultant impediment of prostaglandin synthesis. Ketorolac may exhibit a more potent analgesic effect than some other NSAIDs. It inhibits both COX-1 and COX-2 receptors.
Pharmacokinetics
After oral administration, ketorolac is rapidly absorbed; in dogs peak levels occur in about 50 minutes and oral bioavailability is about 50 – 75%.
Ketorolac is distributed marginally through the body. It does not appear to cross the blood-brain barrier and is highly bound to plasma proteins (99%). The volume of distribution in dogs is reported to be about 0.33 – 0.42 L/kg (similar in humans). The drug does cross the placenta.
Ketorolac is primarily metabolized via glucuronidation and hydroxylation. Both unchanged drug and metabolites are excreted mainly in the urine. Patients with diminished renal function will have longer elimination times than normal. In normal dogs, the elimination half-life is between 4 – 8 hours.
Side effects
The manufacturer indicates that ketorolac tromethamine does not enhance the spread of preexisting corneal fungal, viral or bacterial infections in animal models. Ketorolac tromethamine does not in and of itself induce postoperative pressure elevation other then that which frequently follows cataract extraction in people and animals.
Safety Profile
Ketorolac does cross the placenta. In humans, the FDA categorizes this drug as category C for use during the first two trimesters of pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In humans, all NSAIDs are assigned to category D for use during pregnancy during the third trimester or near delivery (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.) Most NSAIDs are excreted in milk. Ketorolac was detected in human breast milk at a maximum milk:plasma ratio of 0.037. It is unlikely to pose great risk to nursing offspring.
Veterinary Drugs and Treatments
Ketorolac is used primarily for its analgesic effects for short-term
treatment of mild to moderate pain in dogs and rodents. The duration
of analgesic effect in dogs is about 8 – 12 hours, but because of
the availability of approved, safer NSAIDs for dogs, its use is questionable.
Overdosage
Limited information is available. The oral LD50 is 200 mg/kg in mice. GI effects, including GI ulceration are likely in overdoses in small animals. Metabolic acidosis was reported in one human patient. Consider GI emptying in large overdoses; patients should be monitored for GI bleeding. Treat ulcers with sucralfate; consider giving misoprostol early.
Precautions
Ketorolac is relatively contraindicated in patients with a history of, or preexisting, hematologic, renal or hepatic disease. It is contraindicated in patients with active GI ulcers or with a history of hypersensitivity to the drug. It should be used cautiously in patients with a history of GI ulcers, or heart failure (may cause fluid retention), and in geriatric patients. Animals suffering from inflammation secondary to concomitant infection, should receive appropriate antimicrobial therapy. Because ketorolac has a tendency to cause gastric erosion and ulcers in dogs, long-term use (>3 days) is not recommended in this species.
