Ketorolac
Encyclopedia
Ketorolac or ketorolac tromethamine (marketed under the trademarks Toradol and Acular in the US, where generics
have also been approved, and various other brand names "Minolac" (ACI Pharmaceuticals) around the world) is a non-steroidal anti-inflammatory drug
(NSAID) in the family of heterocyclic
acetic acid
derivative
, often used as an analgesic
. Ketorolac acts by inhibiting
the bodily synthesis
of prostaglandin
s. Ketorolac in its oral (tablet
or capsule) and intramuscular
(injected
) preparations is a racemic mixture of both (S)-(−)-ketorolac, the active isomer
, and (R)-(+)-ketorolac. An ophthalmic (i.e., eye-drop
) solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies
.The FDA has approved an intranasal formulation of ketorolac tromethamine (Sprix Nasal Spray) for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.
for short-term management of moderate to severe pain. Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use. In the UK, treatment should be initiated only in hospital. Maximum duration of treatment should not exceed five days for tablets (per package insert), or two days for continuous daily dosing with intravenous or intramuscular formulations. The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (glaucoma
) is to be avoided.
ulcers
, bleeding and perforation; renal (kidney
) events ranging from interstitial nephritis
to complete kidney failure; hemorrhage, and hypersensitivity reactions
.
As with other NSAIDs, fluid and solute retention
and edema
have been reported with ketorolac. Ketorolac also elevates liver protein levels.
When administered intravenously
through the same IV catheter
as morphine
, the two drugs have been known to sometimes combine to form a precipitate
in the IV, which may block the line. Line flushing with a syringe
of saline solution can push the blockage through.
Ketorolac is not recommended for pre-operative
analgesia or co-administration with anesthesia
because it inhibits platelet
aggregation and thus may be associated with an increased risk of bleeding.
Ketorolac is not recommended for obstetric
analgesia because it has not been adequately tested
for obstetrical administration and has demonstrable fetal
toxicity
in laboratory animals
.
Ketorolac is not recommended for long-term chronic pain
patients.
However, ketorolac has been co-administered with meperidine and morphine without apparent adverse effects on patients.
in patients with a previously demonstrated hypersensitivity
to ketorolac, and in patients with the complete or partial syndrome
of nasal polyps, angioedema
, bronchospastic
reactivity or other allergic manifestations to aspirin or other non-steroid
al anti-inflammatory drugs (due to possibility of severe anaphylaxis
). As with all NSAIDs, ketorolac should be avoided in patients with renal (kidney
) dysfunction. (Prostaglandins are needed to dilate the afferent arteriole; NSAIDs effectively reverse this.) The patients at highest risk, especially in the elderly, are those with fluid
imbalances or with compromised renal function (e.g., heart failure, diuretic
use, cirrhosis
, dehydration
, and renal insufficiency).
responsible for ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme
cyclooxygenase
(COX). Ketorolac is a non selective COX inhibitor.
, flurbiprofen
, naproxen
, ibuprofen
, etc.), ketorolac is an isostere
of ketoprofen. More precisely, it is a dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin
.
NSAIDs (non-steroidal anti-inflammatory drug) are not recommended for use with other NSAIDs because of the potential for additive side effects.
The protein-binding effect of most non-aspirin
NSAIDs are inhibited by the presence of aspirin in the blood.
(where it is called ketorolaco, and marketed under various brand names, such as Glicima, from Atlantis Pharma, Dolac, from Syntex
, and Supradol, from Laboratorios Liamont), costing approximately US$10 for 20 tablets. De jure prescription only, but de facto OTC in Russia, US$1 for 30 tablets (Ketorol by Dr. Reddy's).
Injected dosages are 15, 30 and 60 mg; US price for 10 vials of 30 mg each is around US$45, making the intramuscular preparation considerably more expensive per dose. One 60 mg dose would require the administration by injection of two vials, at about $9 per dose. Australian pricing for five vials is around AU$58, or about $23 per dose. Ketorolac is not available on the Pharmaceutical Benefits Scheme
.
In the United States, United Kingdom
, Canada
, and Australia this drug cannot be sold over-the-counter
and must be administered only with a prescription
. It is commonly available over-the-counter in Mexico and other areas of Latin America
, at the pharmacist's discretion.
company, of Palo Alto, California
developed the ophthalmic solution Acular, and holds the registered trademark on that name, as well as on the name Toradol. The actual product using this brand name is manufactured and distributed by Allergan
under license from Syntex.
In Colombia (South America) it is marketed under Ketrón from Laboratorios Bussié.
Apotex
, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac", in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement
of , over the generic ketorolac tomethamine product. In May, 2005, the United States Court of Appeals
for the Federal Circuit handed Apotex a victory, ruling that a lower court upholding the Syntex patent misapplied the rules for judging whether an invention was obvious. Allergan had claimed that the patent was valid until 2009.
Ranbaxy, an Indian manufacturer, makes ketorolac in tablets and ampoules under a name "Ketanov". Another Indian manufacturer Dr. Reddy's makes ketorolac under a name "Ketorol".
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
have also been approved, and various other brand names "Minolac" (ACI Pharmaceuticals) around the world) is a non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
(NSAID) in the family of heterocyclic
Heterocyclic compound
A heterocyclic compound is a cyclic compound which has atoms of at least two different elements as members of its ring. The counterparts of heterocyclic compounds are homocyclic compounds, the rings of which are made of a single element....
acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
derivative
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
, often used as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
. Ketorolac acts by inhibiting
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
the bodily synthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s. Ketorolac in its oral (tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
or capsule) and intramuscular
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
(injected
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
) preparations is a racemic mixture of both (S)-(−)-ketorolac, the active isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
, and (R)-(+)-ketorolac. An ophthalmic (i.e., eye-drop
Eye drop
Eye drops are saline-containing drops used as a route to administer medication in the eye. Depending on the condition being treated, they may contain steroids, antihistamines, sympathomimetics, beta receptor blockers, parasympathomimetics, parasympatholytics, prostaglandins, non-steroidal...
) solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
.The FDA has approved an intranasal formulation of ketorolac tromethamine (Sprix Nasal Spray) for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.
Medical uses
Ketorolac is indicatedIndication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
for short-term management of moderate to severe pain. Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use. In the UK, treatment should be initiated only in hospital. Maximum duration of treatment should not exceed five days for tablets (per package insert), or two days for continuous daily dosing with intravenous or intramuscular formulations. The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
) is to be avoided.
Adverse effects
Concerns over the high incidence of reported side effects with ketorolac trometamol has led to its withdrawal (apart for the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide. A post-marketing surveillance study indicated a dose-response relationship with average daily dose for both gastrointestinal bleeding and operative site bleeding, and an association between gastrointestinal bleeding and therapy for more than five days. Allergic reactions (anaphylactoid reactions, asthma, bronchospasm, Stevens Johnson syndrome, Lyell syndrome) have been reported. Fluid retention and edema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions. When this ophthalmic formulation is instilled into the eye it can lead to an unpleasant short term burning pain for 4–5 seconds. Other adverse effects are similar to the ones associated with other NSAIDs.| Ketorolac adverse effects | |
|---|---|
| Body system | Effects |
| General | Edema Edema Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling... . Less frequently, hypersensitivity Hypersensitivity Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification... reactions (such as anaphylaxis Anaphylaxis Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure... , bronchospasm Bronchospasm Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins... , laryngeal Larynx The larynx , commonly called the voice box, is an organ in the neck of amphibians, reptiles and mammals involved in breathing, sound production, and protecting the trachea against food aspiration. It manipulates pitch and volume... edema, tongue Tongue The tongue is a muscular hydrostat on the floors of the mouths of most vertebrates which manipulates food for mastication. It is the primary organ of taste , as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly... edema, hypotension Hypotension In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the... ), flushing Flushing (physiology) For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or... , weight gain Weight gain Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:... , or fever Fever Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in... . Very infrequently, asthenia. |
| Cardiovascular | Hypertension Hypertension Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and... . Less frequently, palpitation Palpitation A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself... , pallor Pallor Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics.... , or fainting (syncope). |
| Dermatologic Dermatology Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails.... |
Rash Rash A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and... or pruritus. Less frequently, Lyell's syndrome, Stevens–Johnson syndrome, musculo Muscle Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to... -papular Papule A papule is a circumscribed, solid elevation of skin with no visible fluid, varying in size from a pinhead to 1 cm.With regard to the quote "...varying in size from a pinhead to 1cm," depending on which text is referenced, some authors state the cutoff between a papule and a plaque as 0.5cm,... rash Rash A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and... , exfoliative dermatitis, or urticaria Urticaria Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes... . |
| Gastrointestinal Gastrointestinal tract The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. .... |
Nausea Nausea Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting... , dyspepsia Dyspepsia Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating... , gastrointestinal pain Pain Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."... , constipation Constipation Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation... , diarrhea Diarrhea Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and... , flatulence Flatulence Flatulence is the expulsion through the rectum of a mixture of gases that are byproducts of the digestion process of mammals and other animals. The medical term for the mixture of gases is flatus, informally known as a fart, or simply gas... , gastrointestinal fullness, vomiting or stomatitis Stomatitis Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth... . Less frequently, peptic ulcer Peptic ulcer A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm... ation, gastrointestinal hemorrhage, gastrointestinal perforation, melena Melena In medicine, melena or melaena refers to the black, "tarry" feces that are associated with gastrointestinal hemorrhage. The black color is caused by oxidation of the iron in hemoglobin during its passage through the ileum and colon.-Melena vs... , rectal Rectum The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long... bleeding, gastritis Gastritis Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic... , eructation, anorexia Anorexia (symptom) Anorexia is the decreased sensation of appetite... , or increased appetite Appetite The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is... . Very infrequently, pancreatitis Pancreatitis Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years... . |
| Hemic Blood Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells.... and lymphatic Lymphatic system The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated... |
Purpura Purpura Purpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin... . Less frequently, postoperative wound hemorrhage, thrombocytopenia Thrombocytopenia Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease... , epistaxis, or anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... . Very infrequently, leukopenia Leukopenia Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection.... or eosinophilia Eosinophilia Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being... . |
| Neurological Neurology Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,... |
Drowsiness, dizziness Dizziness Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness.... , headache Headache A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the... , sweating Sweating Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals... , injection Injection (medicine) An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body... site pain. Less frequently convulsion Convulsion A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure... s, vertigo Vertigo (medical) Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear... , tremors, abnormal dreams, hallucinations, or euphoria Euphoria (emotion) Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy... . Very infrequently, paresthesia Paresthesia Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"... , depression Depression (mood) Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless... , insomnia Insomnia Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:... , inability to concentrate, nervousness Anxiety Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,... , excessive thirst, dry mouth, abnormal thinking, hyperkinesis Hyperkinesis Hyperkinesia, also known as hyperkinesis, refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both... , or stupor Stupor Stupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs... . |
| Respiratory Respiration (physiology) 'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction... |
Less frequently, dyspnea Dyspnea Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations... , asthma Asthma Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath... and pulmonary edema Edema Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling... . Very infrequently, rhinitis Rhinitis Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or... or cough Cough A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes... . |
| Urogenital | Less frequently, acute renal failure Renal failure Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood... . Very infrequently polyuria Polyuria Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom... or increased urinary Urination Urination, also known as micturition, voiding, peeing, weeing, pissing, and more rarely, emiction, is the ejection of urine from the urinary bladder through the urethra to the outside of the body. In healthy humans the process of urination is under voluntary control... frequency. |
Warnings and precautions
The most serious risks associated with ketorolac are, as with other NSAIDs, gastrointestinalGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
ulcers
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
, bleeding and perforation; renal (kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
) events ranging from interstitial nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
to complete kidney failure; hemorrhage, and hypersensitivity reactions
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
.
As with other NSAIDs, fluid and solute retention
Peripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
and edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
have been reported with ketorolac. Ketorolac also elevates liver protein levels.
When administered intravenously
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
through the same IV catheter
Catheter
In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...
as morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, the two drugs have been known to sometimes combine to form a precipitate
Precipitation (chemistry)
Precipitation is the formation of a solid in a solution or inside anothersolid during a chemical reaction or by diffusion in a solid. When the reaction occurs in a liquid, the solid formed is called the precipitate, or when compacted by a centrifuge, a pellet. The liquid remaining above the solid...
in the IV, which may block the line. Line flushing with a syringe
Syringe
A syringe is a simple pump consisting of a plunger that fits tightly in a tube. The plunger can be pulled and pushed along inside a cylindrical tube , allowing the syringe to take in and expel a liquid or gas through an orifice at the open end of the tube...
of saline solution can push the blockage through.
Ketorolac is not recommended for pre-operative
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
analgesia or co-administration with anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
because it inhibits platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation and thus may be associated with an increased risk of bleeding.
Ketorolac is not recommended for obstetric
Obstetrics
Obstetrics is the medical specialty dealing with the care of all women's reproductive tracts and their children during pregnancy , childbirth and the postnatal period...
analgesia because it has not been adequately tested
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
for obstetrical administration and has demonstrable fetal
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
in laboratory animals
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...
.
Ketorolac is not recommended for long-term chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
patients.
However, ketorolac has been co-administered with meperidine and morphine without apparent adverse effects on patients.
Contraindications
Ketorolac is contraindicatedContraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
in patients with a previously demonstrated hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
to ketorolac, and in patients with the complete or partial syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
of nasal polyps, angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, bronchospastic
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
reactivity or other allergic manifestations to aspirin or other non-steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
al anti-inflammatory drugs (due to possibility of severe anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
). As with all NSAIDs, ketorolac should be avoided in patients with renal (kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
) dysfunction. (Prostaglandins are needed to dilate the afferent arteriole; NSAIDs effectively reverse this.) The patients at highest risk, especially in the elderly, are those with fluid
Bodily fluid
Body fluid or bodily fluids are liquids originating from inside the bodies of living people. They include fluids that are excreted or secreted from the body as well as body water that normally is not.Body fluids include:-Body fluids and health:...
imbalances or with compromised renal function (e.g., heart failure, diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
use, cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, and renal insufficiency).
Mechanism of action
The primary mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
responsible for ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
(COX). Ketorolac is a non selective COX inhibitor.
Chemistry
Although its name does not suggest similarity with propionic acid derivatives (including ketoprofenKetoprofen
Ketoprofen, 2--propionic acid is one of the propionic acid class of non-steroidal anti-inflammatory drug with analgesic and antipyretic effects...
, flurbiprofen
Flurbiprofen
Flurbiprofen is a member of the phenylalkanoic acid derivative family of non-steroidal anti-inflammatory drugs used to treat the inflammation and pain of arthritis...
, naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
, etc.), ketorolac is an isostere
Isostere
Isosteres are molecules or ions with the same number of atoms and the same number of valence electrons.Some examples of isoteres include:*Sodium and hydrogen*Carbon dioxide and nitrous oxide *Silicon and carbon...
of ketoprofen. More precisely, it is a dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin
Indometacin
Indometacin or indomethacin is a non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms...
.
NSAIDs (non-steroidal anti-inflammatory drug) are not recommended for use with other NSAIDs because of the potential for additive side effects.
The protein-binding effect of most non-aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
NSAIDs are inhibited by the presence of aspirin in the blood.
Dosage, availability and cost
Oral dosage is 10 mg; United States price for 20 tablets hovers around US$28. Australian pricing for 20 tablets is around AU$44. It is considerably less expensive in MexicoMexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
(where it is called ketorolaco, and marketed under various brand names, such as Glicima, from Atlantis Pharma, Dolac, from Syntex
Syntex
Laboratorios Syntex SA was a pharmaceutical company formed in Mexico City in 1944 by Russell Marker to manufacture therapeutic steroids from the Mexican yam....
, and Supradol, from Laboratorios Liamont), costing approximately US$10 for 20 tablets. De jure prescription only, but de facto OTC in Russia, US$1 for 30 tablets (Ketorol by Dr. Reddy's).
Injected dosages are 15, 30 and 60 mg; US price for 10 vials of 30 mg each is around US$45, making the intramuscular preparation considerably more expensive per dose. One 60 mg dose would require the administration by injection of two vials, at about $9 per dose. Australian pricing for five vials is around AU$58, or about $23 per dose. Ketorolac is not available on the Pharmaceutical Benefits Scheme
Pharmaceutical Benefits Scheme
The Pharmaceutical Benefits Scheme or PBS is a program of the Australian Government that provides subsidised prescription drugs to residents of Australia. The PBS ensures that all Australians have affordable and reliable access to a wide range of necessary medicines.-History:The PBS was established...
.
In the United States, United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
, and Australia this drug cannot be sold over-the-counter
OTC
OTC may refer to:* Oakwood Technology College* Owatonna Tool Company* Oklahoma Tax Commission* Odenton Town Center* Officer in Tactical Command* Officer Training Corps* Offshore Technology Conference* Ohio Turnpike Commission...
and must be administered only with a prescription
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
. It is commonly available over-the-counter in Mexico and other areas of Latin America
Latin America
Latin America is a region of the Americas where Romance languages – particularly Spanish and Portuguese, and variably French – are primarily spoken. Latin America has an area of approximately 21,069,500 km² , almost 3.9% of the Earth's surface or 14.1% of its land surface area...
, at the pharmacist's discretion.
Patent controversy
The SyntexSyntex
Laboratorios Syntex SA was a pharmaceutical company formed in Mexico City in 1944 by Russell Marker to manufacture therapeutic steroids from the Mexican yam....
company, of Palo Alto, California
Palo Alto, California
Palo Alto is a California charter city located in the northwest corner of Santa Clara County, in the San Francisco Bay Area of California, United States. The city shares its borders with East Palo Alto, Mountain View, Los Altos, Los Altos Hills, Stanford, Portola Valley, and Menlo Park. It is...
developed the ophthalmic solution Acular, and holds the registered trademark on that name, as well as on the name Toradol. The actual product using this brand name is manufactured and distributed by Allergan
Allergan
Allergan, Inc., is a global specialty pharmaceutical company. Their product ranges include ophthalmic pharmaceuticals, dermatology products, and neurological products.-Profile:...
under license from Syntex.
In Colombia (South America) it is marketed under Ketrón from Laboratorios Bussié.
Apotex
Apotex
Apotex is a Canadian pharmaceutical corporation. Founded in 1974, the company is the largest producer of generic drugs in Canada, with sales exceeding one billion dollars a year...
, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac", in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement
Patent infringement
Patent infringement is the commission of a prohibited act with respect to a patented invention without permission from the patent holder. Permission may typically be granted in the form of a license. The definition of patent infringement may vary by jurisdiction, but it typically includes using or...
of , over the generic ketorolac tomethamine product. In May, 2005, the United States Court of Appeals
United States court of appeals
The United States courts of appeals are the intermediate appellate courts of the United States federal court system...
for the Federal Circuit handed Apotex a victory, ruling that a lower court upholding the Syntex patent misapplied the rules for judging whether an invention was obvious. Allergan had claimed that the patent was valid until 2009.
Ranbaxy, an Indian manufacturer, makes ketorolac in tablets and ampoules under a name "Ketanov". Another Indian manufacturer Dr. Reddy's makes ketorolac under a name "Ketorol".
External links
- Published studies related to ketorolac, at DrugLib
- MedicineNet.com information on ophthalmic ketorolac
- cme.medscape.com on nasal ketorolac